Clinical trial NCT00567567
Conditions: Localized Resectable Neuroblastoma Localized Unresectable Neuroblastoma Recurrent Neuroblastoma Regional Neuroblastoma Stage 4 Neuroblastoma Stage 4S Neuroblastoma
Sponsor: Children's Oncology Group
Start date: 2007-11-05; Completion date: 2022-03-31
Enrollment: 665 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial compares two different high-dose chemotherapy regimens followed by a stem cell transplant in treating younger patients with high-risk neuroblastoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments before a peripheral blood stem cell transplant helps kill any tumor cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. High-dose chemotherapy and radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the high- chemotherapy. It is not yet known which regimen of high-dose chemotherapy is more effective for patients with high-risk neuroblastoma undergoing a peripheral blood stem cell transplant.

Detailed description:
PRIMARY OBJECTIVES:

I. To improve the 3-year event-free survival (EFS) rate of high-risk neuroblastoma patients through treatment with a tandem consolidation of thiotepa/cyclophosphamide followed by carboplatin/etoposide/melphalan (CEM) as compared to single CEM consolidation.

II. To improve the rate of end-induction complete response and very good partial response, compared to historical controls, by use of a topotecan-containing induction regimen.

III. To improve the 3-year local control rate, compared to historical controls, by increasing the local dose of radiation to the residual primary tumor for patients with less than a gross total resection.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacogenetic relationship of cyclophosphamide metabolizing enzymes (CYP2B6, CYP2C9, and GSTA1 genotypes) with toxicity and response following dose-intensive cyclophosphamide and topotecan induction chemotherapy.

II. To determine if resection completeness is predictive of a) local control rate; or b) EFS rate in patients with high-risk neuroblastoma.

III. To prospectively describe the complications related to efforts at local control (surgery and radiation therapy) in patients with high-risk neuroblastoma.

IV. To describe the neurologic outcome of patients with paraspinal primary neuroblastoma tumors.

V. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if pharmacokinetics and/or genetic variations correlate with EFS or systemic toxicity as follows: a) To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters. b) To determine if 13-cis-retinoic-acid pharmacokinetic levels are predictive of the EFS rate or associated with systemic toxicity following 13-cis-retinoic acid. c) To determine if pharmacogenomic variations are predictive of the EFS rate or associated with systemic toxicity following 13-cis-retinoic acid.

VI. To evaluate total topotecan pharmacokinetics and correlate with patient specific data for use in an ongoing topotecan population pharmacokinetic analysis.

VII. To evaluate the presence and function of T cells capable of recognizing neuroblastoma by assessing: a) if T cells recognizing the neuroblastoma antigen, survivin, circulate at diagnosis; b) if these T cells can be expanded using autologous antigen presenting cells (APCs); c) if these T cells will kill neuroblastoma cells as detected in functional assays; and d) if the presence and activity of anti-neuroblastoma immunity is decreased by stem cell transplantation.

VIII. To characterize the recovery of T- cell numbers after myeloablative consolidation and hematopoietic stem cell transplant (HSCT) and assess the impact of tandem myeloablative consolidation on T- cell recovery.

IX. To characterize minimal residual disease burden using reverse transcriptase-polymerase chain reaction (RT-PCR) evaluation of a panel of neuroblastoma specific transcripts in patient bone marrow and peripheral blood following induction chemotherapy and after single versus tandem myeloablative chemotherapy and to evaluate impact on EFS.

X. To evaluate the EFS and overall survival (OS) rate for patients 12-18 months with Stage 4, MYCN nonamplified tumor with unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy and patients who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant histology following treatment with single myeloablative transplant.

OUTLINE:

INDUCTION CHEMOTHERAPY:

COURSES 1 AND 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients undergo peripheral blood stem cell (PBSC) mobilization and harvest after course 2.

COURSES 3 AND 5: Patients receive cisplatin IV over 1 hour on days 1-4, etoposide IV over 1 hour on days 1-3, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients undergo surgical resection of soft tissue disease after course 5 (or after course 6 if medically necessary).

COURSES 4 AND 6: Patients receive cyclophosphamide IV over 6 hours on days 1-2, doxorubicin hydrochloride IV over 24 hours on days 1-3, vincristine IV on days 1-3, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses.

Patients are then stratified by initial stage of disease and MYCN status, biologic characteristics, and response to induction chemotherapy (complete response/very good partial response vs partial response vs mixed response/no response). Patients are randomized to 1 of 2 arms. Patients 12?18 months old (i.e., 365-547 days) with stage IV, MYCN nonamplified tumor with unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy AND patients who are 547 days of age with stage III, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant histology will be nonrandomly assigned to Arm A. Patients begin consolidation chemotherapy no later than 8 weeks after the start of induction course 6.

CONSOLIDATION THERAPY:

ARM A (single myeloablative consolidation): Patients receive melphalan IV over 15-30 minutes on days -7 to -5, etoposide IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0.

ARM B (tandem myeloablative consolidation): Patients receive thiotepa IV over 2 hours on days -7 to -5, cyclophosphamide IV over 1 hour on days -5 to -2, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A. Patients undergo autologous PBSCT on day 0.

RADIOTHERAPY: Patients undergo external beam radiation therapy (EBRT) to primary site of disease as well as to MIBG-avid sites seen at pre-transplantation (i.e., end-induction) evaluation between 28-42 days post-transplant. Additional radiotherapy is administered to residual tumor at primary site.

MAINTENANCE THERAPY: Patients are encouraged to enroll onto Children?s Oncology Group (COG)-ANBL0032 following assessment of tumor response after completion of the consolidation phase and radiotherapy. Beginning on day 60 post-transplantation patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tissue sample collection periodically for the following analyses; correlation between peak serum concentration level and the existence of polymorphisms, event-free survival, and toxicity rates; pharmacogenomics for uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), UGT2B7, CYP2C8 and CYP3A7 alleles; topotecan systemic clearance; survivin-specific cytotoxic T-lymphocytes (CTLs) detected using peptide/major histocompatibility complex (MHC) tetramers in human leukocyte antigen (HLA)-A2+ patients; interferon (IFN)-gamma production in enzyme-linked immunospot (ELISPOT) assays to APCs loaded with tumor ribonucleic acid (RNA), survivin RNA, or control RNA; response of APC-stimulated CTL response to neuroblastoma cells; rate of T cell recovery; and proportion of patients with neuroblastoma detected in bone marrow and peripheral blood using RT-PCR and immunohistochemistry (IHC).

After completion of study treatment, patients are followed up periodically for 5 years and then annually for 5 years.

Arms: arm 1: Patients receive melphalan IV over 15-30 minutes on days -7 to -5, etoposide IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo autologous PBSCT on day 0. arm 2: Patients receive thiotepa IV over 2 hours on days -7 to -5, cyclophosphamide IV over 1 hour on days -5 to -2, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A. Patients undergo autologous PBSCT on day 0.
Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Cyclophosphamide intervention 5: Doxorubicin Hydrochloride intervention 6: Etoposide intervention 7: External Beam Radiation Therapy intervention 8: Filgrastim intervention 9: Isotretinoin intervention 10: Laboratory Biomarker Analysis intervention 11: Melphalan intervention 12: Peripheral Blood Stem Cell Transplantation intervention 13: Pharmacological Study intervention 14: Thiotepa intervention 15: Topotecan Hydrochloride intervention 16: Vincristine Sulfate Liposome
Intervention descriptions: intervention 1: Undergo autologous peripheral blood stem cell transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Undergo EBRT intervention 8: Given IV or SC intervention 9: Given orally intervention 10: Correlative studies intervention 11: Given IV intervention 12: Undergo autologous peripheral blood stem cell transplant intervention 13: Correlative studies intervention 14: Given IV intervention 15: Given IV intervention 16: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
 
ANBL0532 
Page 1 
 
Activated: 
11/05/07      
Version Date: 
08/16/11 
Closed: 
2/27/12 
Amd # 
4A 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ANBL0532 
 
Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation Therapy for 
High-Risk Neuroblastoma 
 
 
 
A Groupwide Phase III Study 
 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  
THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY 
PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING 
PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Statistics and Data Center Contact Person see:  https://members.childrensoncologygroup.org 
 
 


 
 
ANBL0532 
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TABLE OF CONTENTS 
 
 
SECTION 
PAGE 
STUDY COMMITTEE 
6 
ABSTRACT 
10 
EXPERIMENTAL DESIGN SCHEMA 
12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
13 
1.1 
Primary Objectives 
13 
1.2 
Secondary Objectives 
13 
2.0 
BACKGROUND 
14 
2.1 
Definition of High-Risk Neuroblastoma 
14 
2.2 
High-risk Neuroblastoma Therapy 
15 
2.3 
Myeloablative regimens 
16 
2.4 
Tandem Myeloablative Regimens 
17 
2.5 
Novel Induction Regimen 
19 
2.6 
Topotecan 
20 
2.7 
Topotecan and Cyclophosphamide 
20 
2.8 
Local Radiation Therapy 
22 
2.9 
Surgery 
23 
2.10 
Neurologic Outcome of Patients with Epidural Neuroblastoma 
24 
2.11  Maintenance Therapy 
24 
2.12 
Biologic Correlative Studies 
25 
2.13 
Gender and Race Differences 
29 
2.14 
Peripheral Blood Stem Cell Immunocytology (Amendment #2) 
30 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
30 
3.1 
Study Enrollment 
30 
3.2 
Patient Criteria 
32 
4.0 
TREATMENT PLAN 
34 
4.1 
General Guidelines 
34 
4.2 
Induction Therapy Administration 
35 
4.3 
Local Control - Surgery 
42 
4.4 
Consolidation Therapy 
42 
4.5 
 Consolidation Therapy Regimen A: Single HSCT (CEM) 
43 
4.6 
Consolidation Therapy Regimen B: Tandem HSCT #1 (Thiotepa and Cyclophosphamide)47 
4.7 
Radiation therapy 
54 
4.8 
Maintenance Phase: Isotretinoin (Accutane) (13-cis-retinoic acid) Therapy 
55 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
56 
5.1 
Myelosuppression During Induction 
56 
5.2 
Hematuria During Induction 
56 
5.3 
Renal Toxicity During Induction 
57 
5.4 
Cardiac Toxicity During Induction 
57 
5.5 
Hepatotoxicity During Induction 
58 
5.6 
Gastrointestinal Toxicity During Induction 
58 
5.7 
Ototoxicity During Induction 
59 
5.8 
Neurologic Toxicity During Induction 
59 
5.9 
Allergic Reactions 
59 
5.10 
Other toxicities During Induction 
59 


 
 
ANBL0532 
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5.11 
Dose Modifications for 13-cis-Retinoic Acid (cis-RA) Therapy 
59 
6.0 
DRUG INFORMATION 
60 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
61 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
61 
7.2 
Required Observations During Follow-up After Completion of 13-cis-Retinoic Acid 
Therapy (for All Patients) 
66 
8.0 
OFF PROTOCOL THERAPY CRITERIA AND OFF STUDY CRITERIA 
67 
8.1 
Off Protocol Therapy Criteria 
67 
8.2 
Off Study Criteria 
67 
9.0 
STATISTICAL CONSIDERATIONS 
68 
9.1 
Statistical Design 
68 
9.2 
Patient Accrual and Expected Duration of Trial 
69 
9.3 
Statistical Analysis Methods 
70 
9.4 
Gender and Minority Accrual Estimates 
77 
10.0 
EVALUATION CRITERIA 
78 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
78 
10.2 
Response Criteria for Patients with Solid Tumors 
78 
10.3 
International Staging System123 
78 
10.4 
International Response Criteria123 
78 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
79 
11.1 
Purpose 
79 
11.2 
Determination of Reporting Requirements 
79 
11.3 
Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway 79 
11.4 
Routine Adverse Event Reporting 
80 
11.5 
Reporting Secondary AML/MDS 
80 
12.0 
RECORDS AND REPORTING 
80 
12.1 
Categories of Research Records 
80 
12.2 
CDUS 
81 
13.0 
SURGICAL GUIDELINES 
81 
13.1 
Surgical rationale 
81 
13.2 
Pre-operative management 
81 
13.3 
Sampling requirements 
81 
13.4 
Operative management 
82 
13.5 
Management of Surgical Complications 
83 
13.6 
Special techniques 
84 
13.7 
Specimen requirements 
85 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
85 
14.1 
Rapid Pathology Review 
85 
14.2 
Specimen Shipping 
87 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
87 
15.1 
Biologic Requirements 
87 
15.2 
Cyclophosphamide Pharmacogenomics 
87 
15.3 
Topotecan Pharmacokinetics 
88 
15.4 
Minimal Residual Disease Studies – Bone Marrow 
89 
15.5 
Minimal Residual Disease – Peripheral Blood Stem Cells 
91 
15.6 
Minimal Residual Disease – Peripheral Blood 
91 


 
 
ANBL0532 
Page 4 
15.7 
13-cis-Retinoic Acid) Pharmacokinetics 
92 
15.8 
Cellular Immunity Against Neuroblastoma 
93 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
94 
16.1 
CT Scans 
94 
16.2 
MRI Scans 
94 
16.3 
Skeletal Scintigraphy 
95 
16.4 
MIBG Scintigraphy 
95 
16.5 
Plain Film Radiography 
95 
16.6 
Tumor Measurement 
95 
16.7 
Central Review of Imaging 
95 
17.0 
RADIATION THERAPY GUIDELINES 
96 
17.1 
Indications for Radiation Therapy 
97 
17.2 
Emergency Irradiation 
98 
17.3 
Equipment 
98 
17.4 
Target Volumes 
98 
17.5 
Target Dose 
101 
17.6 
Treatment Technique 
102 
17.7 
Organs at Risk 
102 
17.8 
Dose Calculations and Reporting 
102 
17.9 
Quality Assurance Documentation 
103 
17.10 
Definitions of Deviations in Protocol Performance 
105 
18.0 
HEMATOPOIETIC TRANSPLANT GUIDELINES 
105 
19.0 
RECOMMENDED PROCEDURE FOR PBSC MOBILIZATION AND COLLECTION 
105 
19.1 
Catheter Use 
105 
19.2 
PBSC Mobilization 
106 
19.3 
PBSC Collection 
106 
19.4 
PBSC Analyses 
107 
19.5 
Cryopreservation of PBSC Products 
107 
19.6 
PBSC Infusion 
107 
APPENDIX I:  PERFORMANCE STATUS SCALES/SCORES 
108 
APPENDIX II:  SUPPORTIVE CARE GUIDELINES 
109 
APPENDIX III:  NB WITH INTRASPINAL EXTENSION +/- SPINAL CORD 
COMPRESSION 
112 
APPENDIX IV:  INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM (INSS) 
113 
APPENDIX V:  TUMOR SIZE MEASUREMENTS BY CROSS-SECTIONAL IMAGING 
114 
APPENDIX VI: NEUROBLASTOMA RESPONSE CRITERIA 
115 
APPENDIX VII:  NEUROBLASTOMA STUDY ASSIGNMENT TABLE 
116 
APPPENIX VIII:  TOPOTECAN PHARMACOKINETICS DATA COLLECTION FORM 
117 
APPENDIX IX: 13-CIS RA PHARMACOKINETIC DATA COLLECTION FORM 
118 
APPENDIX X:  SPECIMEN SUBMISSION SCHEDULE 
119 
APPENDIX XI:  YOUTH SUMMARIES FOR CHILDREN AND TEENS 
120 
REFERENCES 
124 


 
 
ANBL0532 
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SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
131 
PART 1: CONSENT FOR INDUCTION THERAPY 
131 
PART 2 A: CONSENT FOR PATIENTS RANDOMIZED TO CONSOLIDATION THERAPY 
152 
PART 2 B: CONSENT FOR PATIENTS TO BE NON-RANDOMLY ASSIGNED TO SINGLE 
MYELOABLATIVE CONSOLIDATION THERAPY 
177 
 
 
 
 
 


 
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AGENT NSC# AND IND# 
 
Cyclophosphamide NSC# 26271 
 
Topotecan NSC# 609699 
 
Filgrastim NSC# 614629 
 
Cisplatin NSC# 119875 
 
Etoposide NSC# 141540 
 
Mesna NSC# 113891 
 
Doxorubicin NSC# 123127 
 
Vincristine NSC# 67574 
 
Melphalan NSC# 008806 
 
Carboplatin NSC# 241240 
 
Thiotepa NSC# 6396 
 
Isotretinoin NSC# 329481 
 
 
 
 
 
 
 
SEE SECTIONS 14 AND 15 FOR SPECIMEN SHIPPING ADDRESSES 
 
 


 
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ANBL0532 
Page 10 
 
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 
ANBL0532 is a Phase III trial to study the use of intensified consolidation (Primary Aim 1), the use of 
newer agents during induction (Primary Aim 2), and the use of high dose local radiation (Primary Aim 3).  
 
The primary goal of ANBL0532 is to test whether further intensification of myeloablative therapy will 
improve cure rate for high risk neuroblastoma.  
 
Myeloblative consolidation therapy is given at the completion of induction therapy and is categorized into 
Regimen A and Regimen B. Regimen A consists of one myeloablative consolidation with a carboplatin – 
etoposide – melphalan (CEM) preparative regimen. For Regimen B, patients will receive two 
myeloablative consolidations: Thiotepa – cyclophosphamide (TC) preparative regimen followed by CEM 
preparative regimen.  
 
Most patients will be randomized into either Regimen A or Regimen B. Randomization will be 
stratified by stage, MYCN status and response to induction therapy. Patients 365 to 547 days of age (12 
– 18 months) with Stage 4, MYCN nonamplified tumor with unfavorable histopathology or diploid 
DNA content or with indeterminant histology or ploidy and patients who are greater than 547 days of 
age with Stage 3, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant 
histology will be nonrandomly assigned to single myeloablative transplant (Regimen A).   
 
ANBL0532 will also assess the efficacy of a dose intensive topotecan containing induction regimen, 
substituting 2 cycles of dose intensive cyclophosphamide and topotecan for the initial 2 cycles of 
induction utilized on the prior COG A3973 protocol.  Patients will receive 6 cycles of induction 
chemotherapy as outlined in the schema below. Patients will undergo peripheral blood stem cell (PBSC) 
harvest after 2 cycles with no ex vivo manipulation prior to cryopreservation.  PBSC collection will be 
performed prior to randomization.The goal of apheresis will be collection of 10 x 106 CD 34+cells/kg 
divided into 3 aliquots.  A minimum collection of 4 x 106 CD 34+cells/kg, divided into 2 aliquots is 
required for each patient while an additional 3rd aliquot of 2 x 106 CD 34+cells/kg is strongly 
recommended to be stored as backup for delayed engraftment or for future use. Tumor response will be 
assessed after 2 cycles of induction chemotherapy. Patients will undergo surgical resection after Cycle 5 
(or 6 if necessary). Tumor response will be assessed after completion of surgical resection and 6 cycles of 
chemotherapy (end-induction). Patients with progressive disease (PD) at end of induction evaluation will 
be taken off protocol therapy, all other patients will continue on therapy. 
 
ANBL0532 will also test whether additional radiation therapy delivered to gross residual disease 
improves local control for those patients with less than a gross total resection.  After completion of 
transplant and recovery from acute toxicities, patients will undergo radiation to primary site of disease 


 
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ANBL0532 
Page 11 
and to MIBG-avid sites seen at pre-transplant (end-induction) evaluation. Patients who achieve end of 
induction primary site complete response (CR) will receive 21.6 Gy external beam radiation therapy 
(EBRT) to the primary site (standard dose) while patients achieving <CR (> 1 cm3 residual soft tissue) at 
the primary site will receive an additional boost of 14.4 Gy for a total dose of 36 Gy EBRT delivered to 
gross residual primary site disease.  Pre-surgical and end of induction CT or MRI scans and operative 
reports will be centrally reviewed in real time for all patients assessed by the treating institution to have a 
complete response at the primary site at the end of induction.  Tumor response will be assessed after 
completion of radiation therapy.  
 
Patients will be encouraged to enroll onto ANBL0032 or ANBL0931for Maintenance biologic therapy. 
Alternatively, post-transplant Maintenance therapy with cis-RA daily for 14 days every 28 days repeated 
for 6 months will be administered. 
 
Pharmacogenomics studies will be performed to evaluate whether host genetic polymorphisms in 
cyclophosphamide metabolizing enzymes are associated with cyclophosphamide/topotecan – related 
toxicity and tumor response. Cis-RA pharmacokinetics and pharmacogenomic studies will be performed 
to evaluate whether the variability of cis-RA continuous steady state plasma levels and/or genetic 
variations in retinoic acid metabolic enzymes correlate with event-free survival or systemic toxicities in 
high-risk neuroblastoma patients.  Total topotecan levels will be assessed to formulate a population-based 
dosing model for topotecan in children with high-risk neuroblastoma.  
 
Post-operative complications will be studied prospectively in patients with high risk neuroblastoma to 
better characterize the incidence and timing of occurrence. Specifically, the occurrence of bowel 
obstruction, renal atrophy, chylous leak and chronic diarrhea will be evaluated through 12 months from 
completion of therapy. Rates of these complications will be correlated with the surgical and 
radiotherapeutic efforts in obtaining local control as they may impact on future management decisions. 
The neurologic and orthopedic outcome for patients with intraspinal extension of primary tumors 
(referred to as paraspinal tumors) will be studied prospectively on this protocol, to better characterize the 
multiple aspects of disability that these patients may be at risk for.  It is the intent of this study that 
patients with clinical signs of spinal cord compression will be treated with primary chemotherapy; 
however, multidisciplinary discussion among oncology, neurosurgery, and radiation oncology is strongly 
encouraged at the time of diagnosis.  
 
Clinical outcome data for patients treated on this study will be used in conjunction with ongoing biologic 
studies on ANBL00B1 to identify new biological surrogate markers for disease relapse and/or disease 
progression.  In addition, immunologic assays will be employed to assess functional cellular immunity 
against neuroblastoma at diagnosis and after myeloablative therapy and to enumerate T-cell lymphocyte 
recovery following single versus tandem myeloablative therapy. 
 


 
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ANBL0532 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
On study 
INDUCTION THERAPY 
Cycles 1, 2 * – CPM + TOPO 
PBSC Harvest 
Cycles 3, 5 - CDDP + ETOP 
Cycles 4, 6*– CPM + DOXO + VCR 
Surgery (after Cycle 5) 
Progressive 
disease 
No progressive disease 
Non-randomized cohort 
(Refer Section 3.1.8) 
CONSOLIDATION 
THERAPY 
 
REGIMEN – A  
CARBO/ETOP/MEL+      
 
Radiation therapy* (XRT) 
CONSOLIDATION 
THERAPY 
 
REGIMEN – B  
TEPA/CPM  
CARBO/ETOP/MEL+       
 
 Radiation therapy*(XRT)  
MAINTENANCE THERAPY 
13 – cis RA* (6 cycles) 
Eligible for ANBL0032 or ANBL0931 participation 
Footnote: 
 
CPM – cyclophosphamide 
TOPO – topotecan 
CDDP – cisplatin 
ETOP – etoposide 
DOXO – doxorubin 
VCR – vincristine 
CARBO – carboplatin 
MEL – melphalan 
TEPA –thiotepa 
 * - Disease assessment after Induction Cycle 2, 6, after XRT 
and after cis RA Cycles 3 and 6 
Off-protocol therapy 
Randomized cohort 
(Refer Section 3.1.7) 


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objectives 
 
1.1.1 
To improve the 3-year event free survival (EFS) rate of high-risk neuroblastoma patients through 
treatment 
with 
a 
tandem 
consolidation 
of 
Thiotepa/Cyclophosphamide 
followed 
by 
Carboplatin/Etoposide/Melphalan (CEM) as compared to single CEM consolidation. 
 
1.1.2 
To improve the rate of end-induction complete response and very good partial response, compared to 
historical controls, by use of a topotecan-containing induction regimen. 
 
1.1.3 
To improve the 3-year local control rate, compared to historical controls, by increasing the local dose of 
radiation to the residual primary tumor for patients with less than a gross total resection. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To evaluate the pharmacogenetic relationship of cyclophosphamide-metabolizing enzymes (CYP2B6, 
CYP2C9 and GSTA1 genotypes) with toxicity and response following dose intensive cyclophosphamide 
and topotecan induction chemotherapy. 
 
1.2.2 
To determine if resection completeness is predictive of a) local control rate; or b) event free survival rate 
in patients with high-risk neuroblastoma. 
 
1.2.3 
To prospectively describe the complications related to efforts at local control (surgery and radiation 
therapy) in patients with high risk neuroblastoma. 
 
1.2.4 
To describe the neurologic outcome of patients with paraspinal primary neuroblastoma tumors. 
 
1.2.5 
To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to 
pharmacogenomic parameters and determine if pharmacokinetics and/or genetic variations correlate with 
EFS or systemic toxicity as follows: 
a) To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to 
pharmacogenomic parameters. 
 
b) To determine if 13-cis-retinoic-acid pharmacokinetic levels are predictive of the EFS rate or associated 
with systemic toxicity following 13-cis-retinoic acid. 
 
c)  To determine if pharmacogenomic variations are predictive of the EFS rate or associated with systemic 
toxicity following 13-cis-retinoic acid. 
 
 
1.2.6 
To evaluate total topotecan pharmacokinetics and correlate with patient specific data for use in an 
ongoing topotecan population pharmacokinetic analysis. 
 
1.2.7 
To evaluate the presence and function of T cells capable of recognizing neuroblastoma by assessing: 


 
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a) If T cells recognizing the neuroblastoma antigen survivin circulate at diagnosis; 
b) If these T cells can be expanded using autologous antigen presenting cells (APCs); 
c) If these T cells will kill neuroblastoma cells as detected in functional assays; and 
d)   If the presence and activity of anti-neuroblastoma immunity is decreased by stem cell transplant. 
 
1.2.8 
To characterize the recovery of T cell numbers after myeloablative consolidation and hematopoietic stem 
cell transplant (HSCT) and assess the impact of tandem myeloablative consolidation on T cell recovery. 
 
1.2.9  
To characterize minimal residual disease burden using RT-PCR evaluation of a panel of neuroblastoma-
specific transcripts in patient bone marrow and peripheral blood following induction chemotherapy and 
after single versus tandem myeloablative chemotherapy and to evaluate impact on EFS. 
 
1.2.10 
To evaluate the EFS and OS rate for patients 12 – 18 months with Stage 4, MYCN nonamplified tumor with 
unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy and patients 
who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor AND unfavorable 
histopathology or indeterminant histology following treatment with single myeloablative transplant.   
 
 
2.0 
BACKGROUND  
 
Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most extracranial malignant 
solid tumor of childhood.1  The current survival for a child >1 year at diagnosis with Stage 4 
neuroblastoma is only 20-35%.2-7  Novel therapies to improve initial disease response and treatment of 
minimal residual disease are required to improve survival for these children with high-risk neuroblastoma.  
Standard therapy for patients with high-risk neuroblastoma involves at least 4 components: Induction, 
Local Control, Consolidation and Treatment of minimal disease with biologic agents. The use of these 4 
components has evolved over the last 20 years, based upon work by the POG and CCG, international 
cooperative groups and smaller cohort studies. 
 
The primary aim of ANBL0532 is to improve event free survival for children with high-risk 
neuroblastoma.  This study is a logical extension of the COG Neuroblastoma committee’s strategic plan 
and will build upon our previous findings to study the use of intensified consolidation (Primary Aim 1), 
the use of a novel induction regimen (Primary Aim 2), and the use of increased dose local radiation 
therapy (Primary Aim 3).  Specifically, a limited institution pilot study through COG (ANBL00P1) has 
demonstrated the feasibility and tolerable toxicity of the proposed tandem transplant consolidation 
regimen. An additional limited institution pilot study through COG (ANBL02P1) has demonstrated 
feasibility/tolerable toxicity of the dose intensive cyclophosphamide/topotecan administration proposed in 
the induction phase and ability to harvest PBSC following such chemotherapy. ANBL0532 will also test 
whether additional radiation therapy will improve local control for those patients with less than a gross 
total resection, a hypothesis derived directly from retrospective analysis of the prior CCG 3891 high-risk 
neuroblastoma protocol.8  Patients completing this study will be eligible for COG ANBL0032 or 
ANBL0931, a study of immunotherapy as treatment of minimal residual disease. 
 
2.1 
Definition of High-Risk Neuroblastoma 
Patients eligible for ANBL0532 must have high-risk neuroblastoma as defined by risk criteria that include 
age, stage, and the biologic features of MYCN amplification, histopathology, and DNA ploidy (Appendix 
VII).  The stratification algorithm to be used for ANBL0532 and ANBL0531 (Intermediate Risk 
Neuroblastoma clinical trial) has been revised from recent clinical trials and is based upon data from 
legacy CCG and POG clinical trials.  These data suggest that patients up to 18 months of age who are 
diagnosed with biologically favorable stage 4 neuroblastoma share the same excellent prognosis that has 
previously been demonstrated for infants less than 12 months of age with non-amplification of MYCN 


 
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oncogene (MYCN-NA) stage 4 disease.9  Data from CCG 3881 and 3891 trials demonstrated a 6-year 
EFS=90% for infants < 12 months, EFS=86.7% for toddlers 12-18 months, and EFS=36.6% for children 
18-24 months of age at diagnosis of stage 4, MYCN-NA neuroblastoma.10 In this analysis, Shimada 
histology also correlated with age at diagnosis and survival, with nearly all patients with favorable 
Shimada histology (FH) tumors being in the 12-18 month age group.  Data from POG clinical trials also 
suggest a favorable outcome for toddlers ages 12-18 months with stage D, MYCN-NA, hyperdiploid 
tumors, treated on a variety of POG protocols with a 4- year EFS of >80%, > 90%, and < 40% for patients 
age 6-12 months, 12-18 months, and 18-24 months, respectively, at diagnosis.11  Further analyses of CCG 
3891 data reveal an excellent outcome for the rare patient age 12-18 months with stage 3, MYCN-NA but 
unfavorable Shimada histology (UH) disease. Measurement of tumor DNA index was not performed in 
this study.  The 3-year EFS/OS was 100% for patients 12-18 months with Stage 3, MYCN-NA and UH 
neuroblastoma (n=3).12 
 
Based upon these data, ANBL0532 will exclude patients age 12-18 months with stage 4, MYCN-NA, 
hyperdiploid, and FH tumors or stage 3 MYCN-NA, unfavorable histopathology.  These patients will be 
treated on the intermediate-risk protocol, ANBL0531, representing a reduction of therapy in both dose-
intensity and cumulative dose.  Of note, this clinically favorable cohort of 12-18 month old patients with 
stage 4 disease represents only 5% (15/313) of all stage 4 patients enrolled onto CCG3891 for whom 
MYCN analyses were available and only 3% (14/528) of all stage D patients enrolled onto POG trials for 
whom MYCN and DNA ploidy analyses were available.   
 
In contrast, patients 12-18 months of age with stage 4, MCYN-NA tumors characterized by either diploid 
DNA content (4-year EFS 66.6%) or UH tumors (6-year EFS 46%) and patients greater than 18 months 
of age with stage 3 tumors and unfavorable histology (5-year EFS 53%) have a less favorable outcome 
and support further attempts to optimize therapy.10-12 However, given that the majority of these patients 
treated on legacy CCG or POG trials did not receive myeloablative therapy, a further escalation to tandem 
transplantation may not be warranted.  Therefore, patients 12-18 months of age with stage 4 MYCN-NA 
tumors but with diploid DNA content, UH or indeterminant histology or DNA ploidy and children greater 
than 18 months of age with stage 3 MYCN-NA tumors with UH, estimated to be 1-4% of all high risk 
stage patients, will be eligible for treatment on ANBL0532 but will be nonrandomly assigned to single 
myeloablative therapy.  A uniformed treatment approach will allow improved analysis of outcome for this 
relatively rare patient cohort.  
 
2.2 
High-risk Neuroblastoma Therapy  
High-risk neuroblastoma is largely chemotherapy responsive, but despite improvements in complete 
response rates, the majority of patients still relapse. To improve event free survival, COG and legacy 
CCG and POG clinical trials have intensified chemotherapy during induction and consolidation phases of 
therapy and added biologic agents for treatment of minimal residual disease. CCG-3891 study 
demonstrated that increased dose intensity of consolidation with purged bone marrow transplant and 
administration of the biologic agent 13-cis retinoic acid (cis-RA) following consolidation therapy 
improved outcome for patients with high-risk neuroblastoma13.  The 8-year EFS and OS rates for patients 
treated with one transplant and cis-RA (n=50) are 44% + 12% and 54% + 13%, respectively (personal 
communication; K. Matthay and W.London). The recently completed COG Phase III trial, A3973, 
evaluated whether the use of a more intensive induction chemotherapy regimen (N7), reported by 
investigators at Memorial Sloan-Kettering to produce a 85% CR/VGPR rate,14 will result in improved 
EFS and end-induction response rate when compared to CCG-3891. A3973 also tested whether the use of 
anti-neuroblastoma purged PBSC rescue improves EFS for patients with high-risk neuroblastoma. The 
results of COG A3973 indicate no difference in event-free or overall survival with the use of purged 
PBSC products for transplant. Feasibility and toxicity data from COG A3973, ANBL00P1 and ANBL0P2 
cited below support the continued utilization of a dose intensive induction regimen and myeloablative 
chemotherapy consolidation regimen as the “backbone” schema as proposed in this successor study for 
high-risk neuroblastoma. The current COG ANBL0032 has demonstrated that immunotherapy (ch14.18 
antibody plus cytokines) in addition to cis-RA improves EFS. Patients treated on ANBL0532 will be 
eligible for participation on ANBL0032 or ANBL0931. 


 
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2.3 
Myeloablative regimens 
The results of the randomized CCG-3891 protocol demonstrate that a myeloablative therapy with 
carboplatin, etoposide, melphalan and 1000cGy total body irradiation (TBI) and purged autologous bone 
marrow rescue improves EFS for patients with high-risk neuroblastoma. The 3-year EFS was 30% for all 
patients on study, 85% of which had stage 4 neuroblastoma. The 3-year EFS from time of assigned 
randomization was 34% for autologous bone marrow transplantation (ABMT) versus 22% for 
continuation chemotherapy (CC) (p = 0.045).13  Overall survival was not significantly different for the 
two regimens, perhaps partly due to use of ABMT salvage in > 30 patients who progressed after 
chemotherapy consolidation. An apparent advantage was seen for ABMT within strata separated either by 
MYCN amplification, bone marrow immunocytology or stage. More recent evaluation of outcome for 
those children with high-risk neuroblastoma treated on CCG 3891 revealed an overall 8-year EFS and OS 
rate +/- SE from the time of enrollment onto CCG 3891 of 24% +/- 3% and 29% +/- 3% (n=539), 
respectively, with a median follow-up time of patients who did not experience an event of 7.7 years (130 
days – 12.8 years) (Table 1). The 8-year EFS from the time of randomization for patients randomized to 
ABMT (n=189) was 27% +/- 5% vs. 18% +/- 4% for patients randomized to CC (n=190), p=0.0434. The 
8-year OS for ABMT was not statistically significantly higher than for CC, 33% +/- 6% vs. 25% +/- 4%, 
p=0.3917 (personal communication, K. Matthay and W. London). These data continue to suggest that 
therapy intensification diminishes risks for neuroblastoma recurrence. Based on the incremental 
improvement in EFS with ABMT, myeloablative consolidation has become a standard of care for patients 
with high-risk disease in the United States and abroad.  
 
While TBI was used in the initial studies of autologous transplantation for neuroblastoma15 , the 
worldwide trend has been to eliminate this modality due to excessive toxicity including second 
malignancies.16 It is now clear that retrospective comparisons of TBI and non-TBI containing regimens 
showed no difference in patient outcomes. 16 17 Smedler et al. reported a moderate general developmental 
delay; with motor, perceptual and cognitive defects in ten children transplanted for leukemia or 
neuroblastoma with TBI regimens.18   Children transplanted for neuroblastoma with TBI also demonstrate 
abnormal growth rates, in some cases associated with growth hormone deficiency.19  TBI regimens can 
also cause late effects such as cataracts, other endocrine dysfunction, and secondary malignant 
neoplasms.20  There has been no prospective comparative trial to determine whether the addition of TBI 
improves survival from high-risk neuroblastoma. A retrospective review of 51 patients transplanted for 
advanced or poorly responding neuroblastoma from the European BMT Solid Tumor Registry found no 
significant difference in outcome between TBI and non-TBI regimens.17  A separate retrospective review 
of 62 concurrently treated stage 4 neuroblastoma patients with and without TBI also demonstrated 
equivalent survival rates.16 The CHLA group has shown a 3-year EFS rate of 49% +/- 6% in 73 patients 
analyzed from the end of induction therapy who were treated on protocol 91-LA6 with a non-TBI 
regimen of carboplatin, etoposide and melphalan with local irradiation (CEM-LI, Table 1). A preliminary 
comparison of the EFS of patients with stage 4 neuroblastoma over one year of age at diagnosis 
transplanted before progression with CEM-LI (n=47) with the same cohort of patients treated with CEM-
TBI on CCG-321P3 (n=43) showed no significant difference in outcome (p=0.059). Overall, there were 
4/73 (5%) toxic deaths in the patients transplanted before progression with CEM on the 91-LA6 protocol 
as compared to 8.3% toxic deaths following CEM-TBI in similar patients transplanted on CCG-321P3. 
These data suggest that the proposed CEM-LI without TBI is at least as effective as prior TBI regimens 
with the caveats that sample size limited the ability to detect a statistical difference in EFS and that trend 
towards improvement in EFS in this historical comparison could also be attributed to general 
improvements in care and induction regimens used in the 91-LA-6 (personal communication, J. 
Villablanca). 
 
The COG A3973 recently completed Phase III trial utilized the CEM preparative regimen based upon the 
results for the 91LA6 clinical trial noted above. Of the 489 eligible patients enrolled onto A3973, 368 had 
completed preparative regimen of carboplatin, etoposide, melphalan and autologous transplant with either 
purged or unpurged PBSC and reported on toxicity. Nearly 75% of the patients developed Grade 3 or 4 
stomatitis during consolidation. One patient developed Grade 3 cardiac dysfunction, and four had renal 


 
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dysfunction. Three patients developed renal failure requiring dialysis. Two of these patients had severe 
sinusoidal obstruction syndrome (SOS), formerly VOD, the other had severe capillary leak syndrome 
with grade 2 elevation of bilirubin, but no hepatic enlargement. All 3 patients proceeded to post transplant 
therapy on study.  In total, 12 of 368 (3.2 %) patients have died of complications during Consolidation 
phase of therapy, mainly due to infectious complications (n=8).  There have been 20 patients reported 
with SOS, which resulted in death in the 3 patients. These toxicities are similar to those reported using 
alternative myeloablative consolidation regimens13,21-23  and did not meet designed stopping rules. Two-
year EFS for the tranpslanted cohort from time of study enrollment was 48 +/- 3%.  The 91LA6 and COG 
A3973 experience to date suggest tolerable toxicity following CEM-LI consolidation therapy. 
Comparative analysis of 91LA6, CCG 321-P3 and A3973 indicates that the CEM-LI regimen without 
TBI is at least as effective as prior TBI regimens.  Therefore, CEM-LI will be employed in each arm of 
this successor Phase III study comparing single versus tandem consolidation therapy. 
 
2.4 
Tandem Myeloablative Regimens 
High-risk neuroblastoma remains incurable in 60-70% of patients.6,13  Further dose intensity may yield 
further improvements in EFS. To achieve this, tandem, or dual-cycle, transplant approaches have been 
developed. An initial attempt at tandem transplant using marrow support was piloted by the European 
Neuroblastoma Group in the LMCE2.24  Median time to reach the second ABMT was 3 mos. (range 2-6 
mos.), and median time to ANC > 500 was 43 days (15-120).  Overall survival at 2 years was 36% in a 
very high-risk group of patients, but the toxic death rate was high at 24%. 
 
Grupp et al. explored the use of tandem transplant with PBSC support in children with high-risk solid 
tumors.25,26  The myeloablative regimens employed in the CHP-594/DFCI 34-DAT study were an initial 
regimen of 2.4 g/m2 etoposide, 3.6 g/m2 cyclophosphamide and carboplatin 2 g/m2 followed 4-6 weeks 
later by a second regimen of melphalan 180 mg/m2 with 12 Gy of TBI. Initial data on 55 enrolled patients 
(ages 1 to 18 years) demonstrated the feasibility of the approach with 98 cycles of myeloablative therapy 
with stem cell rescue completed. Four patients who completed the first HSCT course did not complete the 
second, and there were three toxic deaths. Median time to neutrophil engraftment was 11 days. One 
patient experienced delayed engraftment but recovered following infusion of back-up PBSC. The 3-year 
EFS was 58% with a median follow-up of 22 months from diagnosis. These data are substantiated by a 
more recent analysis of 97 consecutive children (including the 55 previously published) treated with the 
CHP-594/DFCI 34-DAT that shows a 3-year PFS and OS of 55% (95% CI, 40 – 65%) and 66% (95%CI 
35 – 60%), respectively; a 5-year PFS and OS of 47% (95% CI 35 – 60%) and 55% (95% CI 43 – 68%), 
respectively and a 7-year PFS of 45%.27 Of the 89 patients who received at least one HSCT, the 5-year 
and 7-year PFS was 51% and 49%, respectively (Table 1). 
 
 
Toxicity and feasibility data on tandem transplantation without TBI have been evaluated in POG 9640 
and COG ANBL00P1 studies. POG 9640 enrolled 33 patients and utilized 5 cycles of induction 
chemotherapy followed by tandem transplantation with unpurged PBSC support. The tandem regimens 
were: Carboplatin, etoposide, cyclophosphamide (AT#1) followed by thiotepa and cyclophosphamide 
(AT#2). This regimen was found to be feasible and tolerable. There were no toxic deaths associated with 
the tandem regimen. A total of 21 patients underwent at least one course myeloablative therapy and 17 
patients received tandem regimens.  Of the 17 patients who underwent tandem transplant, 12 were alive 
without evidence of disease at 2 years.  The 5-year EFS and OS rates +/- standard error of the 33 patients 
enrolled was 27% +/- 8% and 39% +/- 9%, respectively.  Twenty-two patients received at least one 
transplant, and the 5-year EFS and OS rates from time of first transplant were 41% +/- 12% and 49% +/- 
12%, respectively (personal communication S. Grupp and W. London, MS in preparation).  
 
The promising results of the CHOP/DFCI experience, the POG 9640 study and the 91LA6 CEM-LI study 
have led the COG Neuroblastoma Committee to consider intensification of CEM-LI in a tandem regimen. 
The feasibility and toxicity of incorporating CEM-LI in a tandem regimen has been studied in COG 
ANBL00P1. This limited-institution pilot study utilized five cycles of induction chemotherapy followed 
by tandem transplantation. The tandem regimens were Thiotepa/Cyclophosphamide followed by CEM-LI. 
Thiotepa/Cyclophosphamide regimen was chosen as the initial transplant based upon the known toxicity 


 
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profile of agents alone and in combination when delivered at myeloablative doses,28-30 the acceptable 
toxicity profile of the combination demonstrated in the POG 9640 tandem transplant study and the known 
anti-neuroblastoma activity of each agent including their ability to cross the blood brain barrier.31  Data 
obtained from a CHOP pilot tandem regimen of Thiotepa/Cyclophosphamide followed by full dose CEM 
(equivalent to A3973 dosing) revealed excessive toxicity following CEM.  Therefore, a 15% dose 
reduction of CEM agents was utilized in the ANBL00P1 protocol and will be utilized in ANBL0532.  The 
observed toxicity following CEM in the CHOP pilot and in the COG A3973 trial suggest that CEM-
related toxicity would interfere with subsequent delivery of myeloablative chemotherapy and support the 
sequence of thiotepa/cyclophosphamide followed by CEM in a tandem myeloablative regimen.   
 
Of the 41 eligible patients enrolled onto ANBL00P1, 8 patients were removed from protocol prior to 
consolidation. Of the remaining 33 patients, 7 received only a single transplant while 26 patients received 
tandem transplants. Reasons for not receiving the 2nd transplant included progressive disease (1 patient), 
family preference (2 patients), mortality following transplant #1 (n=1) and prolonged toxicity following 
transplant #1 (n=3, delayed engraftment, elevated liver transaminases, renal insufficiency). Therefore, 
63% of all patients and 79% of those patients eligible for consolidation therapy received the tandem 
consolidation regimen. This compares favorably to the legacy CCG3891 trial where 68% of patients 
assigned to ABMT received the intended therapy. Overall, 3 patients have experienced treatment related 
mortality.  Twenty-two events occurred in 41 eligible patients enrolled at diagnosis resulting in 2-year 
EFS from time of diagnosis of 38% +/- 11%.  These data support the feasibility of this tandem 
myeloablative chemotherapy regimen, although small numbers of accrued patients limits the ability to 
assess efficacy. 
 
The summary data presented in Table 1 support the investigation of tandem transplant consolidation to 
improve EFS from high risk neuroblastoma.   A comparison of the CCG3891 and CHP/DFCI trials, both 
TBI-containing trials, reveals an improvement in EFS following tandem consolidation; (CCG 3891 from 
time randomized to ABMT: 8-year EFS 27+/- 5% versus CHP/DFCI from diagnosis: 7-year EFS 45+/-
10% versus CHP/DFCI from time on initial myeloablative regimen: 7-year EFS 49 +/- 11%).  A trend 
toward improvement in EFS following tandem transplant is even observed when comparing the highly 
selected cohort of CCG3891 patients who received ABMT and were randomized to receive cis-RA (26% 
of those patients patients randomized to ABMT) versus the CHP/DFCI patients who received the 
intended tandem transplant (84.5% of patients enrolled); CCG 3891:  8-year EFS 44 +/- 12% versus 
CHP/DFCI 7-year EFS 52 +/- 11%.  Furthermore, the 91LA6 data suggests that CEM provides similar 
EFS to the single TBI-CEM containing regimen used in CCG3891, supporting the elimination of TBI 
from a tandem regimen.  The EFS and OS results of the various non-TBI containing tandem regimens 
(ANBL00P1 and POG 9640) vary between studies, reflecting the difficulty in evaluating efficacy of 
therapy regimens in small, non-randomized clinical trials. However, the combined data from the 
CHP/DFCI, the POG 9640 and the ANBL00P1 trials demonstrate that intensification of consolidation 
therapy with PBSC support is feasible, does not increase treatment related mortality and may decrease 
recurrence for patients with high-risk neuroblastoma. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 1.  Comparison of Myeloablative Regimens for Treatment of High Risk Neuroblastoma 
 
CCG3891 
Overall 
N= 539  
(379 ran-
domized) 
CCG3891 
ABMT 
N = 189 
(129 
received 
ABMT) 
CEM-L1 
(91LA6) 
N=73 
CHP594/ 
DFCI34 
N=97 
POG9640 
 
N=33 
ANBL00P1 
 
N=41 
ANBL02P1 
 
N=31 
Pre-
consolidation 
Response 
(%CR/ 
VGPR) 
CR + 
VGPR  
50% 
(190/379) 
 
PD=50/379 
CR+ 
VGPR  
52% 
(98/189) 
 
PD=28/189 
CR + 
V 
GPR  
53% 
CR+VGPR
+PR+MR 
94%  
(91/97)  
 
PD = 6/97 
CR+ 
VGPR 
70% 
(23/33) 
 
PD=5/33 
CR+VGPR+P
R+MR 
 90% 
(37/41) 
 
PD=1/41 
CR/VGPR  
 
50% 
(13/26) 
 
PD=1/31  
% stem cell 
collections 
>4x10e6/kg 
BM source 
BM source 
NA 
NA – 
different 
induction 
NA – 
different 
induction 
NA – 
different 
induction 
88% 
(23/26)6 
%EFS at 2y 
 
 
 
56±6%4 
 
46±9%2 
55±11%4 
 
38±11%2 
39.5±14%3 
Too early 
%EFS at 3y 
30±2%2 
34±4%2 
 
43±6%3 
 
49±6%4 
55±9%2 
59±9%4 
61±10%5 
33±8%2 
41±11%4 
 
 
38±21%4 
NA 
% EFS at 5y 
25±2%2 
 
 
47±6%4 
47±9%2 
51±10%4 
54±11%5 
27±8%2 
41±12%4 
 
Too early 
NA 
% EFS at 7y 
24±3%1,2 
 
27±5%1,2 
44±12%1,3 
 
40±7%4 
45±10%2 
49±11%4 
52±11%5 
 
Too early 
NA 
% local 
relapse 
 
33±7% 
9.9% 
12.4% 
Data not 
available 
Data not 
available 
Data not 
available 
% second 
cancer 
0.55% 
(3/539) 
2 leuk, 1 
clear cell 
sarcoma 
0.5% 
(1/189) 
2.8% 
(2/73) 
2% 
(2/97) 
3% 
(1/33) 
Data not 
available 
Too early 
% HSCT- 
related toxic 
deaths  
4% 
(22/539) 
7% 
(9/129) 
5% 
(4/73) 
5% 
(5/97) 
0% 
(0/22) 
6% 
(2/33) 
6% 
(2/31) 
1  = Data represent 8yr EFS data for CCG 3891; 2 = EFS calculated from time of enrollment at initial diagnosis; 3 = EFS 
calculated from time of initial HSCT for those patients who received ABMT and were randomized to receive cis-RA (CCG3891 
n= 129); 4= EFS calculated from time of initial HSCT (91LA6 n= 73 ), or from time of initial HSCT who received at least one 
HSCT regimen (CHP594/DFCI34 n= 89, POG9640 N=22, ANBL00P1 n=32); 5 = EFS calculated from time of initial HSCT for 
those patients who received tandem HSCT per CHP 594/DFCI34 (n= 82); 6= protocol only required a minimum collection of 2 x 
106 CD34 cells/kg; median collection 32.4 x 106 CD34 cells/kg (range 1.8 – 548). NA= Not available 
 
 
2.5 
Novel Induction Regimen 
The emergence of chemotherapy-resistant tumor cells is the major obstacle to improved initial tumor 
response and to the cure of high-risk neuroblastoma.5,6,13,32 A marked escalation in chemotherapy dose 
intensity has resulted in improved initial tumor response rates.14,33,34  A highly dose intensive combination 
of cyclophosphamide, vincristine and doxorubicin alternating with cisplatin and etoposide has been 
studied in small numbers of patients at Memorial Sloan Kettering Cancer Center with a reported CR plus 
very good partial response rate (VGPR) of 85%.14  Unfortunately, this excellent induction response rate 
was not reproduced in a multi-center trial performed by the French Society of Pediatric Oncology (SFOP) 
where 21 of 47 patients who received the MSKCC induction regimen achieved CR at metastatic sites of 
disease, results that were similar to prior less dose intensive regimens.35  This regimen was further 
evaluated in over 400 patients with high risk neuroblastoma enrolled on the recently completed COG 
Phase III trial (A3973), demonstrating a CR plus VGPR of 52%. Data from the A3973 and SFOP  trials 
suggest that chemotherapy resistance remains an obstacle to the cure of high risk neuroblastoma.  Further 
dose intensification of induction chemotherapy is limited by hematopoietic and mucosal toxicity arguing 
for the addition of new non-cross resistant agents to further improve tumor response rates. 


 
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2.6 
Topotecan 
Topotecan, 9-dimethylaminomethyl-10-hydroxycamptothecin, is a semi-synthetic derivative of 
camptothecin that inhibits topoisomerase I enzyme resulting in double stranded DNA breaks and cellular 
apoptosis.36 Preclinical investigations in murine xenograft models have demonstrated antitumor activity 
against neuroblastoma,37,38 synergistic activity when combined with alkylator and platinum anti-tumor 
compounds 39,40 and both dosage and schedule dependency of anti-tumor activity.41  Anti-tumor activity 
demonstrated in xenograft models is maximal following daily x 5 days administration or daily x 5 days x 
2 weeks at single day systemic exposure of 52 – 88 ng/mL*hr, a systemic exposure proven to be feasible 
in subsequent clinical trials.42 Although topotecan demonstrates a non-cross resistant mechanism of 
action42,43 cross-resistance to etoposide, a topoisomerase II inhibitor commonly used in neuroblastoma 
therapy, has been demonstrated by in vitro analyses of patient-derived neuroblastoma cell lines resistant 
to etoposide.44   Patient-derived neuroblastoma cell lines established early in the clinical course (diagnosis 
or after induction therapy) were more likely to be sensitive to topotecan, supporting the incorporation of 
topotecan into Induction therapy, prior to significant etoposide exposure.  In vivo, topotecan is eliminated 
through hepatic metabolism and renal excretion. Topotecan penetrates the CNS,45 a site of recurrence in 
neuroblastoma.46 Topotecan has a limited toxicity profile notable for dose-limiting myelosuppression and 
mild to moderate nausea, vomiting and mucositis, regardless of administration schedule.47-49  Anti-
neuroblastoma activity has been demonstrated in both Phase I and II trials. A Phase I trial administered 
topotecan at dosages of 1.4 mg/m2/day to 2.4 mg/m2/day for 5 days to pediatric patients with recurrent 
tumors. Of nine patients with neuroblastoma, a partial response was demonstrated in 3 patients while 
stable disease occurred in one patient.42  A Phase II upfront window trial in patients with newly diagnosed 
high-risk neuroblastoma (POG-9341) identified topotecan (2 mg/m2/day for 5 days) as an active anti-
neuroblastoma agent with 38% of patients achieving a complete (n=1) or partial tumor response (n=11) 
following 2 cycles of single agent therapy.32  In a more traditional topotecan single agent Phase II trial 
(topotecan 2 mg/m2/day for 5 days) enrolling 37 patients with refractory neuroblastoma, complete 
response (CR) was achieved in 2 patients, mixed response (MR) in 5 patients and stable disease (SD) in 8 
patients.50  These data are consistent with topotecan’s anti- neuroblastoma efficacy documented in pre-
clinical studies and support the incorporation of topotecan into upfront therapy for neuroblastoma. 
 
2.7 
Topotecan and Cyclophosphamide 
Topotecan and cyclophosphamide have been successfully combined without excessive toxicity and have 
anti-neuroblastoma activity. A phase I trial in pediatric patients with refractory or recurrent solid tumors 
demonstrated the topotecan MTD as 0.75 mg/m2/day administered over 30 minutes daily for 5 days in 
combination with cyclophosphamide 250 mg/m2/day administered daily for 5 days.51  Myelosuppression, 
defined as Grade 4 neutropenia, was the dose limiting toxicity without additional significant toxicity 
observed. Anti-tumor activity was further evaluated in a Phase II trial of topotecan 0.75 mg/m2/day x 5 
days combined with cyclophosphamide 250 mg/m2/day for 5 days administered to 83 pediatric patients 
with refractory solid tumors.52  Six of thirteen patients with refractory/recurrent neuroblastoma (5 
received prior HSCT) achieved a PR (3 had received a prior BMT), while 2 patients achieved mixed 
response or stable disease. Preliminary data from POG-9642, a randomized study of topotecan (2 
mg/m2/day for 5 days) versus topotecan/cyclophosphamide (at Phase II doses noted above) in patients 
with recurrent neuroblastoma demonstrate a trend toward improved CR/PR rate following 
topotecan/cyclophosphamide therapy (34% versus 20%), decreased rate of grade 3 or 4 infectious 
complications and increased time to tumor progression (Frantz C., COG 9462 Public Report, 2/11/2003). 
 
Xenograft models predict that higher systemic exposure (52-88 ng/ml*hr) to topotecan will improve 
tumor response.38  A topotecan systemic exposure of 52 – 88 ng/ml*hr is predicted to be achieved by 
doses of 1.0 to 1.6 mg/m2/day.42  Limited pediatric trials, both non-myeloablative and myeloablative, have 
incorporated such doses of topotecan. Repetitive delivery of a dose-intensive topotecan and 
cyclophosphamide regimen (MSKCC regimen), continuous infusion high-dose cyclophosphamide (4200 
mg/m2/48 hours) combined with continuous infusion topotecan (6 mg/m2/72 hours), has been 
administered to pediatric patients with recurrent solid tumors.53  Severe neutropenia was observed 
following all courses of therapy, with 89% of courses complicated by fever and 5.9% complicated by 


 
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bacteremia. Median duration of neutropenia was 7 days (range 5-12 days); however, all patients recovered 
neutrophil count to > 1000/μl and platelet to 75,000/μl by 28 days. Nonhematologic toxicity was limited 
to Grade 4 hyperbilirubinemia and Grade 3 cardiac dysfunction in one patient during documented sepsis 
and three episodes of Grade 3 mucositis, two associated with herpes simplex infection. There were no 
toxic deaths. Cyclophosphamide and topotecan doses of 1 gram/m2/day for 3 days and 1.25 to 4 
mg/m2/day for 5 days have been successfully combined with melphalan as a myeloablative regimen for 
adult patients with advanced ovarian cancer.54  Non-hematopoietic toxicity was limited to mucositis with 
maximum of Grade 2 toxicity occurring in 16 of 53 patients treated. 
 
The limited toxicity profile following dose-intensive administration of topotecan and cyclophosphamide 
support the potential feasibility for its incorporation into an upfront induction regimen. To this end, COG 
ANBL02P1 examined the feasibility of adding dose intensive topotecan and cyclophosphamide onto the 
N7 backbone chemotherapy administered in COG A3973 study. Escalated doses of topotecan (1.2 
mg/m2/day for 5 days) and cyclophosphamide (400 mg/m2/day for 5 days) (T/C) replace the initial 2 
cycles of A3973 induction chemotherapy allowing incorporation of topotecan while maintaining dose 
intensity of known active agents in the treatment of neuroblastoma (see Table 2).  The topotecan dose of 
1.2 mg/m2/day x 5 days was chosen based upon a predicted topotecan AUC (50 - 70 ng/mL*hr) that is 
within the range known to produce tumor response in murine xenograft models42 and the ability to 
administer with cyclophosphamide.53  Chemotherapy cycles were scheduled every 21 days, PBSC harvest 
occurred after T/C cycles and surgical resection of residual primary tumor after cycle 5.  Thirty-one 
patients, 3 with INSS Stage 3 and 28 with Stage 4 were enrolled.  Pharmacokinetically guided topotecan 
dosing (target systemic exposure of AUC 50 - 70 ng/ml*hr determined by single day topotecan lactone 
levels) demonstrated the ability to achieve the target AUC in 87% (27/31) of patients during T/C Cycle 1 
and in 85% (23/27) of patients during T/C Cycle 2.  Furthermore, the median topotecan dose required to 
achieve the targeted AUC during Cycle 1 and Cycle 2 was 1.2 mg/m2/day and 1.3 mg/m2/day, 
respectively and support the use of 1.2 mg/m2/day dosing in the ANBL0532 induction.  Successful PBSC 
harvest as defined by a minimum of 2 x 106 CD34 cells/kg  was achieved in 25/26 patients for whom data 
are available; median harvest of 32.4 x 106 CD34 cells/kg (range 2.24 - 548) collected over a median of 1 
day (range 1-3 days). A PBSC harvest of > 6 x 106 CD34 cells/kg was achieved in 23 patients (88%). One 
patient was harvested after Cycle 5 due to physician discretion and achieved a PBSC collection of 1.8 x 
106 CD34 cells/kg.  Only one patient required 3 days of apheresis but achieved a total PBSC collection of 
31.4 x 106 CD34 cells/kg.  All PBSC collections were free of tumor contamination using an 
immunocytochemical detection assay.  There were no dose limiting toxicities during Cycles 1 and 2 of 
induction and no induction related moralities.  The majority of patients (85%) experienced Grade 3 or 4 
hematopoietic toxicity. Documented infection occurred in 10.3% patients during T/C cycles compared to 
26% of patients during subsequent induction cycles on ANBL02P1 or 30% patients during initial 3 cycles 
of the MSKCC induction on COG A3973. The intended dose intensity of all chemotherapy agents was 
maintained in 30 of 31 patients.  One patient required a 25% dose reduction of chemotherapy doses 
during Cycle 6 induction due to prolonged myelosuppression.   Complete response or partial response 
was achieved in 36% of patients following 2 cycles of T/C.  End-induction response rate (CR/VGPR) was 
50% (13/26), 1 patient developed progressive disease following completion of induction but prior to 
initiating consolidation therapy. 55 
 
In summary, this dose intensive cyclophosphamide and topotecan containing induction regimen was well 
tolerated with expected and reversible toxicities. Dose intensity of standard induction chemotherapy 
agents was not limited by the addition of dose-intensive topotecan. The ability to achieve sufficient PBSC 
harvest with in vivo tumor purging was demonstrated.  Together these data support the investigation of 
efficacy of this novel induction regimen in ANBL0532. 
 
 
 
 
 
 
 


 
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TABLE 2.  Comparison of Induction Regimen Chemotherapy Dose Intensity 
 
Chemotherapy Dose Intensity (mg/m2/week)^ – Comparison of Therapeutic Regimens 
Drug 
CCG 3891 
15 weeks 
POG 9341 
15 weeks 
COG 
ANBL00P1 
15 weeks 
 
COG A3973  
18 weeks 
COG 
ANBL0532 
18 weeks 
Oxazophosphorine 
equivalents+ 
500 
434 
700 
933 
688 
Doxorubicin 
7.5 
10 
8 
16.6 
8.3 
Platinum 
equivalents# 
15 
29.9 
27.3 
22.2 
22.2 
Etoposide 
50 
110 
100 
66.7 
66.7 
Topotecan 
0 
0 
0 
0 
0.67 
 
^ 
Dose intensities are calculated as mg/m2/week administered over the entire induction regimen. 
+ 
Oxazaphosphorine = Cyclophosphamide + Ifosfamide.  The dose intensity of ifosfamide is 
calculated in cyclophosphamide equivalent using a conversion of 4 mg Ifosfamide is biologically 
equivalent to 1 mg of cyclophosphamide.56 
# 
Platinum equivalents = Cisplatin + Carboplatin.  The dose intensity of carboplatin is calculated in 
cisplatin equivalent using a conversion of 4 mg carboplatin is biologically equivalent to 1 mg of 
cisplatin.   
 
2.8 
Local Radiation Therapy 
For stage III and IV neuroblastoma, local relapse is a major component of treatment failure in several 
published series, all of which included radiation delivered to the site of primary disease.57-59  As systemic 
therapy for high-risk neuroblastoma becomes more aggressive, response rates improve, and survival 
increases, local control becomes a formidable problem. This is evident in a recent analysis of CCG 3891, 
consisting of chemotherapy, primary surgery, 10 Gy of external beam radiation therapy (EBRT) to gross 
residual disease, followed by randomized assignment to continuation chemotherapy (CC) or autologous 
bone marrow transplantation (ABMT).8  ABMT patients received 10 Gy of total body irradiation (TBI). 
Estimated 5-year locoregional recurrence rates were 51% ± 5% and 33% ± 7% for CC and ABMT 
patients, respectively (P=0.004). Results of this trial revealed that for patients who received 10 Gy of 
EBRT to the primary, the addition of 10 Gy of TBI and ABMT decreased local recurrence compared with 
CC (22% ± 12% and 52% ± 8%, P=0.022). This indicates that in combination with EBRT to the primary 
tumors site, the addition of 10 Gy of TBI as a component of high dose chemotherapy with ABMT 
improved local control compared with CC without TBI.  Several single institution reports further support 
the administration of pre-chemotherapy or pre-surgery primary tumor volume and regional lymph nodes 
primary site radiation therapy (21 Gy) results in improved local tumor control.60-62  Based upon these data, 
the currently completed COG A3973 delivered 21.6 Gy EBRT to pre-surgical primary tumor volume 
following recovery from consolidation myeloablative therapy. 
 
Several analyses of outcome for high-risk neuroblastoma suggest that current local therapy for 
incompletely resected patients is inadequate. Wolden et al. reported on a series of patients with stage 4 
neuroblastoma receiving 1.5 Gy twice a day to 21 Gy to pre chemotherapy, pre-surgery primary tumor 
volume and regional lymph nodes.60  The actuarial locoregional control rate at 5 years was 84%. A recent 
update of this experience reported a 10.1% probability of primary-site failure among 99 patients, most of 
whom (92 patients) had no evidence of disease in the primary site at the time of irradiation.61  Among 
seven patients with disease at the primary site at the time of irradiation, three had disease that recurred 
locally. EBRT did not increase acute toxicity, except for increased total parenteral nutrition 
administration.  
 
Published studies have sought to assess the appropriate radiation dose to achieve local control in patients 
with neuroblastoma.  A dose response to radiation is supported by several publications;58,63,64 however, 
these publications describe results in stage III disease or do not incorporate biological prognostic markers.  


 
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In the analysis of radiation therapy in CCG 3891, in combination with EBRT to the primary tumors site, 
the addition of 10 Gy total body irradiation (TBI) as a component of autologous bone marrow transplant 
(ABMT) improved local control compared with continuation chemotherapy (CC) without TBI.  In 
addition, a dose response to radiation administered to the primary tumor site is supported by the patients 
in this study that received 20 Gy for extra-abdominal primary tumors. Of 36 patients with extra-
abdominal primaries, 6 patients received 20 Gy EBRT (2 also received TBI) while 30 patients received no 
EBRT (10 of these received TBI). Local relapse rates at 5 years were 0%  0% and 44%  15% for 
patients with and without EBRT, respectively (P=0.09).8  Jacobson et al. reported on the experience at the 
University of Florida, using radiation doses up to 45 Gy.  The authors noted no evaluable complications 
related to radiation alone, but rather related more commonly to the tumor itself or surgical resection.65 
Investigators at the University of Utah performed a similar analysis of radiation dose response for 
neuroblastoma.  The authors observed local failures after doses up to 45 Gy in children older than three 
years.65  Although authors of both studies state that doses lower than 45 Gy may be adequate for some 
patients with neuroblastoma, the vast minority of patients in these studies had high-risk disease and 
therefore no firm conclusions can be drawn regarding the appropriate dose to the primary site in patients 
with high-risk disease.  In fact, a recent abstract from the University Children’s Hospital in Cologne, 
Germany, reported that 36 Gy of external beam radiation therapy (EBRT) administered to patients with 
incompletely resected primary tumors could compensate for “the disadvantage of incomplete response to 
induction chemotherapy.”  In this report of the NB97 trial for patients one year of age or older with stage 
4 neuroblastoma, patients with isolated localized residual disease had improved outcome following EBRT 
(3-y-EFS 100%, 3-y-OS 100%) compared those not receiving EBRT despite residual tumor tissue (3-y-
EFS 20±18%, p<0.001; 3-y-OS 20±18%, p<0.001).66  
 
Given the high rates of local recurrence, particularly following an incomplete surgical resection, and the 
tolerable toxicity of EBRT evident in multi-institutional trials, patients enrolled onto ANBL0532 who 
have an incomplete surgical resection of the primary tumor will receive 21.6 Gy EBRT to the post-
induction chemotherapy, pre-operative primary tumor volume and an additional boost of 14.4 Gy EBRT 
to the gross residual volume (total dose 36 Gy to gross residual tumor volume).  The additional dose of 
14.4 Gy to gross residual disease is unlikely to result in significantly increased toxicities.  In CCG 3891, 
the administration of EBRT was not associated with enhanced toxicities with the exception of parenteral 
nutrition requirement, which occurred in 55% and 44% of patients who did and did not receive EBRT, 
respectively (P=0.049).  Furthermore, 36 Gy is well within normal tissue tolerance for most organs within 
the field of radiation.  Kidneys and liver will likely prove to be the dose-limiting structures and the same 
guidelines for maximal doses to normal structures will be followed, as is standard in all current 
neuroblastoma protocols.  It should also be noted that the boost for patients with incomplete resections 
will deliver an additional 14.4 Gy (from 21.6 Gy to 36.0 Gy) only to regions of gross residual disease, a 
target that generally is substantially smaller than the original pre-operative tumor volume that receives 
21.6 Gy. 
 
2.9 
Surgery 
Biopsy at initial diagnosis is necessary to obtain adequate tissue for biologic studies and enrollment on 
the Neuroblastoma Biology Protocol.  Resection of the primary tumor and bulky metastatic disease is 
usually necessary to achieve CR or VGPR after induction chemotherapy. A retrospective analysis of high 
risk neuroblastoma patients enrolled onto CCG 3891 demonstrated improved resectability of primary 
tumor after initial chemotherapy and revealed a trend toward improved survival for those patients who 
underwent gross total resection of primary tumor, 5-year EFS 30 +/- 3% and 25 +/- 3%, respectively 
(p=0.1010).67 Acute surgical complication rates and characteristics were independent of timing of primary 
tumor resection. Based upon these data, patients enrolled onto the recently completed A3973 underwent 
delayed surgical resection of the primary tumor after 5 cycles of chemotherapy. Tumor biopsy at 
diagnosis was required to obtain adequate tissue for assessment of biologic characteristics.  ANBL0532 
will utilize this treatment strategy and prospectively evaluate if complete primary tumor resection is 
predictive of local control and EFS in high risk neuroblastoma patients. 
 


 
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Early and late postoperative complications are known to occur following extensive tumor resection for 
neuroblastoma.  These complications may include adhesive bowel obstruction, chylous leak, ipsilateral 
renal injury, atrophy or loss, and chronic diarrhea.  Group wide studies have regularly sought data on 
intraoperative and 30 day postoperative complications.  Adkins et al. reported normal organ removal in 
19% of high risk neuroblastoma patients who underwent complete resection of primary tumor.  There was 
no statistical difference in acute intra-operative or peri-operative complications, including risk for 
hemorrhage, renal injury, wound complication or acute bowel obstruction, regardless of extent of surgical 
resection.67  There is potential for bias in this study, given the retrospective collection of data.  Extended 
observations are necessary to detect late postoperative complications, as they may relate to the extent of 
resection and subsequent surgical and radiotherapeutic efforts to achieve local control.  Specifically, 
extended follow up will be necessary to detect the occurrence of adhesive bowel obstruction and renal 
atrophy related to surgically induced ischemic events while the risk for chylous leak or diarrhea may be 
related to extensive retroperitoneal dissection.  Rates of these complications should be correlated with the 
surgical and radiotherapeutic efforts in obtaining local control as they may impact on future management 
decisions. 
 
2.10 
Neurologic Outcome of Patients with Epidural Neuroblastoma  
Epidural or intradural extension of tumor occurs in approximately 5-15% of patients diagnosed with 
neuroblastoma, and may occur with or without neurologic impairment.8,68  Epidural neuroblastoma with 
spinal cord compression is an oncologic emergency that warrants immediate intervention.  However, the 
choice of emergent therapy remains somewhat controversial, with pediatric oncologists favoring 
chemotherapy and neurosurgeons favoring laminectomy with surgical decompression.69  There are several 
retrospective reports of similar neurologic outcome for patients treated with chemotherapy versus 
laminectomy,70-73 and therefore emergent chemotherapy has become a preferable alternative to 
laminectomy in most cases, in an effort to diminish the devastating late orthopedic effects of laminectomy 
in infants or young children.  Radiation therapy has generally been reserved for situations of progressive 
or persistent neurologic dysfunction despite chemotherapy and laminectomy. 
 
This study will prospectively characterize multiple aspects of neurologic disability at diagnosis and 
during the follow-up period in an effort to systematically study the neurologic outcome of patients with 
primary neuroblastoma tumors with intraspinal extension (see Appendix III).  A multidisciplinary 
evaluation at the time of diagnosis, including oncology, neurosurgery, and radiation oncology, is strongly 
encouraged.  It is the intent of this study that patients with clinical signs of spinal cord compression will 
be treated with primary chemotherapy, unless the multidisciplinary evaluation determines that surgical 
decompression would be more appropriate.  Radiation therapy should be reserved for patients whose 
neurologic status deteriorates despite chemotherapy and surgical decompression. 
 
2.11  Maintenance Therapy 
The presence of minimal residual disease despite achievement of maximal response to induction and 
consolidation therapy results in continued risk for neuroblastoma relapse. This was demonstrated in the 
CCG-3891 study where the benefit of additional non-cross resistant therapy, 13-cis Retinoid acid (cis-
RA) administered following myeloablative consolidation therapy was observed. Patients with newly 
diagnosed high-risk neuroblastoma enrolled in CCG3891 were randomized at week 34 of therapy 
(following either chemotherapy or ABMT consolidation) to no further therapy versus cis-RA for six 
months. Cis-RA or isotretinoin is a synthetic retinoid derived from the naturally occurring all transretinoic 
acid by modification of the terminal carboxyl group. When neuroblastoma cell lines are exposed to all-
trans-retinoic acid (trans-RA) or cis-RA in vitro, they exhibit decreased proliferation, decreased 
expression of the MYCN oncogene, and morphological differentiation.74-77  Growth arrest and 
differentiation in response to cis-RA have been observed in neuroblastoma cell lines initiated from tumors 
at the time of progression after chemoradiotherapy, 74,75 suggesting that resistance to cytotoxic 
chemotherapy does not induce resistance to cis-RA. cis-RA was well tolerated in a pediatric Phase I trial 
using an intermittent administration schedule of twice daily administration for 14 days followed by 14 
days with no therapy.74  cis-RA toxicities are generally mild; consisting primarily of chelitis, dry skin, and 
hypertriglyceridemia,78  with hypercalcemia seen at higher doses.79  A significant difference in the three 


 
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year EFS from the time of this randomization in the patients receiving cis-RA (46%) versus those with no 
further therapy (29%), with p value of 0.027 in a test of proportions.13  This advantage for EFS was seen 
in subgroups by prior randomization, such that the best overall EFS was for patients treated with ABMT 
with cis-RA (55% EFS), second was ABMT without cis-RA (39%), third was chemotherapy 
consolidation with cis-RA (32%), and fourth was chemotherapy without cis-RA (18%).  
 
Despite the use of cis-RA, greater than 40% of children will develop recurrent neuroblastoma. To further 
improve outcome, the efficacy of novel, anti-neuroblastoma targeted immunotherapy to eliminate 
minimal residual disease has been evaluated. Anti-gangliosidase (GD2) monoclonal antibody ch14.18 has 
shown preclinical and early clinical activity against neuroblastoma, which was enhanced when combined 
with GM-CSF or IL2. COG ANBL0032 was designed to determine if adding ch14.18 + GM-CSF + IL2 
to standard therapy of isotretinoin after intensive multimodality therapy improved outcome for high-risk 
neuroblastoma patients. High-risk neuroblastoma patients who responded to induction therapy and stem 
cell transplant were randomized to 6 cycles of isotretinoin (standard therapy) or 6 cycles of isotretinoin 
with 5 concomitant cycles of ch14.18 combined with GM-CSF or IL2 in alternating cycles 
(immunotherapy). An intent-to-treat randomized comparison (Lan-DeMets interim monitoring, 
cumulative alpha=0.025) was performed for event free survival (EFS). A total of 226 eligible patients 
were evenly randomized to standard or immunotherapy. Immunotherapy was associated with grade ≥3 
pain, vascular leak syndrome and hypersensitivity reactions in 51%, 23% and 25% of patients, 
respectively. With 61% of expected events observed, the study met criteria for early stopping for efficacy. 
Median follow-up was 2.1 years. Two-year EFS estimates were 66%±5% for patients randomized to 
immunotherapy versus 46%±5% for standard therapy (p=0.01). OS was also superior (p=0.02, unadjusted 
for interim looks) for immunotherapy: (86%±4%*) versus isotretinoin alone (75%±5%*). Moreover, for 
the major subgroup of patients ≥1 year of age with stage 4 disease, EFS was significantly greater (p= 
0.02) for the immunotherapy group (63%6%*), as compared to isotretinoin alone (42%6%*).  (*2-year 
estimates) (Alice Yu; personal communication, COG ANBL0032 study report). 
 
Immunotherapy consisting of ch14.18 with GM-CSF and IL2 significantly improves outcome for high-
risk neuroblastoma patients. Ch14.18 remains under clinical investigation through COG ANBL0032 and 
ANBL0931 protocols to further evaluate efficacy and toxicity. Given the significant improvement in 
survival from high risk neuroblastoma following antiGD2 antibody therapy, patients enrolled onto 
ANBL0532 should be encouraged to participate in actively enrolling clinical trials of ch14.18 antibody, 
(i.e. ANBL0032 or ANBL0931). Patients who are not eligible to receive ch14.18 antibody therapy or 
decline immunotherapy will remain on ANBL0532 and receive six months of cis-RA post ASCT based 
on the significant improvement in EFS with cis-RA documented by CCG3891 trial. 
 
2.12 
Biologic Correlative Studies 
 
2.12.1 Enrollment on COG ANBL00B1 
Enrollment on COG ANBL00B1 (Neuroblastoma Biology Study) is an eligibility requirement for 
ANBL0532 as assignment to clinical risks groups and different COG neuroblastoma therapeutic clinical 
trials is dependent upon accurate histologic and biologic diagnosis.  Although submission of paraffin-
embedded tissue is acceptable for enrollment onto ANBL00B1, the COG Neuroblastoma committee 
encourages the submission of fresh or snap-frozen tissue, peripheral blood, or bone marrow specimen.  
The acquisition of these primary tumor specimens will enable additional correlative biologic studies.  
Enrollment on both COG ANBL0532 and ANBL00B1 has the significant advantage of allowing the 
correlation of novel biologic parameters with a clinically well-characterized (including treatment and 
outcome) cohort of patients. 
 
 
2.12.2 Cyclophosphamide Pharmacogenomics in Pediatric Patients  
 
Although the efficacy of cyclophosphamide is well established in NB patients, considerable inter-patient 
variability exists in response and toxicity.  Variability in cyclophosphamide metabolism may result in 
such clinical variability.  Cyclophosphamide dosing based on body weight (mg/kg) or BSA (mg/m2) 


 
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results in a wide area under the concentration-time curve (AUC) range of the parent drug, and an even 
greater variability in the AUC of its metabolites.80  Children have a faster clearance of cyclophosphamide 
relative to adults,81  although the clinical significance of this difference in disposition is unclear.82  Recent 
studies have revealed an association between the AUC of cyclophosphamide and its metabolites to the 
risk of recurrence in children receiving standard dose cyclophosphamide (i.e., 300-1000 mg/m2) for 
treatment of B-cell non-Hodgkin lymphoma.82,83  
 
The pharmacokinetics of cyclophosphamide and its metabolites HCY and CEPM were evaluated in 18 of 
the 31 patients with newly diagnosed high-risk neuroblastoma enrolled in COG ANBL02P1.  Median 
patient age was 2.5 years (range:  0.9-9.4).   
 
 
Table 3:  Pharmacokinetics of CY/topotecan 
 
Dose 1 
Dose 4 
AUCCY 
529 
(332 - 1042) 
329 
(168-922) 
AUCHCY 
31.9 
(12.2-102.3) 
42.4 
(16.3-81.5) 
AUCCEPM 
27.3 
(8.3-69.2) 
30.4 
(10.4-92.4) 
AUC HCY/CY Ratio 
0.058 
(0.031-0.181) 
0.113 
(0.039-0.286) 
Median (range) 
 
The median clearance was 2.43 L/hr*m2 (range: 0.0.88 – 4.32) after dose 1 and 4.35 (1.55-8.54) after 
dose 4, consistent with previous reports 81,83-85  Topotecan did not appear to effect cyclophosphamide 
clearance. Similar to our observations in patients receiving Cyclophosphamide/TBI, there was 
considerable interpatient variability in the AUC of cyclophosphamide with even greater interpatient 
variability in exposure to the metabolites. After dose 1, variability of the AUC of cyclophosphamide (3.1 
fold), HCY (8.4 fold) and CEPM (8.3 fold) was comparable to that measured in cyclophosphamide/TBI 
patients (i.e., 3.3, 7.8 and 16.1 fold, personal communication J. McCune).  Auto-induction of 
cyclophosphamide clearance was observed in 14 of the 15 children for whom cyclophosphamide AUC 
was available after doses 1 and 4, again similar to other reports.86-89 The AUCHCY and AUCCEPM increased 
in four and three children, respectively.   
 
Multivariate analysis was conducted to evaluate for determinants of AUC of cyclophosphamide, HCY 
and CEPM.  Two of the 21 children received cyclophosphamide 13.3 mg/kg; their AUCs were 
normalized to cyclophosphamide 400 mg/m2 to allow for inclusion in this multivariate analysis.  
Multivariate regression analysis indicated that age, weight and body surface area explained only 23% of 
the variability in CY clearance after dose 1.  Furthermore, the AUC of cyclophosphamide and its 
metabolites were not consistently correlated.   
 
Cyclophosphamide pharmacokinetic assessments are unlikely to be used clinically given the variability in 
cyclophosphamide metabolism and the resource intensity of cyclophosphamide pharmacokinetic 
evaluations.  Alternatively, genetic polymorphisms in genes involved in cyclophosphamide metabolism 
may correlate with cyclophosphamide pharmacokinetics and may predict toxicity and anti-tumor activity 
of the ANBL0532 cyclophosphamide containing induction regimen.  Cyclophosphamide is activated by 
several cytochrome P450 enzymes which have genetic polymorphisms, specifically CYP3A4/5, 
CYP2C19, CYP2C9 and CYP2B6.90 CYP2B6 *5 and *6 alleles have been associated with either altered 
activation of HCY or clinical outcome. Their frequencies in Caucasians are 25% and 26-41%, 
respectively.91 Several genetic polymorphisms in CYP2C9 have functional consequences on the enzyme’s 
activity; CYP2C9*2 and CYP2C9*3 are the most common variants. 92  In Caucasians, 65% of individuals 
are homozygotes for CYP2C9*1, 22% are heterozygous or homozygous for CYP2C9*2 and 13% carry 
CYP2C9*3. The expression of these alleles is less common in African-Americans or Chinese (<2% - 


 
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3.5%, respectively). 92,93 The CYP2C9*2 allele is characterized by an arginine to cysteine exchange at 
position 144 (Cys144 – Ile 359), while in CYP2C9*3 isoleucine 359 is changed to leucine (Arg144 – 
Leu359). Both CYP2C9*2 and CYP2C9*3 are non-null alleles which code for functional protein with 
reduced levels of enzyme activity. CYP2C9*2 carriers have a moderate reduction in activity, while the 
reduction in activity is most marked for CYP2C9*3.92,93  GSTA1, the predominant GST involved in the 
metabolism of cyclophosphamide, exhibits a polymorphism that influences its hepatic expression. 
GSTA1*B, which is several linked single nucleotide polymorphisms in the proximal promoter region of 
the GSTA1 gene, has reduced levels of GSTA1 enzyme. The expression of GSTA1*B does not differ by 
ethnic group; GSTA1*A/*B occurs in 49% and GSTA1*B/*B occurs in 16% of a population of breast 
cancer patients.94  
 
ANBL0532 will assess whether host genetic polymorphisms in CYP2B6, CYP2C9 and GSTA1 
genotypes involved in the metabolic activation and clearance of cyclophosphamide are correlated with 
Cyclophosphamide/Topo associated toxicity and tumor response.  Prior studies have established 
genotype-phenotype relationships for the CYP2B6, CYP2C9 and GSTA1 genes for both in vitro 
analyses95 and in metastatic breast cancer patients receiving high dose cyclophosphamide as a component 
of a HSCT preparative regimen.96  The pharmacology laboratory at the Fred Hutchinson Cancer Research 
Center is currently conducting an analysis of CYP2B6, CYP2C9, CYP3A5, ABCC2, GSTA1, GSTM1, 
GSTT1 genetic polymorphisms in 147 patients who received CY in combination with TBI in preparation 
for HSCT. Preliminary analysis suggests that polymorphisms in CYP2B6, CYP2C9, and GSTA1 are key 
enzymes associated with toxicity (personal communication, J. McCune).  An exploratory analysis of co-
variance (ANCOVA) was conducted using limited ANBL02P1 data.  Age was used as a co-variate for 
three genes (GST, CYP2C9, CYP2C19) upon the following endpoints after the first cyclophosphamide 
dose (i.e., dose 1):  AUCCY, CY clearance, AUCHCY, AUCCEPM.  CYP2C9 was the only gene that 
trended towards statistical significance with AUCCY, cyclophosphamide clearance (p=0.37), AUCHCY 
(p=0.89), AUCCEPM (p=0.80).   
 
2.12.3 13-cis Retinoic acid Pharmacokinetics 
The variability of cis-RA continuous steady state (CSS) plasma levels and/or genetic variations in retinoic 
acid metabolic enzymes may correlate with event-free survival or systemic toxicity (CTC Grade 3/4 skin, 
hypercalcemia and hepatic toxicity) in high-risk neuroblastoma patients. Pharmacokinetics studies 
performed on patients in the Phase I trial of cis-RA showed significant interpatient and intrapatient 
variability in peak serum levels (mean peak serum cis-RA concentration: 7.2 ± 5.3μM; trough 
concentration: 4.1 ± 2.7μM). It was noted that peak serum concentrations above 10 μM were associated 
with a higher incidence of grade 3 and 4 toxicities in patients.97,98 cis-RA may be subject to first-pass 
metabolism and subsequent plasma (and tumor) concentrations will depend on the rate of metabolism to 
its inactive 4-oxo metabolite. Preliminary data from a pilot study in the UK (UKCCSG Study PK 2000 
08) has shown that plasma concentrations of 4-oxo-13-cis-RA can accumulate to exceed those of the 
parent compound. A ~10- fold variation in 4-oxo-13-cis-RA peak plasma concentrations was found. It is 
proposed that increased levels of this metabolite in vivo may lead to a diminished efficacy of cis-RA.99   
 
A number of cytochrome P450 (CYP) enzymes have been identified as playing a role in the metabolism 
of cis-RA.100,101  CYP2C8 is most important in terms of activity and level of expression in the liver.  
Genetic polymorphisms in the CYP2C8 gene have been described 100  which result in a lower rate of 
paclitaxel metabolism and are commonly seen in a Caucasian population.102,103  Thus, genetic variation in 
CYP2C8 activity could underlie individual differences in cis-RA metabolism and bioavailability. The 
fetal isoform CYP3A7, which is expressed post-natally in a significant number of individuals, also 
metabolizes cis-RA 100.  The expression of CYP3A7, and thus the contribution of this isoform to cis-RA 
metabolism, may be predicted by genotyping in a pediatric population.  A further aspect of cis-RA 
metabolism is glucuronidation, both of the parent drug and of 4-hydroxy-metabolites. This conjugation 
may be mediated by UGT1A1 or UGT2B7, 104 both enzymes that are subject to genetic polymorphisms.105  
Results from this study will provide an insight into whether modulation of cis-RA dosing according to 
blood levels achieved and/or genotype, could be used in future studies to optimize the treatment of high-


 
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risk neuroblastoma. This study will be conducted in collaboration with the United Kingdom Children’s 
Cancer Study Group (UKCCSG). 
 
2.12.4 Topotecan Pharmacokinetics 
Many individual pharmacokinetic studies of topotecan in children with cancer have been conducted, and 
results have shown wide interindividual variability in topotecan clearance.42,45,49  Due to the inherent 
variability in topotecan disposition, investigators have used pharmacokinetically guided dosing to 
individualize the topotecan dosage for each patient based upon their systemic clearance and the goals of 
the clinical trial.  The response rate for this approach has been promising.106,107  Although 
pharmacokinetically guided topotecan is a promising approach to dosing topotecan, it has limitations and 
it is important to find ways to simplify the current pharmacokinetic dosing strategy.   
 
One approach would be to use a dosing model based upon patient specific covariates identified in a 
population pharmacokinetic analysis.  Such an analysis of topotecan lactone pharmacokinetics has been 
conducted in a large pediatric patient population, which includes patients with many different diagnoses.  
The covariates identified in this analysis included BSA, age, phenytoin coadministration, calculated 
glomerular filtration rate, and serum creatinine.  However, for the current application the patient 
population will be limited to children with high-risk neuroblastoma and only total topotecan (combination 
of lactone and carboxylate forms) will be available for pharmacokinetic analysis.  Thus, a more limited 
population pharmacokinetic analysis was undertaken of the ANBL02P1 total topotecan plasma 
concentration-time data.  In this analysis, the only patient covariate identified as significantly related to 
topotecan total clearance was sex with females having a lower clearance.  Clearly this covariate will not 
be very informative in a dosing model.  Thus, it would be helpful to gain additional covariate data in this 
patient population, and relate that to total topotecan clearance determined using a limited sampling model.  
Ultimately, data collected in this Phase III clinical trial will be used to derive a dosing algorithm for 
topotecan in children with high-risk neuroblastoma that will either not need plasma topotecan 
concentrations or at most use only one plasma concentration.  By using this dosing model, the interpatient 
variability in topotecan systemic exposure can be minimized, and the full therapeutic efficacy of this 
compound can be realized. 
 
2.12.5 Cellular Immune Responses to Neuroblastoma 
Despite low or absent expression of MHC class I, T cells capable of recognizing neuroblastoma cells and 
acting as effector cells have been described. Survivin has the potential to be a relevant tumor antigen in 
neuroblastoma, as it is widely expressed108 and expression is inversely correlated with prognosis.109 
Moreover, as a key inhibitor of apoptosis, survivin may be required for tumor growth and development, 
making its potential loss as a means of escape of the tumor from immune surveillance difficult. We 
hypothesize that cytolytic T lymphocytes (CTL) directed against survivin+ targets will be detectable in 
the blood of neuroblastoma patients. Additionally, these CTL will be expanded by exposure to two 
different preparations of antigen presenting cells (APCs). One APC type will be transfected with survivin 
mRNA, providing surviving peptides to the MHC of the APC, while the second APC type will be loaded 
with neuroblastoma RNA. The APC used in our studies has been an activated B cell, referred to as a 
CD40-B. Relevant prior work from the Grupp and Vonderheide labs110 show that: 1) CD40-B cells serve 
as efficient APCs, inducing antigen-specific and anti-tumor CTL. 2) Large numbers of CD40-B APCs can 
be grown from small volumes of peripheral blood, as opposed to dendritic cells, which require pheresis to 
collect in adequate numbers. 3) RNA transfection efficiently transduces CD40-B APC, allowing 
expansion of tumor-specific CTL from patient blood samples even in a tumor like neuroblastoma in 
which tumor antigens are not known. 4) Neuroblastoma expresses survivin. 5) Survivin-specific CTL can 
be detected at diagnosis in up to 50% of neuroblastoma patients and expanded using either survivin-
transfected CD40-B or CD40-B transfected with neuroblastoma RNA.110 Iinitial studies demonstrate that 
T cells active against survivin+ targets emerge whether survivin RNA or whole tumor RNA is used as the 
antigenic stimulus. 6) Survivin-specific CTL secretes IFN-gamma in response to tumor and effectively 
lyse survivin+ neuroblastoma targets. 7) CD107a is a marker of CTL function111 and can also be used to 
demonstrate that CTL specific for the immunodominant epitope of survivin are responsible for anti-
neuroblastoma killing activity. 


 
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These data point to survivin as an important tumor antigen in neuroblastoma, show feasibility of using 
tumor RNA to provide an antigenic payload to APCs and confirm that neuroblastoma is a tumor 
susceptible to immune recognition. Data revealing tumor RNA-loaded APC produce tetramer+ CTL 
directed against survivin that are capable lysing autologous tumor provides key evidence of the 
importance of survivin in neuroblastoma. These results need to be confirmed in the larger number of 
samples available from the patients on this clinical trial. These experiments will allow us to further 
characterize survivin as a potential tumor antigen in neuroblastoma. 
 
2.12.6 Cellular Immunity after Myeloablative Chemotherapy  
Increasing intensity of therapy has the potential to increase extent and duration of immune suppression, 
especially of adaptive immunity. This was apparent in the CHOP/DFCI tandem HSCT experience27 where 
a combination of tandem HSCT, use of TBI and, potentially, use of CD34 selection of PBSC produced 
significant T cell immune suppression.112 We hypothesize that patients on the tandem HSCT arm will 
experience slower T cell recovery, specifically of CD4+ T cells. Enumeration of CD3, CD4 and CD8 
cells post HSCT is available at all FACT-approved HSCT centers, and is part of post-HSCT routine 
follow up at many centers. There is also value in following CD4 recovery to guide the level of viral 
surveillance and isolation precautions that may or may not be required for an individual patient. Thus, we 
propose to perform these assays at 1, 3 and 6 months post-HSCT, comparing T cell recovery across arms 
of the study. These assessments will provide a valuable baseline for studies that may utilize either of the 
ANBL0532 regimens, especially in the context of immunotherapies that may require functional T cell 
recovery. 
 
2.12.7 Minimal Residual Disease 
Despite initial response to therapy, the majority of children with high-risk neuroblastoma will develop 
recurrent or progressive disease.  More sensitive methods for the detection of minimal residual disease 
(MRD) are needed.  Several reports demonstrated the high sensitivity (1 x 10-4 to 10-6 normal cells) of 
immunocytological assays in bone marrow,113-115  bone marrow autograft116 and peripheral blood 
samples.117 Quantitative levels of bone marrow infiltration using immunocytological assays have been 
predictive of outcome for patients with stage 3 and 4 disease.118,119. More recently amplification of tissue-
specific mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) has been used to detect 
minimal disease burden (reviewed in120).  Investigators have employed an RT-PCR assay, using both 
tyrosine hydroxylase (TH) and the neuronal gene (PGP 9.5) which has a sensitivity of 1 tumor cell per 
million hematopoietic cells.121  Although IC and RT-PCR appear to be ideal tools for monitoring MRD, 
reaching a sensitivity of one tumor cell detected in 1 x 105 to 106 normal cells, their introduction into 
clinical management of children with neuroblastoma has been slow. ANBL0532 will evaluate the clinical 
relevance of tumor cells detected by these techniques. Immunocytology and RT-PCR studies will be used 
on bone marrow, peripheral blood, and PBSC collections to examine the question of tumor 
contamination. The incidence of RT-PCR positivity in stem cell products infused will be prospectively 
monitored.  Furthermore, the incidence of RT-PCR positivity in bone marrow and peripheral blood will 
be compared following consolidation therapy between single verus tandem myeloablative therapy.  
 
2.13 
Gender and Race Differences 
In CCG-3891, stage at diagnosis and EFS were similar between genders, however there was a trend for 
males to have better EFS than females on the ABMT arm of the study.  There was a significant interactive 
effect, in which the benefit of ABMT was restricted to males.  No differences in outcome by gender were 
observed in the earlier 321P3 transplant study.  There were no differences on CCG-3891 with respect to 
gender, regarding the effect of 13-cis-RA on EFS.  Data from CCG-3891 also showed a lower overall 
EFS for African Americans versus Whites or Hispanics.  African Americans had equivalent outcome on 
the ABMT arm, but lower EFS if treated on the chemotherapy arm in comparison with Whites.  No ethnic 
differences were seen in the outcomes of patients treated with cis-RA. 
 


 
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2.14 
Peripheral Blood Stem Cell Immunocytology (Amendment #2) 
Patients will undergo collection of peripheral blood stem cell product following 2 cycles of induction 
chemotherapy.  The ANBL0532 study has previously mandated immunocytology assessment of 
peripheral blood stem cell (PBSC) product for tumor contamination. The laboratory at Children’s 
Hospital of Los Angeles (CHLA) that has previously performed the immunocytology assay for CCG 
3891, COG A3973 and COG ANBL0532 no longer has CLIA certification and no validated CLIA-
approved alternative laboratory testing exists. 
 
ANBL0532 Amendment #2 will NOT REQUIRE immunocytology assessment of PBSC for tumor 
contamination. The amendment to this study will also remove mandatory PBSC specimen shipment to 
CHLA for immunocytology testing. Data from the most recent generation of COG high-risk 
neuroblastoma trials show that tumor contamination is rare and is not an independent prognostic 
determinate of outcome. COG A3973 determined tumor cell contamination of PBSC by immunocytologic 
assessment in only 5 of 487 (1%) of PBSC products collected after 2 cycles of induction chemotherapy. 
More importantly, COG A3973 demonstrated no benefit from anti-tumor purging of PBSC product using 
the same antibodies used for immunocytologic detection and support the conclusion that tumor recurrence 
is not directly related to tumor cell re-infusion from the PBSC product. Taken together, the COG 
neuroblastoma committee has concluded that there are no data to support the clinical utility of 
immunocytological testing of PBSC products for patients with high-risk neuroblastoma.  
 
 
 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment  
 
3.1.1 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. Sites must 
submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory Office and 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), 
emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.  
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a “Time of 
Need” registration.  For Time of Need registrations, 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. 
 
3.1.2 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID number.  This number is 
obtained via the eRDE system once authorization for the release of protected health information (PHI) has 
been obtained.  The assigned COG patient identification number will be used to identify the patient in all 
future interactions with the COG. If you have problems with registration, please refer to the online help in 
the eRDE area of the COG website. 
 
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).  
 


 
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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.   Each patient will be assigned only one PBC 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.  
 
3.1.3 
Enrollment on Biology Study ANBL00B1 
Enrollment on ANBL00B1 is required for all newly diagnosed patients within 21 days of diagnosis.  Tissue 
procurement is mandatory for biology study registration.  For patients with stage 4S disease who are very ill 
and in whom an open biopsy to obtain tissue for diagnosis and biologic studies is considered medically 
contraindicated, every effort should be made to obtain some tumor tissue by either fine needle aspiration of a 
metastatic site of disease and/or sampling of involved bone marrow, so that this tumor sample can be 
submitted for MYCN determination.  Consent for ANBL00B1 must be obtained at the time of tissue 
submission and should be within one week of surgery.  Needle biopsies are not sufficient for histologic 
classification.  Investigators are strongly encouraged to obtain adequate tissue (see Sections 13.0, 14.0, and 
15.0) via open biopsy techniques.  For patients with Stage 4 disease who are > 547 days of age with 
unequivocal neuroblasts in the bone marrow, in whom a diagnostic biopsy is not obtained, a minimum of 
2-3 mL of involved bone marrow and a blood specimen must be sent to the reference lab per the 
requirements of ANBL00B1 to be eligible for this study. (See ANBL00B1 protocol for specifics) 
 
3.1.4 
Study Enrollment on ANBL0532 
Patients may be enrolled on the study once all eligibility requirements for the study have been met.  Study 
enrollment is accomplished by going to the Enrollment application in the eRDE system.  If you have 
problems with enrollment, refer to online help in the Applications area of the COG website. 
 
3.1.5 
Timing 
Patients must be enrolled on ANBL00B1 prior to the time of enrollment on ANBL0532. In emergency 
situations (or if in the opinion of the treating physician, it is in the patient’s best interest) consent can be 
obtained and patient enrolled on ANBL00B1 and subsequently enrolled on ANBL0532 as soon as the 
assignment of “High-Risk” has been made in the eRDE system.  When ANBL0532 enrollment is done 
prior to start of beginning protocol therapy, the date protocol therapy is projected to start must be no later 
than five (5) calendar days after enrollment. In a case of a need for emergency therapy, protocol therapy 
may start before enrollment on ANBL0532; however, ANBL0532 consent part 1 must be obtained prior 
to start of therapy AND enrollment must take place within fourteen (14) calendar days of beginning 
protocol therapy. Study enrollment must occur within 4 weeks of diagnosis or after only one cycle of 
chemotherapy on the low/intermediate risk neuroblastoma studies, or within 4 weeks of progression to 
stage 4 for INSS stage 1, 2, 4S. 
 
3.1.6 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
 
3.1.7 
Randomization 
Randomization will take place at completion of Induction phase of therapy via RDE.  Patients will be 
assigned to either single myeloablative therapy or tandem myeloablative therapy.  Randomization will be 
stratified by initial stage of disease, biologic characteristics and response to induction chemotherapy.     
 
3.1.8 
Non-Randomized Consolidation therapy: 
Patients 365 to 547 days of age (12 – 18 months) with Stage 4, MYCN nonamplified tumor with 
unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy and 
patients who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor AND 
unfavorable histopathology or indeterminant histology will be nonrandomly assigned to single 
myeloablative transplant arm.   
 


 
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3.2 
Patient Criteria 
Important note:  The eligibility criteria listed below are interpreted literally and cannot be waived 
(per COG policy posted 5/11/01).  All clinical and laboratory data required for determining 
eligibility of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
3.2.1 
Age 
Patients must be  30 years of age at the time of initial diagnosis. 
 
3.2.2 
Diagnosis  
Patients must have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) or ganglioneuroblastoma 
verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary 
catecholamine metabolites.  Patients with the following disease stages at diagnosis are eligible, if they meet 
the other specified criteria. See Appendix VII. 
 
3.2.2.1 
Patients with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following: 
 
a. 
MYCN amplification (greater than four-fold increase in MYCN signals as compared to 
reference signals), regardless of age or additional biologic features. 
b. 
Age > 18 months (>547 days) regardless of biologic features. 
c. 
Age 12 – 18 months (365-547 days) with any of the following three unfavorable biologic 
features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or any 
biologic feature that is indeterminant/unsatisfactory/unknown. 
 
3.2.2.2 
Patients with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following: 
a. 
MYCN amplification (greater than four-fold increase in MYCN signals as compared to 
reference signals), regardless of age or additional biologic features 
b. 
Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status. 
 
3.2.2.3 
Patients with newly diagnosed INSS Stage 2a/2b with MYCN amplification (greater than four-fold 
increase in MYCN signals as compared to reference signals), regardless of age or additional biologic 
features. 
 
3.2.2.4 
Patients with newly diagnosed INSS Stage 4s with MYCN amplification (greater than four-fold increase 
in MYCN signals as compared to reference signals), regardless of additional biologic features. 
 
3.2.2.5 
Patients  365 days initially diagnosed with:  INSS stage 1, 2, 4S who progressed to a stage 4 without 
interval chemotherapy.  These patients must have been enrolled on ANBL00B1. It is to be noted that 
study enrollment must occur within 4 weeks of progression to Stage 4 for INSS Stage 1, 2, 4S.  
 
3.2.3 
Prior Therapy 
Patients must have had no prior systemic therapy except for localized emergency radiation to sites of life-
threatening or function-threatening disease and/or no more than one cycle of chemotherapy per low or 
intermediate risk neuroblastoma therapy (P9641, A3961, ANBL0531) prior to determination of MYCN 
amplification and histology. 
 
3.2.4 
Organ Function Requirements:  
3.2.4.1 Adequate renal function defined as: 
- 
Creatinine clearance (CrCl) or radioisotope GFR  70 mL/min/1.73 m2 or 
          


 
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- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 
3.2.4.2 Adequate liver function defined as: 
 
 
- 
Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and 
 
 
- 
SGOT (AST) or SGPT (ALT) < 10 x upper limit of normal (ULN) for age.  
 
3.2.4.3 Adequate cardiac function defined as: 
 
 
- 
Shortening fraction of   27% by echocardiogram, or  
 
- 
Ejection fraction of   50% by radionuclide angiogram.  
 
3.2.4.4   Ability to Tolerate PBSC Collection:  
 
No known contraindication to PBSC collection.  Examples of contraindications might be a weight or size 
less than the collecting institution finds feasible, or a physical condition that would limit the ability of the 
child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.  
 
 
3.2.5 
Regulatory 
 
3.2.5.1  
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.5.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
Identification of COG Approved Transplant Center:  Patients entered on study must have their stem cell 
transplant performed at a COG approved transplant center.  A COG-approved transplant center must be 
identified at the time of study registration.   This center may be changed to another COG-approved 
transplant center after registration if required due to personal or financial patient issues. 
 
3.2.6 
Exclusion Criteria 
 
3.2.6.1 Females of childbearing potential must have a negative pregnancy test. Patients of childbearing 
potential must agree to use an effective birth control method. 
 
3.2.6.2 Female patients who are lactating must agree to stop breast-feeding. 
 
3.2.6.3 Patients that are 12-18 months of age with INSS Stage 4 and all 3 favorable biologic features (ie, 
non-amplified MYCN, favorable pathology, and DNA index > 1) are not eligible. 


 
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4.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
 
4.1 
General Guidelines 
This study will be a Phase III trial that analyses the use of intensified consolidation in high-risk 
neuroblastoma. 
 
 Myeloblative consolidation therapy is given at the completion of induction therapy and is categorized 
into Regimen A and Regimen B.  Regimen A consists of one myeloablative consolidation with a 
CARBOplatin – etoposide – melphalan (CEM) preparative regimen. For Regimen B, patients will receive 
two myeloablative consolidations: Thiotepa – cyclophosphamide (TC) preparative regimen followed by 
CEM preparative regimen.  
 
Most patients will be randomized into either Regimen A or Regimen B. Randomization will be 
stratified by stage, MYCN status and response to induction therapy.  
 
The following patients will be nonrandomly assigned to single myeloablative transplant (Regimen A): 
 
Patients who are 365 to 547 days of age (12 – 18 months) with Stage 4, MYCN nonamplified 
tumor with any of the following potentially unfavorable biologic features: 
o unfavorable histopathology 
o diploid DNA content 
o indeterminant histopathology 
o indeterminate ploidy 
 
Patients who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor with 
either of the following: 
o unfavorable histopathology  
o indeterminant histopathology   
 
Patients who develop progressive disease (PD) at the end of induction, those who are unable to obtain 
adequate PBSC for transplant or who have GFR < 60 ml/min/1.73 m2 will be taken off protocol therapy. 
Refer to protocol section 8.1.1 for complete definition of off protocol therapy criteria. 
 
4.1.1 
Central Line 
All patients will have a double lumen central venous line placed prior to beginning induction 
chemotherapy. 
 
4.1.2 
Chemotherapy doses for all drugs EXCEPT topotecan will be adjusted for patients who weigh < 12 kg; 
these patients will have chemotherapy dosed per kg rather than per body surface area (BSA).  Dosing 
will be adjusted only during cycles when patient’s weight is < 12 kg. Topotecan dosing will be based on 
BSA regardless of age or weight.   
 
 
4.1.3 
Induction Therapy 
Patients will receive 6 cycles of induction chemotherapy.  Chemotherapy cycles (except Cycle 1) may 
begin when the ANC ≥ 750/µL and platelets ≥ 75,000/µL after post-chemotherapy nadir.  There are no 
hematologic criteria to begin Cycle 1. 
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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Patients who received one cycle of chemotherapy per low or intermediate risk neuroblastoma therapy 
(P9641, A3961, ANBL0531) prior to determination of MYCN amplification and histology will receive all 
6 cycles of ANBL0532 induction therapy. 
 
4.1.3.1 
Patients will undergo surgical resection after Cycle 5 (or Cycle 6, if medically necessary).  Begin next 
chemotherapy cycle as soon as possible following surgery.  Therapy should not be delayed by more than 
one week unless complications arise.  If surgery cannot be scheduled after Cycle 5, it should occur after 
Cycle 6. 
 
4.1.3.2 
Primary and metastatic tumor response will be assessed after 2 cycles and at completion of induction 
chemotherapy.  Primary site tumor assessment prior to surgical resection (Cycle 5 or Cycle 6, if 
medically necessary) is mandatory as the pre-surgical primary tumor volume will be used to 
establish radiation fields. 
 
4.1.3.3 
Patients with progressive disease (PD) at the end of induction evaluation will be taken off protocol 
therapy. 
 
4.1.3.4 Peripheral Blood Stem Cell Harvest (PBSC) (See Section 19.0 for complete details) 
Patients will undergo PBSC harvest after 2 cycles REGARDLESS of persistent bone marrow metastatic 
disease. There will not be any no ex vivo manipulation of PBSC prior to cryopreservation as results from 
the randomized question in A3973 did not demonstrate a benefit in survival following ex vivo purging of 
PBSC product.   
 
 PBSC collection will be performed prior to randomization.  Therefore, all patients must have a PBSC 
collection that is sufficient for tandem transplant with a goal for collection of 10 x 106 CD 34+cells/kg 
divided into 3 separate aliquots.  A minimum number of frozen PBSC of 4 x 106 CD34 cells/kg divided 
into 2 aliquots is required for all patients (2 x 106 CD34 cells/kg for each transplant) to remain eligible for 
transplant while an additional 3rd aliquot of 2 x 106 CD34 cells/kg is strongly recommended to be stored 
for back-up.  
 
4.2 
Induction Therapy Administration 
 
 
For patients > 12 kg, chemotherapy doses will be calculated by body surface area (BSA). 
 
For patients < 12 kg, chemotherapy doses for all drugs EXCEPT topotecan will be dosed per 
kg rather than per BSA.   
 
Topotecan dosing will be based on BSA regardless of age or weight. 
 
Note specific dosing instructions for vinCRIStine in Cycles 4 and 6 of induction. 
 
Myeloid Growth Factors: During induction cycles 1 and 3-6 (all induction cycles except cycle 2 or other 
cycles in which PBSC collections are planned), cytokine support need not be limited to G-CSF i.e: other 
growth factors are permitted according to an institution’s standard guidelines. Choice of myeloid growth 
factor must be recorded appropriately in the therapy delivery maps. Myeloid growth factors (including G-
CSF) should be administered 24 – 48 hours after the last dose of chemotherapy. Daily myeloid growth 
factor therapy should be continued until the ANC > 1500/µL. Discontinue daily myeloid growth factor 
support a minimum of 24 hours prior to administration of the next chemotherapy cycle. See Appendix II 
for supportive care guidelines. 
 
Institutions are permitted to use their standard guidelines for hydration/monitoring parameters pertaining 
to chemotherapy agents utilized in this protocol.  In the absence of institutional standards, suggested 
guidelines are included in the therapy delivery maps that follow. 
 


 
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4.2.1 
Induction Therapy Cycle 1 
 
 
 
COG #____________________ 
Induction Therapy  Cycle 1  
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
No hematologic criteria to begin Cycle 1. This course lasts 21 days. This Therapy Delivery Map is on one page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Cyclophosph
amide 
(CPM) 
IV over 
30-60 
minutes 
400 mg/m2/dose 
(or if < 12 kg, 
13.3 mg/kg) once 
daily x 5 doses.  
 
Days 1-5 
Suggest hydrating at 
125 mL/m2/hr with 
fluid containing at least 
0.45% NaCl for 2 hours 
prior to and 2 hours 
after each dose. 
a. Physical, Ht, Wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr, Ca, Phos, Mg 
d. ALT, AST, Bilirubin, Urinalysis, Albumin 
e. See Section 7.1.1 for pre-treatment 
evaluations. 
f. Pharmacogenomics (Section 15.2) 
g.  BM ICC and PCR (Section 15.4) 
h. Peripheral blood PCR (Section 15.6) 
i. Peripheral blood for immune assessments 
(Section 15.8) 
j. Topotecan Pharmacokinetics (Section 15.3) 
Refer to Protocol Section 7.0 for complete list 
of observations and Section 15.0 for sample 
acquisition or shipment guidelines 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
Topotecan 
(TOPO) 
IV over 
30 
minutes 
1.2 mg/m2/dose 
(all patients) once 
daily x 5 doses.  
 
Days 1-5 
Topotecan dosing will 
be based on BSA 
regardless of age or 
weight. 
Myeloid growth factor Adminsitration: Begin 24 – 48 hours after completion of 
chemotherapy.If given daily, continue until post-nadir ANC > 1500/µL.  See sections 
4.2 and Appendix II for specific directions. 
 
 Therapy Delivery Map 
 Cycle 1  
Ht______cm 
        Wt______kg  
BSA______m2 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
TOPO 
____mg 
Myeloid growth factor  
used: ____________  
_____mcg 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered  
below 
 a,b,c,d,e,f,g,h,i 
 
 
 
1 
CPM______mg 
TOPO_____mg 
 
j 
 
 
 
2 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
3 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
4 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
5 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
6 
 
 
        ______mcg 
b (obtain twice weekly while 
on myeloid growth factor) 
Date of last dose: 
__________ 
 
 
21 
End of cycle 
 
 
 
 
22 
Begin next cycle on Day 22 
 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
 
 
 
NOTE: For eRDEs reporting: use Day 22 (or treatment start date for next cycle if > Day 22) as the end date 
for the current cycle.
Page 1 of 1 


 
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4.2.2 
Induction Therapy Cycle 2 
 
 
 
 
 
 
 
 
 
COG #____________________ 
Induction Therapy Cycle 2  
 
                     _________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Patients should begin therapy on day 22 of the prior cycle or as soon thereafter as ANC > 750/µL and platelets > 75,000/µL. 
This course lasts 21 days. This Therapy Delivery Map is on one page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Cyclophosphamide 
(CPM) 
IV over 30 – 
60 minutes 
400 mg/m2/dose (or if 
< 12 kg, 13.3 
mg/kg/dose) once 
daily x 5 doses.  
 
Days 1-5 
Suggest hydrating at 
125 mL/m2/hr with 
fluid containing at 
least 0.45% NaCl 
for 2 hours prior to 
and 2 hours after 
each dose. 
a. Physical, Ht, Wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr, Ca, Phos, 
Mg 
d. ALT, AST, Bilirubin, Urinalysis    
e. Topotecan Pharmacokinetics 
(Section 15.3) 
f. PBSC PCR (Section 15.5) 
g. Bilateral BM Asp/Bx 
h. BM PCR (Section 15.4) 
i. Tumor Imaging, Bone scan, MIBG 
(Section 7.1.1) 
j. MRI Spine & Neuro Eval (tumors 
with intraspinal extension only) 
k. VMA, HVA (if elevated at 
diagnosis) 
 
Refer to Protocol Section 7.0 for 
complete list of observations and 
Section 15.0 for sample acquisition or 
shipment guidelines 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Topotecan (TOPO) 
IV over 30 
minutes 
1.2 mg/m2/dose (all 
patients) once daily x 
5 doses.  
 
Days 1-5 
Topotecan dosing 
will be based on 
BSA regardless of 
age or weight. 
Filgrastim 
(GCSF) 
SubQ or IV 
(SubQ 
preferred)  
5 micrograms/kg 
beginning 24 hours 
after completion of 
chemotherapy and 
continuing once daily 
until post-nadir ANC 
> 1000/µL. Once post-
nadir ANC > 1000/µL, 
increase dose to 10 
micrograms/kg and 
continue once daily 
until PBSC harvest is 
complete. 
Day 6 
Discontinue at least 
24 hours prior to 
next chemotherapy 
cycle. 
 
Therapy Delivery Map Cycle 2  
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
TOPO 
____mg 
GCSF 
_____mcg 
 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
 
 
 
 a,b,c,d, 
 
 
 
1 
CPM______mg 
TOPO_____mg 
 
 e  
 
 
 
2 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
3 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
4 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
5 
CPM______mg 
TOPO_____mg 
 
 
 
 
 
6 
 
 
GCSF_____mcg 
b (obtain twice 
weekly while on 
GCSF) 
Date of last dose: 
__________ 
 
 
14 
Collect PBSCs (See Protocol Section 19.0) 
f 
 
 
 
21 
End of cycle 
g,h,i,j,k 
 
 
 
22 
Begin next cycle on Day 22 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
 
NOTE: For eRDEs reporting: use Day 22 (or treatment start date for next cycle if > Day 22) as the end date for 
the current cycle.
Page 1 of 1 


 
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4.2.3 
Induction Therapy Cycle 3 
 
 
 
 
 
 
 
 
 
 
COG #____________________ 
Induction Therapy Cycle  3  
 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Patients should begin each cycle of induction therapy on Day 22 of the prior cycle or as soon thereafter as ANC > 750/µL 
and platelets > 75,000/µL. 
This course lasts 21 days. This Therapy Delivery Map is on one page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin 
(CDDP) 
IV over 1 
hour 
50 mg/m2/dose (or if < 
12 kg, 1.66 mg/kg/dose) 
once daily x 4 doses.   
Days 1-4 
Suggest hydrating at 3000 
mL/m2/day using fluid 
containing at least 0.45% 
NaCl.  Suggest achieving 
urine specific gravity < 
1.010 prior to start of 
CISplatin.  Hydration fluids 
may contain supplemental 
magnesium, calcium and 
potassium to decrease 
electrolyte losses associated 
with cisplatin. 
Administration of mannitol 
per institutional guidelines 
is recommended. 
a. Physical, Ht, Wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr, Ca,    
    Phos, Mg 
d. ALT, AST, Bilirubin, 
Urinalysis    
 
Refer to Protocol Section 7.0 
for complete list of 
observations 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR 
GOOD PATIENT CARE 
Etoposide 
(ETOP) 
IV over 1 
hour 
200 mg/m2/dose (or if < 
12 kg, 6.67 mg/kg/dose) 
once daily x 3 doses.  
Days 1-3 
 
Myeloid growth factor Adminsitration: Begin 24 – 48 hours after completion of chemotherapy.If 
given daily, continue until post-nadir ANC > 1500/µL.  See sections 4.2 and Appendix II for specific 
directions. 
 
Therapy Delivery Map Cycle 3 
  
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
CDDP 
____mg 
ETOP 
____mg 
Myeloid Growth Factor: 
___________ 
Dose: ____mcg 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered  below 
a,b,c,d 
 
 
 
1 
CDDP______mg 
ETOP_____mg 
 
c@ 
 
 
 
2 
CDDP______mg 
ETOP_____mg 
 
c@ 
 
 
 
3 
CDDP______mg 
ETOP_____mg 
 
c@ 
 
 
 
4 
CDDP______mg 
 
 
c@ 
 
 
 
5 
 
 
_______mcg 
b (obtain twice 
weekly while 
on myeloid 
growth factor) 
Date of last dose: 
__________ 
 
 
21 
End of cycle 
 
 
 
 
22 
Begin next cycle on Day 22 
 
 
@ - Please note that this test is only recommended to be done on Days 1, 2 , 3 and 4 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
NOTE: For eRDEs reporting: use Day 22 (or treatment start date for next cycle if > Day 22) as the end date for 
the current cycle. 
 
Page 1of 1 


 
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4.2.4 
Induction Therapy Cycle 4 
 
 
 
 
COG #____________________ 
Induction Therapy Cycle 4  
Note specific dosing instructions for vinCRIStine.  
 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
Patients should begin each cycle of induction therapy on day 22 of the prior cycle or as soon thereafter as ANC > 750/µL 
and platelets > 75,000/µL. This cycle lasts 21 days.  This Therapy Delivery Map is on one page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Cyclophosphamide 
(CPM) 
IV over 6 
hours 
2100 mg/m2/dose (or if < 12 kg, 70 
mg/kg/dose) once daily x 2 doses.  
Days 1-2 
Suggest hydrating at 3000 
mL/m2/day using fluid 
containing at least 0.45% 
NaCl.  Suggest achieving 
urine specific gravity < 
1.010 prior to start of 
cyclophosphamide.   
 
a. Physical, Ht, Wt 
b. CBC with diff and 
platelets 
c. Electrolytes, BUN,   
    Cr, Ca, Phos, Mg 
d. ALT, AST,   
    Bilirubin, Urinalysis 
 
Refer to Protocol Section 
7.0 for complete list of 
observations. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
  
Mesna 
(MESNA) 
IV over 15 
minutes 
420 mg/m2/dose (or if < 12 kg, 14 
mg/kg/dose) immediately prior to each 
cyclophosphamide and again at 4 and 8 
hours after each cyclophosphamide 
infusion 
Days 1-2 
 
DOXOrubicin 
(DOXO) 
IV over 24 
hours 
25 mg/m2/dose (or if < 12 kg, 0.83 
mg/kg/dose) once daily x 3 doses.   
Days 1-3 
 
VinCRIStine 
(VCR) 
IV push 
over 1 
minute (or) 
infusion via 
minibag as 
per 
institutional 
policy 
Patients < 12 months of age: 0.017 
mg/kg/dose once daily x 3 doses 
Patients > 12 months and > 12 kg:  
0.67 mg/m2/dose or 0.022 mg/kg/dose 
(whichever is LOWER for all patients > 
12 kg) once daily x 3 doses 
Patients >12 months and < 12 kg:  
0.022 mg/kg/dose once daily x 3 doses 
Days 1-3 
NOTE: total dose may 
not exceed  2 mg in 72 
hours or  0.67 mg/day 
for any patient  
 
VinCRIStine should be 
administered prior to start 
of DOXOrubicin infusion 
and then daily for a total  
of 3 doses. 
Myeloid growth factor Adminsitration: Begin 24 – 48 hours after completion of chemotherapy. If given 
daily, continue until post-nadir ANC > 1500/µL.  See sections Section 4.2 and Appendix II for specific 
directions. 
Therapy Delivery Map Cycle 4  
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
CPM 
_____mg 
Mesna 
_____mg 
Doxo 
_____mg 
VCR 
_____mg 
Myeloid Growth 
Factor: ________ 
_____mcg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
 Enter calculated dose above and actual dose administered  
below 
 
a, b, c, d 
 
 
 
1 
CPM____mg 
Mesna____mg 
Doxo____mg 
VCR____mg 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
2 
CPM____mg 
Mesna____mg 
Doxo____mg 
VCR____mg 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
3 
 
 
Doxo____mg 
VCR____mg 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
____mcg 
b (obtain 
twice weekly 
while on 
myeloid 
growth factor) 
Date of last dose: 
__________ 
 
 
21 
 
 
 
 
 
22 
Begin next cycle on day 22  
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
 
 NOTE: For eRDEs reporting: use Day 22 (or treatment start date for next cycle if > Day 22) as the end date for the 
current cycle. 
Page 1of 1 


 
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4.2.5 
Induction Therapy Cycle 5 
 
 
 
 
 
 
 
 
 
COG #____________________ 
Induction Therapy Cycle 5 
Patients will undergo surgical resection after Cycle 5 (or Cycle 6, if 
medically necessary).  Begin next chemotherapy cycle as soon as 
possible following surgery.  Therapy should not be delayed by more 
than one week unless complications arise.  If surgery cannot be 
scheduled after Cycle 5, it should occur after Cycle 6.
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
Patients should begin each cycle of induction therapy on Day 22 of the prior cycle or as soon thereafter as ANC > 750/µL 
and platelets > 75,000/µL. This course lasts 21 days. This Therapy Delivery Map is on one page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin (CDDP) 
IV over 1 hour 
50 mg/m2/dose (or 
if < 12 kg, 1.66 
mg/kg/dose) once 
daily x 4 doses.   
Days 1-4 
Suggest hydrating at 3000 
mL/m2/day using fluid 
containing at least 0.45% 
NaCl.  Suggest achieving 
urine specific gravity < 1.010 
prior to start of CISplatin.  
Hydration fluids may contain 
supplemental magnesium, 
calcium and potassium to 
decrease electrolyte losses 
associated with CISplatin. 
Administration of mannitol 
per institutional guidelines is 
recommended. 
a. Physical, Ht, Wt 
b. CBC with diff and 
platelets 
c. Electrolytes, BUN, Cr, 
Ca, Phos, Mg 
d. ALT, AST, Bilirubin, 
Urinalysis   
e. Primary tumor imaging 
 
Refer to Protocol Section 
7.0 for complete list of 
observations. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT CARE 
Etoposide (ETOP) 
IV over 1 hour 
200 mg/m2/dose 
(or if < 12 kg, 
6.67 mg/kg/dose) 
once daily x 3 
doses.   
Days 1-3 
 
Myeloid growth factor Administration: Begin 24 - 48 hours after completion of chemotherapy. If given 
daily, continue until post-nadir ANC > 1500/µL.  See sections 4.2 and Appendix II for specific directions. 
Therapy Delivery Map 
 Cycle 5  
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
CDDP 
____mg 
ETOP 
____mg 
Myeloid Growth 
Factor : 
__________ 
_____mcg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered  
below 
a,b,c,d 
 
 
 
1 
CDDP_____mg 
ETOP____mg 
 
c@
 
 
 
2 
CDDP_____mg 
ETOP____mg 
 
c@
 
 
 
3 
CDDP_____mg 
ETOP____mg 
 
c@
 
 
 
4 
CDDP_____mg 
 
 
c@
 
 
 
5 
 
 
_____mcg 
b (obtain twice 
weekly while on 
myeloid growth 
factor) 
Date of last dose: 
__________ 
 
 
21 
Surgery following Cycle 5 
Begin next cycle on Day 22 
e(prior to 
surgery) 
 
@  -  Please note that this test is only recommended to be done on Days 1, 2 , 3 and 4 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
 NOTE: For eRDEs reporting: use Day 22 (or treatment start date for next cycle if > Day 22) as the end date for 
the current cycle. 
 
 
Page 1  


 
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Page 41 
 
 
4.2.6 
Induction Therapy Cycle 6 
 
 
 
 
 
 
 
 
 
COG #____________________ 
Induction Therapy Cycle 6  
Note specific dosing instructions for vinCRIStine. 
 
______________________________ 
             Patient name or initials 
____________________________ 
DOB   
Patients should begin each cycle of induction therapy on Day 22 of the prior cycle or as soon thereafter as ANC > 750/µL 
and platelets > 75,000/µL. This cycle lasts 21 days and this Therapy Delivery Map is on one page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Cyclophosphamide 
(CPM) 
IV over 6 
hours 
2100 mg/m2/dose (or if < 12 kg, 70 
mg/kg/dose) once daily x 2 doses.  
Days 1-2 
Hydrate at 3000 
mL/m2/day using fluid 
containing at least 
0.45% NaCl.  Achieve 
urine specific gravity 
< 1.010 prior to start 
of cyclophosphamide.   
a. Physical, Ht, Wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr, Ca,    
    Phos, Mg 
d. ALT, AST, Bilirubin, Urinalysis, 
Albumin 
e. ECG, MUGA/EHCO, CrCl or 
GFR, Audiogram/BAER (see 
Section 7.1.1) 
f. Bilateral BM ASP/Bx 
g. BM ICC and PCR (Section 15.4)  
h. Peripheral Blood PCR (Section 
15.6) 
i. Tumor Imaging, Bone scan, 
MIBG (Section 7.1.1) 
j. MRI Spine & Neuro Eval (tumors 
with intraspinal extension only) 
k. VMA, HVA (if elevated at 
diagnosis) 
 
Refer to Protocol Section 7.0 for 
complete list of observations and 
Section 15.0 for sample acquisition 
or shipment guidelines 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Mesna 
(MESNA) 
IV over 15 
minutes 
420 mg/m2/dose (or if < 12 kg, 14 
mg/kg/dose) immediately prior to 
each cyclophosphamide and again at 
4 and 8 hours after each 
cyclophosphamide infusion. 
Days 1-2 
 
DOXOrubicin 
(DOXO) 
IV over 24 
hours 
25 mg/m2/dose (or if < 12 kg, 0.83 
mg/kg/dose) once daily x 3 doses.   
Days 1-3 
 
VinCRIStine 
(VCR) 
IV push over 
1 minute (or) 
infusion via 
minibag as per 
institutional 
policy 
Patients < 12 months of age: 0.017 
mg/kg/dose once daily x 3 doses 
Patients > 12 months and > 12 kg:  
0.67 mg/m2/dose or 0.022 
mg/kg/dose (whichever is LOWER 
for all patients > 12 kg) once daily x 
3 doses 
Patients > 12 months and < 12 kg:  
0.022 mg/kg/dose once daily x 3 
doses 
Days 1-3 
NOTE: Total dose 
may not exceed  2 mg 
in 72 hours or  0.67 
mg/day for any 
patient  
 
VinCRIStine should 
be administered prior 
to start of 
DOXOrubicin infusion 
and then daily for a 
total of 3 doses. 
Myeloid growth factor Administration: Begin 24 - 48 hours after completion of chemotherapy. If given daily, 
continue until post-nadir ANC > 1500/µL.  See sections 4.2 and Appendix II for specific directions. 
Therapy Delivery Map 
Cycle 6  
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
Mesna 
____mg 
Doxo 
____mg 
VCR 
____mg 
Myeloid Growth 
Factor :_______ 
____mcg 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered  
below 
 
a, b, c, d 
 
 
 
1 
CPM_____mg 
Mesna____mg 
Doxo____mg 
VCR____mg 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
2 
CPM_____mg 
Mesna____mg 
Doxo____mg 
VCR____mg 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
3 
 
 
Doxo____mg 
VCR____mg 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
____mcg 
b (obtain twice  
weekly while on  
myeloid growth factor) 
Date of last dose: 
__________ 
 
 
21 
Proceed to randomization once staging and organ function evaluations are complete 
Proceed to Consolidation Therapy (see Section 4.4) 
a,b,c,d,e,f,g,h,i,j,k 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
NOTE: For eRDEs reporting: use Day 22 (or treatment start date for next cycle if > Day 22) as the end date for 
the current cycle. 
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4.3 
Local Control - Surgery 
Surgical resection of soft tissue disease will occur during induction therapy.  Refer to section 13.0 for 
complete details.  
 
4.3.1 
Timing of Surgery 
Second look surgery  
Residual persistent mass after initial chemotherapy is common, and in previous analyses is not correlated 
with patient outcome.  All patients will undergo attempt at complete surgical resection of primary tumor 
following Cycle 5 (or Cycle 6, if medically necessary) of induction chemotherapy. 
 
 
4.4 
Consolidation Therapy  
 
Eligibility to proceed to Consolidation Therapy/Transplant:  Only patients who have a minimum number 
of frozen PBSC of 4 x 106 CD 34+ cells/kg (minimum of 2 x 106 CD 34+ cells/kg/transplant), who have 
adequate organ function, who do not have progressive disease at end of induction AND who have 
consented to Consent Part 2 are eligible for transplantation.   
 
Eligibility for randomization:  Patients must first be eligible to proceed to transplant in order to be eligible for 
randomization.  Patients will be randomly assigned to either single myeloablative therapy (Regimen A) with 
a CARBOplatin, etoposide, melphalan (CEM) preparative regimen and autologous PBSC rescue 
(representing the standard arm of the study), OR to the experimental arm of tandem myeloablative therapy 
(Regimen B) with the regimen used in the COG ANBL00P1 (thiotepa and cyclophosphamide followed by 
CEM).  
The following patients will be nonrandomly assigned to single myeloablative transplant (Regimen A): 
 
Patients who are 365 to 547 days of age (12 – 18 months) with Stage 4, MYCN nonamplified 
tumor with any of the following potentially unfavorable biologic features: 
o unfavorable histopathology 
o diploid DNA content 
o indeterminant histopathology 
o indeterminate ploidy 
 
Patients who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor with 
either of the following: 
o unfavorable histopathology  
o indeterminant histopathology   
 
 Patients should begin consolidation chemotherapy no later than 8 weeks after the start of Induction Cycle 
#6.  (It is strongly recommended to begin consolidation within 4-6 weeks after starting Induction Cycle 
#6.) Patients who are delayed beyond 8 weeks, but who still meet organ function criteria should remain 
on protocol therapy and proceed to transplant.  Delay in starting transplant will be considered a protocol 
deviation. 
 
Patients with progressive disease at end of induction therapy are NOT eligible to continue on protocol 
therapy.  Patients with mixed response or stable disease evaluation may remain on protocol therapy as per 
investigator preference.  However, such patients are encouraged to come off protocol therapy for entry 
onto available COG Phase I and Phase II studies. 
 
No restaging will be performed between Hematopoietic Stem Cell Transplants (HSCT) or prior to 
radiation therapy unless clinically indicated.  Patients randomized to Regimen B will proceed to HSCT #2 
(CEM) no less than 6 and prior to 10 weeks from day 0 of HSCT #1, providing they have recovered from 
acute toxicities of HSCT#1 and meet organ eligibility criteria for HSCT #2. 
 


 
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4.5 
 Consolidation Therapy Regimen A: Single HSCT (CEM) 
 
 
 
 
 
 
 
 
 
COG #____________________ 
Regimen A: single myeloablative therapy with a CARBOplatin,    
etoposide, melphalan (CEM) preparative regimen and 
autologous PBSC rescue (representing the standard arm of the 
study). 
                 
____________________________ 
Pt name or initials 
____________________________ 
DOB 
    Patients should begin consolidation therapy within 8 weeks of beginning Cycle 6 of induction.  This Therapy      
    Delivery Map is on FOUR pages.  This cycle lasts 36 days.  
Criteria to Start Consolidation Regimen A: 
1. 
No evidence of disease progression: defined as increase in tumor size of >25% or new lesions. 
2. 
Recovery from last induction course of chemotherapy. 
3. 
No uncontrolled infection. 
4. 
Minimum frozen PBSC of 4 x 106 CD34 cells/kg as 2 aliquots; 2 x 106 CD34 cells/kg for transplant 
are mandatory and 2 x 106 CD34 cells/kg for back-up are strongly recommended. 
5. 
AST < 3 x upper normal 
6. 
Shortening fraction  27%, or ejection fraction  50%, no clinical congestive heart failure. 
7. 
Creatinine clearance or GFR > 60 mL/min/1.73m2 (If a creatinine clearance is performed at end 
induction and the result is < 100 ml/min/1.73m2, a GFR must then be performed using a nuclear 
blood sampling method or iothalamate clearance method.  Camera method is NOT allowed as 
measure of GFR prior to or during Consolidation therapy for patients with GFR or creatinine 
clearance of < 100 ml/min/1.73m2.) 
PATIENTS WITH CREATININE CLEARANCE OR GFR > 100 ML/MIN/1.73M2  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Melphalan 
(MEL) 
IV over 
15-30 
minutes 
70 mg/m2/dose (or if < 12 
kg, 2.3 mg/kg/dose) once 
daily x 3 doses.   
Days -7, -
6 and -5 
Must be infused 
within 1 hour of 
preparation. 
a. Physical exam, ht, wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr  
d. Ca++, PO4, Mg++ 
e. ALT, AST, Bilirubin, Albumin 
f. Triglycerides  
g. ECG, MUGA/ECHO, GFR, urinalysis 
h. Bilateral BM aspirate/bx., 
Audiogram/BAER (Section 7.1.2) 
i. BM PCR (Section 15.4) 
j. Peripheral blood PCR (Section 15.6) 
k. Tumor imaging, Bone scan, MIBG 
(Section 7.1.2) 
l. MRI spine & neurologic evaluation   
(tumors with intraspinal extension only) 
m. VMA/HVA (if elevated at diagnosis) 
n. Peripheral Blood Immune assessments 
(Section 15.8) 
o. Peripheral blood for Immune recovery 
(Section 7.1.2) 
 
Refer to Protocol Section 7.0 for complete 
list of observations and Section 15.0 for 
sample acquisition or shipment guidelines 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE
Etoposide 
(ETOP) 
IV over 24 
hours 
338 mg/m2/dose (or if < 12 
kg, 11.3 mg/kg/dose) once 
daily x 4 doses.   
Days -7, -
6, -5 and -
4 
 
CARBOplatin 
(CARB) 
IV over 24 
hours 
425 mg/m2/dose (or if < 12 
kg, 14.2 mg/kg/dose) once 
daily x 4 doses.   
Days -7, -
6, -5 and -
4 
 
Filgrastim 
(GCSF) 
SubQ 
(OR) IV 
(SubQ 
preferred) 
5 micrograms/kg once 
daily and continuing once 
daily until post-nadir ANC 
> 2000/µL for 3 
consecutive days. 
Day 0 
until ANC 
recovery 
 
 
 
 
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Consolidation Therapy Regimen A: Single HSCT (CEM):  Patients with altered renal function who are > 
12 kg      
 
PATIENTS WITH GFR < 100 ML/MIN/1.73M2 and ≥ 60 ML/MIN/1.73M2 AND ARE > 12 KG 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Melphalan 
(MEL) 
IV over 15-
30 minutes 
60 mg/m2/dose once daily x 
3 doses.   
Days -7, -6 and -5 
Must be infused within 
1 hour of preparation. 
a. Physical exam, ht, wt          
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr        
 d. Ca++, PO4, Mg++ 
e. ALT, AST, Bili Albumin     
f. Triglycerides  
g. ECG, MUGA/ECHO, GFR, 
urinalysis 
h. Bilateral BM aspirate/bx., 
Audiogram/BAER (7.1.2) 
i. BM PCR (15.4) 
j. Peripheral blood PCR (15.6)   
k. Tumor imaging, Bone scan, 
MIBG (7.1.2) 
l. MRI spine & neurologic eval  
(tumors with intraspinal 
extension only)  
m. VMA/HVA (if elevated at dx) 
n. Peripheral Blood Immune 
assessments (15.8) 
o. Peripheral blood for Immune 
recovery (.1.2) 
 
Refer to Protocol Section 7.0 for 
complete list of observations and 
Section 15.0 for sample acquisition 
or shipment guidelines 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE
Etoposide 
(ETOP) 
IV over 24 
hours 
200 mg/m2/dose once daily x 
4 doses.   
Days -7, -6, -5 and -4 
 
CARBOplatin 
(CARB) 
IV over 24 
hours 
See Calvert Formula* below 
for dose calculation; give 
dose once daily x 4 doses.  
Daily dose should not 
exceed 300 mg/m2 
Days -7, -6, -5 and -4 
*See sample Calvert 
dose calculation below. 
 
Filgrastim 
(GCSF) 
SubQ (OR) 
IV (SubQ 
preferred) 
5 micrograms/kg once daily 
and continuing once daily 
until post-nadir ANC > 
2000/µL for 3 consecutive 
days. 
Day 0 until ANC 
recovery 
 
 
 
*Calvert Formula for CARBOplatin dosing: 
 
  Patients with GFR < 100 ml/min/1.73 m2 who are > 12 kg will be dosed according to the formula below to 
achieve an area under the concentration versus time curve (AUC) of  4.1 per dose.  GFR will be calculated 
using a blood sampling method.  Daily dose should not exceed 300 mg/m2.   
 
Total Dose (mg)/day =  
      (Corrected GFR x surface area)    +   (15 x surface area)              x  4.1 
 
                          1.73 
 
 
Example:  Patient’s GFR is 86 mL/min/1.73 m2, they weigh 14.6 kg and their BSA is 0.61 m2: 
 
  
Total dose (mg)/day = { (86 mL/min/1.73 m2  x  0.61 m2)     +    (15 x 0.61 m2) }   x  4.1    =   162 mg 
 
 
 
 
          1.73 
NOTE: if lab reports raw GFR in mL/min instead of corrected GFR in mL/min/1.73 m2, convert Raw GFR to corrected GFR as 
follows: 
     Divide Raw GFR in mL/min by the patient’s surface area in m2, then multiply result by 1.73 m2.  
     Example: Raw GFR is 30.3 mL/min, BSA = 0.61 m2:    30.3 mL/min divided by 0.61 m2 then multiplied by 1.73 m2  =  86 
mL/min/m2 
 
 
 
 
Page 2 of 4 


 
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      Consolidation Regimen A: Single HSCT (CEM): Patients with altered renal function who are < 12 kg 
      PATIENTS WITH GFR < 100 ML/MIN/1.73M2 and ≥ 60 ML/MIN/1.73M2 AND ARE < 12 KG 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Melphalan 
(MEL) 
IV over 
15-30 
minutes 
2 mg/kg/dose once daily x 
3 doses.   
Days -7, -6 
and -5 
Must be infused 
within 1 hour of 
preparation. 
a. Physical exam, ht, wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr  
d. Ca++, PO4, Mg++ 
e. ALT, AST, Bilirubin, Albumin 
f. Triglycerides  
g. ECG, MUGA/ECHO, GFR, 
urinalysis 
h. Bilateral BM aspirate/bx., 
Audiogram/BAER (Section 7.1.2) 
i. BM PCR (Section 15.4) 
j. Peripheral blood PCR (Section 
15.6) 
k. Tumor imaging, Bone scan, MIBG 
(Section 7.1.2) 
l. MRI spine & neurologic evaluation   
(tumors with intraspinal extension 
only)  
m. VMA/HVA (if elevated at 
diagnosis) 
n. Peripheral Blood Immune 
assessments (Section 15.8) 
o. Peripheral blood for Immune 
recovery (Section 7.1.2) 
 
Refer to Protocol Section 7.0 for 
complete list of observations and 
Section 15.0 for sample acquisition or 
shipment guidelines 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE
Etoposide 
(ETOP) 
IV over 
24 hours 
6.7 mg/kg/dose once daily 
x 4 doses.   
Days -7, -6, 
-5 and -4 
 
CARBOplatin 
(CARB) 
IV over 
24 hours 
See Calvert Formula* 
below for dose 
calculation; give dose 
once daily x 4 doses. Also 
calculate dose as 10 
mg/kg and give LOWEST 
calculated dose as 
described below  
Days -7, -6, 
-5 and -4 
*See sample 
Calvert dose 
calculation below.   
Filgrastim 
(GCSF) 
SubQ 
(OR) IV 
(SubQ 
preferred) 
5 micrograms/kg once 
daily and continuing once 
daily until post-nadir 
ANC > 2000/µL for 3 
consecutive days. 
Day 0 until 
ANC 
recovery 
 
 
*Calvert Formula for CARBOplatin dosing: 
 
  Patients with GFR < 100 mL/min/1.73 m2 who are < 12 kg will be dosed according to the formula below to 
achieve an area under the concentration versus time curve (AUC) of  4.1 per dose.  GFR will be calculated 
using a blood sampling method.  Daily dose should not exceed 10 mg/kg.  Calculate dose by Calvert formula 
below and also calculate dose by weight (10 mg/kg).  Give LOWER of the two calculated doses.   
 
Total Dose (mg)/day = 
{ Raw GFR  +  (0.36 x weight in kg) }  x 4.1 
 
   
Example:  Patient’s GFR is 74 mL/min/1.73 m2, they weigh 10.2 kg and their BSA is 0.45 m2: 
 
 
To convert corrected GFR reported as mL/min/1.73 m2 to Raw GFR reported as mL/min, multiply 
corrected GFR by the patient’s BSA, then divide by 1.73 m2: 
 
 
74 mL/min/1.73 m2 x 0.45 m2 then divided by 1.73 m2 = 19.2 mL/min 
 
 
Total dose (mg/day) = {19.2 mL/min   +    (0.36 x 10.2 kg)}   x   4.1 = 94 mg 
 
 
 
 
 
Page 3 of 4 


 
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Consolidation Regimen A: Single HSCT (CEM) 
 
For tests required prior to consolidation, please refer to Section 7.1.2 
 
       Therapy Delivery Map   
Ht______cm 
        Wt______kg  
BSA______m2 
Date 
Due 
Date 
Given 
Day 
MEL 
_____mg 
ETOP 
_____mg 
 
CARB 
_____mg 
GCSF 
_____mcg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below
 
 
 
 
-7 
MEL_____mg 
ETOP_____mg 
CARB_____mg 
 
a,b,c,d,e 
 
 
 
-6 
MEL_____mg 
ETOP_____mg 
CARB_____mg 
 
b 
 
 
 
-5 
MEL_____mg 
ETOP_____mg 
CARB_____mg 
 
b,c 
 
 
 
-4 
 
ETOP_____mg 
CARB_____mg 
 
b 
 
 
 
-3 
 
 
 
 
b 
 
 
 
-2 
 
 
 
 
b,c 
 
 
 
-1 
 
 
 
 
b 
 
 
 
0 
PBSC infusion  
GCSF_____mcg 
a, b (daily until 
neutrophil 
engraftment), c 
(every other day if 
stable), d, e (twice 
weekly if stable) 
Date of last dose: 
__________ 
 
 
28 
Begin radiation therapy no sooner than 28 days post transplant, and 
recommended to begin within 42 days post transplant (See Protocol Section 
17.0) 
o (1 month post HSCT), b (weekly 
through radiation therapy), 
End of radiation 
therapy:a,b,c,d,e,f,g,h,i,j,k,l,m,n,o  
 
 
Please note that tests from Day -6 to Day -1 are recommended only.  
 
Page 4 of 4 


 
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Page 47 
4.6 
Consolidation Therapy Regimen B: Tandem HSCT #1 (Thiotepa and Cyclophosphamide) 
COG #__________________ 
 
Regimen B: Experimental arm of tandem myeloablative 
therapy (Regimen B) with thiotepa and 
cyclophosphamide regimen followed by CEM.   
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
Patients should begin consolidation therapy within 8 weeks of beginning Cycle 6 of induction.   
This Therapy Delivery Map is on two pages. This cycle lasts 50 days 
Criteria to Start Consolidation Regimen B: Tandem HSCT #1 (Thiotepa and Cyclophosphamide) 
 
1. No evidence of disease progression: defined as increase in tumor size of >25% or new lesions. 
 
2. Recovery from last induction course of chemotherapy. 
 
3. No uncontrolled infection. 
 
4. Minimum frozen PBSC of 4 x 106 CD34 cells/kg as 2 aliquots; i.e. 2 x 106 CD34 cells/kg for each 
transplant are mandatory. A third aliquot of 2 x 106 CD34 cells/kg is strongly recommended for 
back-up. 
 
5. AST < 3 x upper normal 
 
6. Shortening fraction  27%, or ejection fraction  50%, no clinical congestive heart failure. 
 
7. Creatinine clearance or GFR > 60 ml/min/1.73m2 (If a creatinine clearance is performed at end of 
induction and the result is < 100 ml/min/1.73m2, a GFR must be performed using a nuclear blood 
sampling method or iothalamate clearance method. Camera method is NOT allowed as measure 
of GFR prior to or during Consolidation therapy for patients with GFR or creatinine clearance of 
< 100 ml/min/1.73m2.) 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Thiotepa  
(TEPA) 
IV over 2 
hours 
300 mg/m2/dose (or if < 12 
kg, 10 mg/kg/dose) once 
daily x 3 doses.   
Days -7, -6 
and -5 
Thiotepa can cause 
significant skin toxicity 
with sloughing of skin.  
Bathe patient frequently in 
water only.  Avoid large 
occlusive dressings, use of 
any skin creams and 
remove adhesive residue 
from prior dressings and 
leads. 
a. Physical exam, ht, wt 
b. CBC with diff and 
platelets 
c. Electrolytes, BUN, Cr,  
d. Ca++, PO4, Mg++ 
e. ALT, AST, bilirubin, 
albumin 
 
Refer to Protocol Section 
7.0 for complete list of 
observations. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD 
PATIENT CARE 
  
Cyclophosphamide 
(CPM) 
IV over 1 
hour 
1500 mg/m2/dose (or if < 12 
kg, 50 mg/kg/dose) once 
daily x 4 doses.  
Days -5, -4, 
-3, and -2 
Suggest hydrating at 3000 
mL/m2/day using fluid 
containing at least 0.45% 
NaCl. Suggest achieving 
urine specific gravity < 
1.010 prior to start of 
cyclophosphamide.   
Mesna 
IV over 
15 
minutes 
300 mg/m2/dose (or if  <  12 
kg, 10 mg/kg/dose) 
immediately prior to each 
cyclophosphamide dose and 
then 4 hours and 8 hours 
after each cyclophosphamide 
dose 
Days -5, -4, 
-3, and -2 
 
Filgrastim 
(GCSF) 
SubQ 
(or) IV 
(SubQ 
preferred) 
5 micrograms/kg once daily 
and continuing once daily 
until post-nadir ANC > 
2000/µL for 3 consecutive 
days. 
Day 0 until 
ANC 
recovery 
 
 
Page 1 of 2 


 
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Page 48 
 
Consolidation Therapy Regimen B: Tandem HSCT #1 (Thiotepa and Cyclophosphamide) 
 
For tests required prior to consolidation, please refer to Section 7.1.2   
 
Therapy Delivery Map   
 
 
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
 
TEPA 
____mg 
 
CPM 
____mg 
 
Mesna 
_____mg 
 
GCSF 
_____mcg 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
-7 
TEPA____mg 
 
 
 
a,b,c,d,e 
 
 
 
-6 
TEPA____mg 
 
 
 
b,c 
 
 
 
-5 
TEPA____mg 
CPM_____mg 
Mesna____mg 
 
b 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
-4 
 
CPM_____mg 
Mesna____mg 
 
b,c 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
-3 
 
CPM_____mg 
Mesna____mg 
 
b 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
-2 
 
CPM_____mg 
Mesna____mg 
 
b,c 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
 
 
 
Mesna____mg 
 
 
 
 
 
-1 
 
 
 
 
 
 
 
 
0 
PBSC infusion (HSCT #1) 
GCSF_____mcg 
a, b (daily until   
neutrophil 
engraftment),  
c (every other 
day if stable), 
d, e (twice 
weekly if 
stable) 
Date of last dose: 
__________ 
 
 
42 
Proceed to HSCT #2 (CEM) no less than 6 weeks and prior to 10 weeks from day 0 of 
HSCT #1 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
 
Please note that tests from Day -6 to Day -1 are recommended only.  
 
Page 2 of 2  


 
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Page 49 
4.6.1 
Consolidation Regimen B: HSCT #2 (CEM) 
 
 
 
 
 
 
 
 
 
COG #____________________ 
Regimen B: Experimental arm of tandem myeloablative therapy 
(Regimen B) with the thiotepa and cyclophosphamide regimen 
followed by CEM.  
 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
   Criteria to Start Consolidation Regimen B HSCT#2:   
 
No restaging will be performed between transplants or prior to radiation therapy unless clinically indicated.  Patients 
randomized to Regimen B will proceed to HSCT #2 (CEM) no less than 6 weeks and prior to 10 weeks from Day 0 of 
HSCT #1, providing they have recovered from acute toxicities of HSCT#1 and meet organ eligibility criteria for HSCT 
#2.   
1. 
All patients must have repeat GFR after recovery from HSCT #1 and prior to HSCT #2. If a creatinine 
clearance is performed and the result is < 100 ml/min/1.73m2, a GFR must be performed using a nuclear 
blood sampling method or iothalamate clearance method.  Camera method is NOT allowed as measure of GFR 
prior to or during Consolidation therapy if GFR/creatinine clearance is < 100 ml/min/1.73 m2. Patient is ineligible to 
receive HSCT #2 if CrCl or GFR is < 60 mL/min/1.73m2. If the GFR is < 100 ml/min/1.73m2, then modified 
dosing is used as noted below. It is recommended that the Study Chair be notified of patients with low glomerular 
filtration rates. 
2. 
Resolution of acute hepatic, pulmonary or cardiac toxicities developed during HSCT #1.  
3. 
AST  < 3 x upper normal 
4. 
Shortening fraction  27%, or ejection fraction  50%, no clinical congestive heart failure. 
5. No uncontrolled infection. 
6. 
No moderate or severe  sinusoidal obstruction syndrome (SOS)  (formerly veno-occlusive disease (VOD) ) during 
HDC/SCR #1 
Definition of  sinusoidal obstruction syndrome (SOS)  
SOS (formerly known as VOD) is a syndrome of hepatic dysfunction, which develops by Day+21 post stem cell 
transplant, and is characterized by hyperbilirubinemia ≥2 mg/dL, with at least two of the following three findings: 
ascites, hepatomegaly, which is usually painful, and weight gain >5% over baseline. Patients with SOS during SCT 
#1, with hepatic function meeting eligibility for SCT#2 and NOT meeting definitions for moderate or severe SOS 
(see below), may proceed to SCT#2. 
 
Definition of severe SOS: 
 Severe SOS is defined as a SOS episode accompanied by specific organ failure (hepatic encephalopathy (CTC 
Grade 4 liver dysfunction/failure, clinical will be referred as “Hepatic failure” per CTCAE v.4.0 followed starting 
July 1st, 2011), continuous oxygen requirement (CTC Grade 3 hypoxia), serum creatinine > 3 times the upper limit 
of normal (CTC Grade 3 creatinine), requirement for ventilatory support or dialysis not clearly attributable to 
another cause. Patients with a history of severe SOS, even if resolved, should not undergo SCT#2. 
 
Definition of moderate SOS: 
 Moderate SOS is defined as a SOS episode where the peak total bilirubin was 10 mg/dL or greater (personal 
communication, Paul Richardson).  Patients with a history of moderate SOS, even if resolved, should not undergo 
SCT#2. 
 
7. 
Minimum frozen PBSC of 2 x 106 CD34 cells/kg is mandatory to proceed with second transplant.   
8. 
No clinical evidence of disease progression defined as increase in tumor size by 25% or new lesions; restaging 
studies between HSCT courses only as clinically indicated. 
9. 
ANC recovery to > 750/µL after HSCT #1  
10. Platelet count > 20,000/µL or < 20,000/µL and responsive to platelet transfusion 
 
This Therapy Delivery Map is on FIVE pages. This Cycle lasts 36 days.  
 
Page 1 of 5 


 
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Page 50 
 
    Consolidation Regimen B: HSCT #2 (CEM) 
 
    PATIENTS WITH CREATININE CLEARANCE OR GFR > 100 ML/MIN/1.73M2  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Melphalan (MEL) 
IV over 
15-30 
minutes 
60 mg/m2/dose (or if < 12 
kg, 2 mg/kg/dose) once 
daily x 3 doses.   
Days -7, -
6 and -5 
Must be infused 
within 1 hour of 
preparation. 
a. Physical exam, ht, wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr  
d. Ca++, PO4, Mg++ 
e. ALT, AST, Bilirubin, 
Albumin 
f. Triglycerides  
g. ECG, MUGA/ECHO, CrCl 
or GFR, urinalysis 
h. Bilateral BM aspirate/bx., 
Audiogram/BAER (Section 
7.1.2) 
i. BM PCR (Section 15.4) 
j. Peripheral blood PCR 
(Section 15.6) 
k. Tumor imaging, Bone scan, 
MIBG (Section 7.1.2) 
l. MRI spine & neurologic 
evaluation (tumors with 
intraspinal extension only)  
m. VMA/HVA (if elevated at 
diagnosis) 
n. Peripheral Blood Immune 
assessments (Section 15.8) 
o. Peripheral blood for Immune 
recovery (Section 7.1.2) 
 
Refer to Protocol Section 7.0 
for complete list of 
observations and Section 15.0 
for sample acquisition or 
shipment guidelines 
 
OBTAIN OTHER STUDIES 
AS 
REQUIRED FOR GOOD 
PATIENT CARE
Etoposide (ETOP) 
IV over 24 
hours 
300 mg/m2/dose (or if < 
12 kg, 10 mg/kg/dose) 
once daily x 4 doses.   
Days -7, -
6, -5 and -
4 
 
CARBOplatin 
(CARB) 
IV over 24 
hours 
375 mg/m2/dose (or if < 
12 kg, 12.5 mg/kg/dose) 
once daily x 4 doses.  . 
Days -7, -
6, -5 and -
4 
 
Filgrastim 
(GCSF) 
SubQ 
(OR) IV 
(SubQ 
preferred) 
5 micrograms/kg once 
daily and continuing once 
daily until post-nadir 
ANC > 2000/µL for 3 
consecutive days. 
Day 0 
until ANC 
recovery 
 
 
Page 2 of 5 


 
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ANBL0532 
Page 51 
 
      Consolidation Regimen B: HSCT #2 (CEM): Patients with altered renal function who are > 12 kg 
      PATIENTS WITH GFR < 100 ML/MIN/1.73M2 and ≥ 60 ML/MIN/1.73M2 AND ARE > 12 KG 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Melphalan 
(MEL) 
IV over 
15-30 
minutes 
60 mg/m2/dose once 
daily x 3 doses.   
Days -7, 
-6 and -5 
Must be 
infused within 
1 hour of 
preparation. 
a. Physical exam, ht, wt 
b. CBC with diff and 
platelets 
c. Electrolytes, BUN, Cr  
d. Ca++, PO4, Mg++ 
e. ALT, AST, Bilirubin, 
Albumin 
f. Triglycerides  
g. ECG, MUGA/ECHO, 
CrCl or GFR, urinalysis  
h. Bilateral BM aspirate/bx., 
Audiogram/BAER 
(Section 7.1.2) 
i. BM PCR (Section 15.4) 
j. Peripheral blood PCR 
(Section 15.6) 
k. Tumor imaging, Bone 
scan, MIBG (Section 
7.1.2) 
l. MRI spine & neurologic 
evaluation (tumors with 
intraspinal extension 
only)   
m. VMA/HVA (if elevated 
at diagnosis) 
n. Peripheral Blood Immune 
assessments (Section 15.8) 
o. Peripheral blood for 
Immune recovery (Section 
7.1.2) 
Refer to Protocol Section 7.0 
for complete list of 
observations and Section 
15.0 for sample acquisition 
or shipment guidelines 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE
Etoposide 
(ETOP) 
IV over 24 
hours 
200 mg/m2/dose 
once daily x 4 doses.  
Days -7, 
-6, -5 and 
-4 
 
CARBOplatin 
(CARB) 
IV over 24 
hours 
See Calvert 
Formula* below for 
dose calculation; 
give dose once daily 
x 4 doses.   
Days -7, 
-6, -5 and 
-4 
*See sample 
Calvert dose 
calculation 
below 
Filgrastim 
(GCSF) 
SubQ 
(OR) IV 
(SubQ 
preferred)  
5 micrograms/kg 
once daily and 
continuing once 
daily until post-nadir 
ANC > 2000/µL for 
3 consecutive days. 
Day 0 
until 
ANC 
recovery 
 
*Calvert Formula for CARBOplatin dosing: 
 
  Patients with GFR < 100 ml/min/1.73 m2 who are > 12 kg will be dosed according to the formula below to 
achieve an area under the concentration versus time curve (AUC) 
  of 4.1 per dose.  GFR will be calculated using a blood sampling method.  Daily dose should not exceed 300 
mg/m2.   
 
Total Dose (mg)/day =  
      (Corrected GFR x surface area)    +   (15 x surface area)                          x  4.1 
 
                          1.73 
 
 
Example:  Patient’s GFR is 86 mL/min/1.73 m2, they weigh 14.6 kg and their BSA is 0.61 m2: 
 
  
Total dose (mg)/day = { (86 mL/min/1.73 m2  x  0.61 m2)     +    (15 x 0.61 m2) }   x  4.1    =   162 mg 
 
 
 
 
          1.73 
NOTE: if lab reports raw GFR in mL/min instead of corrected GFR in mL/min/1.73 m2, convert Raw GFR to corrected 
GFR as follows: 
Divide Raw GFR in mL/min by the patient’s surface area in m2, then multiply result by 1.73 m2.  
Example: Raw GFR is 30.3 mL/min, BSA = 0.61 m2:    30.3 mL/min divided by 0.61 m2 then multiplied by 1.73 m2  
=  86 mL/min/m2 
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      Consolidation Regimen B: HSCT #2 (CEM): Patients with altered renal function who are < 12 kg 
      PATIENTS WITH GFR < 100 ML/MIN/1.73M2 and ≥ 60 ML/MIN/1.73M2 AND ARE < 12 KG 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Melphalan 
(MEL) 
IV over 
15-30 
minutes 
2 mg/kg/dose once daily x 
3 doses.  . 
Days -7, -6 
and -5 
Must be infused 
within 1 hour of 
preparation. 
a. Physical exam, ht, wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr  
d. Ca++, PO4, Mg++ 
e. ALT, AST, Bilirubin, Albumin 
f. Triglycerides  
g. ECG, MUGA/ECHO, CrCl or 
GFR, urinalysis  
h. Bilateral BM aspirate/bx., 
Audiogram/BAER (Section 7.1.2) 
i. BM PCR (Section 15.4) 
j. Peripheral blood PCR (Section 
15.6) 
k. Tumor imaging, Bone scan, MIBG 
(Section 7.1.2) 
l. MRI spine & neurologic evaluation   
(tumors with intraspinal extension 
only) 
m. VMA/HVA (if elevated at 
diagnosis) 
n. Peripheral Blood Immune 
assessments (Section 15.8) 
o. Peripheral blood for Immune 
recovery (Section 7.1.2) 
 
Refer to Protocol Section 7.0 for 
complete list of observations and 
Section 15.0 for sample acquisition or 
shipment guidelines 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE
Etoposide 
(ETOP) 
IV over 
24 hours 
6.7 mg/kg/dose once daily 
x 4 doses.   
Days -7, -6, 
-5 and -4 
 
CARBOplatin 
(CARB) 
IV over 
24 hours 
See Calvert Formula* 
below for dose 
calculation; give dose 
once daily x 4 doses.  . 
Also calculate dose as 10 
mg/kg and give LOWEST 
calculated dose as 
described below 
Days -7, -6, 
-5 and -4 
*See sample 
Calvert dose 
calculation below.   
Filgrastim 
(GCSF) 
SubQ 
(OR) IV 
(SubQ 
preferred)  
5 micrograms/kg once 
daily and continuing once 
daily until post-nadir 
ANC > 2000/µL for 3 
consecutive days. 
Day 0 until 
ANC 
recovery 
 
 
*Calvert Formula for CARBOplatin dosing: 
 
  Patients with GFR < 100 mL/min/1.73 m2 who are < 12 kg will be dosed according to the formula below to 
achieve an area under the concentration versus time curve (AUC) of  4.1 per dose.  GFR will be calculated 
using a blood  sampling method.  Daily dose should not exceed 10 mg/kg.  Calculate dose by Calvert formula 
below and also calculate dose by weight (10 mg/kg).  Give LOWER of the two calculated doses.   
 
Total Dose (mg)/day = 
{ Raw GFR  +  (0.36 x weight in kg) }  x 4.1 
 
   
Example:  Patient’s GFR is 74 mL/min/1.73 m2, they weigh 10.2 kg and their BSA is 0.45 m2: 
 
 
To convert corrected GFR reported as mL/min/1.73 m2 to Raw GFR reported as mL/min, multiply 
corrected GFR by the patient’s BSA, then divide by 1.73 m2: 
 
 
74 mL/min/1.73 m2 x 0.45 m2 then divided by 1.73 m2 = 19.2 mL/min 
 
 
Total dose (mg/day) = {19.2 mL/min   +    (0.36 x 10.2 kg)}   x   4.1 = 94 mg 
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       Consolidation Regimen B: HSCT #2 (CEM) 
 
For tests required prior to consolidation, please refer to Section 7.1.2 
 
 
      Therapy Delivery Map   
 
 
Ht______cm 
        Wt______kg 
BSA______m2 
Date 
Due 
Date 
Given 
Day 
 
MEL 
_____mg 
 
ETOP 
_____mg 
 
CARB 
_____mg 
 
GCSF 
_____mcg 
Studies 
Comments 
(Include any 
held doses, or 
dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
-7 
MEL___mg 
ETOP____mg 
CARB____mg 
 
a,b,c,d, e 
 
 
 
-6 
MEL___mg 
ETOP____mg 
CARB____mg 
 
b,c 
 
 
 
-5 
MEL___mg 
ETOP____mg 
CARB____mg 
 
b, 
 
 
 
-4 
 
ETOP____mg 
CARB____mg 
 
b,c 
 
 
 
-3 
 
 
 
 
b 
 
 
 
-2 
 
 
 
 
b,c 
 
 
 
-1 
 
 
 
 
b 
 
 
 
0 
PBSC infusion (HSCT #2) 
GCSF_____mcg 
a, b (daily until 
neutrophil 
engraftment), c 
(every other day 
if stable), d, e 
(twice weekly if 
stable), g 
Date of last 
dose: 
__________ 
 
 
28 
Begin radiation therapy no sooner than 28 days post transplant, and 
recommended to begin by 42 days post transplant (see Protocol section 
17.0). 
o (1 month post 
HSCT), 
b(weekly 
through radiation 
therapy), 
End of radiation 
therapy:a,b,c,d,e,
f,g,h,i,j,k,l,m,n,o 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR 
SUPPORTIVE CARE 
 
 
Please note that tests from Day -6 to Day -1 are recommended only.  
 
 
 
 
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4.7 
Radiation therapy 
After completion of stem cell transplantation and recovery from acute toxicity, patients will receive 
radiation therapy to the primary site of disease as well as to MIBG-avid sites that were documented at 
pre-transplant (end-induction) evaluation. Patients who have a complete surgical resection of the primary 
tumor will receive 21.6 Gy external beam radiation therapy (EBRT) to the post-induction chemotherapy, 
pre-operative primary tumor volume while those who have an incomplete surgical resection of the 
primary tumor (residual soft tissue mass measuring >1 cm3) will receive 21.6 Gy EBRT to the post-
induction chemotherapy, pre-operative primary tumor volume and an additional boost of 14.4 Gy EBRT 
to the gross residual tumor (total dose 36 Gy to gross residual tumor volume).   
 
Timing of Radiation Therapy:  Radiation will be given after stem cell transplantation and should start no 
sooner than 28 days post transplant. Organ toxicity within radiation field should have resolved or meet the 
protocol criteria for starting radiation therapy that are included in Section 17.0.  It is recommended to start 
radiation therapy within 42 days after stem cell transplant.   
 


 
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4.8 
Maintenance Phase: Isotretinoin (Accutane) (13-cis-retinoic acid) Therapy 
ANBL0032 demonstrated an improvement in EFS for patients who recieved ch14.18 immunotherapy plus cytokines in addition 
to cis-RA. Patients should be encouraged to participate in clinical trials of ch14.18 immunotherapy (ie. ANBL0032 or 
ANBL0931).  Patients ineligible for immunotherapy or who decline participation will remain on ANBL0532 for Maintenance 
Phase using cis-RA alone. 
 
 
 
 
 
 
 
 
COG #____________________ 
Maintenance Phase: Post-transplant Maintenance therapy with 
cis-RA daily for 14 days every 28 days repeated for 6 months 
will be administered. To begin after completion of radiation 
therapy and criteria below are met. 
 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 Criteria to Begin Each Cycle of Isotretinoin (Accutane) (13-cis-Retinoic Acid)  
Prior to each cycle a patient must have:  ALT < 5 X normal, Skin toxicity no greater than Grade 1; Serum Triglycerides < 300 mg/dl; No 
hematuria and/or proteinuria on urinalysis; Serum creatinine < 1.5 times normal value based upon age and gender (see Section 3.2.4.1). This 
Therapy Delivery Map is one page.  
DRUG 
ROUTE 
DOSAGE 
Patients  < 12 kg 
DOSAGE 
Patients > 12kg 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
 
Isotretinoin 
(ISOT) 
(Accutane) 
Orally 
5.33 mg/kg/day 
divided BID 
160 mg/m2/day 
divided BID 
Days 
1-14 
Round up to 
nearest 10 mg 
a. Physical, Ht, Wt 
b. CBC with diff and platelets 
c. Electrolytes, BUN, Cr, Ca,    
    Phos, Mg 
d. ALT, AST, Bilirubin, Albumin, 
Triglyceride, Urinalysis  
e.  Cis-RA PK (Section 15.7) 
f.  Bilateral BMA/Bx 
g. BM PCR (Section 15.4)  
h. Peripheral Blood for Immune recovery 
(Section 7.1.3) 
i. Tumor Imaging, Bone scan, MIBG 
(Section 7.1.3) 
j. MRI Spine & Neuro Eval (tumors with 
intraspinal extension only) 
k. VMA, HVA (if elevated at diagnosis) 
l. ECG, MUGA/ECHO, GFR, 
Audiogram/BAER (see Section 7.1.3) 
m. Peripheral Blood PCR (Section 15.6) 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Therapy Delivery Map 
Cycle_____ of 6      Ht_____cm 
             Wt____kg 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
ISOT 
____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
 
a,b,c,d (prior to each cycle) 
 
 
 
1 
ISOT ____mg 
 
 
 
 
2 
ISOT ____mg 
 
 
 
 
3 
ISOT ____mg 
 
 
 
 
4 
ISOT ____mg 
 
 
 
 
5 
ISOT ____mg 
 
 
 
 
6 
ISOT ____mg 
 
 
 
 
7 
ISOT ____mg 
 
 
 
 
8 
ISOT ____mg 
 
 
 
 
9 
ISOT ____mg 
 
 
 
 
10 
ISOT ____mg 
 
 
 
 
11 
ISOT ____mg 
 
 
 
 
12 
ISOT ____mg 
 
 
 
 
13 
ISOT ____mg 
 
 
 
 
14 
ISOT ____mg 
e (Course #1 only) 
 
 
 
15-28 
Rest Period  
f,,h,i,k (before Cycle 4)  a-d, f, g, i-m (end of Cycle 6 only) 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX II FOR SUPPORTIVE CARE 
 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
All toxicities should be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) v3.0 (Starting July 1st 2011, it will be graded according to CTCAE V.4.0). 
 
5.1 
Myelosuppression During Induction 
 
5.1.1 
Dose adjustments will be made based on the neutrophil count and platelet count on Day 29 of each cycle. 
Following any cycle, if the ANC < 750/L and/or platelet count is < 75,000/L on Day 22, delay next 
cycle until recovery occurs or meets criteria to continue based on bone marrow tumor involvement (see 
below).  If patient recovers to ANC > 750/L and platelets > 75,000/L by Day 29, proceed with next 
cycle at full dose.  If patient has not met hematopoietic recovery criteria on or before Day 29, perform 
bone marrow aspirate and biopsy.  Proceed based on hematopoietic recovery criteria (see Section 5.1.2). 
 
5.1.2 
Hematopoietic Recovery Criteria 
If the marrow is positive for tumor at diagnosis or at last evaluation, still contains tumor and is 
normocellular or mildly hypocellular with trilineage hematopoiesis proceed with the next cycle of 
chemotherapy without alteration in dose regardless of ANC and platelets. If the marrow has no tumor and 
is severely hypocellular without tri-lineage hematopoiesis, delay the next cycle of therapy until the ANC 
> 750/L and platelets > 75,000/L. 
 
 
If recovery occurs between Day 30-43 for any cycle of Induction, reduce the doses of all 
drugs except vincristine by 25%. 
 
If recovery occurs after Day 43 of any cycle, reduce drug doses by 50%, except for 
vincristine. 
 
5.2 
Hematuria During Induction 
For Cycles 1 and 2: If microscopic (> 2 abnormal urinalyses during a cycle of therapy with < Grade 2 
hematuria) or gross hematuria occurs after Induction Cycle 1 cyclophosphamide, give MESNA with 
Induction Cycle 2 cyclophosphamide as follows: MESNA 80 mg/m² (or 2.67 mg/kg if < 12 kg) with 
cyclophosphamide infusion, then MESNA 80 mg/m² (or 2.67 mg/kg if < 12 kg) IV over 15 minutes at 
Hours 4 and 8 from start of cyclophosphamide infusion.  If hematuria resolves prior to start of cycle 4 
cyclophosphamide, administer cyclophosphamide and mesna in cycles 4 and 6 without modification.  
 
For Cycles 4 and 6: If microscopic (> 2 abnormal urinalyses during a cycle of therapy with < Grade 2 
hematuria) or gross hematuria occurs after Induction Cycle 4 cyclophosphamide, give mesna as a 24 hour 
continuous infusion with Induction Cycle 6 cyclophosphamide as follows:  MESNA 560 mg/m²(or 18.7 
mg/kg if < 12 kg) with each cyclophosphamide infusion, then MESNA 1800 mg/m² (or 60 mg/kg if < 12 
kg) in required fluid over 18 hours after cyclophosphamide infusion completed.   
 
If Grade 3 or 4 hematuria occurs following a cycle of cyclophosphamide, do not give another cycle of 
cyclophosphamide, topotecan (CT) or cyclophosphamide, doxorubicin and vincristine (CDV) until 
hematuria resolves to Grade 2 or less.  If patient is due to begin next cycle of cyclophosphamide 
containing chemotherapy prior to resolution of hematuria to  Grade 2, substitute cisplatin and etoposide 
cycle. Make notation of substitution on data forms.  The intent of Induction is to give a total of 2 cycles 
each of CT, cisplatin/etoposide and CDV, therefore if substitution of cisplatin/ etoposide is made for 
CDV cycle or a CT cycle, make-up this missed cyclophosphamide-containing cycle later in therapy. If 
gross hematuria from cyclophosphamide recurs, delete cyclophosphamide from subsequent cycles.   
 


 
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5.3 
Renal Toxicity During Induction  
 
5.3.1 
Cisplatin 
No dose reductions in cisplatin will be made for a decrease in the baseline GFR or creatinine clearance as 
long as the value remains > 60 mL/min/1.73 m².  If the serum creatinine increases > 50% during a cycle 
of cisplatin-containing chemotherapy, or increased to greater than maximum serum creatinine for age as 
listed in table below, omit the remainder of the cisplatin from that cycle. 
 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 
If GFR or creatinine clearance is < 60 mL/min/1.73 m² prior to cisplatin/etoposide cycle substitute CDV 
cycle.  Make notation of substitution on data forms.  The intent of Induction is to give a total of 2 cycles 
of CT, 2 cycles of cisplatin/etoposide, and 2 cycles of CDV, therefore if substitution of CDV cycle is 
made for cisplatin/etoposide cycle, give the cisplatin/etoposide cycle later in therapy. Omit further cycles 
of cisplatin therapy if GFR or creatinine clearance remains < 60 mL/min/1.73m². 
 
5.3.2 
Cyclophosphamide, Doxorubicin, Vincristine, Topotecan and Etoposide  
No dose reductions in cyclophosphamide, doxorubicin, vincristine, topotecan or etoposide are necessary 
for decrease in creatinine clearance. 
 
5.4 
Cardiac Toxicity During Induction 
 
5.4.1 
For Change In Ejection/Shortening Fraction 
If the cardiac ejection fraction falls below 50% or shortening fraction below 27% and patient is 
asymptomatic following a cycle of doxorubicin, repeat the study in one week.  If the ejection fraction or 
shortening fraction remains abnormal one week later proceed as follows: 
 
If cardiac toxicity occurs prior to Cycle 4, substitute cycle of cisplatin/etoposide for CDV.  Make notation 
of substitution on data forms.  The intent of Induction is to give a total of 2 cycles of CDV and 2 cycles of 
cisplatin/etoposide, therefore if cisplatin/etoposide cycle substituted for CDV, give CDV cycle later in 
therapy if possible.  If cardiac function does not return to normal prior to cycle 6 or is initially noted to be 
abnormal prior to cycle 6 scheduled CDV, omit doxorubicin. 
 
5.4.2 
For Symptomatic Congestive Heart Failure (CHF)  
If at any time, the patient develops Grade 3 congestive heart failure or dysrhythmia or any Grade 4 
cardiac toxicity not related to underlying infection or metabolic abnormality, omit doxorubicin from all 
subsequent cycles.  If cardiac toxicity is resolved to < Grade 2 congestive heart failure or dysrhythmia, 


 
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decrease the dose of cyclophosphamide to 50% for the next cycle containing cyclophosphamide.  If this 
dose of cyclophosphamide is tolerated without > Grade 2 congestive heart failure or dysrhythmia, then 
administer full dose of cyclophosphamide in subsequent cycles of chemotherapy.   
 
Congestive Heart Failure will be referred as “Heart Failure” per CTCAE v4.0 followed starting July 1st, 
2011. 
 
5.4.3 
For Dysrhythmia 
If the patient develops Grade 2 cardiac dysrhythmia as defined in the Common Toxicity Criteria, repeat in 
one week.  If Grade 2 toxicity resolves to Grade 0 or 1 toxicity, patient may continue on therapy without 
chemotherapy dose alterations.   
 
If Grade 2 toxicity occurs prior to Cycle 4, substitute cisplatin/etoposide for CDV cycle until dysrhythmia 
resolves. Make a notation of chemotherapy substitution on data form.  The intent of Induction is to give a 
total of 2 cycles of CDV and 2 cycles of cisplatin/etoposide, therefore if cisplatin/etoposide cycle 
substituted for CDV, give CDV cycle later in therapy. If dysrhythmia symptoms occur prior to Cycle 6, 
proceed with cyclophosphamide, vincristine but omit doxorubicin.  
 
5.4.4 
Hypertension 
Hypertension due to neuroblastoma will not be considered reason for removal from protocol therapy or 
alteration in chemotherapy doses. 
 
5.5 
Hepatotoxicity During Induction 
If direct bilirubin is > 3 mg/dL prior to Cycle 4 chemotherapy, substitute cisplatin/etoposide for CDV 
cycle.  If direct bilirubin is > 3 mg/dL prior to Cycle 6 chemotherapy, omit doxorubicin and vincristine.  
If direct bilirubin is > 1.5 but < 3 (Grade 3 toxicity) prior to Cycle 4 or 6 chemotherapy, reduce 
doxorubicin and vincristine dose by 50%. 
 
5.6 
Gastrointestinal Toxicity During Induction 
 
5.6.1 
Mucositis 
If patient develops Grade 3 or 4 mucositis that resolves to < Grade 2 by Day 22-29 of next cycle, no dose 
adjustments will be made in chemotherapy. If patient develops Grade 3 or 4 mucositis that is NOT 
attributable to infectious etiology AND recovery to < Grade 2 occurs between Day 30-43 for any cycle of 
Induction, reduce the dose of doxorubicin or etoposide in the next 2 cycles of chemotherapy by 25%.  If 
subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 GI toxicity then resume full doses 
of chemotherapy agents in all subsequent cycles of induction.   
 
If patient develops Grade 3 or 4 mucositis that is NOT attributable to infectious etiology AND recovery to 
< Grade 2 occurs after Day 43 of any cycle, reduce dose of doxorubicin or etoposide in the next 2 cycles 
of chemotherapy by 50%. If subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 GI 
toxicity then escalate dose by 25% in subsequent cycles of induction.   
 
If patient develops mucositis that requires intubation for airway management or if patient develops grade 
4 typhlitis or other grade 4 gastrointestinal toxicity hold subsequent chemotherapy until toxicity resolved 
to < Grade 2.  If the toxicity resolves to < Grade 2 by Day 43, proceed with next 2 cycles of 
chemotherapy but reduce dose of doxorubicin or etoposide by 25%.  If recovery to < Grade 2 occurs after 
Day 43 of any cycle, reduce dose of doxorubicin or etoposide in the next 2 cycles of chemotherapy by 
50%.  If subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 GI toxicity then escalate 
dose by 25% in subsequent cycles of induction.   


 
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5.6.2 
Diarrhea 
If patient develops severe diarrhea (Grade 3 or 4) attributable to chemotherapy and not underlying 
infection (i.e. C. difficile), that resolves by Day 22-29 of cycle, no dose adjustments will be made in 
chemotherapy. If recovery to < Grade 2 occurs between Day 30-43 for any cycle of Induction, reduce the 
dose of doxorubicin or etoposide in next cycle of chemotherapy by 25%.  If subsequent chemotherapy 
tolerated without recurrence of Grade 3 or 4 GI toxicity then resume full doses of chemotherapy agents in 
all subsequent cycles of induction.  If recovery to < Grade 2 occurs after Day 43 of any cycle, reduce dose 
of doxorubicin or etoposide in the next cycle of chemotherapy by 50%.  If subsequent chemotherapy 
tolerated without recurrence of Grade 3 or 4 GI toxicity then escalate dose by 25% in subsequent cycles 
of induction. 
 
5.7 
Ototoxicity During Induction  
For an inner ear/hearing toxicity  Grade 3, decrease cisplatin dose by 50% for subsequent cycles.  If loss 
extends below 2000 Hz, delete further cisplatin/etoposide cycles.  If cisplatin is deleted, then complete 
total of 2 cycles of CDV, then proceed to consolidation therapy. Make notation of cisplatin deletion on 
data form. 
 
5.8 
Neurologic Toxicity During Induction 
If severe peripheral neuropathy (vocal cord paralysis, inability to walk or perform usual motor functions) 
or ileus develops from vincristine, vincristine therapy should be stopped or withheld until the ileus 
resolves or the peripheral neuropathy improves.  Restart vincristine at 50% dose and escalate by 25% if 
tolerated with next course.  If neuropathy recurs on escalating dose, return to previously tolerated dose 
once neuropathy improved. 
 
 
5.9 
Allergic Reactions 
5.9.1 
Etoposide  
Etoposide allergic reactions may be managed with pre-medications such as diphenhydramine 1mg/kg IV 
(maximum single dose 50 mg), ranitidine 1mg/kg IV (maximum single dose 50 mg) and Hydrocortisone 
1-4 mg/kg IV and by slowing the rate of the infusion. For those reactions which are unable to be 
controlled with pre-medication and the 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.   
 
 
5.9.2 
Cisplatin and Carboplatin 
Platinum allergic reactions may be managed with pre-medications such as diphenhydramine 1mg/kg IV 
(maximum dose 50mg), ranitidine 1mg/kg IV (maximum single dose 50 mg) and Hydrocortisone 1-4 
mg/kg IV. 
 
5.10 
Other toxicities During Induction 
For any Grade 3 or 4 toxicity not mentioned above, the treatment should be withheld until patients 
recover to Grade 2 or less toxicity.  For any non-hematologic Grade 3 or 4 organ toxicity attributed to 
chemotherapy AND not related to underlying infection or metabolic derangement that is not discussed in 
Sections 5.1 – 5.8, and resolves to < Grade 2 by Day 43, reduce the subsequent dose of that chemotherapy 
agent by 25%. For any non-hematologic Grade 3 or 4 toxicity attributed to chemotherapy AND not 
related to underlying infection or metabolic derangement that is not discussed in Sections 5.1 – 5.8  
resolves to < Grade 2 greater than Day 43, reduce the subsequent dose of that chemotherapy by 50%. 
 
 
5.11 
Dose Modifications for 13-cis-Retinoic Acid (cis-RA) Therapy 
 
 


 
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5.11.1 
A dose reduction of 25% (to 120 mg/m²/day or 4 mg/kg/day if child weighs < 12 kg) for subsequent 
cycles should be made for the occurrence of any Grade 3 or 4 toxicities EXCLUDING: Grade 3 or 4 
hematologic, Grade 3 hepatic, Grade 3 nausea, Grade 3 vomiting, or Grade 3 fever.  If the same Grade 3 
or 4 toxicity recurs at a 25% dose reduction, then decrease dose another 20% (to 100 mg/m²/day or 3.33 
mg/kg/day if child weighs  12 kg).  If the same Grade 3 or 4 toxicity recurs after two dose reductions, 
and toxicity cannot be attributed to an alternative etiology, then withhold further therapy.  
 
5.11.2 
It has been reported (rarely) that some patients treated with cis-RA develop new areas of abnormal uptake 
on bone scan, likely due to increased bone resorption.  If such changes occur during retinoic acid phase in 
absence of other evidence of tumor recurrence do not report as progressive disease.    
 
5.11.3 
If criteria (Section 4.8.1) to begin next cycle are not met by the date cycle is due to begin, delay cycle for 
one week.  If criteria still not met, hold therapy until criteria are met, and treat at 25% dose reduction (120 
mg/m²/day or 4 mg/kg/day if child weighs  12 kg). An additional dose reduction to 100 mg/m²/day (3.33 
mg/kg/day if child weighs  12 kg) should occur if criteria are not met within one week after due date for 
subsequent cycles. 
 
5.11.4 
If serum creatinine increases by > 50% in any cycle of therapy, creatinine clearance or GFR should be 
done prior to starting next cycle, and a urinalysis. If creatinine clearance and/or GFR are < 50 
mL/min/1.73 m² reduce cis-RA by 50%.  If serum creatinine continues to increase or GFR decreased to < 
40 mL/min/1.73 m² then withhold further therapy. 
 
5.11.5 
If patient > Grade 1 develops hematuria, proteinuria, and/or hypertension during any cycle of therapy, 
hold medication until resolves to < Grade 1 then reduce cis-RA dose by 25%. 
 
5.11.6 
For localized cheilitis, apply topical vitamin E to lips for subsequent cycles.  If this does not control 
symptoms sufficiently to allow sufficient oral intake, then decrease dose by 25% (120 mg/m²/day or 4 
mg/kg/day if child weighs  12 kg). 
 
5.11.7 
If serum triglycerides are > 300 mg/dL when next cycle is due, delay starting therapy for two weeks.  If 
still > 300 mg/dL, then start patient on medical therapy for serum triglyceride reduction (consider 
cardiology consultation) and begin cycle at previous cis-RA dosage.  If serum triglycerides are < 300 
mg/dL by time subsequent cycle is due, then continue at same dosage cis-RA.  If triglycerides are still > 
300 mg/dL after one cycle on medical therapy, then reduce cis-RA acid dosage by 25% for subsequent 
cycles. 
 
 
 
6.0 
DRUG INFORMATION 
 
See the consent document for toxicities. All other information is available on the COG website in 
the manual titled “Drug Information for Commercial Agents used by the  Children’s 
Oncology 
Group” at: https://members.childrensoncologygroup.org/prot/reference_materials.asp under 
Standard Sections for Protocols. 
 


 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
All baseline studies must be performed prior to starting protocol therapy unless otherwise note below.  
 
 
 
 
 
 
 
 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
 
7.1.1 
Required Observations Pre-Treatment and During Induction 
 
Observation 
Pre-Treatment 
Prior to 
Each Cycle
During 
Cycle 1, 2
Following 
Cycle 2 
At PBSC 
Harvest 
Prior to 
Surgery 
End of 
Induction 
At 
Relapse 
Physical Exam 
X 
X
 
X
Height, Weight 
X 
X
 
X
CBC  with diff/platelets 
X 
X1
 
X
Electrolytes, BUN, Cr., Ca, 
Phos, Mg 
X 
X2 
 
 
 
X 
 
ALT, AST, Bilirubin, 
Urinalysis, albumin3 
X 
X 
 
 
 
X 
 
ECG and MUGA or ECHO 
X 
 
X
GFR or Creatinine Clearance 4 
X 
 
X4
Audiogram or BAERs 
X 
 
X
Bilateral BM Asp/Bx 
X 
X5
 
X
X6
BM PCR 
X7 
X7
 
X7
BM ICC 
X7 
 
X7
Peripheral Blood PCR 
X8 
 
X8
Peripheral blood for immune 
assessments 
X9 
 
 
 
 
 
 
Topotecan pharmacokinetics10 
 
X
 
Pharmacogenetics 11 
X 
 
PBSC PCR12 
 
X12
 
Tumor Imaging13 
X 
X
X 
X
X
MRI Spine and Neurologic 
Evaluation14 
X 
 
X 
 
 
X 
 
Bone Scan15 
X 
X15
 
X15
X
MIBG 16 
X16 
X16
 
X16
X
Catecholamines (VMA, HVA) 
X 
 
 
X17 
 
 
X17 
 
Pregnancy Test 18 
X 
 
 
 
1 
Obtain 2x weekly while on G-CSF (recommended) 
2 
Obtain as scheduled and daily during cisplatin administration (recommended) 
3 
Obtain serum albumin pre-treatment only and then as clinically indicated. 
4 
No restriction on method for GFR calculation.   If a creatinine clearance is performed at end of induction/prior to 
consolidation and the result is < 100 ml/min/1.73m2, the test must be repeated and a GFR performed.  The GFR must 
be obtained by blood sampling method or iothalamate clearance method for all patients with GFR/creatinine clearance 
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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< 100 ml/min/1.73m2.  Camera method IS NOT allowed as measure of GFR prior to or during Consolidation therapy if 
GFR/ creatinine clearance is < 100 ml/min/1.73m2. 
5 
BM studies to be done prior to starting Cycle 3 (This sample may be obtained prior to PBSC harvest for convenience if 
patient is undergoing anesthesia for apheresis line placement.  DO NOT NEED results to proceed to PBSC collection). 
6 
Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor.  Ship per ANBL00B1 
guidelines. Label “relapse” specimen.   
7 
Diagnosis & End of Induction: Obtain 10 cc of bone marrow (5 cc from each side) in sodium heparin tube. Following 
cycle 2 obtain 0.5cc from a single BM site for PCR only. See Section 15.4 for details regarding bone marrow 
immunocytochemistry and PCR analyses. 
8 
Obtain 2 mL peripheral blood in sodium heparin or EDTA tube.  See section 15.6 for details. 
9 
 Obtain 20 cc peripheral blood in sodium heparin tubes prior to initiation of chemotherapy. See Section 15.8 for details  
10 
Collect 2 cc in green top tube 15 minutes after completion of topotecan infusion on day 1 of Cycles 1 and 2.  See 
Section 15.3 for details and ordering of sample collection kit. 
11 
Collect one time sample of 10 cc in purple top tube (ETDA tube) prior to start of therapy (preferable) or when patient is 
not leukopenic (WBC > 2000).  See section 15. 2 for details. 
12 
Collect 1 cc of PBSC into sodium heparin tube and then transfer to PAX gene tubes.  See Section 15.5 for details. 
13 
Tumor imaging = CT/MRI as needed for optimum visualization of all areas of bulk tumor (primary and tastases). 
CT/MRI required prior to surgical resection. Repeat imaging of surgical sites within 4-6 weeks post-operatively 
(can be the same as end of induction scans if this is within 4-6 weeks of surgical resection). If patient has radiographic 
CR at end of induction submit these scans for Central Review. 
14 
 Obtain for tumors with intraspinal extension only.  See Section 13.4 and Appendix III for details. 
15 
Obtain if positive at diagnosis and results discordant with MIBG scan or tumor MIBG non-avid 
16 
MIBG scan can be performed within 2 weeks of starting chemotherapy if it is not possible to obtain scan prior to 
starting chemotherapy.  Repeat MIBG later in therapy only if positive at diagnosis. I123 MIBG scan preferred, see 
section 16.4 for details. 
17 
Repeat catecholamine levels if elevated at diagnosis. 
18 
Perform for all females of childbearing age. 
 
 
PLEASE NOTE THAT END OF INDUCTION (Section 7.1.1) AND PRIOR TO CONSOLIDATION (Section 7.1.2) TESTS 
REQUIRED ARE THE SAME AND ARE NOT TO BE PERFORMED TWICE UNLESS SPECIFIED 


 
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7.1.2 
Required Observations During Consolidation Therapy, Regimen A and Regimen B 
 
Observation 
Prior to 
Consolidation1
During HSCT 
#1 chemo 
  Regimen 
 A and B  
During 
Consolidation 
HSCT #1 Regimen 
A and B 
Prior to HSCT 
# 2 
Regimen B  
During 
Consolidation
HSCT #2 
Regimen B 
Post HSCT #1 
(regimen A) or 
HSCT #2 
(regimen B) 
End of 
Consolidation 
Phase (after 
radiation)  
At 
Relapse 
Physical Exam, Ht., Wt. 
X 
 
X  
 
X  
 
X 
 
CBC with diff./platelets 
X 
 
X2 
 X 
X2 
 
X 
 
Electrolytes, BUN,  Cr 
X 
X2 
X3 
 X 
X3 
 
X 
 
Triglycerides 
 
 
 
 
 
 
X 
 
Ca, Mg, Phos 
X 
X3  
X4 
 X 
X4 
 
X 
 
AST, ALT, Bilirubin, Albumin 
X 
 
X4 
 X 
X4 
 
X 
 
Urinalysis 
X 
 
 
 X 
 
 
X 
 
ECG and  MUGA or ECHO 
X6 
 
 
 X 
 
 
X 
 
GFR or Creatinine Clearance5 
X6 
 
 
X 
 
 
X 
 
Audiogram or BAERs 
X6 
 
 
 
 
 
X 
 
Bilateral BM Asp/Bx  
X6 
 
 
 
 
 
X 
X7 
BM PCR8 
X6 
 
 
 
 
 
X 
 
BM ICC8 
X6 
 
 
 
 
 
 
 
Peripheral Blood PCR 9 
X6 
 
 
 
 
 
X 
 
Peripheral blood for immune 
assessments 
 
 
 
 
 
 
X10 
 
Peripheral blood for immune 
recovery 
 
 
 
 
 
X11 
X11 
 
Tumor Imaging12 
X6 
 
 
 
 
 
X 
X 
MRI Spine and Neurologic 
Assessment13 
X6 
 
 
 
 
 
X 
 
Bone Scan14 
X6 
 
 
 
 
 
X 
X 
MIBG 15 
X6 
 
 
 
 
 
X 
X 
Catecholamines VMA, HVA16 
X6 
 
 
 
 
 
X 
 
 
1      Must be performed within the 2 weeks prior to start of consolidation therapy unless otherwise noted.   
2 
Daily during consolidation chemotherapy administration and day of PBSC infusion. CBC daily until neutrophil engraftment, then weekly through radiation therapy.* 
3 
Obtain every other day if stable.  Obtain on day of PBSC infusion*. 


 
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4 
Obtain twice weekly if stable* 
5 
No restriction on method for GFR calculation.  If a creatinine clearance is performed prior to beginning consolidation therapy after completing induction and 
/or before Regimen B HSCT #2 if applicable and the result is <100ml/min/1.73m2 then the test must be repeated and a GFR performed. The GFR must be 
obtained by blood sampling method or iothalamate clearance method for all patients with GFR/creatinine clearance < 100 ml/min/1.73m2.  Camera method 
is NOT allowed as measure of GFR prior to or during Consolidation therapy for patients whose GFR/creatinine clearance is < 100 ml/min/1.73m2. 
6 
Must be performed within 1 month prior to start of consolidation therapy.  These observations should have been performed at the end of induction and do not need to be 
repeated unless consolidation begins > 4 weeks after the end of induction.MIBG obtained only if positive at diagnosis. Repeat catecholamine levels if elevated at diagnosis. 
7 
Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor.  Ship per ANBL00B1 guidelines. Label “relapse” specimen.  
8 
Obtain 10 cc of bone marrow (5 cc from each side) in sodium heparin tube.  See section 15.4 for details regarding bone marrow immunocytochemistry (ICC) and PCR 
analyses. 
9 
Obtain 2 ml peripheral blood in sodium heparin or EDTA tube.  See section 15.6 for details. 
10    Obtain 20 cc peripheral blood in sodium heparin tubes 2-3 months after final HSCT procedure, preferably prior to initiation of Accutane therapy or at the        
       time of enrollment on ANBL0032 or ANBL0931. See section 15.8 for details. 
11  Send CBC with differential and measurement by flow cytometry of peripheral blood CD3, CD4 and CD8 at 1, 3 and 6 months post the final HSCT 
procedure (HSCT on Regimen A or HSCT #2 on Regimen B).  To be performed at local institutions. 
12 Tumor imaging = CT/MRI as needed for optimum visualization of all areas of prior or persistent bulk tumor (primary and metastases). 
13 Obtain for tumors with intraspinal extension only.  See section 13.4 and Appendix III for details. 
14 Bone scan required only if positive at diagnosis and results discordant with MIBG scan or MIBG non-avid tumor 
15  MIBG scans performed only if the tumor is MIBG avid at diagnosis. I-123 MIBG scans is preferable, see section 16.4. 
16 Obtain catecholamine levels if elevated at diagnosis 
 
* Please follow your institutional guidelines. In the absence of such guidelines you may follow the recommendations listed 
above in footnotes 2, 3 and 4. 
 
PLEASE NOTE THAT END OF INDUCTION (Section 7.1.1) AND PRIOR TO CONSOLIDATION (Section 7.1.2) TESTS REQUIRED ARE THE SAME AND ARE 
NOT TO BE PERFORMED TWICE UNLESS SPECIFIED 
 


 
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7.1.3 
Required Observations During 13-cis-Retinoic Acid (Maintenance) 
 
 
Observation 
Prior to each 
cycle of cis-RA
Before 
 4th Cycle 
cis-RA 
End of 
Therapy 
At Relapse 
Physical Exam, Ht., Wt. 
X 
 
X 
 
CBC with diff./platelets 
X 
 
X 
 
Electrolytes, BUN,  Cr 
X 
 
X 
 
Triglycerides 
X 
 
X 
 
Ca, Mg, Phos 
X 
 
X 
 
AST, ALT, Bilirubin, 
Albumin 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
ECG and  MUGA or ECHO 
 
 
X 
 
GFR or Creatinine Clearance 
 
 
X 
 
Audiogram or BAERs 
 
 
X 
 
Bilateral BM Asp/Bx 
 
X 
X 
X1 
BM PCR2 
 
 
X 
 
Peripheral Blood PCR3 
 
 
X 
 
Peripheral blood for immune 
recovery 
 
X4 
 
 
Cis-RA PK5 
 X5 
 
 
 
Tumor Imaging6 
 
X 
X 
X 
MRI Spine and Neurologic 
Assessment7 
 
 
X 
 
Bone Scan8 
 
X 
X 
X 
MIBG9 
 
X 
X 
X 
Catecholamines VMA, HVA10 
 
   X10 
   X10 
 
 
1 
Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor.  Ship per ANBL00B1 guidelines. 
Label “relapse” specimen.  
2 
Obtain 10 cc of bone marrow (5 cc from each side) in sodium heparin tube.  See section 15.4 for details regarding 
immunohistochemistry (ICC) and PCR analyses. 
3 
Obtain 2 ml peripheral blood in sodium heparin tube.  See section 15.6 for details. 
4  
Send CBC with differential and measurement of CD3, CD4 and CD8 by flow cytometry at 1, 3 and 6 months post the final 
HSCT procedure (HSCT on Regimen A or HSCT #2 on Regimen B) 
5 
Collect 5 cc blood into sodium heparin tube wrapped in foil 4 hours after cisRA dose on Day 14 of Cycle 1.  See section 15.7 for 
details. 
6  
Tumor imaging = CT/MRI as needed for optimum visualization of all areas of prior or persistent bulk tumor (primary and 
metastases). 
7 
Obtain for tumors with intraspinal extension only.  See Section 13.4 and Appendix III for details. 
8 
Bone scan required only if positive at diagnosis and results discordant with MIBG scan or MIBG non-avid tumor 
9  
MIBG scans performed only if the tumor is MIBG avid at diagnosis. I-123 MIBG scans is preferable, see Section 16.4. 
10 Obtain catecholamine levels if elevated at diagnosis 
 
 
 


 
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7.2 
Required Observations During Follow-up After Completion of 13-cis-Retinoic Acid 
Therapy (for All Patients) 
Count time 0 as date of disease evaluation after completion of last cycle of cis-RA. 
 
 
 
 
 
 
 
Observation 
 
3 
Months 
 
6 
Months 
 
9 
Months 
 
1 
Year
 
1.5 
Year
 
2 
Years
 
2.5 
Years
 
3 
Years
 
3.5 
Years
 
4 
Years
 
4.5 
Years 
 
5 
Years 
Annually 
After 5 
Years8 
At 
Relapse
Physical Exam1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height, Weight1 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
CBC with 
differential and 
platelets1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MUGA or ECHO, 
ECG  
 
 
 
X5 
 
 
 
 
 
 
 
X 
 
 
Bilateral BM3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
Tumor Imaging4 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Bone Scan4 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
MIBG3  
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Catecholamines2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TSH, T4, 
Pulmonary Function 
tests 
 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Perform physical exam and CBC monthly for one year after transplant (recommended). 
2. Perform if positive at diagnosis. 
3. Bone marrow evaluations and MIBG scans only if positive after completion of Cis-retinoic acid therapy. 
4. Perform as scheduled, then as clinically indicated. Bone scan required only if positive at diagnosis and results 
discordant with MIBG scan or MIBG non-avid tumor.  For patients with tumors with intraspinal extension obtain MRI 
of spine and perform neurologic assessments per Appendix III at 6, 12, 24, 36 months and annually through year 5. 
5. If abnormal, repeat at 2 years and as needed.  If child is < 5 years when tested as directed, an additional test 
should be performed when child becomes age 5. 
6. Send bone marrow and if biopsy performed, send sample of fresh and snap frozen tumor.  Ship per 
ANBL00B1 guidelines.  Label “relapse” specimen. 
7. Perform PFTs only if child has pulmonary symptoms and if child is  5 years.  Perform thyroid function 
tests only for patients with poor linear growth or other concern about poor thyroid function. 
(recommended) 
8. Patient’s clinical status will be tracked annually through 10 years after enrollment onto study. 
 
 


 
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8.0 
OFF PROTOCOL THERAPY CRITERIA AND OFF STUDY CRITERIA 
 
8.1 
Off Protocol Therapy Criteria 
 
8.1.1 
During Induction Therapy 
a) 
Patient with progressive disease at end of Induction therapy will be off protocol therapy.  
Patients with mixed response, stable disease or persistent tumor in bone marrow by 
morphologic evaluation may remain on protocol therapy as per investigator preference. 
These patients are encouraged to come off protocol therapy for entry onto available COG 
Phase I and Phase II studies.  
b) 
Patient develops any Grade 4 organ toxicity not related to underlying infection or metabolic 
derangement that fails to resolve to < Grade 2 by 8 weeks from last cycle of chemotherapy 
EXCEPT: 
Patients with Grade 4 toxicities of fever, infection, ileus, nausea, transaminases, renal 
electrolyte wasting, vomiting, diarrhea, and stomatitis (not requiring intubation) who may 
continue on therapy if these toxicities resolve or are controlled with medication by Day 56 
of cycle.  
c) 
Unable to obtain adequate stem cell product for transplant. 
d) Patient with GFR < 60 ml/min/1.73m2 at the end of induction. It is to be noted that GFR must 
be confirmed using nuclear blood sampling method or iothalamate clearance method ONLY 
and NOT camera method. 
e) Patients with left ventricular cardiac dysfunction at the end of induction with ejection fraction 
< 50% or shortening fraction < 27%. 
 
8.1.2 
During Stem Cell Transplant 
a)  Patients who develop progressive disease (PD) at any time after stem cell transplant are off 
protocol therapy and may receive alternate therapy.If the patient has PR or SD after stem cell 
transplant i.e., questionable residual tumor, a biopsy should be done to obtain histological 
diagnosis, if possible, to determine if there is residual disease. If active malignant tumor 
remains, notify the Study Chair prior to additional therapy. Surgical removal is not 
encouraged unless it would alter therapy. Additional local irradiation should also be 
considered.   
 
8.1.3 
Treatment Completed Per Protocol 
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. 
 
8.1.4  Entire therapy 
a. Patient/Parent refuses further treatment (including patient/parent who refuses randomization) 
b. Patient/parent withdraws consent for any further data submission. 
c. Physician determines it is in patient’s best interest. 
d. Development of a 2nd malignancy 
 
 
8.2 
Off Study Criteria 
a) Death 
b) Lost to follow-up 
c) Entry onto another COG study with tumor therapeutic intent (e.g., alternative maintenance 
therapy protocol or at recurrence) 
d) Withdrawal of consent for further data submission 
e) Tenth anniversary of study entry 


 
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9.0 
STATISTICAL CONSIDERATIONS 
 
Overview 
This study will address the issue of whether an additional myeloablative consolidation results in better 
EFS than a single myeloablative consolidation, sufficient to justify the additional toxicity and duration of 
therapy.   
 
9.1 
Statistical Design 
Randomization 
This is a prospective study with a delayed two-arm randomization. With delayed randomization, early 
induction failures will be excluded from the EFS comparison and will prevent dilution of treatment effect.  
Randomization will be stratified by stage and MYCN status (the two factors most highly prognostic of 
outcome in neuroblastoma), and also by the end of induction response (CR/VGPR vs PR vs MR/NR).   
 
Timing: Randomization will occur after the completion of 6 cycles of induction therapy (including 
surgery) prior to transplant. 
 
Eligibility to proceed to Consolidation Therapy/Transplant:  Only patients who have a minimum PBSC 
harvest of 4 x 106 CD 34+ cells/kg (minimum of 2 x 106 CD 34+ cells/kg/transplant), who have adequate 
organ function, who do not have progressive disease at end of induction AND who have consented to 
Consent Part 2 are eligible for transplantation. 
 
Eligibility for randomization:  Patients must first be eligible to proceed to transplant in order to be eligible for 
randomization.  Patients will be randomly assigned to either single myeloablative therapy (Regimen A) with 
a carboplatin, etoposide, melphalan (CEM) preparative regimen and autologous PBSC rescue (representing 
the standard arm of the study), OR to the experimental arm of tandem myeloablative therapy (Regimen B) 
with the regimen used in the COG ANBL00P1 (thiotepa and cyclophosphamide followed by CEM).  
 
Nonrandom Assignment to Single Transplant 
 
The following patients will be nonrandomly assigned to single myeloablative transplant (Regimen A): 
 
Patients who are 365 to 547 days of age (12 – 18 months) with Stage 4, MYCN nonamplified 
tumor with any of the following potentially unfavorable biologic features: 
o unfavorable histopathology 
o diploid DNA content 
o indeterminant histopathology 
o indeterminate ploidy 
 
Patients who are greater than 547 days of age with Stage 3, MYCN nonamplified tumor with 
either of the following: 
o unfavorable histopathology  
o indeterminant histopathology   
 
 
Treatment Groups   
10 =  Single HSCT (CEM) 
20 =  Tandem HSCT (TC, then CEM) 
30 =  Induction  
 
HSCT – Hematopoietic Stem Cell Therapy 
 


 
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Strata 
Strata (cont.) 
01 = non-randomly assigned to Trt 01:AT-CEM 
(stg 3, MYCN not amp; OR stg 4, MYCN not amp, 
12-18 mo) 
 
 
09 = stage 3; MYCN amp; PR 
02 = stage 4s; MYCN amp; CR/VGPR 
10 = stage 4; MYCN not amp or 
indeterminant; PR* 
03 = stage 2a/2b; MYCN amp; CR/VGPR 
11 = stage 4; MYCN amp; PR 
04 = stage 3; MYCN amp; CR/VGPR 
12 = stage 4s; MYCN amp; MR/NR 
05 = stage 4; MYCN not amp or indeterminant; 
CR/VGPR* 
13 = stage 2a/2b; MYCN amp; MR/NR 
06 = stage 4; MYCN amp; CR/VGPR 
14 = stage 3; MYCN amp; MR/NR 
07 = stage 4s; MYCN amp; PR 
15 = stage 4; MYCN not amp or 
indeterminant; MR/NR* 
08 = stage 2a/2b; MYCN amp; PR 
16 = stage 4; MYCN amp; MR/NR 
 
17 = All patients (induction) 
 
* - Excludes patients 12-18 months old 
CR - Complete response 
VGPR - Very Good Partial Response 
PR - Partial Response 
MR - Mixed Response 
NR - No Response 
 
9.2 
Patient Accrual and Expected Duration of Trial 
 
9.2.1 
Accrual 
Based on A3973 and CCG-3891, annual accrual was expected to be about 140 patients/yr. Of these, 30% 
(42/yr) are expected to go off protocol therapy or off study prior to randomization due to physician 
discretion, tumor progression, death, or inability to achieve the 4 x 106 CD 34+ cells/kg needed to proceed 
to randomization/transplantation. Of the remaining 98 patients/year, 13 are estimated to be stratum 01 
patients who are non-randomly assigned to receive a single transplant (AT).  Furthermore, the delayed 
timing of randomization and the criteria to discontinue protocol therapy for those with progressive disease 
should result in a very low rate for refusal of randomization (about 5%).  Therefore, the original estimate 
was for 81 patients/year (69/year of which are Stage 4) to be randomized.  However, as of the second 
quarter of 2011, the annual accrual rate has reached 230 patients/year and the randomization rate is 50%, 
so the new estimate of the randomized patient rate is 115 patients/year. 
 
 
In the original plans, a total of 329 randomized patients were needed for sufficient power for an analysis 
of the primary EFS treatment comparison.  At an accrual rate of 81 patients per year, 329 would be 
accrued in about 4.1 years, plus 3 of follow-up, for a total study duration of about 7 years. Including 
stratum 01 patients and patients who go off protocol therapy or off study prior to randomization, the total 
study accrual was originally planned as 574 patients (140/year for 4.1 years).  Based on the observation of 
higher EFS rates than anticipated in A3973 and ANBL0032, the power calculations below have been 
revised, and a new total enrollment of up to 664 patients will be required. 
 
To increase the homogeneity of the patient cohort, patients will be strongly encouraged to enroll on 
ANBL0032 or ANBL0931 after ANBL0532.  The DSMC will be kept apprised of the proportion of 
patients who enroll on ANBL0032 or ANBL0931, overall and by ANBL0032 treatment arm.  (Prior to 
closure of randomization, ANBL0032 randomization was stratified by ANBL0532 treatment arm.) 
 
 


 
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9.2.2 
Power Calculations 
In the original plan: Power for EFS treatment comparison:  n=329 randomized patients can detect a 12% 
difference in the 3-year EFS rate starting from the time of randomization (from 46% for AT versus 58% 
for AT1+AT2, which is a hazard ratio of 0.7) with 80% power in a one-sided logrank test at a 0.05 
significance level.  The 46% 3-year EFS was chosen for the control group in this study based on the 
national trend for improvement in local control rates, use of more dose intensive therapy, and better 
supportive care occurring since the design of 3891 with 38% 2-year EFS.  A 3 year follow-up provides 
time for sufficient events for 80% power and allows for some normalization of the EFS time post-
transplant for 1 versus 2 transplants. The more patient-years of follow-up there are, the smaller the 
proportion of time represented by the additional EFS time post-transplant of the tandem transplant 
patients. 
 
For the new plan (Aug 2011): 
The new control arm 3-year EFS will be 60%, starting from the time of randomization.  In order to 
detect a 12% difference in the 3-year EFS rate starting from the time of randomization (from 60% 
for AT1 versus 72% for AT1+AT2) with 80% power in a one-sided logrank test at a 0.05 
significance level, and taking into account a 6% crossover rate from AT1+AT2 to AT1, a total of 
332 randomized patients will be required.  (This results in a change from the originally planned 
hazard ratio (HR) [AT1+AT2: AT1] of 0.7 to a new HR of 0.64.)  In order to accrue 332 
randomized patients, we will need to enroll 664 patients (which assumes that the randomization 
rate might drop to as low as 50%). 
 
The choice was made to limit accrual duration to 4 years, and so the sample size of stage 4 patients 
provides too little power for the study to be designed/powered on the basis of this subgroup.  A 12% 3-
year EFS difference can be detected with 72% power based on the 276 stage 4 patients expected to be 
randomized.One-hundred and seventy-seven events are expected to be observed within the cohort of 
randomized patients after completion of 3 years follow-up after the last patient is accrued. 
 
 
9.3 
Statistical Analysis Methods 
 
9.3.1 
Endpoints 
 
9.3.1.1 Primary Endpoint 
The primary end point to determine benefit of a 2nd myeloablative consolidation procedure is the event-
free survival (EFS) rate.  A potential inherent bias exists due to the longer duration of therapy for patients 
who get two myeloablative consolidations.  Ideally the duration of treatment for two randomized groups 
would be the same, such that all patients complete their treatment at about the same time from 
randomization.  However, in this study the patients randomized to two transplants will take longer to 
finish their treatment than those randomized to one transplant.  There will be an inherent bias in the 
calculation of the EFS time. However, the longer duration is considered a clinical drawback, and so there 
will be no statistical adjustment in the EFS time for the extra treatment.  The EFS analysis will be intent-
to-treat starting from the time of randomization, i.e., just prior to the first transplant.  
 
9.3.1.2 Endpoints for Additional Primary Objectives 
The endpoint to determine benefit of topotecan addition is response at the end of induction therapy.  The 
proportion of Responders (end of induction CR/VGPR) will be compared to an analogous cohort of 
Responders on A3973. 
 
 
 
 
 
The endpoint for determination of local control will be the incidence rate of local recurrence (local 
recurrence events: progression or relapse at site of primary, to be determined by central review).  


 
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9.3.2 
Non-compliance with randomization (i.e., CROSSOVERS): 
A crossover is defined as a patient who does not receive the second myeloablative regimen, except for 
reasons of disease progression. 
 
The majority of crossovers are anticipated to be patients randomized to receive two myeloablative 
consolidations, but only receive one.  Very few crossovers, if any, will be patients who were randomized 
to receive one myeloablative consolidation but were treated with two.  If patients cross over to the other 
treatment arm, the detectable difference between treatment groups will increase.  If the detection of a 12% 
difference is to be maintained, a greater number of events (i.e., larger sample size) would be needed in 
order to overcome the diluting effect (Table A).  Updated power calculations have been performed 
assuming a 6% crossover rate from AT1+AT2 to AT1; this update obviates the need for Tables A and B 
below. 
 
 
Table A – Effect of the Proportion of Crossovers on the number of events and sample size required to 
maintain detection of 12% difference in the 3-year EFS rate 
Detectable 3-yr 
EFS difference 
Proportion of 
Crossovers 
Inflation 
Factor* 
Number of 
Events 
Number of 
Eligible Stage 4 
Randomized Pts 
Accrual 
Duration# 
(years) 
12% 
0 
1 
199 
329 
4.06 
12% 
0.05 
1.09 
211 
359 
4.43 
12% 
0.10 
1.20 
232 
395 
4.88 
12% 
0.15 
1.33 
256 
438 
5.41 
12% 
0.20 
1.47 
284 
484 
5.98 
12% 
0.25 
1.63 
318 
536 
6.62 
12% 
0.30 
1.84 
359 
605 
7.47 
12% 
0.35 
2.09 
409 
688 
8.49 
* extension of Piantadosi 122 
# annual accrual rate of 81 patients per year 
 
If we are unwilling to increase the sample size to compensate for the diluting effect of crossovers, the 
detectable EFS difference will increase (Table B). 
 
Table B. – Detectable difference in 3-year EFS rate based on the proportion of crossovers 
Proportion of 
Crossovers 
Inflation Factor 
Relative Risk* 
3-year EFS rate (%) 
with two transplants 
Detectable 
Difference in 2-yr 
EFS rate (%) 
0 
1 
0.703 
58.0 
12.0 
0.05 
1.09 
0.692 
58.4 
12.4 
0.10 
1.20 
0.680 
59.0 
13.0 
0.15 
1.33 
0.666 
59.6 
13.6 
0.20 
1.47 
0.652 
60.3 
14.1 
0.25 
1.63 
0.638 
60.9 
14.7 
0.30 
1.84 
0.620 
61.8 
15.4 
0.35 
2.09 
0.601 
62.7 
16.3 
* decreased risk for an event with two transplants 
 
For the first 79 patients randomized to the two-transplant arm, the proportion of crossovers will be 
monitored using the two-stage rule below.  Thereafter, it will be monitored using an upper bound of 35% 
crossovers from AT1+AT2 to AT.  If the proportion of crossovers from AT1+AT2 to AT reaches 35%, 
then the detectable difference in an intent-to-treat analysis will have increased beyond a clinically 


 
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reasonable value of 16.3% (i.e., beyond the expectation of increased benefit of two transplants).  At that 
time, consideration should be given to modifying for increased accrual, modifying the study design, or 
abandoning the study due to infeasibility.  Due to the dilution effect of the crossovers, an intent-to-treat 
comparison of treatment groups after 35% of patients have crossed from AT1+AT2 to AT would permit 
detection of a 16.3% difference (47% vs. 63%) in the 3-year EFS rate.  Stated another way, if 35% of 
AT1+AT2 patients cross to AT, an underlying true difference of 16.3% would need to exist in order for 
the study to be able to detect a difference of 12% in an intent-to-treat analysis with n=329.  Per Table B, if 
the underlying true difference is only 12%, and there are 35% crossovers, then 688 patients would be 
required to detect the 12% difference. 
 
9.3.3 
Power for detection of difference in proportion of induction responders 
All n= 664 patients on this study will be compared to n=486 patients on A3973, for a total of 1,150 
patients in the test of proportions.  The power and detectable different were already very good per Table 
C, but with the increase in sample size from what was originally planned, the available power will be 
higher and/or the detectable difference will be smaller than what was originally planned (Table C).  The 
A3973 cohort will be nearly identical to the cohort on this study with the exception of the change in the 
induction therapy under study and the later timeframe of this study.  Comparison will be made to assess 
ability to achieve CR + VGPR. 
 
Table C. – Detectable difference in CR + VGPR response rates with n=1060   
Potential post-induction response rate on 
A3973  (n=486) 
Response rate on this study  
(n=574) 
Detectable 
difference 
 
Power 
50% 
58% 
8% 
79% 
60% 
68% 
8% 
82% 
70% 
78% 
8% 
87% 
 
9.3.4 
Power for detection of a difference in the risk of local recurrence  
There are two differences between ANBL0532 and A3973 in the cohort of patients who have pre-
transplant <CR of the primary: 1) the number of transplants; and 2) the use of purging.  For an unbiased 
comparison of analogous patients who achieve pre-transplant <CR of the primary, the Treatment 01 
patients on ANBL0532 (36 Gy EBRT) will be compared to the unpurged patients (n=245) on A3973 
(21.6 Gy EBRT) in terms of their risk for local recurrence. The following projections are based on 
response rates from prior protocols. We assume 45% (n=110) of unpurged patients on A3973, and 45% 
(n=149) of patients randomized to receive one transplant on this study will achieve less than CR at 
primary site at end of induction therapy.  If 75% of the A3973 patients and 90 % of the ANBL0532 
patients make it from randomization to consolidation and XRT, then the total number of patients utilized 
for the local recurrence risk comparison is n=217 (83 from A3973 and 134 from ANBL0532).  This will 
provide more than 80% power to detect a clinically significant decrease of 13% (from 19% to 6%) in the 
risk for local recurrence after 36 Gy, and more than 87% power to detect an 14% decrease (from 19% to 
5%) in a one-sided Fisher’s Exact test at a significance level of 0.05.  
 
9.3.5 
Monitoring  
 
a) Monitoring for the proportion of “crossovers” from the two-transplant arm to the one-transplant 
arm: 
Of the eligible patients randomized to two transplants, patients who are unable to receive the second 
transplant except for reasons of disease progression (“crossovers”) will be identified.  The complement 
cohort who are compliant with their randomized assignment shall be called the “compliers”.  A two-stage 
rule will be used to monitor the proportion of “compliers” within the cohort of eligible patients 
randomized to receive two transplants.   


 
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 
Stage 1:  Accrue 33 patients randomized to the two-transplant arm.  If 20 or fewer patients 
are “compliers”, then consider modifying the study design to maintain power.  If more than 
20 patients are “compliers”, then proceed to Stage 2. 
 
Stage 2:  Accrue an additional 46 patients to the two-transplant arm for a total of 79.  If 53 
or fewer patients are “compliers”, then consider modifying the study design to maintain 
power.   
 
 
 
 
This two-stage design has the following characteristics:  The proportion of “compliers” is 0.61 under the 
null, and 0.75 under the alternative. This exact test will have >90% power and a significance level of 
<0.10. 
 
b) Interim monitoring for futility or superiority of the experimental arm (AT1-TC & AT2-CEM) 
will start after 20% of the total expected information (177 events) has been observed, and will be 
performed on an annual basis.  If issues of concern arise that require more frequent looks, then monitoring 
can be performed every six months.  
 
There will be cause to stop the trial early if the AT1 + AT2 arm appears to be insufficiently efficacious or 
significantly more efficacious.  The need for curtailment for non-significance of the AT1 + AT2 arm will 
be assessed using Fleming-Harrington-O’Brien boundaries for the hazard ratio (AT: AT1+AT2) at 
each interim analysis (Table D).  The interim analyses of EFS will take place every year starting after 
20% (40) of the planned events have occurred.  The lower bound is calculated based on repeated testing 
of the alternative hypothesis that the relative risk is equal to 1.42 at a p-value of 0.005.  This relative risk 
is calculated as control: experimental using the planning parameters for 3-year EFS.  The upper bound 
uses an alpha*t2 spending function for a cumulative alpha level of 0.05. 
 
Table D - Fleming-Harrington-O’Brien interim monitoring boundary values for log-rank EFS 
comparison of treatment arms 
Timepoint from 
monitoring start 
(years) 
Cumulative 
number of 
events expected 
Proportion of 
Total Expected 
Information 
Lower 
Boundary 
 z-value 
Upper 
Boundary 
 z-value 
0 
36 
0.201 
-1.459 
2.878 
1 
71 
0.402 
 -0.996 
2.470 
2 
102 
0.578 
 -0.682 
2.227 
3 
134 
0.759 
 -0.406 
2.033 
4 
158 
0.889 
 -0.227 
1.918 
5 
177 
1.000 
 -0.085 
1.840 
 
c) Descriptive monitoring:  In addition, the following descriptive monitoring will be performed.  If 
descriptive results present a concern, then a formal statistical monitoring rule will be developed: 
i) 
the proportion of local recurrences within the cohort of patients who have pre-
transplant <CR (about 25% expected); 
ii) 
the induction toxic death rate (about 3% expected); 
iii) 
end of induction response rate (about 50% for CR+VGPR);  
iv) 
rate of PBSC contamination as determined by ICC (about 3% expected) (this 
monitoring was discontinued starting with Amendment #2);  
v) 
the toxic death rate post-consolidation attributed to TC or TC + CEM (about 5% 
expected); and, 
vi) 
by ANBL0532 treatment arm, the proportion of patients who choose to enroll on 
ANBL0032 or ANBL0931 (difference less than 5%). 
 
9.3.6 
Assessment of Study Objectives 
 


 
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Primary Objective 1.1.1: Intent-to-treat log-rank test comparison of EFS curves, starting from the time 
of randomization, by treatment group (AT-CEM vs. AT1-TC & AT2-CEM). Kaplan-Meier curves will be 
generated starting from a) the time of randomization (this is the definitive analysis); b) the time of 
transplant; c) the time of completion of the last transplant (for descriptive purposes); and d) the time of 
diagnosis (for descriptive purposes). 
 
 
Primary Objective 1.1.2: Chi-square test of proportions in all patients to compare the proportion of 
Responders (CR+VGPRs) at the end of induction in this study to the analogous proportion in A3973.  
There is no reason to believe that the characteristics of the induction cohort on this study will differ from 
that of the induction cohort on A3973, so this will be a fair and appropriate comparison. 
 
Primary Objective 1.1.3: Log-rank test to compare the risk for local recurrence within the subset of 
patients who obtain a pre-transplant primary site < CR, i.e., comparing ANBL0532 patients randomized 
to get one transplant versus the historical A3973 patients who were randomized to unpurged transplant. 
 
Secondary Objective 1.2.1: The endpoints for this correlative aim are a) the duration of grade >=3 
neutropenia during cycle one; b) the duration of grade >=3 thrombocytopenia during cycle one; and, c) 
the response rate after two cycles of induction therapy.  Of the total 664 patients, we will assume that 
78% (n= 518) will have biologic samples submitted for this correlative study.  For a) and b), a logistic 
regression model will be used to test the ability of the number of days of neutropenia or 
thrombocytopenia to predict the presence of a polymorphism.  For c), a chi-square test of association will 
be used to compare the proportion of responders with versus without a polymorphism. 
 
For a particular genetic polymorphism, if the prevalence of homozygocity is 30%, the resulting sample 
sizes of 155 homozygous patients and 363 non-homozygous patients will result in more than 80% power 
to detect a difference in response rates of 45% versus 30%, respectively, assuming a 2-sided 0.05 alpha 
level.  If the prevalence of homozygocity for a particular genetic polymorphism is 50%, the resulting 
sample sizes of 259 homozygous patients and 259 non-homozygous patients will result in more than 80% 
power to detect a difference in response rates of 44% versus 30%, respectively, assuming a 2-sided 0.05 
alpha level.  If the prevalence of homozygocity for a particular genetic polymorphism is 10%, the 
resulting sample sizes of 52 homozygous patients and 466 non-homozygous patients will result in more 
than 80% power to detect a difference in response rates of 53% versus 30%, respectively, assuming a 2-
sided 0.05 alpha level. 
 
Secondary Objective 1.2.2:  A chi-square test of proportions will be used to test for association between 
the proportion of patients who achieve a surgical CR and the proportion of patients who do not relapse in 
the primary.  A logrank test will compare the EFS curves for degree of surgical response (CR vs. <CR). 
 
Secondary Objective 1.2.3: The proportion of patients by type of surgical complication and type of 
radiation therapy complication will be descriptively tabulated.  The complications, described in more 
detail in section 13.5.2, are: bowel obstruction, chylous leak, renal injury/atrophy/loss and diarrhea. 
 
Secondary Objective 1.2.4:  For the patients with primary tumors with intraspinal extension: descriptive 
tabulation of the proportion of patients with resolution of neurologic symptoms by type of symptom. 
 
Secondary Objective 1.2.5:  The cohort of patients for this analysis of the cis-RA PK data are patients 
enrolled on either A3973, ANBL0032, ANBL0931, ANBL0532, and future high risk studies who receive cis-
RA.  The analyses will be conducted in the overall cohort as well as within the subset of patients who receive 
only one transplant and cis-RA without the addition of antibody.  Patients will be pooled across these studies 
until at least 195 patients are available for analysis.  We would not stop consenting patients to this aim or 
collecting blood specimens in the middle of a study simply because the minimum accrual goal of n=195 had 


 
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been reached; accrual of patients towards this aim would continue until that study’s overall accrual was 
completed.  A larger cohort would permit this aim to be addressed with greater accuracy.    
 
1.2.5 a)  For each patient, the peak serum concentration level will be determined.   Pilot data 97,98 indicate the 
mean peak serum concentration level will be approximately 7 µM.  Given a mean peak serum concentration 
level of 7 µM, a sample size of n=195 will permit placement of a 90% confidence interval on the mean peak 
serum concentration level with a precision of +/- 0.24 µM.  This confidence interval will provide a 
descriptive assessment of the inter-patient variability of the cis-RA plasma levels. 
 
 
To determine the relationship of peak serum concentration level with the existence of polymorphisms, 
Kendall’s Tau statistic will be calculated.  The allelic frequency of the known polymorphisms in 
UGT1A1 and UGT2B7 are such that the expected numbers of homozygotes for the variant forms are 25% 
in caucasians.  Therefore, collection of 80 patient samples would allow us to detect a 2-fold difference in 
the peak serum concentration level of 13-cis retinoic acid with an expected power of greater than 90 % 
and a 50% difference with a power of 50%.  The allelic frequency of the CYP2C8 variant, CYP2C8*3 in 
Caucasians is 0.13, giving a frequency of only 2% for homozygotes.  However, the influence of this 
variant in those heterozygous for CYP2C8*3 has not been determined and evidence for variation between 
heterozygotes and those possessing the homozygous wild-type genotype exists for other genes.  
Combining heterozygotes and homozygous variants for this gene (CYP2C8) gives similar statistical 
power to that applied to the UGT polymorphisms. 
 
1.2.5 b)  To determine if there is a relationship of the peak serum concentration level with event-free survival, 
the term for this level will be tested in a Cox proportional hazards model.  If the level is statistically 
significant, then a) the hazard ratio will provide a measure of increased risk for an event for a unit change in 
the level; and, b) a cut-off in serum concentration level (low vs. high) will be identified that optimizes the 
difference in EFS between the low and high serum concentration groups. 
 
To determine if there is a relationship of the peak serum concentration level with toxicity rates (CTC 
grade 3 or 4 skin, hypercalcemia, or hepatic toxicity), Kendall’s Tau statistic will be calculated.   
 
1.2.5 c) To determine if pharmacogenomic variations are predictive of EFS, a logrank test comparison of 
patients with vs without a given polymorphism will be made. 
 
A Fisher’s exact test will test for association of the presence of a polymorphism with the occurrence of 
systemic toxicity (CTC grade 3 or 4 skin, hypercalcemia, or hepatic toxicity). 
 
These tests will be performed for UGT1A1, UGT2B7, CYP2C8 and CYP3A7 alleles. 
 
Secondary Objective 1.2.6: The hypothesis for this aim is that topotecan systemic clearance can be 
calculated with acceptable accuracy and precision using patient specific covariates in a dosing model. The 
topotecan total clearance value will be calculated from a single sample using Bayesian modeling 
techniques and population priors established from a similar patient population studied by Dr. Stewart’s 
laboratory.  The two clearance values from course 1 and 2 will be used in the analysis separately and as 
an average value.  In addition to this topotecan clearance, a “calculated” topotecan clearance value will be 
determined from a topotecan dosing model, which consists of patient specific covariates determined from 
a) previous population pharmacokinetic analyses, b) planned population pharmacokinetic analyses of 
already collected data, and c) population pharmacokinetic analyses of data that will be collected during 
this clinical trial. The relation between the topotecan clearance value determined by pharmacokinetic 
analysis (limited sampling; Bayesian modeling) and the topotecan clearance value determined by the 
topotecan dosing model (patient covariates) will be investigated using regression analysis and simulation 
studies.  The long-term goal is to identify relevant patient covariates that will enable the development of a 


 
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clinically useful dosing nomogram for topotecan in children with cancer.  This approach will minimize 
the interpatient variability in topotecan systemic exposure by individualizing the topotecan dosage.   
 
Secondary Objective 1.2.7. We hypothesize that: i) T cells recognizing antigens expressed on 
neuroblastoma cells circulate at diagnosis, and ii) anti-neuroblastoma T cells can demonstrate effector 
function against neuroblastoma cells, We will assess functional immunity against neuroblastoma in 
patient samples, including T cells collected at diagnosis and in patients after myeloablative therapy. We 
will look for functional T cell responses using both a specific tumor antigen (survivin) as well as 
allogeneic tumor RNA as a source of antigenic stimulus. 
 
Assays used will include: 
1.  Survivin-specific cytotoxic T lymphocytes detected using peptide/MHC tetramers in HLA-A2+ 
patients. This assay provides measures of the presence of T-cells that are capable of recognizing 
neuroblastoma.  For objective 1.2.7.a, the median number of survivin-specific T-cells will be calculated 
at diagnosis and post-transplant. The proportion of patients who are positive for survivin-specific 
immunity will be calculated at diagnosis and post-transplant.  For objective 1.2.7.d, of the patients who 
were positive for survivin-specific immunity at diagnosis, the proportion of patients who remain positive 
post-transplant will be calculated. 
 
2. IFN-gamma production in ELISPOT assays to antigen presenting cells (APCs) loaded with 
tumor RNA, survivin RNA, or control RNA. This assay provides a measure of the number of T-cells 
that are capable of recognizing neuroblastoma.  A sample of peripheral blood mononuclear cells 
(PBMC) will be exposed to  
 
APCs loaded with mRNA for survivin, mRNA from neuroblastoma cells and irrelevant mRNA.  This 
assay does not require that the patient be HLA-A2+.  For objective 1.2.7.b, the median number of T-cells 
and the median number of IFN-gamma-producing T-cells will be calculated using T-cells collected at 
diagnosis and after completion of myeloablative therapy for each stimulating APC type.  For each 
stimulating APC type, the median number of T-cells after transplant will be descriptively compared to a) 
the median number of T-cells at diagnosis; and, b) the median number of IFN-gamma-producing T-cells 
at diagnosis. 
 
3. Response of APC-stimulated cytotoxic T-lymphocytes (CTL) response to neuroblastoma cells.  
The ability to lyse neuroblastoma cells will be evaluated for T cells stimulated by exposure to APCs 
loaded with mRNA for survivin, mRNA from neuroblastoma cells and irrelevant mRNA.  The ability 
of stimulated T-cells to lyse neuroblastoma cells will be calculated at diagnosis and after myeloablative 
therapy. This assay provides a measure of the ability of stimulated T-cells to kill neuroblastoma cells.  
For objective 1.2.7.c, the proportion of patients whose stimulated T-cells lyse neuroblastoma cells will be 
descriptively compared between diagnosis and after completion of myeloablative therapy. 
 
It is not necessary to perform treatment arm comparisons to assess this objective. 
 
Secondary Objective 1.2.8. We hypothesize that patients who received the tandem myeloablative 
chemotherapy regimen will experience slower T cell recovery, specifically of CD4+ T cells when 
compared to patients who received a single myeloablative chemotherapy regimen. Enumeration of 
peripheral blood CD3, CD4 and CD8 cells will be performed at 1, 3 and 6 months after completion of 
assigned myeloablative therapy.  For each timepoint (1, 3, 6 months post-myeloablative therapy), we will 
perform a descriptive comparison of the median number of T-cells (CD3, CD4, CD8) between treatment 
arms (single vs. tandem myeloablative regimens).  
 


 
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Secondary Objective 1.2.9 - The proportion of patients with neuroblastoma detected in bone marrow and 
peripheral blood using RT-PCR technique will be calculated overall and by treatment arm.  Data from 
CCG-3891 indicate that by immunocytology ~15% of patients prior to myeloablative therapy show 
minimal residual disease in bone marrow,119 and ~ 5% of patients in peripheral blood at the time of bone 
marrow harvest. Presumably residual disease found after transplant will be less than this figure, although 
the sensitivity of RT-PCR may increase the proportion of neuroblastoma positive specimens. If 15% of 
the n=478 randomized patients are positive for neuroblastoma by bone marrow RT-PCR or 
immunocytochemistry and if the EFS from time of transplant of the positive group is two thirds that of 
the negative group, this study will have good power (>80%) to detect this difference. The same 
considerations apply to peripheral blood; unless the EFS difference is quite large between the groups this 
study will have limited power to detect differences by peripheral blood positivity. The statistical tool used 
will be the log rank test, stratified by any other variables of interest. Cox regression techniques will be 
used for multivariate analysis, in particular for determination of whether these variables add independent 
prognostic information. 
 
Secondary Objective 1.2.10 
A descriptive analysis of outcome will be performed of patients 12 – 18 months with Stage 4, MYCN 
nonamplified tumor with unfavorable histopathology or diploid DNA content or with indeterminant 
histology or ploidy and patients who are greater than 547 days of age with Stage 3, MYCN nonamplified 
tumor AND unfavorable histopathology or indeterminant histology.  Kaplan-Meier curves of EFS and OS 
will be plotted, and the proportion of responders to induction therapy will be tabulated. 
 
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 
27 
35 
62 
Not Hispanic or Latino 
257 
345 
602 
Ethnic Category: Total of all subjects 
284 
380 
*664 
Racial Category 
 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
10 
21 
31 
Black or African American 
37 
54 
91 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
235 
303 
538 
Racial Category: Total of all subjects 
284 
380 
*664 
 
 
 
 
* These totals must agree 
 
This distribution was derived from ____A3973___________. 
 


 
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10.0 
EVALUATION CRITERIA  
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and performance 
reporting. The descriptions and grading scales found in the revised CTCAE version 4.0 will be 
utilized for reporting beginning July 1st, 2011.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0, which can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).   
 
10.2 
Response Criteria for Patients with Solid Tumors 
This study will use the International Neuroblastoma Staging System (INSS) Response Evaluation 
Criteria. This will allow direct comparison with legacy COG studies as well as Phase 3 trials performed 
abroad. 
 
10.3 
International Staging System123 
Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; 
representative ipsilateral lymph nodes negative microscopically (nodes attached to and removed with the 
primary tumor may be positive). 
 
Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph 
nodes negative for tumor microscopically. 
 
Stage 2B: Localized tumor with or without complete gross excision; with ipsilateral nonadherent lymph 
nodes positive for tumor.  Enlarged contralateral lymph nodes must be negative microscopically. 
 
Stage 3: Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node 
involvement; or, localized unilateral tumor with contralateral regional lymph node involvement; or, 
midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The 
midline is defined as the vertebral column.  Tumors originating on one side and crossing the midline must 
infiltrate to or beyond the opposite side of the vertebral column. 
 
Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin 
and/or other organs (except as defined for Stage 4S). 
 
Stage 4S: Localized primary tumor (as defined for Stage 1 or 2A or 2B), with dissemination limited to 
liver, skin, and/or bone marrow (limited to infants < 1 year of age).  Marrow involvement should be < 
10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate.  
MIBG scan (if performed) should be negative in the marrow. 
 
10.4 
International Response Criteria123  
Measurable tumor is defined as the product of the longest x widest perpendicular diameter.  The third 
dimension is added when possible.  Elevated catecholamine metabolite levels and tumor cell invasion of 
bone marrow also is considered measurable tumor. See Appendix VI. 
 
10.4.1 Complete Response (CR)** 
No evidence of primary tumor, no evidence of metastases (chest, abdomen, liver, bone, bone marrow, 
nodes, etc.), and HVA/VMA normal. 
 
10.4.2 Very Good Partial Response (VGPR) 
Greater than 90% reduction of primary tumor; no metastatic tumor (as above except bone); no new bone 
lesions, all pre-existing lesions improved on bone scan; HVA/VMA normal. 


 
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10.4.3 Partial Response (PR) 
Fifty-90% reduction of primary tumor; 50% or greater reduction in measurable sites of metastases; 0-1 
bone marrow samples with tumor; number of positive bone sites decreased by > 50%. 
 
10.4.4 Mixed Response (MR) 
Greater than 50% reduction of any measurable lesion (primary or metastases) with, < 50% reduction in 
any other site; no new lesions; <25% increase in any existing lesion (exclude bone marrow evaluation). 
 
10.4.5 No Response (NR) 
No new lesions; <50% reduction but <25% increase in any existing lesion (exclude bone marrow 
evaluation). 
 
10.4.6 Progressive disease (PD)** 
Any new lesion or increase of a measurable lesion by >25%; previous negative marrow positive for 
tumor. 
 
** MIBG scan must be negative for patient to be classified as having a complete response. New site of 
disease documented by MIBG scan qualifies patient as having progressive disease. 
 
 
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. The CTCAE (v 4.0 will be used starting from July 1st, 
2011) provides descriptive terminology and a grading scale for each adverse event listed. 
 
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 NCI Agent-Specific Adverse Event List (provided in the Drug Information 
Section of this protocol); or 
 
the drug package insert (for treatments with commercially available agents). 
 
11.3 
Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway 
Commercial reporting requirements are provided in Table B.  The commercial agent(s) used in this study 
are listed in the Drug Information Section of this protocol.   


 
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COG requires the AdEERS report to be submitted within 5 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. 
 
 
 
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. 
 
AdEERS 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 
 
 
AdEERS 
Possible, 
Probable, 
Definite 
AdEERS 
 
AdEERS 
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 AdEERS. 
 
11.4 
Routine Adverse Event Reporting 
 
The NCI defines both routine and expedited AE reporting.  Routine reporting is accomplished via the 
Adverse Event (AE) Case Report Form (CRF) within the study database.  For this study, routine reporting 
will include all AdEERS reportable events and Grade 4 and higher non-hematologic Adverse Events 
with any attribution.  Reporting of hematologic adverse events will not be required as a part of 
routine AE reporting for this study.  Exceptions to the routine reporting criteria above are the 
following which are necessary to meet study aims: 
 
Grade 3 or higher neutropenia and/or thrombocytopenia during induction Cycle 1 
 
Grade 2 or higher diarrhea or gastrointestinal obstruction which may occur at any time 
after surgical resection of primary tumor. 
 
11.5 
Reporting Secondary AML/MDS 
As of August 25, 2010, all secondary malignancies should be reported via AdEERS. 
 
 
 
 
12.0 
RECORDS AND REPORTING 
 
12.1 
Categories of Research Records 
 
Research records for this study can be divided into three categories: 
 
1. 
Non-computerized Information:  Pathology Narrative Reports and Surgical Reports.  These forms 
are submitted through the Document Imaging System in the eRDES  
 


 
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2. 
Reference Labs’ required reports, and QARC data:  These data accompany submissions to these 
centers, which forward their review data electronically to the COG Statistics and Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other computerized data will be entered 
in the COG Remote Data Entry System with the aid of schedules and worksheets (essentially 
paper copies of the RDE screens) provided in the data form packet. 
 
See separate Data Form Packet posted on the COG web site, which includes submission schedule. 
 
12.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS).  Cumulative CDUS data will 
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and 
October 31. This is not a responsibility of institutions participating in this trial. 
 
 
13.0 
SURGICAL GUIDELINES 
 
13.1 
Surgical rationale 
The overall surgical goal in high-risk patients with neuroblastoma is the most complete tumor 
resection with preservation of full organ and neurologic function if possible. In addition, the surgeon 
is responsible for the preservation and delivery of an adequate surgical specimen to the appropriate 
laboratory for crucial biologic analyses; including determination of MYCN amplification, ploidy, and 
molecular genetic analyses. Titanium clips should be placed around sites of residual disease.  
 
 
13.2 
Pre-operative management 
Adequate pre-operative imaging of the primary tumor and sites of regional spread is done by either 
computerized axial tomography, magnetic resonance imaging, or a combination of the modalities. Sites of 
distant metastases should be evaluated by a combination of clinical and bone marrow assessment as well 
as bone scan and MIBG scans. When dealing with paraspinal or epidural lesions pre-operative 
neurosurgical consultation is recommended and a baseline neurologic assessment carried out (see section 
13.4.3 and Appendix III). The planned operation should be discussed with the attending pediatric 
oncologist and, if possible, at tumor board and the goals of the surgery should be clearly understood by all 
involved services pre-operatively.  
 
13.3 
Sampling requirements 
In all patients, the primary purpose of the initial surgical procedure is to obtain enough tissue to establish 
the diagnosis, determine stage, and secure enough properly preserved tumor for biological studies. Refer 
to ANBL00B1 for complete details of specimen requirements. All patients must be enrolled onto 
ANBL00B1 to be eligible to participate in ANBL0532.  An adequate biopsy to determine the diagnosis 
and assess biological variables like histopathologic classification, MYCN amplification and ploidy is 
required. Usually more than 1 cubic centimeter of viable tissue is needed for all these assays. Needle 
biopsies are not sufficient for histologic classification.  The surgeon should remember that a significant 
portion of the tumor may be necrotic. Frozen section examination of a small amount of tissue will verify 
that viable neuroblastoma is being biopsied. The anesthesia time while awaiting frozen section analysis 
can also be used to obtain bone marrow aspirations and biopsies, and for placement of a vascular access 
device. 
 
For patients with stage 4S disease who are very ill and in whom an open biopsy to obtain tissue for 
diagnosis and biologic studies is considered medically contraindicated, every effort should be made to 
obtain some tumor tissue by fine needle aspiration of a metastatic site for at minimum the determination 
of MYCN status.  


 
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13.4 
Operative management 
 
13.4.1 Central Line Placement 
Patients will require central venous access both for treatment and apheresis.  It is usually feasible and 
efficient to place a vascular access device and obtain a bone marrow aspirate and biopsy during the same 
anesthetic.  The appropriate catheter should be placed from initiation of therapy.  
 
Medcomp or similar catheters are specifically designed as tunneled, permanent apheresis catheters.  It 
may not be possible to draw at a sufficient rate from a non-apheresis catheter that is smaller than 10Fr. If 
a smaller double lumen must be placed, or if it is not possible to draw at a sufficient rate (2 mL/kg/min) 
then it may be necessary to place an additional 8-10 Fr single lumen catheter for the apheresis. If a 
second, single-lumen line is needed, it is best to place it electively PRIOR to starting the mobilization 
cycle of chemotherapy (i.e., Cycle 2 induction chemotherapy). 
 
13.4.2 Diagnostic Surgery 
In all patients, the primary purpose of the initial surgical procedure is to obtain enough tissue to establish 
the diagnosis, determine stage, and secure enough properly preserved tumor for biological studies.  The 
great majority of high-risk patients will undergo initial diagnostic biopsy without resection.  Biopsy of the 
primary tumor or an accessible metastatic site is acceptable.  The goal of the biopsy procedure is to obtain 
enough tissue for a histopathological diagnosis as well as MYCN determination, cytogenetics, and other 
biological studies.  The surgeon should try to obtain at least one cm3 of viable tumor tissue, if feasible, 
according to the surgeon’s judgment.  Complete excision of the primary tumor can occasionally be 
performed if the tumor is easily resectable without a lengthy procedure or extensive dissection. However, 
a resection should not be undertaken if it might result in significant delay in the initiation of 
chemotherapy or great morbidity. In some institutions the diagnosis is established by finding 
neuroblastoma in bone marrow specimens in conjunction with elevated urinary catecholamines.  
 
13.4.3 Tumors with Intraspinal Extension 
When the tumor approaches the spinal canal on imaging (see Section 16.2), a detailed examination must 
assess neurological function. The format for the examination, a modification of the ASCIA scale, is 
detailed in Appendix III and should be used to document the degree of neurologic dysfunction at 
diagnosis and at subsequent time points during and post-therapy. 
 
Laminectomy should not be performed in patients who are neurologically asymptomatic.  Patients with 
symptomatic spinal cord compression secondary to intraspinal/epidural extension of neuroblastoma 
through a neural foramina may require laminectomy, or osteoplastic laminotomy at diagnosis to prevent 
permanent paralysis.  However, treatment with chemotherapy alone or chemotherapy and radiation 
therapy will frequently be sufficient to rapidly reverse symptoms of cord compression. Therapeutic 
decisions in neuroblastoma patients with spinal cord compression should be made with the 
multidisciplinary involvement of the attending pediatric oncologist, general pediatric surgeon, and 
pediatric neurosurgeon. 
If neurologic deterioration occurs during chemotherapy, neurosurgical evaluation should be sought and 
operative decompression strongly considered.  Appropriate to the degree of neurological impairment, the 
treating physicians may decide that operative neurosurgical decompression is indicated under these 
circumstances. If feasible, the neurosurgeon should perform an osteoplastic laminotomy, with secure 
replacement of the laminae after decompression has been accomplished. Operative details will be 
recorded in the RDE. 
 
Assessment of neurological function will be performed prior to start of treatment, after 2 cycles of 
inductions, end-induction therapy, end consolidation therapy and end of cisRA therapy for all patients 


 
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with intraspinal extension of tumors (see Section 7.0).   Neurologic and orthopedic evaluations will be 
a routine part of off therapy follow-up for patients with intraspinal extension of tumors, and will be 
performed at 6, 12, 24, and 36 months post therapy, and then annually thereafter.  Orthopedic 
evaluation will include assessment of scoliosis and of extremity deformity by upright spine x-ray at these 
time points (see Appendix III). 
 
13.4.4 Operative management of primary tumors after chemotherapy 
The majority of patients will undergo resection of the primary tumor after initial induction chemotherapy.  
Surgical resection should be performed when the ANC > 500/µL and the patient is medically stable after 
Cycle 5 of Induction.  This is to allow maximal tumor reduction by chemotherapy prior to resection and 
to reduce vascularity.  Surgical resection may be performed later in Induction, if necessary, but must 
occur prior to Consolidation. Surgical scheduling SHOULD AVOID DELAYS OF MORE THAN SIX  
WEEKS BETWEEN CHEMOTHERAPY CYCLES.  
 
 
 
 
The goal of delayed surgery is gross total resection of residual tumor in the primary site as well as tumor 
in areas of regional dissemination (usually lymph nodes).  Resection with microscopically negative 
margins may not be feasible because of proximity to major vascular structures and the spine.  Instead, the 
surgeon should concentrate on removing, as completely as possible, all gross disease.  It is acceptable, 
and often necessary, to incise the tumor and remove it in a segmental fashion. Titianium clips should be 
used to mark all areas of residual disease. All attempts should be made to preserve organs, especially the 
kidney.  Rarely, nephrectomy may be necessary for complete tumor removal but this should only be 
planned if the involved kidney has greatly diminished function.  If pre-operatively a nephrectomy is being 
considered, then a differential GFR should be obtained to determine what the renal function will be in the 
remaining kidney.  This is extremely important because carboplatin is used for consolidation and toxicity 
may be greater for patients with a GFR < 100 ml/min/1.73m2. The surgical committee of the Children’s 
Oncology Group strongly recommends kidney preservation when feasible.  
 
It is vital that the operating surgeon dictate a detailed operative note, which should include: the 
completeness of resection, areas of residual disease, estimated blood loss, and any operative complication 
such as identification of injury to adjacent structures, removal of normal organs, renal injury and vascular 
injury. 
 
Surgical resection of residual disease following HSCT is not encouraged, unless it would alter therapy. 
 
13.5 
Management of Surgical Complications 
 
13.5.1 Intraoperative Complications 
 
Intraoperative complications are site-dependent. Major hemorrhage from either venous or arterial 
structures is always possible with these infiltrative tumors.  The principles of vascular surgery, including 
proximal and distal control, pertain.  Appropriate intraoperative vascular consultation should be sought if 
necessary.  Crucial vessels like the carotid, subclavian, hepatic, superior mesenteric or renal arteries 
should be repaired and flow restored even if bypass grafting is required.  Nerve injuries may also be 
incurred and should be primarily repaired using magnification. 
 
13.5.2 Post-operative Complications 
 
This topic is too broad for simple discussion. Generally, large neuroblastoma resections result in 
significant third space losses and require vigorous fluid replacement.  Because of this fluid requirement 
patients may require significant periods of post-operative ventilation.  The need for post-operative 
monitoring in an intensive care environment should be anticipated.  Acute and long-term complications 
and duration of complications will be prospectively monitored, including chylous leak (thoracic and 


 
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abdominal); secretory non-infectious diarrhea; bowel obstruction due to post-surgical adhesions and renal 
dysfunction due to vascular injury. 
 
Pulmonary Complications:  Resection of large abdominal neuroblastoma may result in significant third 
space losses and require vigorous fluid replacement intraoperatively and postoperatively.  Because of this 
fluid requirement patients may require significant periods of post-operative ventilation.  The need for 
post-operative monitoring in an intensive care environment should be anticipated.  Pneumonias or other 
pulmonary complications related to ICU and postoperative course (including incubation >7 days) should 
be reported 
 
Bowel Obstruction:  Small bowel obstruction may occur for many reasons, including injury, exposure, or 
blunt trauma during the resection, postoperative intussusception, formation of adhesions, or related to 
radiation injury.  Obstruction may occur in the early postoperative period, or may occur months to years 
later.  This study will collect long term data on the occurrence, etiology, and management of small bowel 
obstruction in this patient population, with the aims of reporting accurate occurrence rates, along with 
correlation of occurrence to the extent of resection and other efforts at local control. 
 
Chylous Leak: Extensive dissection of the retroperitoneum or mediastinum may result in either frank 
disruption of chylous channels, or interruption causing intraluminal lymphatic hypertension and leak.  
This study will collect long term data on the occurrence and evaluation of abdominal distension, chylous 
ascites, and chylothorax as they relate to chylous leak, with the aims of reporting accurate occurrence 
rates, along with correlation of occurrence to extent of resection and other attempts at local control 
 
Renal Injury/Atrophy: Renal injury may manifest in many forms, related to the nature of the injury or 
insult.  While nephrectomy is strongly discouraged, extensive perirenal dissection and kidney sparing 
surgery may still result in vascular occlusion, infarction, traumatic compression, or other injury 
mechanisms sufficient to cause long term dysfunction or atrophy.  Additionally, radiation therapy may 
lead to kidney damage, again with the long term finding of atrophy.  This study will collect long term data 
on renal function, identifying the occurrence of renal injury and atrophy, with the aims of reporting 
accurate occurrence rates, along with correlation to extent of resection and other attempts at local control. 
 
Diarrhea: Extensive sympathetic denervation associated with aggressive retroperitoneal dissection may 
result in increased frequency of stooling or diarrhea.  This study will collect long term data on the 
occurrence and interventions necessary for the control of postoperative diarrhea, with the aims of 
reporting accurate occurrence rates, along with correlation to extent of resection and other attempts at 
local control. 
 
 
13.6 
Special techniques 
 
13.6.1 Nerve Stimulation 
 
Nerve stimulation can be useful in detecting motor nerves in the brachial or lumbo-sacral plexus.  This 
requires cooperation from the anesthesiologist as muscle relaxation must be allowed to wear off.  Nerve 
stimulation should always be used when dissection along the pelvic sidewall or in the neck or thoracic 
inlet. 
 
13.6.2 Ultrasonic Dissector-aspirators 
 
Some authors have described the use of ultrasonic dissectors (CUSA) to debulk the interior of large 
tumors allowing an easier capsular dissection.  The technique is useful for friable tumors but not those 
that are stroma rich.  The surgeon should try to perform a generous incisional biopsy prior to ultrasonic 
dissection as it is difficult to capture the tumor specimen after it has been aspirated into the device. 
 


 
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13.6.3 Thoracoscopy 
 
Video-assisted thoracoscopy can be used to remove small posterior mediastinal or thoracic inlet tumors 
provided there is no vascular encasement.  One-lung ventilation is mandatory. 
 
13.6.4 Laparoscopy 
 
Laparoscopic resection of small adrenal or pelvic primaries can be done.  Extensive tumors or those with 
significant vascular encasement, or locoregional nodal spread can be more completely resected using 
standard open approaches. 
 
13.6.5 Radiofrequency Ablation, Cryosurgery 
 
 
These techniques have significant drawbacks when applied to lesions in proximity to major vascular 
structures and should be avoided when treating neuroblastoma.  
 
13.7 
Specimen requirements 
 
As noted above an initial biopsy should obtain greater than 1 cubic centimeter of viable tumor tissue. 
Placement of the specimen in formalin should be avoided. Rather, the pathologist should be alerted and 
the specimen rapidly transferred from the operating room fresh and sterile. The surgeon should verify 
with the pathologist that viable tissue was sent and is being processed for COG biological studies and 
histopathology. Since it is hoped to extract RNA from these specimens, rapid freezing of some of the 
tissue is required. 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
14.1 
Rapid Pathology Review 
A rapid review of histology (under ANBL00B1) is required to determine eligibility of patients for this 
study. See COG ANBL00B1 for complete details on specimen requirements. Recently, as part of the 
international cooperative effort to develop a complete set of International Neuroblastoma Risk Groups, 
the International Neuroblastoma Pathology Committee devised a morphologic classification of 
neuroblastoma tumors that is modeled on the one proposed by Shimada and colleagues124,125  In 
ANBL00B1, tumor sections will be centrally reviewed, and classified as favorable or unfavorable 
according to the criteria described by the International Neuroblastoma Pathology Committee (INPC). 
 
Send representative slides to the COG Pathology Center via Federal Express for overnight delivery.  The 
slides will then be forwarded to Dr Hiroyuki Shimada, who will determine the histologic classification 
(INPC) and will notify the Neuroblastoma Biology Tracking Center.  The Tracking Center will then 
determine protocol assignment (low, intermediate, and high-risk) and will notify the treating institution of 
the results. 
 
14.1.1 Tracking Center Activity 
 
Institutions will first enroll patients on ANBL00B1 once the patient’s age, stage of disease and diagnosis 
have been determined.  The COG Statistical Office will notify the Tracking Center with the enrollment 
information.  Results of MYCN and ploidy status will be sent to the Tracking Center and to the treating 
institution by the Neuroblastoma Biology Reference Laboratory as soon as the results are available.  The 
Tracking Center will notify immediately Dr Shimada in the event that a patient’s stage, age, MYCN, and 
ploidy status mandate immediate review of histology for risk-grouping and treatment assignment.  The 
Tracking Center will then notify the Statistical Office and the treating institution of the patient’s risk 
group and protocol assignment.  Patients will then be enrolled on the appropriate therapeutic study. 
 
14.1.2 Diagnostic Concordance Study 


 
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In order to perform a concordance study between local institution and central review determination of the 
INPC classification, the Neuroblastoma Pathology Checklist is required to be completed by the 
institutional pathologist when tumor tissue is obtained at diagnosis. 
 
 
14.1.3 Review Material Required (See ANBL00B1 for complete submission details) 
 
Review materials are submitted through ANBL00B1. Do not submit separate pathology review materials 
for each protocol. Required for submission: 
 
a. 
2 H&E stained slides from each paraffin block. 
b. 
Representative paraffin blocks are preferred.  If blocks are not available and slides are sent, 
please send 10 unstained sections from the most representative block(s) on coated slides for 
immunohistochemistry use  
 
c. 
Copies of institutional Operative and Pathology reports 
d. 
Copy of electron microscopy report, if available 
e. 
Copy of Neuroblastoma Pathology checklist completed by the institutional pathologist 
f. 
COG Neuroblastoma Biology Data Sheet and Shipping Form 
 
Label pathology review materials with the COG patient ID number and the Surgical Pathology ID (SPID) 
number from the corresponding pathology report. Ship by Federal Express Priority Overnight (2504-
6481-9) to the Biopathology Center. 
 
14.1.4 Review Material at Second Look or Definitive Surgery and/or Relapse 
Pathology materials must be submitted at the time of second look surgery, whether this procedure is a 
biopsy, partial resection, or complete resection, and/also at the time of relapse (see ANBL00B1 for fresh 
specimen requirements). 
 
At subsequent surgeries and at relapse send: 
a. 
2 H&E and 6 unstained slides of residual tumor, both primary and metastatic, or send 
paraffin blocks. 
b. 
Copies of institutional Operative and Pathology reports 
c. 
Copy of electron microscopy report, if available 
d. 
Copy of Neuroblastoma Pathology checklist completed by the institutional pathologist 
e. 
COG Neuroblastoma Biology Data Sheet and Shipping Form 
Label pathology review materials with the COG patient ID number and the Surgical Pathology ID (SPID) 
number from the corresponding pathology report.  Ship to the Biopathology Center by regular mail or 
using your institution’s courier account. 
 
14.1.5 Autopsy Review 
 
If autopsy permission is obtained, please send the following material: 
 
a     H&E sections of each major organ or paraffin blocks 
b 
2 H&E and 6 unstained slides of residual tumor, both primary and metastatic, or send paraffin 
blocks. 
c 
Copy of the autopsy report. 
d 
COG Neuroblastoma Biology Data Sheet and Shipping Form 
Label the autopsy materials with the COG patient ID number and the Surgical Pathology ID (SPID) 
number from the corresponding pathology report.  Ship to the Biopathology Center by regular mail or 
using your institution’s courier account. 
 
 


 
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14.2 
Specimen Shipping 
Submit materials to: 
 
COG Biopathology Center 
Nationwide Children’s Hospital, 
700 Children’s Drive, Room WA 1340 
Columbus, OH 43205 
Phone: (614) 722-2894 
Fax: (614) 722-2897 
Contact:  Wanda Smith 
 
Study Pathologist of record: 
 
Hiroyuki Shimada, M.D. 
Department of Pathology 
Children’s Hospital Los Angeles 
4650 Sunset Blvd 
Los Angeles, CA 90027 
Phone: (323) 361-2377 
Fax: (323) 667-1123 
Email: hshimada@chla.usc.edu 
 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
 
15.1 
Biologic Requirements 
 
Patients must be enrolled on ANBL00B1 prior to the time of enrollment on ANBL0532.  Enrollment on 
ANBL00B1 is required for all newly diagnosed patients within 21 days of diagnosis for all patients, with 
the exception of infants with stage 4S neuroblastoma who are too ill to undergo a diagnostic biopsy 
procedure.  Tissue procurement is mandatory for biology study registration.  Consent for ANBL00B1 
must be obtained at the time of tissue submission and should be within one week of surgery.  Needle 
biopsies are not sufficient for histologic classification.  Investigators are strongly encouraged to obtain 
adequate tissue (see sections 13.0 and 14.0) via open biopsy techniques.  See protocol ANBL00B1 for 
details on the type of specimen to be obtained, how the specimen should be prepared, when the specimen 
should be shipped and the appropriate contact information. 
 
ANBL00B1 enrollment allows tumor tissue and blood samples obtained at the time of diagnosis to be 
tested for the determination of INPC histologic classification, MYCN copy number and tumor cell ploidy. 
These results are used in real time to determine risk categorization and treatment assignment, especially 
for patients age 12-18 months with stage 4 disease or stage 3 disease.   Residual tissues may be used for 
additional research testing and/or banking if informed consent for these options are indicated on the 
patient’s ANBL00B1 consent document.   
 
Study enrollment on ANBL0532 must be within 4 weeks of diagnosis, with confirmed biology status for 
initial risk group assignment. 
 
15.2 
Cyclophosphamide Pharmacogenomics 
Patients may opt to participate in the pharmacogenomics study of cyclophosphamide. For these studies, 
peripheral blood should be drawn prior to starting therapy. The sample is, however, acceptable at any time 
the patient is not neutropenic. 
 
Handling 
Blood samples (10mL) are to be collected in a purple top tube (EDTA).  Please label tubes with date of 
collection and patient COG identification number.  The samples should be kept at room temperature. 


 
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Shipping 
The samples should be packaged to prevent damage and may be shipped at room temperature.  Samples 
should be sent by Federal Express OVERNIGHT DELIVERY (2504-6481-9) for delivery only on Monday 
through Friday (samples obtained on Friday should be shipped on Monday by OVERNIGHT DELIVERY). 
 
 
Send Samples to: 
Linda Risler   
Shen/McCune Lab 
UW Dept of Environmental Health 
4225 Roosevelt Way NE Suite 100 
Seattle WA 98105. 
Phone prior to shipping: 206-685-1650 
Fax: 206-543-3835 
 
15.3 
Topotecan Pharmacokinetics 
Specimen collection for this test is optional depending on whether or not the patient has signed an informed 
consent for them. 
 
 
Topotecan Pharmacokinetic Studies Methods: 
Samples for topotecan pharmacokinetics will be obtained from consenting patients 15 (+/- 10) minutes 
after the end of the topotecan infusion on Day 1 of Cycles 1 and 2. 
 
Sample Timing, Processing, and Shipping 
- At least two weekdays prior to enrolling a patient on study, contact the Stewart Lab (St Jude 
Children’s Research Hospital) at (901) 595-2400 between 8:00 am and 5:00 pm Central Time to 
request a Sample Collection Kit. The Sample Collection Kit will contain all paperwork and 
materials needed for sample collection, processing, and shipping.  If chemotherapy must be 
started prior to arrival of kit, contact the Stewart Lab to obtain instructions for sample 
acquisition. 
 
 
Sample Timing 
On Day 1 of Cycles 1 and 2, obtain 2 mL of whole blood 15 (+10) minutes after the end of the 
topotecan infusion.  Please draw blood from a lumen other than the one from which topotecan 
was infused. Record the start and end time the topotecan infusion, along with the date and time of 
sample collection on the Pharmacokinetics Data Collection Form. 
 
Instructions for Sample Processing and Shipping: 
1. Place the whole blood specimen (2 mL) in a green-top heparin tube (provided), and mix by 
inversion five times. Record the exact time of day that the sample is obtained along with the 
time of day that the drug is administered on the Pharmacokinetics Data Collection Form 
provided in the kit. 
2. Divide the whole blood sample equally into two properly labeled screw top tubes (provided) 
by using the transfer pipette provided in the pharmacokinetics kit. 
3. Immediately place the whole blood samples on wet ice and store at - 80°C within 15 minutes 
of collection. 
4.  Document on the Pharmacokinetic Data Collection Form all concomitant medications that the 
patient has taken within 48 hours of the pharmacokinetic study, including doses and dates 
started/stopped, especially dexamethasone and sulfamethoxazole/trimethoprim (Bactrim® or 
Septra®). 


 
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4. The whole blood samples may be stored in a -80°C freezer until shipped. "Batching" of 
multiple patient samples must be approved by Dr. Clinton Stewart or his designee. 
5. When ready to ship, place all vials in a plastic bag.  Place the Pharmacokinetics Data 
Collection Form in a separate plastic bag.  Place samples and five pounds of dry ice in the 
box provided along with paper towels or other absorbent packing material.  
6. Whole blood samples and the Pharmacokinetic Data Collection Form should be sent by FED-
EX OVERNIGHT DELIVERY for delivery Tuesday through Friday only. Samples obtained 
on Friday should be refrigerated until they can be shipped on Monday by OVERNIGHT 
DELIVERY. 
7. Use the postage paid Federal Express shipping slip provided, which is already addressed to St. 
Jude.  Before shipment contact the CRA, at (901) 595-5113.   Call Federal Express at 1-800-
238-5355.  
 
NOTE: Use the Federal Express airbill included in the Sample Collection Kit for shipping 
samples at NO CHARGE. 
 
Shipping Address 
Stewart Laboratory 
Pharmaceutical Sciences Department, 
Chili’s Care Center I5500 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Tel. (901) 595-2400 
Fax (901) 525-6869 
 
15.4 
Minimal Residual Disease Studies – Bone Marrow 
Specimen collection for this test is optional depending on whether or not the patient has signed an informed 
consent for them. 
 
 
1.  Specimen Timing:   
Bone marrow (BM) will be analysed for minimal residual disease by RT-PCR and immunocytochemistry 
(ICC) analyses. Marrow specimens for RT-PCR will be obtained at diagnosis, following Cycle 2 
induction therapy, end of induction (before transplantation), prior to treatment for MRD and at the end of 
therapy.  ICC analyses will be performed on specimens obtained at the time of diagnosis and at the end of 
induction (following induction cycle 6) only.  
 
2. Specimen Collection:  
 
Diagnosis and End of Induction: 
Specimen Collection: Obtain BM aspirate (5 mL) from each iliac crest and place into separate 
anticoagulant (Sodium Heparin) tubes.  Aspirate and anticoagulant are gently mixed by inverting the tube 
3 to 5 times.  Withdraw 0.5 mL of one sample (either sample can be used but label side obtained from on 
shipment form) and place immediately into a PAXgeneTM blood RNA tube (Becton and Dickinson, cat. 
No. 762165), mix gently.   
 
All Other Time Points:  Obtain BM aspirate (0.5 mL) from one iliac crest (either sample can be used but 
label side obtained from on shipment form) and place immediately into a PAXgeneTM blood RNA tube 
(Becton and Dickinson, cat. No. 762165), mix gently.   
 


 
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Label sodium heparin tubes (from applicable time points) with the Biopathology Center (BPC) Number, 
COG  number, specimen type, collection date, Birth Date and include this information on the transmittal 
forms for immunocytochemical analyses. The sodium heparin tubes should be shipped overnight to 
Dr.Seeger’s lab (see below) at room temperature for immunocytological analysis.  
 
Label the PAXgene tubes with the BPC number, COG patient ID, specimen type and collection date. The 
PAX gene tube for RT-PCR analysis may be shipped to BPC at room temperature or stored at -20ºC and 
below for future shipment.  If tubes are to be kept at temperatures below -20ºC, freeze them first at -20ºC 
for 24 hours, then transfer them to -70ºC or -80ºC. Ship frozen specimens on dry ice. 
 
 
3.  Shipping Instructions for RT-PCR Specimen 
The PAXgeneTM RNA tube can be shipped at room temperature to arrive at the reference laboratory in 
less than 48 hours. Alternatively, samples can be stored frozen at (see below) and shipped on dry ice as 
single samples or batched.  Ship via Federal Express Priority Overnight using the BPC Federal Express 
Account number (1290-2562-0).   If the specimen is collected on a Friday and will be shipped room 
temperature, Saturday delivery is available. When a specimen is shipped on Friday, please mark For 
Saturday Delivery on the air bill and contact the BPC with the tracking number before shipping.  
Specimens that are frozen should be held and shipped for a weekday delivery. 
 
Shipping Address: 
COG Biopathology Center 
Nationwide Children’s Hospital,  
700 Children’s Drive, Room WA1340 
Columbus, OH  43205 
Phone:  (614) 722-2865 
 
Institutions are expected to purchase PAXgene tubes for use in ANBL0532 and other COG studies. They 
are a PreAnalytiX product and can be purchased through their website (catalog #762165; 
www.preanalytix.com; or through the US vendor VWR, catalog #77776-026; www.vwrsp.com). If 
PAXgene tubes are not available at your institution and can not be obtained in a timely fashion, please 
call the Biopathology Center at (800) 347-2486 or BPCBank@Nationwidechildrens.org to arrange 
delivery for patients anticipated to have high-risk neuroblastoma. 
 
4.  Shipping Instructions for Immunocytochemistry Sample 
The bilateral bone marrow aspirate samples collected in sodium heparin tubes sample will be shipped 
overnight at room temperature for immunocytological analysis. Ship via Federal Express Prior Overnight 
using the COG Federal Express account number (2504-6481-9).  Specimens may be shipped to CHLA on 
Monday – Thursday for Tuesday – Friday delivery. 
 
 
Shipping Address: 
 
Robert C. Seeger, M.D. 
Neuroblastoma Biology Reference Laboratory 
Smith Research Tower, Room #509 
Children's Hospital of Los Angeles 
4546 Sunset Blvd. 
Los Angeles, CA 90027 
Telephone: (323) 361-5630 
Fax :( 323) 361-3889 


 
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15.5 
Minimal Residual Disease – Peripheral Blood Stem Cells 
Specimen collection for this test is optional depending on whether or not the patient has signed an informed 
consent for them. 
 
 
15.5.1 PBSC RT-PCR analysis   
1.  Specimen Collection:  Withdraw 1 cc PBSC (Day 1 collection) and place into sodium heparin tube.  
PBSC sample is gently mixed by inverting heparin tube 3 to 5 times 
2.  .  Withdraw sample from tube and place immediately into 2 PAXgeneTM blood RNA tubes, 0.5 cc per 
tube. 
3.  Label tubes with the BPC Number, COG Patient ID, specimen type and collection date. 
 
Shipping Instructions:  RT-PCR Specimen 
The PAXgeneTM RNA tube can be shipped at room temperature to arrive at the reference laboratory in 
less than 48 hours.  Alternatively, samples can be stored at -20ºC and below for future shipment.  If tubes 
are to be kept at temperatures below -20ºC, freeze them first at -20ºC for 24 hours, then transfer them to   
-70ºC or -80ºC.  Ship frozen specimens on dry ice as single samples or batched. Ship via Federal Express 
Priority Overnight using the BPC Federal Express Account number (1290-2562-0).   
If the specimen is collected on a Friday and will be shipped room temperature, Saturday delivery is 
available. When shipping a specimen on a Friday, please mark For Saturday Delivery on the air bill and 
contact the BPC with the tracking number before shipping.  Specimens that are frozen should be held and 
shipped for a weekday delivery. 
 
COG Biopathology Center 
Nationwide Children’s Hospital  
700 Children’s Drive, Room WA1340 
Columbus, OH  43205 
Phone:  (614) 722-2865 
 
15.6 
Minimal Residual Disease – Peripheral Blood 
Specimen collection for this test is optional depending on whether or not the patient has signed an informed 
consent for them. 
 
Although several studies have shown that the number of circulating neuroblastoma cells is approximately 
2 log higher in bone marrow than in peripheral blood,117 peripheral blood samples should also be screened 
for MRD because sampling peripheral blood is less invasive and better tolerated by most patients.126 
Specimen will be obtained at diagnosis, end of induction (before transplantation), prior to treatment for 
MRD (end consolidation) and at the end of therapy.   
 
RT-PCR Analysis: 
Peripheral Blood:  2 mL is drawn and placed into an anticoagulant (Sodium heparin or EDTA) tube. 
Peripheral blood and anticoagulant are gently mixed by inverting the tube 3 to 5 times.  The specimen is 
then withdrawn and placed immediately into a PAXgeneTM blood RNA tube.  Label tube with the BPC 
Number, COG Patient ID, specimen type and collection date. On PAXgene tube also include type of 
anticoagulant used (Heparin or EDTA).  
 
Shipping: PAXgeneTM blood RNA tubes can be shipped at room temperature to arrive at the reference 
laboratory in less than 48 hours.  Alternatively, samples in PAXgeneTM blood RNA tubes can be stored at 
-20ºC and below for future shipment. If tubes are to be kept at temperatures below -20ºC, freeze them 
first at -20ºC for 24 hours, then transfer them to -70ºC or -80ºC. Ship frozen specimens on dry ice as 
single samples or batched.  Ship via Federal Express Priority Overnight using the BPC  
Federal Express Account number (1290-2562-0).  If the specimen is collected on a Friday and will be 
shipped room temperature, Saturday delivery is available. When shipping a specimen on a Friday, please 


 
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mark For Saturday Delivery on the air bill and contact the BPC with the tracking number before shipping.  
Specimens that are frozen should be held and shipped for a weekday delivery. 
 
 
Shipping Address: 
COG Biopathology Center 
Nationwide Children’s Hospital  
700 Children’s Drive, Room WA1340 
Columbus, OH  43205 
Phone:  (614) 722-2865 
 
15.7 
13-cis-Retinoic Acid) Pharmacokinetics 
Specimen collection for this test is optional depending on whether or not the patient has signed an informed 
consent for them. 
 
 
cis-RA Pharmacokinetics and Pharmacogenomics Sample Collection and Shipping 
 
Sample Collection: 
ALL SAMPLES MUST BE PROTECTED FROM LIGHT AT ALL TIMES BY WRAPPING IN FOIL 
IMMEDIATELY. 
One 5mL blood sample will be collected into sodium heparin tube 4 hours after administration of cis-
RA on Day 14 of Course 1 of cis-RA treatment.  Unseparated blood and plasma must be protected from 
light at all times (i.e. wrapped in aluminum foil).  The blood will be immediately chilled in an ice-water 
bath and plasma will be separated by low speed centrifugation (1500-2000 rpm for 15 minutes at 4C). 
The plasma will be transferred to a polypropylene tube, immediately frozen and stored at – 20 °C 
wrapped in foil for pharmacokinetic drug analysis.  The cell pellet (RBC and WBC) will be frozen and 
stored at –80 °C for the pharmacogenomic studies.  Each tube must be labeled with patient identifier, 
study number, date and time the sample was drawn. Data should also be recorded on the 13 Cis Retinoic 
Acid Pharmacokinetic Shipping (PKS) Form (RDE) to be returned with the samples. Data will also be 
collected to indicate whether cis-RA was taken by capsule or out of capsule (i.e., capsules snipped and 
contents mixed with fatty food).  Do not label the tubes or PKS form with the patient’s name. 
 
Shipment of Samples 
Send samples on dry ice WRAPPED IN FOIL, (with a copy of the PKS Form) prepaid via overnight 
Federal Express, (Account 2504-6481-9), Monday through Thursday WITHIN ONE MONTH OF 
OBTAINING SAMPLE to: 
 
C Patrick Reynolds, MD PhD  
Cancer Center Core Labs STOP 9450 
Texas Tech University Health Sciences Center 
3601 4th Street 
Lubbock, TX  79430-6540 
Office Phone:  806-743-1558 
Fax: 806-743-2691 
Email:  PATRICK.REYNOLDS@TTUHSC.EDU 
Lab phone:  806-743-2707 
Contact in lab:  TITO WOODBURN 
Email:  TITO.WOODBURN@TTUHSC.EDU 
(Batch shipping of several patients is encouraged to decrease costs. TTUHSC will collect and batch 
the samples for PK analysis.  
 
Description of Assay 


 
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Plasma concentrations of cis-RA, ATRA and the metabolite 4-oxo-13-cis-RA, will be determined by 
HPLC analysis. DNA obtained from this sample will be genotyped for metabolising enzymes thought to 
be involved in the metabolism of cis-RA, such as CYP2C8 and CYP3A7, using PCR methodology 
 
15.8 
Cellular Immunity Against Neuroblastoma  
Specimen collection for this test is optional depending on whether or not the patient has signed an informed 
consent for them. 
 
 
Two samples will be collected for assessments of T-cell responses to neuroblastoma and the tumor 
antigen Survivin. The first will occur at diagnosis (prior to Cycle 1 of chemotherapy), and the second at 
the end of consolidation prior to maintenance therapy (after radiation). Ideally, this should occur prior to 
initiation of Isotretinoin (Accutane) therapy or enrollment on ANBL0032 or ANBL0931. 
 
Sample collection: 20cc peripheral blood in a sodium heparin tube at room temperature. Label the tubes 
with the COG Patient ID, specimen type and collection date. 
 
Shipment of Samples 
Send samples at room temperature. To limit thermal fluctuation, ship in a Styrofoam container with a 
ROOM TEMPERATURE “ice pack”. Do NOT freeze specimen or use a frozen ice pack. Ship overnight 
for arrival Monday – Friday.   
The samples have to be sent with the specimen transmittal form available in the COG website at: 
https://members.childrensoncologygroup.org/prot/generic.asp. 
 
 Ship via overnight Federal Express (2504-6481-9) to:  
Stephan Grupp 
Division of Oncology 
3006 CTRB,  
Children’s Hospital of Philadelphia 
3501 Civic Center Blvd. 
Philadelphia, PA   19104 
Phone 215-590-5475 
Cell 215-847-2957 
 
Description of assays 
The central intent of these studies is to assess survivin as a tumor antigen in neuroblastoma. Three 
immunoassays are available to these studies to measure functional cellular and antitumor 
immunity110,127,128. These assays depend on the ability to isolate and utilize autologous antigen presenting 
cells (APCs) to activate and expand antigen-specific T cells. We have used a system of RNA transfection 
into engineered antigen presenting cells to examine immune responses in patients with neuroblastoma and 
to develop a system to engineer cellular cancer vaccines applicable to pediatric tumors127. The RNA 
transfection uses the Amaxa technology, and is capable of transfecting RNA driving the expression of 
specific proteins such as the tumor antigen survivin as well as tumor RNA to express potential tumor 
antigens. The APC technology utilizes RNA-loaded CD40-activated B cells (CD40-B) as an alternative 
APC to induce cytolytic T lymphocyte (CTL) responses. We have shown that we can use these techniques 
to detect antigen-specific CTL by tetramer staining, demonstrate antigen- or tumor-specific CTL function 
using ELISPOT or target cell cytolysis, and detect antigen specific CTL using tetramers. Routine assays 
necessary for these assessments have been established in the lab and the Penn Human Immunology Core 
(HIC)110,127. These assays include: (i) Flow cytometric T cell assays using monoclonal antibodies and 
HLA-A2/peptide tetramer complexes, (ii) ELISPOT assay for cytokine release from single peptide-
specific T cells, and (iii) T cell cytotoxicity assays in response to survivin expressing targets. This 
combination of immunoassessment assays will permit the evaluation of whether survivin-specific CD8+ 


 
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cells in patients both before after HSCT can be directly enumerated by peptide/MHC tetramers, 
proliferate and secrete IFN-gamma, and possess phenotypic and functional characteristics of tumor-lytic 
CD8+ T cells. 
 
We have used HLA-A2/survivin1M2 tetramer to detect survivin-specific CD8+ CTL in HLA-A2+ 
patients (about half of patients will be A2+). These cells can be detected in the T cell samples collected at 
diagnosis, and we can use RNA-transfected CD40-B cells as APC to expand anti-tumor CD8+ T cells 
from patient samples. We will compare the numbers of survivin+ CTL generated using total autologous 
tumor RNA transfected into CD40-B cells to CTL generated using survivin mRNA. From the initial 
sample, CD40-B will be generated and electroporated with total autologous tumor RNA or survivin 
mRNA. After coculture with autologous patient PBMC for one week, tetramer analysis will be 
performed. Survivin-specific CD8+ CTL will be measured using our HLA-A2/survivin1M2 tetramer, 
comparing the percentage of CD8+/tetramer+ cells in cultures stimulated with either survivin mRNA or 
total tumor RNA, with GFP-stimulated cultures serving as negative controls. We will measure anti-tumor 
CTL cytotoxicty using the standard chromium51-release assay. For cytotoxicity assays, HLA-matched 
allogenic cell lines will be used as targets, with HLA-mismatched neuroblastoma cells as negative control 
targets.  We will also use the CD107a mobilization assay as a marker of CTL function111.  
 
 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
 
 
 
 
 
 
 
 
 
16.1 
CT Scans 
Axial imaging of the site of the primary tumor will be performed using low-dose technique according to 
the ALARA concept. 129  The studies will be performed using current-generation single or multi-detector 
systems. CT slice thickness should be 5 mm or less.  Imaging will be performed during the administration 
of intravenous contrast, generally at 2 mL/kg.  The use of oral contrast will be determined by the 
individual radiologist performing the study, but may be helpful in abdominal imaging.  Images will be 
reconstructed in soft tissue and edge-enhanced bone/lung and liver algorithms.  Coronal and sagittal 
multiplanar reconstructions may be helpful. 
 
For all patients who achieve CR at end of induction therapy, pre-surgical and end of induction CT scans 
(or MRI if used instead of CT) will be submitted for central review  
 
16.2 
MRI Scans 
Typically MRI will be performed on 1.5 T MRI units.  Axial and at least one additional plane (coronal or 
sagittal) of the primary tumor will be performed using at least two pulse sequences (T1, T2, STIR, 
FLAIR, in/out phase, post contrast).  The use of intravenous gadolinium (0.2 mL/kg) will be determined 
by the radiologist performing the study.  Slice thickness will be determined by patient size, and region 
covered, but should be less than 7 mm.  The smallest appropriate coil should be used.  Measurements 
should be made using the same axial sequence best showing the tumor in follow-up for comparisons. 
 
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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MRI is superior to CT in characterizing epidural tumor extension or leptomeningeal disease, and is the 
preferred imaging modality in such cases (neck, chest, nonadrenal retroperitoneum) with spinal cord or 
canal encroachment.130  It may also be useful in evaluating an MIBG-avid focus detected in the skeleton 
or soft tissues.   
 
The lack of ionizing radiation also makes MRI attractive for younger children, but this must be balanced 
with the need for sedation in these patients.  With the exceptions noted above, the choice of MRI or CT 
will be left to the referring pediatric radiologist. 
 
 
16.3 
Skeletal Scintigraphy 
Technetium 99m methylene diphosphonate scans will include the entire skeleton, including multiple 
overlapping spot images. Scans will be performed using a large field-of-view gamma camera with a high-
resolution collimator.  The typical dose of Tc-99m MDP is 10.4MBq/kg, with a minimum dose of 74 
MBq.131  In patients with stage 4 disease, if the diagnostic MIBG and bone scans are concordant for all 
positive sites, then only MIBG scans, but not bone scans, will be required for follow up. 
 
16.4 
MIBG Scintigraphy 
123I-MIBG studies of the entire body will be performed following pretreatment with supersaturated 
solution of potassium iodide (SSKI) (typical dose is 1 drop/3 years of age one day prior and two days 
following 123I-MIBG administration, with a maximum of 3 drops/day).  This isotope has significantly less 
risk to the thyroid gland compared to 131I-MIBG.132  A typical dose of 123I-MIBG is 3.7 MBq/kg.  Planar 
and, as appropriate, SPECT imaging will be performed.  In patients with stage 4 disease, if the diagnostic 
MIBG and bone scans are concordant for all positive sites, then only MIBG scans, but not bone scans, 
will be required for follow up. 
 
 
16.5 
Plain Film Radiography 
This will be performed as needed using ALARA technique.  If gonadal shielding does not interfere with 
diagnostic accuracy, it should be utilized.  Breast shielding should also be utilized in scoliosis screening 
unless clinically there is a reason why it should be omitted.  In patients with paraspinal disease on MRI at 
presentation, scoliosis will be evaluated by upright (or supine, if necessary) spine x-ray and measured 
according to Cobb angle, at presentation and at follow-up (see Section 7.3). 
 
16.6 
Tumor Measurement  
Tumors will be measured according to the COG radiology group guideline. Diameter of a “measurable 
mass” must be at least twice the reconstructed slice thickness.  Target lesions at baseline must be greater 
than 1 cm.  When multiple or metastatic masses are present, all masses will be described, and up to 5 
target masses will be measured using the same method in subsequent follow-ups. 
 
Measurement of each mass (see Appendix V) will consist of the maximal perpendicular diameters (x and 
y dimensions) on the slice showing the largest surface area.  The length (z axis) will then be determined 
by either (a) the difference in table position of the first and last slices showing the tumor plus one slice 
thickness or (b) the product of [slice thickness + gap] times the number of slices showing the tumor minus 
one gap distance.  According to the elliptical model, the lesion volume is then calculated as 0.5 x [length 
x width x height]. 
 
16.7 
Central Review of Imaging 
As quality assurance, central review of CT/MRI scans will be performed to correlate with institutional 
end-induction response assessment.  Central review of diagnosis, pre-surgical and end-induction CT 
and/or MRI studies will be performed for all patients who are considered to have a gross total resection of 
primary tumor (< 1 cm3 residual soft tissue density AND negative MIBG avidity at primary tumor site) 
OR who are coded by the treating institution as a CR (< 1 cm3 residual soft tissue density and normal 


 
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MIBG scan) at the primary site at completion of induction therapy. CT/MRI studies should be 
submitted to QARC within 2 weeks of end-induction restaging evaluation.  Results of central review 
will be performed by Day 35 of Consolidation therapy and results will be forwarded to treating institution 
prior to start of local radiotherapy planning.  
 
Images should preferably be submitted electronically using DICOM format to QARC.   Alternatively, 
they may be submitted on CD using DICOM format.  The third option would be hard copy submission of 
images including soft tissue (abdomen) windows as well as edge-enhanced lung, liver, and bone windows 
(for CT), or hard copy submission of all pulse sequences obtained (for MRI). Studies should not be 
photographed smaller than 20 images/page.   
 
 
16.7.1 QARC address and contact information 
 
Radiology images should be forwarded to: 
QARC 
272 West Exchange St, Ste 101 
Providence, RI 02903-1025 
(401) 454 4301 
 
 
 
17.0 
RADIATION THERAPY GUIDELINES 
 
 
 
 
 
 
 
 
 
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT facilities 
(see COG Administrative Policy 3.9)  
 
General Guidelines 
Radiation therapy will be given following myeloblative stem cell transplantation. Radiation will be given 
to the primary tumor site and metastatic sites as outlined in this section. The primary site will be 
irradiated even if complete resection was achieved. Given the high rates of local recurrence following 
incomplete surgical resection, this study includes boost irradiation of gross residual disease for patients 
following an incomplete surgical resection.  In summary, all patients will receive 21.6Gy to the primary 
site. Those with residual disease after induction therapy will receive an additional 14.4 Gy for a total dose 
of 36.0 Gy. 
 
Required Benchmark and Questionnaires: 
Conventional (CT-based 2-dimensional) radiation therapy using photons or electrons, 3D-Conformal 
Radiotherapy (3D-CRT) and Intensity Modulated Radiation Therapy (IMRT) using photons will be 
allowed in this study. Patients may not receive intraoperative radiation therapy or proton therapy 
on this protocol.  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 (see 
Section 17.8). Benchmark materials and questionnaires may be obtained from the Quality Assurance 
Review Center (www.qarc.org) and must be submitted before patients on this protocol can be evaluated. 
Contact the RPC (http://rpc.mdanderson.org/rpc) for information regarding their IMRT phantoms.   
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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Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of IMRT 
in National Cancer Institute sponsored cooperative group trials. These guidelines are available through 
www.qarc.org. These guidelines require that the protocol explicitly state their requirements and methods 
for localization and immobilization; the use of volumetric imaging; target and organ motion management; 
nomenclature, definitions and rationale for targets and organs at risk; target volume coverage and normal 
tissue dose constraints; effects of heterogeneity in tissues; and quality assurance. 
 
17.1 
Indications for Radiation Therapy  
 
17.1.1 Treatment Sites and Dose 
All patients will be irradiated and volumetric targeting for radiation therapy planning should be priority. 
Table 17.1.1 
Site or Volume (see Section 17.4) 
Dose (see Section 17.5) 
Primary tumor site (PTV1) 
21.6Gy 
Residual primary tumor after induction/surgery (PTV2) 
14.4Gy 
Metastatic disease after induction 
21.6Gy 
Emergent treatment for organ or life-threatening disease 
Contact Study RT Coordinators 
 
17.1.2 Tailoring Fields by Site  
Unless constrained in meeting target volume coverage requirements and organ at risk dose 
recommendations, the dose to the entire vertebral body should be uniform to avoid growth asymmetry. 
No pelvic irradiation should be given prior to bone marrow or stem cell harvest. 
 
Table 17.1.2 
Treatment Site(s) 
Methods to anatomically confine CTV 
Intra-Abdominal: adrenal and paraspinal ganglia 
primary sites, involved nodal and metastatic disease 
Adjust CTV to avoid kidneys, liver, vertebral 
bodies 
Cervico-Thoracic: 
 
Adjust CTV to avoid uninvolved heart, lung and 
vertebral bodies 
Pelvic: 
Adjust CTV to avoid bowel, bladder, and 
uninvolved bone 
Head and Neck: 
Adjust CTV to avoid uninvolved critical 
structures and bone 
Footnote: for further details, review special site considerations (Section 17.4.3) and recommendations 
for organs at risk (Section 17.7). 
 
17.1.3 Timing of Radiation Therapy  
Radiation will be given post-stem cell transplant and should start no sooner than 28 days post transplant. 
Organ toxicity within radiation field should have resolved. Radiotherapy should be initiated within 42 
days after stem cell transplantation.   
 
17.1.4 Criteria to Start Radiation Therapy 
 
 
 
 
 
 


 
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 Table 17.1.4 
Organ System 
Criteria to Start Radiation Therapy 
Hematologic 
Absolute phagocyte count > 1,000/µL* 
No requirement for platelet count 
Mucous Membranes  
Mucosa/clinical exam < Grade 2 (TPN and enteral 
feeds are allowed) 
 
Liver Irradiation (Any) 
ALT ≤ 5 times normal (Grade 2 or less)  
Bilirubin ≤ 3 times ULN (Grade 2 or less)  
No evidence of sinusoidal-obstruction syndrome 
Tracheal Irradiation (Any) 
Patient stable on room air 
< Grade 2 airway edema. 
Abdominal Irradiation (Any) 
albumin > 3 g/dL 
No albumin infusions for 1 week. 
Kidney Irradiation* 
serum creatinine should be < 1.5 x normal for age 
Renal scintigraphy** 
Bladder Irradiation 
No hematuria 
*Can be achieved with growth factor support. 
**Renal scintigraphy is recommended but not required for patients with two functioning kidneys when > 20% of one kidney will be irradiated.   
 
17.2 
Emergency Irradiation 
Patients are allowed to have received radiation therapy at diagnosis to sites of life-threatening or function-
threatening disease. This information must be reported as a part of the quality assurance data.  This 
treatment will not be considered part of the planned primary radiation course that is delivered at a later 
time provided normal tissue dose constraints are met. Potential deviations from normal tissue dose 
constraints should be discussed with the study RT coordinators. Emergency irradiation is subject to the 
same data submission requirements as the primary site (Section 17.8). 
 
17.3 
Equipment 
Modality: X-rays with a nominal energy of  4MV. In the unusual circumstance of a superficial lesion, 
electron fields may be used. Conventional, conformal, and IMRT techniques are allowed in this study. 
Patients may not receive intraoperative radiation therapy or proton beam therapy on this protocol. 
 
Calibration: The calibration of therapy machines used in this protocol shall be verified by the 
Radiological Physics Center (RPC). 
 
CT treatment planning: All patients will undergo CT treatment planning for this protocol. Slices no more 
than 5 mm thick (2-3 mm is recommended) shall be taken throughout the extent of the irradiated volume. 
 
17.4 
Target Volumes 
 
The International Commission on Radiation Units and Measurements (ICRU-50 and 62) prescription 
methods and nomenclature shall be utilized for this study. This will apply to conformal and non-
conformal techniques. Although the post-surgical CT is used for treatment planning, the target volume is 
based on the extent of disease on pre-operative CT, with modifications noted below, regardless of extent 
and timing of the surgical resection. If the primary tumor was grossly resected at diagnosis, the radiation 
therapy should be given to the primary site based on the initial diagnostic tumor volume.  No pelvic 
irradiation should be given prior to bone marrow/PBSC harvest.The GTV, CTV and PTV and normal 
tissues must be outlined on all CT slices in which the structures exist.  Beam’s eye view display must be 
used to design beam apertures.  
 


 
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17.4.1 Primary Site 
 
Gross Tumor Volume 1 (GTV1) 
 
The GTV1 is the volume of tissue containing the highest concentration of residual tumor cells. 
 
The GTV1 includes disease defined by CT, MR and MIBG imaging PRIOR to surgery. 
 
The GTV1 includes disease (tumor and lymph nodes) identified intra-operatively. 
 
The GTV1 is corrected volumetrically after surgical resection but not at the point of attachment.  
 
The GTV1 does NOT include the extent of disease PRIOR to chemotherapy. 
 
The GTV1 does NOT include uninvolved draining lymph node regions. 
 
Special Circumstances (GTV1) 
 
If the primary tumor was grossly resected at diagnosis, GTV1 will be based on the initial 
diagnostic tumor volume. 
 
In cases where there is discrepancy between imaging studies or intraoperative findings, the larger 
volume will define GTV1. 
 
When the primary tumor expands into a body cavity such as the lung or displaces a normal 
structure such as the liver without infiltration, if following surgical resection the normal structure 
now occupies the space previously occupied by tumor, normal tissue volume should not be 
included within GTV1. 
 
Gross Tumor Volume 2 (GTV2) 
 
The GTV2 is defined as the volume of residual tumor AFTER induction surgery and 
chemotherapy measuring >1cm3 
 
The GTV2 includes disease defined by CT, MR and MIBG imaging. 
 
Special Circumstances (GTV2) 
 
GTV2 will NOT be altered even when there is a complete response after consolidative 
chemotherapy. 
Clinical Target Volume 1 (CTV1) 
 
The CTV is defined as the volume of tissue containing subclinical microscopic disease: 
 
The CTV1 margin should be an expansion of the GTV1 to encompass microscopic disease. 
 
The CTV1 for this protocol is the GTV1 with an anatomically confined margin of 1.5 cm. 
 
The CTV1 should be tailored at tissue interfaces where invasion/infiltration is not likely. 
 
Clinical Target Volume 2 (CTV2) 
 
The CTV is defined as the volume of tissue containing subclinical microscopic disease 
surrounding the post-surgical residual tumor (GTV2). 
 
The CTV2 margin should be an expansion of the GTV2 to encompass microscopic disease. 
 
The CTV2 for this protocol is the GTV2 with an anatomically confined margin of 1.0 cm. 
 
The CTV2 should be tailored at tissue interfaces where invasion/infiltration is not likely. 
 
Planning Target Volume (PTV1) 
 
The PTV1 is a geometric concept and includes a margin surrounding the CTV1. 
 
The PTV1 should account for physiologic change or motion in the CTV1 and set-up uncertainty. 
 
The PTV1 is defined as the CTV1 with a geometric margin of 0.5-1.0 cm. 
 
The PTV1 may vary depending on immobilization and cooperation, 0.5cm is the minimum extent 
of the margin surrounding CTV1 to form PTV1. 
 
The PTV1 margin does not have to be uniform in all dimensions, especially if it compromises 
normal tissue volumes or if directional target or normal tissue motion is assessed and understood.    


 
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Planning Target Volume (PTV2) 
 
The PTV2 is a geometric concept and includes a margin surrounding the CTV2. 
 
The PTV2 should account for physiologic change or motion in the CTV2 and set-up uncertainty. 
 
The PTV2 is defined as the CTV2 with a geometric margin of 0.5-1.0 cm. 
 
The PTV2 may vary depending on immobilization and cooperation, 0.5cm is the minimum extent 
of the margin surrounding CTV2 to form PTV2. 
 
The PTV1 margin does not have to be uniform in all dimensions; especially if it compromises 
normal tissue volumes or if directional target or normal tissue motion is assessed and understood. 
 
Motion Management and Margins to Account for Target Volume and Organ Motion 
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 of the CTV. The planning organ at risk volume (PRV) includes the OR surrounded by a margin to 
compensate for physiologic change in the target volume. 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 of at least 0.5 cm should be added to any OR to form the PRV. 
 
For a CTV susceptible to physiologic motion, a margin of at least 0.5 cm should be added to the 
CTV prior to PTV margin expansion or a PTV margin of 1.0 cm should be chosen. 
 
For tumors of the thorax or abdomen, an assessment should be made to determine the extent of 
motion present. PTV margins should include this motion as a component.  
 
IMRT may be used for tumors of the thorax only if the degree of tumor motion is assessed and can 
be limited to 0.5 cm in any direction. If required to achieve this goal, techniques for managing or 
suppressing tumor motion shall be applied. 
 
A description of the method used and evidence (i.e., observed motion during fluoroscopy, motion 
of surrogate markers using camera systems, or analysis of 4D CT) of the remaining tumor motion 
should be submitted with the Quality Assurance Documentation materials as noted in section 17.8. 
 
17.4.2 Metastatic Sites 
Criteria for Treatment of Metastases:  While the primary site is always irradiated, radiation is only given 
to those metastatic sites with persistent active disease demonstrated on the pre-HSCT evaluation (after 
Cycle #6 of induction).  Sites that are negative on the pre-HSCT scans will NOT be irradiated, even if 
they had enhanced uptake on MIBG and/or bone scan at diagnosis.  
 
For patients with > 5 MIBG positive metastatic sites on pre-HSCT evaluation 
If the patient had > 5 persistently positive MIBG metastatic sites identified after Cycle #6 of induction, 
the MIBG scan should be repeated on Day 28+ post-HSCT.  Only sites still MIBG positive post-
transplant should be irradiated.  If there are still > 5 MIBG positive sites contact Radiation Therapy Study 
Coordinator to discuss treatment plan prior to starting radiation. 
 
In patients with > 5 MIBG positive lesions prior to transplant, consideration should be given to reserving 
a portion of the collected PBSC product to use as a boost after radiation if counts fall and fail to recover 
2+ weeks after radiation is completed.  THE STUDY CHAIR OR VICE CHAIR MUST BE NOTIFIED 
BEFORE REINFUSING PBSC BOOST.  
 
The planning target volume for metastatic sites is the area of residual tumor defined on MIBG, CT, or MR 
scan with a 1 cm margin.  In cases where there is a discrepancy in volume between the scans, the larger 
volume will be irradiated.  For osseous metastases, the margin need not extend more than 1 cm outside 
the bone or across a joint space.  


 
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17.5 
Target Dose 
Table 17.5 Prescribed Dose and Fractionation 
Nominal Dose by Site 
Target Volume 
Dose/fraction 
Number of Fractions 
Primary Site 21.6 Gy 
PTV1 
1.8 Gy 
12 
Primary Site Boost 14.4 Gy 
PTV2 
1.8 Gy 
8 
Metastatic Sites 21.6 Gy 
 
1.8 Gy 
12 
 
Prescribed dose: If conventional methods are used, the prescription point should be at or near the centroid 
of the target volume. If 3DCRT or IMRT is used, dose should be prescribed to an isodose surface that 
encompasses the PTV and allows the dose uniformity requirements to be satisfied as noted below.   
 
 
Dose Definition: Dose is to be specified in centigray (cGy)-to-muscle. 
 
Tissue Heterogeneity:  Heterogeneity corrections are required even when conventional planning methods 
are used and shall be applied for IMRT in compliance with current guidelines for the use of IMRT in 
clinical trials (guidelines available at www.QARC.org). When IMRT is used in lung, the heterogeneity 
correction algorithm must be approved by QARC. For questions about heterogeneity corrections or 
approved algorithms, please contact QARC (www.QARC.org). 
 
Prescription Dose and Fractionation:  
 
Primary Site:  The total dose to the PTV will be 21.6Gy given in 12 fractions.  The patient will be treated 
with one fraction per day, all fields each day, giving 1.8 Gy per fraction to the prescription volume. For 
patients undergoing an incomplete surgical resection (> 1 cm3 residual soft tissue density) as assessed at 
the end of induction scans, a boost of 14.4 Gy will be delivered to the gross-residual volume for a total 
dose of 36 Gy. 
 
Metastatic Sites:  Sites of persistent active metastatic disease will be irradiated concurrently with the 
primary site once daily to a total dose of 21.6 Gy given in 12 equal fractions of 1.8 Gy. 
 
Dose Uniformity:  For 2D treatment, the dose variations shall be within +7%, -5% of the prescription 
dose. For volume-based treatment plans, the entire PTV should be encompassed within the 95% isodose 
surface and no more than 10% of the PTV should receive greater than 110% of the prescription dose as 
evaluated by DVH. Wedges, compensators, and other methods of generating more uniform dose 
distributions are encouraged.  
 
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 hematologic toxicity defined as ANC < 300/L or platelets less than 
40,000/L during the course of treatment. Under these circumstances, radiation therapy shall be delayed 
until the counts have recovered. 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’s treatment chart and submitted with the QA documentation. There should be no 
modifications in dose fractionation due to age or field size. If any area has been previously treated 
(emergently), care should be taken not to exceed normal tissue tolerance levels. 


 
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17.6 
Treatment Technique 
 
Beam Configuration:  Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Although simple opposed field plans are acceptable, the use 
of oblique fields, or 3-dimensional conformal therapy (coplanar or non-coplanar), or IMRT is encouraged 
to minimize dose to normal surrounding structures.  
 
Patient Position: Reproducible setups are critical and the use of immobilization devices is strongly 
encouraged. Use of anesthesia is permitted if necessary for proper positioning. 
Field Shaping: Field shaping shall be done with either customized cerrobend blocking or multileaf 
collimation. 
 
17.7 
Organs at Risk 
 
The organ at risk guidelines in this section are recommendations. If the recommended doses to the organs 
at risk are exceeded because of target volume coverage requirements or other conditions (See 
Section 17.1.2), an explanation should be included in the quality assurance documentation. In some cases, 
IMRT may be the preferred treatment method to meet these recommendations and the required target 
volume coverage guidelines. 
 
 
Peritoneal Cavity:  When the entire peritoneal cavity must be irradiated, the volume to be treated extends 
from the diaphragmatic domes to the level of the bottom of the obturator foramina. The principles of 
tailoring fields by site should be considered (Table 17.1.2) and the recommendations for organs at risk 
should be followed. 
 
Liver:  The liver dose should be minimized to reduce the risk of sinusoidal obstruction syndrome 
(SOS), formerly known as veno-occlusive disease. No more than 50% of the liver shall receive a 
cumulative dose greater than 900 cGy and no more than 25% of the liver shall receive a dose greater than 
1800 cGy.   
 
Kidney:  The kidney doses should be minimized to reduce the risk of chronic renal failure.  
 
If the primary tumor demonstrates laterality to the right or left side, an ipsilateral and contralateral kidney 
should be designated. In such a case, 100% of the ipsilateral kidney may receive 1440 cGy and 50% of 
the same kidney may receive 1980 cGy. For the contralateral kidney, no more that 50% should receive a 
cumulative dose greater than 800 cGy and no more than 20% should receive a cumulative dose greater 
than 1200 cGy. 
 
If the primary site does NOT demonstrate laterality, both kidneys may receive a mean dose of 14.4 Gy 
and no more than 50% of each kidney should receive 1980 cGy.   
 
Lung:  When a major portion of both lungs must be treated because of a large intrathoracic tumor volume, 
effort should be made to minimize the irradiated lung volume. No more than one-third of the entire lung 
volume shall receive a cumulative dose greater than 1500cGy. 
 
17.8 
Dose Calculations and Reporting 
 
If 3D conformal techniques are used to treat patients on this study, a 3D benchmark needs to be 
completed and submitted to QARC. Institutions treating with IMRT must complete the IMRT 
Questionnaire and either the QARC Benchmark or irradiate the RPC’s IMRT head and neck phantom. 


 
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The Benchmark material can be obtained from the Quality Assurance Review Center (www.QARC.org). 
Contact the RPC (http://rpc.mdanderson.org/rpc) for information regarding their IMRT phantoms.  
Patients will be considered unevaluable if approved benchmarks are not on file at QARC.   
 
Prescribed Dose:  
The monitor units required to deliver the prescribed dose shall be calculated and submitted using the RT-1 
or IMRT Dosimetry Summary Form.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 total prescribed dose shall be calculated and reported on the RT-2 Radiotherapy Total 
Dose Record. If 3DCRT or IMRT is used, dose should be prescribed to an isodose surface that 
encompasses the PTV and allows the dose uniformity requirements to be satisfied.   
 
Dose Uniformity 
The maximum and minimum doses in the PTV shall be calculated and reported on the RT-1 or IMRT 
Dosimetry Summary form. These doses may be extracted from isodose distributions, calculated separately 
or derived from DVH data. 
 
 
Normal Tissue Dosimetry 
The daily dose to the critical organs indicated should be calculated whenever they are directly included in 
a radiation field. For 2D techniques they should be reported on the RT-1 Dosimetry Summary form.  The 
total dose shall be calculated and reported on the RT-2 Radiotherapy Total Dose Record form.  For 
patients treated with volume-based techniques, the appropriate dose-volume histograms should be 
submitted and RT-1 or IMRT form completed.  If IMRT is used, a DVH must be submitted for a category 
of tissue called “unspecified tissue,” which is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure. 
 
Table 17.8 Required normal tissue DVH data according to primary treatment site 
Treatment Area 
Required DVH 
Neck 
Thyroid 
Chest 
Right Lung 
 
Left Lung 
 
Heart 
Abdomen 
Liver 
 
Right Kidney 
 
Left Kidney 
 
17.9 
Quality Assurance Documentation 
 
On-treatment review is NOT required for this study. Within one week of the completion of radiation 
therapy, detailed treatment data shall be submitted for the primary site; only the RT-2 form and a copy of 
the radiotherapy record (treatment chart) need to be submitted for the metastatic site(s). 
 
Please submit the following for the Primary Site Target Volume: 
 
Treatment Planning System Output: 
 
Digitally reconstructed radiographs (DRR) or simulator films for each treatment field and 
orthogonal (anterior/posterior and lateral) images for isocenter localization for each group 
of concurrently treated beams.  When using IMRT, orthogonal isocenter images are 
sufficient. 


 
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 
Isodose distributions for the composite treatment plan in the axial, sagittal and coronal 
planes at the center of the treatment or planning target volume.  The planning target 
volume, isocenter and the normalization method must be clearly indicated. 
 
Dose volume histograms (DVH) for the composite treatment plan for all target volumes and 
required organs at risk. This shall include GTV1, CTV1, PTV1, and GTV2, CTV2 and 
PTV2, when indicated. A DVH shall be submitted for the organs at risk specified in section 
17.8.  When using IMRT, a DVH shall be submitted for a category of tissue called 
“unspecified tissue.” This is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure. 
 
Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics. 
 
Beams-eye-view (BEV) of portals showing collimator, beam aperture, target volume and 
critical structures are required when not using IMRT. 
 
Room-eye-view (REV), if available from the planning system, illustrating all treatment 
beams and their angles. 
 
 
Digital Data: 
 
Submission of the treatment plan in digital format is required.  Please refer to 
www.QARC.org<http://www.QARC.org> under "Digital Data" for guidelines regarding 
digital submission.  All submissions, including those that are digital, require hard copy 
submission of the other items included in this list. 
 
Supportive Data: 
 
 
All diagnostic imaging used to plan the target volume. This includes CT, MRI and MIBG 
scans PRIOR to attempted surgical resection of the primary tumor. Digital format is 
preferred. 
 
Radiotherapy record (treatment chart) including prescription and daily and cumulative 
doses to all required areas and organs at risk. 
 
Documentation of an independent check of the calculated dose when IMRT is used. 
 
Description of the method used to account for respiratory motion should be documented for 
review by QARC (when indicated in section 17.4.1). 
 
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. 
 
If emergency RT is administered, documentation should be provided in the form of the RT-
2 Total Dose Record Form and the radiotherapy record (treatment chart). 
Forms: 
 
RT-1 or IMRT Dosimetry Summary Form. 
 
The RT-2 Radiotherapy Total Dose Record Form. 
 
 
 
Please submit the following for Metastatic Sites: 
 
Forms: 
 
The 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. 
 
These data should be forwarded to: 
Quality Assurance Review Center 


 
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272 West Exchange St., Suite 101 
Providence, Rhode Island 02903-1025 
Phone:  (401) 454-4301 
FAX:  (401) 454 4683 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
Quality Assurance Review Center 
272 West Exchange St., Suite 101 
Providence, Rhode Island 02903-1025 
 
 
17.10 Definitions of Deviations in Protocol Performance 
Prescription Dose: 
Minor Deviation: The prescribed dose differs from that in the protocol by between 6% and 10% 
Major Deviation: The prescribed dose differs from that in the protocol by more than 10% 
 
Dose Uniformity: 
Minor Deviation for 3D conformal and IMRT treatments: 
 
The entire PTV is not encompassed within the isodose surface representing 95% of the prescription dose 
or more than 10% of the PTV receives more than 110% of the prescription dose. 
 
Minor Deviation for 2D treatments: 
The dose variation in the treated volume shall be within +7, -5% of the prescription point dose. 
 
Volume: 
Minor Deviation: Margins less than specified or fields excessively large as deemed by the study reviewer. 
Major Deviation: A portion of the tumor (GTV) or potentially tumor bearing area (CTV) is not included 
in the treated volume. 
 
Critical structures: 
A minor or major deviation will be assessed at the time of data review (depending on the details of each 
case) if the critical structure dose limits are exceeded. 
 
 
 
18.0 
HEMATOPOIETIC TRANSPLANT GUIDELINES 
 
All transplants performed on COG trials must occur at COG-accredited HSCT programs with the 
exception of adolescents/adults being treated on COG trials who are referred to an adult transplant 
facility.  See the COG Administrative Policy 3.3 regarding the agreement requirements for these cases. 
 
 
19.0 
RECOMMENDED PROCEDURE FOR PBSC MOBILIZATION AND COLLECTION 
 
19.1 
Catheter Use 
PBSC may be collected using a large bore double lumen central venous catheter that will allow the 1-2 
ml/kg/min flow rates required for apheresis.  Many institutions use temporary or tunneled apheresis 
catheters (such as the 8 Fr Medcomp catheter) in neuroblastoma patients. Femoral line placement is 
generally not required.  
 


 
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19.2 
PBSC Mobilization 
Institutional standard operating procedures (SOPs) will be used for mobilization and pheresis. Patients 
should begin G-CSF starting one day after completing a cycle of chemotherapy.  They should continue on 
G-CSF 5 mcg/kg/day while recovering from the cycle of chemotherapy until the post-nadir ANC > 500-
1000/L, at which point it is recommended to increase the dose of G-CSF to at least 10mcg/kg/day per 
institutional policies. 
 
Institutions which time collections using circulating CD34 cell counts will generally begin when the 
count is > 10-20 cells/L. Otherwise, the timing of collection is often within 1-3 days of increasing the G-
CSF dose, when WBC is >2000 (usually Day 14 from start of chemotherapy), although rapid 
hematopoetic recovery as indicated by a significant left shift and/or a rapidly rising WBC count, may 
provide an opportunity for earlier collection.  It is critical that G-CSF be given daily until PBSC 
collection is complete. If the WBC is > 60,000, decrease G-CSF dose to 5 micrograms/kg. 
 
If patients are off  G-CSF prior to planned PBSC harvest, they should receive G-CSF 10-16 mcg/kg/day, 
max dose 600 mcg, for 3 days prior to the first day of scheduled PBSC harvest (timing and cytokine 
regimens per institutional policies), harvest on Day 4 of G-CSF treatment, and continue daily G-CSF until 
PBSC collections are completed. Such patients should be off their G-CSF for 5-7 days before restarting it 
for mobilization. If the WBC is > 60,000, decrease G-CSF dose to 5 micrograms/kg. 
 
 
19.3 
PBSC Collection 
 
19.3.1 Laboratory Studies 
For patients < 25 kg, a type and cross for PRBC should be performed one day prior to procedure to avoid 
apheresis delays.  
 
19.3.2 Apheresis Machine 
The Cobe Spectra or the Fenwal CS 3000+ is recommended because the continuous flow centrifugation 
devices are better tolerated than discontinuous flow machines. Institutional SOPs will be used.   
 
19.3.3 Blood Priming 
For patients less than 25 kg, priming of the apheresis machine with IRRADIATED, leukocyte-poor red 
blood cells may be required. 
 
 
19.3.4 Collection Goals 
It is recommended that large volume apheresis be performed on all patients for each collection.  During 
each leukopheresis procedure, the typical target volume of whole blood processed will be approximately 
480 mL/kg (6 blood volumes). 
 
Optimal collection goal (total for all collections) is 10 x 106 CD 34+ cells/kg for PBSC.  The targeted 
number of cells can usually be obtained in 1-3 collection days. It is recommended that the collection be 
stored in at least 3 aliquots of cells: 
 
2-4x106 CD34+ cells/kg for the first HSCT procedure 
 
2-4x106 CD34+ cells/kg for the second HSCT procedure 
 
2-3x106 CD34+ cells/kg as a backup for delayed engraftment, or for potential subsequent use. 
Because of the advantages of collecting these backup cells during this pheresis episode (as 
opposed to later in the patient’s clinical course) ,133 it is highly recommended that these cells be 
collected, even if this requires an additional day of apheresis. 
 


 
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CD 34+ cell counts should be done at local institution on all collections as per institutional SOPs.   
 
19.4 
PBSC Analyses 
The following studies should be performed on each PBSC collection: 
1) 
Culture for bacterial and fungal contamination, 
2) 
Nucleated cell count and differential, 
3) 
CD34+ cell enumeration, 
4 
PCR analysis for tumor cell content (sent to COG Biopath Center) – see Section 15.5 for 
details. 
 
19.4.1 PBSC timing: 
PBSC mobilization is strongly recommended following cycle 2 REGARDLESS of disease status in the 
marrow. However, should the patient’s medical condition prohibit use of apheresis, it is appropriate to 
delay PBSC mobilization and harvest after subsequent induction therapy. 
PBSC IMMUNOCYTOLOGY IS NOT REQUIRED FOR STUDY PARTICIPATION OR CELL 
INFUSION. An aliquot of each peripheral stem cell collection may be analyzed for tumor cell 
content by immunocytochemical analyses per institutional standards.  In the rare circumstance that 
a PBSC collection following Cycle 2 induction is shown to be positive by immunocytology for tumor 
cell content, patient will require another harvest after Cycle 3 or Cycle 4. 
 
19.5 
Cryopreservation of PBSC Products 
Each aliquot (as detailed above) should be processed and cryopreserved on the day of collection as per 
Institutional SOPs. These SOPs include the use of 7.5-10% dimethyl sulfoxide final concentration in the 
cryopreservation medium, use of a monitored, controlled-rate freezer, and storage in liquid nitrogen with 
appropriate monitoring. The goal is to have 3 separate aliquots cryopreserved in separate bags – 1 for 
each HSCT procedure and 1 for a potential backup.   
 
19.6 
PBSC Infusion 
The PBSC product should NEVER be irradiated prior to infusion.  
 
19.6.1 Premedication 
DMSO may cause a histamine-like reaction when infused into the patient.  Therefore premedication with 
Benadryl and Tylenol is recommended. 
 
 
19.6.2 Thawing of PBSC 
PBSC are thawed in a 37C water bath. Only one bag of PBSC should be thawed at a time - when the 
infusion of one bag is completed, the next bag should be thawed.  
 
Thawed PBSC should be infused as rapidly as tolerated through a central venous catheter.  The unit may 
be infused by gravity, or the cells may be drawn up into a syringe and pushed by trained personnel.  
Microaggregate filters and leukodepletion filters MUST NOT be used for infusion of PBSC.  If a thawed 
unit appears clumpy or stringy and these particles cannot be dispersed with gentle kneading, the PBSC 
product could be infused through a standard 170 micron blood filter. 
 
19.6.3 Possible Symptoms During Infusion 
Precipitating Factor 
Possible Symptoms 
hemolyzed red cells 
fever, chills, hemoglobinuria 
cellular clumps and debris 
chest pain, hypoxia, hypertension 
cold 10% DMSO 
nausea, headache 
microbial contamination 
fever, chills, hypotension 
plasma proteins 
urticaria 


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


 
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APPENDIX II:  SUPPORTIVE CARE GUIDELINES 
 
These are provided for institutional consideration. The Supportive Care Manual of COG (A Altman 
editor) can also be referenced for a more detailed discussion of treatment recommendations than can be 
provided in this appendix.   Investigator discretion should be used, and individual considerations made for 
specific patient situations and institutional practices.  
During Induction Therapy 
 
1.  Anti-Emetics 
 
Give anti-emetics to control nausea and vomiting as per institutional guidelines.  Document all 
concomitant use of dexamethasone during Cycle 1 and 2 on the topotecan pharmacokinetics data 
collection form as dexamethasone may alter drug metabolism. 
 
2.  Cytokine Support 
Only for induction cycles 1 and 3-6:  Patients will receive Myeloid growth factor (cytokine) support per 
institutional guidelines beginning 24-48 hours after chemotherapy until ANC > 1500/ µL post nadir.   
For eg: Filgrastim (G-CSF) 5 mcg/kg/day is given as a single daily Sub Qor IV dose.  
 
Growth factor support should be stopped at least 24 hr before the next chemotherapy cycle. ANC must be 
> 750/μL and platelets > 75,000/μL before starting next course of therapy. The ANC frequently falls after 
discontinuing myeloid growth factor support (secondary neutrophil nadir). If the ANC recovers to > 
750/μL after nadir but then falls to < 750/μL after the myeloid growth factor is stopped, the next cycle of 
therapy can be given despite ANC < 750/μL if all other criteria for the next cycle of chemotherapy are 
met. 
 
For induction cycle 2 (or subsequent PBSC collection cycle) 
During cycle when PBSC are to be harvested, filgrasatim (G-CSF) must be used for myeloid growth 
factor support.  G-CSF should be continued until harvest is completed.  See guidelines for G-CSF dosing 
during PBSC harvest (See Section 19.2). 
 
3.  Blood Product Support 
Recommend that patients receive prophylactic platelet transfusions as per institutional guidelines. Use 
irradiated, CMV appropriate products.  Patients should have platelet count of > 50,000 on the day of 
apheresis.  May receive a platelet transfusion to reach 50,000 requirement. 
 
Recommend that patients receive packed red blood cell transfusions to maintain their hemoglobin > 7.0 
gm/dl. Use irradiated, CMV appropriate products. 
 
Irradiation 
Blood products should be irradiated following the current FDA guidelines found at: 
http://www.fda.gov/cber/gdlns/gamma.htm  
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components 
CAN/CSA-Z902-04 issued in March 2004 and available at http://www.shopcsa.ca. 
 
4.  Pneumocystis Prophylaxis 
Patients should be given prophylactic co-trimoxazole (sulfamethoxazole/trimethoprim) based on 5 mg 
trimethoprim/kg/day divided BID orally administered on 3 consecutive days a week.  For sulfa-intolerant 
patients it is recommended that inhaled pentamidine or oral dapsone be used as prophylaxis.  Co- 


 
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trimoxazole should be held if patients fail to recover hematopoiesis by Day 21 of any cycle.  It can be 
re-started once the next chemotherapy cycle is given or patient can be changed to pentamidine or dapsone 
if there is concern about continued myelosuppression from co-trimoxazole. 
 
5.  Treatment of Fever and Neutropenia 
Patients should be admitted to the hospital and treated with antibiotic therapy that is appropriate to that 
institution’s infections experience and antibiotic sensitivity patterns. 
 
 
6.  Herpes Simplex Virus Prophylaxis 
Antiviral prophylaxis against HSV is recommended for all patients who are HSV 1 or HSV 2 
seropositive.  Recommend use of acyclovir 1200 mg/m2/day PO divided BID, rounded to the nearest 100 
mg (max dose 800 mg PO BID) OR 500 mg/m2/day IV divided q12 hours (if unable to take PO meds for 
reasons other than mucositis) to begin on the day of completion of chemotherapy administration, continue 
throughout neutropenia, and stop when neutropenia (post-nadir ANC > 1500/L) and mucositis have 
resolved. 
 
7.  Nephrotoxic Agents 
Due to risk for nephrotoxicity following dose intensive platinum therapy, minimize use of additional 
nephrotoxic antibiotic therapy.  Whenever possible monitor blood levels of the antibiotics used. When 
empiric or directed anti-fungal therapy is required, utilize lipid-based amphotericin or non-amphotericin 
antifungal therapy as clinically indicated for patient. 
 
Supportive Care During BMT 
1.  Isolation 
Protective isolation per local institutional guidelines.   
 
2.  Skin Care 
Thiotepa can cause significant skin toxicity with sloughing of skin.  To avoid skin toxicity, patient 
should be bathed 4-6 times daily during the three days of Thiotepa administration and the day following. 
Avoid large occlusive dressings and use of any skin creams and remove adhesive residue from prior 
dressings and leads. Change sheets with bathing and bathe with water only, avoiding soap. Consider 
placement of a Foley catheter during the days of Thiotepa use in younger children to avoid perineal burns.  
Perineal burns may be more related to sweating induced by diapers than contact with urine. 
 
3. Blood Product Support  
Patients should receive prophylactic platelet transfusions and packed red blood cell transfusions as per 
institutional guidelines.  Blood products should be irradiated following the current FDA guidelines found 
at: http://www.fda.gov/cber/gdlns/gamma.htm  
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood Components 
CAN/CSA-Z902-04 issued in March 2004 and available at http://www.shopcsa.ca. 
 
4. Bacterial Prophlyaxis 
Patient will receive empiric broad spectrum antibiotic therapy for treatment of neutropenia or febrile 
neutropenia per institutional guidelines. 
 
5. Fungal Prophylaxis 
Recommend use per institutional guidelines.  Fluconazole 5 mg/kg/day daily until neutrophil engraftment 
is a standard approach. 
 
6.  Pneumocystis Pneumonia Prophylaxis 


 
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Day -10 to day -2 before BMT:  trimethoprim (150 mg/m²/d) and sulfamethoxazole (750 mg/m²/d); divide 
into two doses and give q12 hr. for prophylaxis against P. carinii.  After engraftment, administer PCP 
prophylaxis) per institutional guidelines. 
 
7.  Viral Prophylaxis 
Prophylaxis against HSV and/or VZV will be given in seropositive patients as per institutional guidelines.  
In addition, patients should be monitored for EBV and CMV reactivation per institutional guidelines.  
Recommendation to screen EBV by PCR and CMV as per institutional practice (i.e. antigenemia or PCR) 
q2-4 weeks through day 120 for CMV+ and/or EBV+ patients. 
 
Suggested supportive care during cis-RA therapy 
Topical Vitamin E should be applied to lips BID during cis-RA therapy if cheilitis develops.  All patients 
should avoid direct sun exposure while on cis-RA.  All patients should avoid exposure to Vitamin A 
products during cis-RA therapy. 


 
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APPENDIX III:  NB WITH INTRASPINAL EXTENSION +/- SPINAL CORD COMPRESSION 
Evaluation and grading of neurologic and orthopedic dysfunction  
 
Neurological symptoms: 
 
Yes ____     No____ 
 
Duration of neurologic symptoms: 
 
 
 
 
<  7 days 
 
_____  
 
 
 
 
8 – 28 days 
 
_____ 
 
 
 
 
> 28 days 
 
_____ 
Motor deficit*:  
 
 
Grade 0  
 
None 
 
 
_____ 
Grade 1 
 
Mild weakness  
_____  
Grade 2 
 
Moderate weakness 
_____   
Grade 3 
 
Severe weakness 
_____ 
 
Sensory deficit:  
 
Yes _____            No 
_____ 
 
Sphincter dysfunction^:  
 
Bladder               
Yes _____ 
     No _____ 
 
Bowel                
Yes _____ 
     No _____ 
 
Pain 
 
 
 
Yes _____ 
     No _____ 
 
Orthopedic  findings: 
 
Scoliosis (by spine x-ray):  None 
 
_____ 
 
 
Mild         (<20 degree curve) 
 
_____ 
 
 
Moderate (20-40 degree curve)  
_____ 
 
 
Severe      (>40 degree curve) 
 
_____ 
 
 
Extremity abnormality: 
 
 
Leg length discrepancy      
 
Yes 
_____  No _____ 
Foot size discrepancy/foot deformity 
Yes      _____ No _____ 
 
*Motor Deficit: 
Grade I = mild weakness 
1.  Legs =  walking disability  
2.  Arms = difficulty raising arms above head 
Grade II = moderate weakness 
1.  Legs = inability to walk &/or make movements against gravity 
2.  Arms = inability to raise arms above head 
Grade III = severe weakness 
        1.  Paraplegia 
        2.  No elicitable DTRs 
        3.  No muscular movements 
 
^ Sphincter Deficit: 
       1.  Distended bladder 
       2.  Patulous anus 
       3.  Constant urine dripping 
       4.  Stress incontinence 
       5.  Any significant change/deterioration from prior bowel or bladder function 


 
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APPENDIX IV:  INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM (INSS) 
 
Stage 1 
 
 
Localized tumor with complete gross excision, with or without microscopic residual disease; 
representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and 
removed with the primary tumor may be positive). 
 
Stage 2A 
 
 
Localized tumor with incomplete gross resection; representative ipsilateral non-adherent lymph 
nodes negative for tumor microscopically. 
 
Stage 2B 
 
 
Localized tumor with or without complete gross excision, with ipsilateral non-adherent lymph 
nodes positive for tumor; enlarged contralateral lymph nodes must be negative microscopically. 
 
Stage 3 
 
 
Unresectable unilateral tumor infiltrating across the midline2, with or without regional lymph 
node involvement; or localized unilateral tumor with contralateral regional lymph node 
involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph 
node involvement. 
 
Stage 4 
 
 
Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, 
and/or other organs (except as defined for Stage 4S). 
 
Stage 4S 
 
 
Localized primary tumor (as defined for Stage 1, 2A or 2B) with dissemination limited to skin, 
liver, and/or bone marrow3 (limited to infants <1 year of age). 
 
 
1. 
Multifocal primary tumors (e.g., bilateral adrenal primary tumors) should be staged according to 
the greatest extent of disease, as defined above, and followed by a subscript “M” (e.g. 3M). 
 
2. 
The midline is defined as the vertebral column.  Tumors originating on one side and crossing the 
midline must infiltrate to or beyond the opposite side of the vertebral column. 
 
3. 
Marrow involvement in Stage 4S should be minimal, i.e., less than 10% of total nucleated cells 
identified as malignant on bone marrow biopsy or marrow aspirate.  More extensive marrow 
involvement would be considered to be Stage 4.  The MIBG scan (if performed) should be 
negative in the marrow. 
 
4. 
Proven malignant effusion within the thoracic cavity if it is bilateral or the abdominal cavity 
upstages the patient to INSS 3 
 


 
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APPENDIX V:  TUMOR SIZE MEASUREMENTS BY CROSS-SECTIONAL IMAGING 
 
 
RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), PRODUCT OF 
TWO DIAMETERS (WHO), AND THREE PERPENDICULAR DIAMETERS (“VOLUME”) 
 
 
 
 
Target lesions at baseline must measure greater than 1 cm; if these target lesions decrease in size to below 
1 cm, care should be taken in measuring and inadvertently progressing a patient due to minimal changes 
in measurement from a nadir value below 1 cm, which may be within measurement error. When multiple 
primary or metastatic masses are present, all masses will be described. However, up to 5 target masses 
should be measured, using the same method in subsequent follow ups.  
 
 
 
 
 
 
 
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 plus one slice
thickness), or [b] the product of ([slice 
thickness + gap] and the number of slices 
showing the tumor) minus one gap distance
• WHO criteria: TxW is used
• RECIST: the larger of the two (T & W) is      
used (W in this example)
• Elliptical model volume=0.5 LxWxT
• The same modality and measurement method 
used in the initial imaging should be used in 
follow ups
X-Y
PLANE
L


 
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APPENDIX VI: NEUROBLASTOMA RESPONSE CRITERIA 
 
(International Recommendations)6 
 
SITE 
TEST 
COMPLETE 
RESPONSE 
VERY GOOD 
PARTIAL 
RESPONSE 
PARTIAL RESPONSE 
MIXED 
RESPONSE 
NO 
RESPONSE 
PROGRESSI
VE DISEASE 
Primary 
3 dimensional CT or 
MRI imaging (determine 
volume from product of 
three dimensions 
physical exam and/or 
surgical measurement) 
no tumor 
>90% reduction in 
 3-dimensional 
tumor volume 
50-90% reduction in 3-
dimensional tumor 
volume 
 
 
 
Metastases 
Bone marrow1 (aspirate 
x 2 and biopsy x 2) 
 
Bone x-rays and 
scintigraphy (Tc and/or 
MIBG) 
 
Liver imaging 
(ultrasound, CT, or 
MRI) 
 
Chest x-ray, chest CT 
scans  
if x-ray abnormal 
 
Physical exam5 
no tumor 
 
 
 
no lesions 
 
 
 
no tumor 
 
 
 
no tumor 
 
 
 
no tumor 
no tumor 
 
 
 
all lesions 
improved; no new 
lesions3 
 
 
no tumor 
 
 
 
no tumor 
 
 
 
no tumor 
no or only one sample 
with tumor2 
 
 
all lesions improved; no 
new lesions4 
 
50-90% reduction 
 
 
 
50-90% reduction 
 
 
 
50-90% reduction 
50-90% 
reduction of 
any measurable 
lesion (primary 
or metastases); 
no new lesions; 
<25% increase 
in any existing 
lesions, exclude 
bone marrow 
evaluation 
no new lesions; 
<25% increase 
in any lesion; 
exclude bone 
marrow 
evaluation 
any new 
lesion; 
increase of 
any 
measurable 
lesion by 
>25%; 
previous 
negative bone 
marrow 
positive 
Tumor 
marker 
Urine catecholamine 
metabolites (HVA & 
VMA) 
Normal 
normal or both 
decreased >90% 
both decreased 50-90% 
 
 
 
 
Response must be evaluated before and after surgery for the primary site.  If complete response, very good partial response, or partial response is 
achieved surgically, indicate such when reporting the response. 
 
The total response can be no better than the worst response in any subcategory (e.g., if primary = complete response, metastases = partial 
response, and, tumor marker = very good partial response, the total response = partial response). 
1)  Immunocytology results are not used to determine response. 
 
2)  One sample may be positive only if there is a reduction in the number of sites originally positive for tumor at diagnosis. 
 
3)  99Tc bone scan may show residual abnormalities but the MIBG scan (if performed) must be negative. 
 
4)  99Tc bone scan and/or MIBG scan (if performed) must show improvement, but residual abnormalities may be present on either scan. 
 
5)  Measure palpable lymph nodes in 3 dimensions and calculate tumor volume. 
 
6)  Brodeur G et al:  JCO 1993; 11:1466-1477     
 


 
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APPENDIX VII:  NEUROBLASTOMA STUDY ASSIGNMENT TABLE 
 
Study 
Stage 
Age 
MYCN 
Ploidy 
Histology 
Other 
ANBL00B1 
1 
any 
any 
any 
any 
  
  
  
  
  
  
  
  
ANBL00B1 
2a/2b 
any 
not amp 
any 
any 
resection >50% 
ANBL0531 
2a/2b 
any 
not amp 
any 
any 
resection <50% 
ANBL0531 
2a/2b 
any 
not amp 
any 
any 
biopsy only 
ANBL0532 
2a/2b 
any 
amp 
any 
any 
any degree of 
resection 
  
  
  
  
  
  
  
ANBL0531 
3 
<547d 
not amp 
any 
any 
  
ANBL0531 
3 
>547d 
not amp 
any 
FH 
  
ANBL0532 
3 
any 
amp 
any 
any 
  
ANBL0532 
3 
>547d 
not amp 
any 
UH 
  
  
  
  
  
  
  
  
ANBL0532 
4 
<365d 
amp 
any 
any 
  
ANBL0531 
4 
<365d 
not amp 
any 
any 
  
ANBL0532 
4 
365-<547d 
amp 
any 
any 
  
ANBL0532 
4 
365-<547d 
any 
DI=1 
any 
  
ANBL0532 
4 
365-<547d 
any 
any 
UH 
  
ANBL0531 
4 
365-<547d 
not amp 
DI>1 
FH 
  
ANBL0532 
4 
>547d 
any 
any 
any 
  
  
  
  
  
  
  
  
ANBL00B1 
4s 
<365d 
not amp 
DI>1 
FH 
asymptomatic 
ANBL0531 
4s 
<365d 
not amp 
DI=1 
any 
asymp or symp 
ANBL0531 
4s 
<365d 
missing 
missing 
missing 
too sick for biopsy 
ANBL0531 
4s 
<365d 
not amp 
any 
any 
symptomatic 
ANBL0531 
4s 
<365d 
not amp 
any 
UH 
asymp or symp 
ANBL0532 
4s 
<365d 
amp 
any 
any 
asymp or symp 
FOOTNOTE: 
DI -    DNA Index 
FH -   Favourable (Shimada) Histology 
UH -   Unfavourable (Shimada) Histology 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPPENIX VIII:  TOPOTECAN PHARMACOKINETICS DATA COLLECTION FORM  
 
This form comes with your specimen package form and must be completed and returned with specimens 
when shipped. ALL FIELDS ARE REQUIRED. 
 Please note that the PK topotecan evaluation form completed on eRDES is different from this form and 
ALSO has to be completed. 
 
COG No.:  
Acc. No.: 
Institution: 
Gender: 
Race: 
Height: 
Weight: 
BSA: 
Topotecan dosage (mg/m2): 
Date Administered: 
Date of Birth:   
 
Has the patient received prior chemotherapy? Circle one: Yes or No 
If yes, please indicate names and dates of all prior chemotherapy on an additional sheet. 
 
2. List the name, dose and regimen of other drugs the patient has received within 48 hours of topotecan 
therapy (for more space use an additional sheet):  
NOTE:   YOU ARE REQUIRED TO DOCUMENT ALL CONCOMITANT USE OF DEXAMETHASONE 
DURING CYCLE 1 AND 2 AS IT MAY ALTER DRUG METABOLISM 
 
Drug Name 
Drug Dose 
When Administered 
 
 
 
 
 
 
 
 
 
 
3.  Please fill in course and day of therapy, time dose was administered, time blood was scheduled to be 
drawn and actual time blood was drawn: 
Course _______    Day _______ 
Scheduled Time 
Actual Time 
START of infusion 
END of infusion 
 
 
15 minutes after 
end of infusion (+ 10 min) 
 
 
 
Name of person completing form ________________________________________________________ 
Phone: ________________________________________________________ 
 
Date: _________________________ 
Please send this completed form with the sample to: 
Stewart Laboratory 
Pharmaceutical Sciences Department 
Chili’s Care Center I5500 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Ph: (901) 595-2400 


 
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APPENDIX IX: 13-CIS RA PHARMACOKINETIC DATA COLLECTION FORM  
13-CIS RA PHARMACOKINETIC DATA COLLECTION FORM 
ANBL0532 -  Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation 
Therapy for High-Risk Neuroblastoma 
DATE OF SUBMISSION:  
 
 
 
 
 
 
 
 
     (Mm/dd/yyyy) 
DATE OF BIRTH :  
 
 
 
 
 
 
 
 
     (Mm/dd/yyyy) 
 COG REG. NO:  
 
 
 
 
 
 
 
Height  
Weight: 
BSA: 
1. Name of the Institution: 
2. 13 - cis-RA Administration:  
     a.   Date(mm/dd/yyyy) : 
     b.  Time : 
     c.  Cycle (number): 
     d.  Day of cycle: 
3. PK collection: 
    a. Date(mm/dd/yyyy):         
    b. Time of collection: 
Please check the relevant boxes as directed for Qs 4 and 5: 
4  Type of cis-RA administration:  
    a.  Capsule (directly)    
    b.  Out of capsule (i.e., capsules snipped and contents mixed with fatty food)  
If out of capsule, please specify: ________________________________________________ 
Route:   by mouth,   NG tube,  G-Tube,  other, _____________________________ 
Fatty foods mixed with drug: _____________________________________________________
5.   Gender 
     Male:                       
     Female:                        
6. Filled out by: 
      Name: ________________________________  Contact number:____________________ 
 
     Signature: ________________________________________ 
INSTRUCTIONS FOR PK COLLECTION AND SHIPPING: 
ALL SAMPLES MUST BE PROTECTED FROM LIGHT AT ALL TIMES BY WRAPPING IN 
FOIL IMMEDIATELY. 
The blood sample (5 mL) will be collected into sodium heparin tubes 4 hours after 
administration of cis-RA on Day 14 of Course 1 of cis-RA treatment. Refer to Section 15.7 
of the protocol for more details. 
Please send this completed form with the sample to: 
C Patrick Reynolds, MD PhD  
Cancer Center Core Labs STOP 9450 
Texas Tech University Health Sciences Center 
3601 4th Street, Lubbock, TX  79430-6540 
Office Phone:  806-743-1558 
Email:  Patrick.Reynolds@TTUHSC.edu 
Lab phone:  806-743-2707 
Contact in lab: TITO WOODBURN 
Email: TITO.WOODBURN@TTUHSC.EDU  
 


 
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APPENDIX X:  SPECIMEN SUBMISSION SCHEDULE 
Required specimens are found in shaded boxes only; all other specimens are optional 
 
 
Immunocytochemistry 
Sections 15.4  
 Optional (BM at CHLA) 
Cellular Immunity 
(CHOP) 
Section 15.8 
Optional 
RT-PCR (BPC) Sections 15.4 & 15.6 
** Contact BPC for questions regarding 
PAX Gene tubes  Optional 
Place in sodium heparin tube (green), 
mix and transfer to PAX tubes 
Cyclophosphamide 
Pharmacogenomics  
(SCCA) Section 15.2  
Optional 
Diagnosis 
Bone marrow 5ml each side in 
sodium heparin tube (green) 
Peripheral Blood 
20ml in sodium 
heparin tube 
1. Bone marrow 0.5ml in PAX** tube  
2. Peripheral blood 2ml in PAX  tube 
Peripheral Blood 10ml 
in EDTA tube (purple) 
Induction Cycle 1, D1 Topotecan 
PKs Section 15.3 Optional 
Contact St.Jude (Stewart Laboratory ) for Topotecan PK kit.   If treatment starts before arrival of kit, access Memos on COG website 
(12-14-07b; 5-8-08b) for instructions on sample acquisition or contact Stewart lab at 901-595-2400. Peripheral blood 2mL sodium 
heparin tube (green) 15 +/- 10 minutes after end of topotecan infusion.  Send to:  St Jude/ Stewart Lab. 
Induction Cycle 2, D1 Topotecan 
PKs Section 15.3 Optional 
Peripheral blood 2 mL sodium heparin tube (green) 15 +/- 10 minutes after end of topotecan infusion. Send to: St Jude/ Stewart Lab. 
Induction Cycle 2, END  
                and  
Day 1 of stem cell collection 
 
 
   1. Bone marrow 0.5ml in PAX tube 
2. 1ml of PBSC product in 2 PAX  tubes 
(0.5 ml each) 
 
Surgery (2nd Look) 
Required for ANBL00B1: Tumor Tissue to BPC. 1. 2 H&E slides from paraffin block; 2. Representative paraffin blocks or 10 
unstained slides from most representative blocks on coated slides for IHC use. 3. Snap frozen tissue 4. Viable fresh tissue  
Induction, End 
Bone marrow 5ml each side in 
sodium heparin tubes  
 
1. Bone marrow 0.5ml PAX tube  
2. Peripheral blood 2ml in PAX tube 
 
Consolidation, End 
Bone marrow 5ml each side in 
sodium heparin tube (green) 
ONLY IF ENROLLING onto 
ANBL0032 or ANBL0931  
Peripheral Blood 
20ml in sodium 
heparin tube 60-90D 
post HSCT 
  1. Bone marrow 0.5ml in PAX tube 
 2. Peripheral blood 2ml in PAX tube 
 
Maintenance Course 1, D14 
Isotretinoin  Pharmacogenomics 
Section 15.7 Optional   
Peripheral Blood 5 ml in sodium heparin tube wrapped in foil 4 hours after cis-RA. Send to: C. Patrick Reynolds,  
Cancer Center Core Labs STOP 9450, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX  79430-6540 
  Office Phone:  806-743-1558   Lab phone:  806-743-2707 Email:  Patrick.Reynolds@TTUHSC.edu. 
Contact in lab:  TITO WOODBURN  Email:  TITO.WOODBURN@TTUHSC.EDU 
End of therapy 
 
 
1. Bone marrow 0.5ml in PAX tube 
2. Peripheral blood 2ml in PAX tube 
 
Relapse 
Same specimens as at the time of surgery to be sent to BPC 
BPC: COG Biopathology Center, Nationwide Children’s Hospital 700 Children’s Dr, Rm WA 1340 Columbus OH 43205 _ Ph.no:  614-722-2810. 
St Jude: Stewart Laboratory. Chili’s Care Center I5500, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. 
CHLA: Robert Seeger, Childrens Hospital Los Angeles 4546 Sunset Blvd, NBL Biology Reference Lab, Smith Research Tower-Rm #509,Los Angeles, CA 90027 Ph.no: 323-361-5630. 
CHOP: Stephan Grupp Division of Oncology Abramson 902, Children’s Hospital of Philadelphia 3615 Civic Center Blvd. Philadelphia, PA 19104  Ph.no:  215-590-.5475 
SCCA: Linda Risler, Shen/McCune Lab, 4225 Roosevelt Way NE Suite 100, Seattle WA 98105. Phone prior to shipping: 206-685-1650 Fax: 206-543-3835  
Refer to Protocols ANBL00B1 & ANBL0532 for specific collection, processing & shipping instructions 


 
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APPENDIX XI:  YOUTH SUMMARIES FOR CHILDREN AND TEENS  
  
INFORMATION SHEET REGARDING RESEARCH STUDY ANBL0532 
(for children from 7 through 12 years of age) 
A Study of Neuroblastoma (that has spread from where it started) Treatment Comparing One versus Two 
High Dose Chemotherapy Regimens in Consolidation 
 
1. We have been talking with you about neuroblastoma.  Neuroblastoma is a type of cancer that 
grows mostly in the nervous system outside the brain. We have done special tests, scans and 
blood tests on you to find out if you have high-risk neuroblastoma.  The tests tell us that you have 
neuroblastoma that is hard to treat because it has spread from where it started.  
 
2. We are asking you to take part in a research study because you have the type of neuroblastoma 
that is hard to treat.  A research study is when doctors work together to try out new ways to help 
people who are sick. In this study, we are trying to learn more about how to treat high-risk 
neuroblastoma.  We will do this by: 
a. adding a new anti-cancer medicine, called Topotecan,  to the usual chemotherapy that 
children with neuroblastoma receive 
b. giving higher doses of radiation (or x-ray treatments) to children who still have tumor 
after getting induction chemotherapy medicine 
c. giving some children one cycle of high dose chemotherapy and some children two cycles 
of high dose chemotherapy, followed by either one or two stem cell transplants,  to see if 
this will keep the neuroblastoma from coming back after treatment is stopped 
d. studying how your body responds to the medicines. 
 
We want to see if these things can help more children can get rid of their neuroblastoma.  We 
don’t know if these approaches will help or not.  That is why we are doing this study.  
 
3. Children who are part of this study will be treated first with chemotherapy that will include the 
newer medicine, Topotecan, as well as several other chemotherapy medicines.  Chemotherapy is 
a type of medicine that destroys cancer cells. Some children may also have surgery or radiation to 
get rid of as much of the neuroblastoma as possible. After this first part of therapy, some children 
will get one cycle, while others may get two cycles of high dose chemotherapy followed by a  
stem cell transplant. All children in this study will get the medicine, Accutane, after the 
chemotherapy, stem cell transplant, surgery and radiation are done. Sometimes you will have 
extra blood drawn for special research tests.   
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.”  A benefit of being part of this study may be a chance that your 
cancer will go away for as long as possible. We don’t know for sure if there is any benefit of 
being part of this study. We expect that the information learned from this study will help other 
patients with high-risk neuroblastoma in the future. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad 
things are called “risks.”  The risks to you from this study are possibly having more side  
effects or the therapy may not work to make the cancer go away. With this treatment you 
can have problems, both during and after the treatment. We will check you closely so we 
can treat the problems you may have. Other things may happen to you that we don’t yet 
know about. 
 


 
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6. Your family can choose to be part of this study or not.  Your family can also decide to stop being 
in this study at any time once you start.  There may be other treatments for your illness that your 
doctor can tell you about.  Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood and bone marrow specimens.  We want 
to see if there are ways to tell how the cancer will respond to treatment. These samples would be 
taken when other standard blood tests are being performed, so there would be no extra 
procedures. This part of the study is optional. You can still take part in this study even if you 
don't allow us to collect the extra blood or bone marrow samples for research. 
 
 


 
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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
A Study of Neuroblastoma (that has spread from where it started) Treatment Comparing One versus Two 
High Dose Chemotherapy Regimens in Consolidation 
 
1. We have been talking with you about neuroblastoma.  Neuroblastoma is a type of cancer that 
grows mostly in the nervous system outside the brain. It can also be found anywhere in the body.  
We have done special tests, scans and blood tests on you to find out if you have high-risk 
neuroblastoma.  The tests tell us that you have neuroblastoma that is hard to treat because it has 
spread from where it started.   
 
2. We are asking you to take part in a research study because you have the type of neuroblastoma 
that is hard to treat.  A research study is when doctors work together to try out new ways to help 
people who are sick. In this study, we are trying to learn more about how to treat neuroblastoma.  
We will do this by: 
a. adding a new anti-cancer medicine, called Topotecan,  to the usual chemotherapy that 
children with neuroblastoma receive 
b. giving higher doses of radiation (or x-ray treatments) to children who still have tumor 
after getting induction chemotherapy medicine 
c. giving some children one cycle of high dose chemotherapy and some children two cycles 
of high dose chemotherapy, followed by either one or two stem cell transplants,  to see if 
this will keep the neuroblastoma from coming back after treatment is stopped in more 
children 
d. studying how your body responds to medicines.  
 
We want to see if these things can help more children can get rid of their neuroblastoma.  We 
don’t know if these approaches will help or not.  That is why we are doing this study.  
 
3.   Children who are part of this study will be treated with chemotherapy, surgery, radiation 
treatment and stem cell transplant(s). The treatment is given in three phases: Induction, 
Consolidation and Maintenance.  Chemotherapy is a type of strong medicine that destroys cancer 
cells. The chemotherapy in this study is very strong and may make you feel pretty sick at times. 
The doctors will give you medicines to help you when you are sick. You will be in the hospital a 
lot to get the chemotherapy.  In the induction phase, you will receive chemotherapy, including the 
new combination, cyclophosphamide and topotecan and you will also have a procedure(s) called 
a stem cell harvest. You will be connected to a machine that will remove blood from you, take out 
the baby cells (stem cells) that grow up to be normal blood cells, and then give the rest of the 
blood back to you.  During consolidation, you will get either one or two cycles of very high doses 
of chemotherapy, followed by either one or two stem cell transplants. The last phase of therapy is 
called maintenance. During this phase you will be taking pills by mouth twice a day for two 
weeks. Then you will have 2 weeks that you do not take the pills. This phase lasts for six months. 
Throughout the treatment you will have some extra blood draws for special research tests.   
 
4. 
Sometimes good things can happen to people when they are in a research study.    These good 
things are called “benefits.”  A benefit of being part of this study may be a chance that your 
cancer will go away for as long as possible. We don’t know for sure if there is any benefit of 
being part of this study. We expect that the information learned from this study will help other 
patients with high-risk neuroblastoma in the future. 
 


 
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5.  Sometimes bad things can happen to people when they are in a research study.  These bad 
things are called “risks.”  With this treatment you can have problems, both during and 
after the treatment. The risks to you from this study involve very low blood counts, possible  
infections and organ damage. You will be given medicines to help your blood counts recover 
after the treatment, to prevent infection, and to reduce organ damage. There is also a 
chance of the cancer cells growing back. We will check you closely so we can treat the 
problems you may have. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not.  Your family can also decide to stop being 
in this study at any time once you start.  There may be other treatments for your illness that your 
doctor can tell you about.  Make sure to ask your doctors any questions that you have. 
 
7.  We are asking your permission to collect additional blood and bone marrow specimens.  We want 
to see if there are ways to tell how the cancer will respond to treatment. These samples would be 
taken when other standard blood tests are being performed, so there would be no extra 
procedures. This part of the study is optional. You can still take part in this study even if you 
don't allow us to collect the extra blood or bone marrow samples for research. 
 
 


 
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Reynolds CP, Moss TJ, Seeger RC, et al: Sensitive detection of neuroblastoma cells in bone 
marrow for monitoring the efficacy of marrow purging procedures. Prog Clin Biol Res 175:425-
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Piantadosi S: Clinical Trials: A Methodologic Perspective. Hoboken, NJ, John Wiley and Sons, 
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Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for 
neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466-77, 1993 
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Shimada H, Ambros IM, Dehner LP, et al: Terminology and morphologic criteria of neuroblastic 
tumors: recommendations by the International Neuroblastoma Pathology Committee. . Cancer 
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Shimada H, Ambros IM, Dehner LP, et al: The International Neuroblastoma Pathology 
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reverse transcriptase-polymerase chain reaction analysis.  . Cancer 101:2303-8, 2004 
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Coughlin CM, Vance BA, Grupp SA, et al: RNA-transfected CD40-activated B cells induce 
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Cancer 46(7):719-22, 2006 


 
 
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SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH  
 
 
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed. (Institutions 
should attempt to use sections of this document which are in bold type in their entirety.) Editorial 
changes to these sections may be made as long as they do not change information or intent. If 
the local IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they must be justified in writing by the investigator and approved by the 
IRB.  
 
 
ANBL0532, Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation 
Therapy for High-Risk Neuroblastoma 
 
PART 1: CONSENT FOR INDUCTION THERAPY  
 
When the word “you” appears in this consent form, it refers to you or your son or daughter; “we” 
means the doctors and other staff. 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY? 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you.    
 
The Children's Oncology Group (COG) is carrying out this study. COG is an international 
research group that conducts clinical trials for children with cancer at more than 200 hospitals in 
the United States, Canada, Australia, New Zealand, the Netherlands, and Switzerland. It is 
common medical practice to treat children with cancer on research studies like this one. 
 
You are being asked to take part in this study because you have high risk neuroblastoma. 
Neuroblastoma is a type of cancer.  Neuroblastoma shows up as a lump or mass in the belly or 
around the spinal cord in the chest, neck, or pelvis. Neuroblastoma is a cancer of nerve cells. It 
develops in nerve cells that are outside of the brain.  It often spreads to bone, liver, lymph nodes 
and bone marrow, which is the soft tissue in the center of bones where blood cells are made. 
You have the type of neuroblastoma that is called High Risk because your tumor has spread 
from where it started or because your type of tumor is harder to treat.   
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard treatment for High Risk neuroblastoma and this clinical 
trial. Please take your time to make your decision about taking part in this clinical trial.  You may 
discuss your decision with your friends and family.  You can also discuss it with your health care 
team.  We encourage you to include your child in the discussion and decision to the extent that 
she or he is able to understand and take part.  If you have any questions, you can ask your 
study doctor for more explanation.  
 


 
 
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WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE? 
 
The treatment for neuroblastoma includes 3 parts (phases) of therapy called Induction, 
Consolidation and Maintenance.  During Induction therapy anti-cancer drugs (chemotherapy) 
and surgery are used to kill and remove as much tumor as possible.  Blood stem cells are 
collected during the Induction phase of therapy.  After collection the blood stem cells are frozen 
and stored to be used during Consolidation phase of treatment.  Blood stem cells are the cells 
that create new blood cells, such as red blood cells, white blood cells, and platelets. Blood stem 
cells can be collected from the blood by using a machine that can separate out the part of blood 
that has stem cells and then return the remaining blood back to the patient. 
 
During the Consolidation phase of treatment extremely high doses of chemotherapy are given to 
better kill any remaining neuroblastoma cells. The extremely high doses of chemotherapy 
destroy healthy bone marrow. Bone marrow is the soft tissue in the hollow of flat bones of the 
body that produces new blood cells.  The peripheral blood stem cells that were stored during the 
Induction phase of treatment are given back to the patient after the high dose Consolidation 
chemotherapy.  These stems cells allow the bone marrow to return to normal so that new blood 
cells can be made. This type of therapy is called a Hematopoietic Stem Cell Transplant. Once 
the patient has healed from the effects of high doses of chemotherapy, radiation therapy is 
given to the first place the tumor was found and to any additional places where the tumor was 
found after Induction therapy.   
 
During the third phase of therapy, Maintenance, an oral drug, called cis-retinoic acid (Accutane) 
is given. 
 
WHY IS THIS STUDY BEING DONE? 
 
This study is being done because more than half of the patients with high risk neuroblastoma 
will not be cured of their disease. 
 
The main purpose of this research study is to find out if using 2 cycles of high dose 
Consolidation chemotherapy, instead of 1 cycle, will decrease the chance that the 
neuroblastoma will grow back after therapy.  This research study will also find out if adding a 
new anti-cancer drug to Induction therapy will decrease the number of patients who have tumor 
present at the end of the Induction phase of therapy.  This research study will also find out if 
patients whose tumor does not go away with initial therapy will need a higher dose of radiation 
therapy. 
 
The treatment will be described in two separate consent forms.  Part 1 will discuss the use of a 
drug added to the standard anti-cancer drugs used in the Induction phase of neuroblastoma 
treatment.  It will also explain standard blood stem cell collection and surgery.  Part 1 of the 
consent is being given to you now. 
 
Your doctor will give you Part 2 (the second consent form) of the study to you after you have 
completed the Induction phase of therapy.  You will not be able to participate in Part 2 of this 
study if your tumor has grown larger or spread to new areas in your body.  The second consent 
(Part 2) will discuss the Consolidation and Maintenance phases of therapy.  You do not have to 
take part in Part 2 of the study.  You can discuss this with your doctor and make that decision 
after you have finished the Induction therapy.   


 
 
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Part 1 of this study will collect information about your neuroblastoma and about the effects of 
the first phase of treatment, Induction which lasts about 20 weeks (5 months).  
 
Part 1 of this study will test the addition of the combination of chemotherapy, 
cyclophosphamide/topotecan, to the standard chemotherapy combinations used in the Induction 
phase of treatment for high risk neuroblastoma.  The use of cyclophosphamide and topotecan 
during induction phase of treatment is experimental.  This study is designed to help understand 
whether this new treatment will increase our ability to kill or remove your tumor cells.   
 
During this part of the study, we will: 
 
 
Look at how well high risk neuroblastoma responds to this new Induction therapy. 
 
Study how certain genes (genes direct activities of cells) affect how you respond to the 
cyclophosphamide and topotecan induction chemotherapy. 
 
Study whether your immune system (blood cells that help fight infection) can produce 
cells that will find and kill neuroblastoma.   
 
Study how topotecan is broken down by your body. 
 
Study whether new tests can be used to find small amounts of neuroblastoma cells. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 664 subjects will take part in this study. The study will last about 3-4 years.   
 
WHAT WILL HAPPEN ON THIS STUDY? 
 
You will need to have the following exams, tests or procedures to find out if you can be 
in the study and to check how you are doing during treatment.  These exams, tests or 
procedures are part of regular cancer care and may be done even if you do not join the 
study.  If you have had some of them recently, they may not need to be repeated.  This 
will be up to your study doctor.   
 
 
Physical exam 
 
Blood tests 
 
Bone marrow tests 
 
Pregnancy test for females of childbearing potential 
prior to treatment 
 
Various scans (x-ray tests to determine whether your 
tumor is responding to therapy) 
 
Tests of kidney function 
 
Tests of lung and heart          
        function 
 
Hearing tests 
 
Urine Tests 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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A diagram of treatment can be seen below.   
Diagram of treatment 
 
On Study  
 
 
 
 
* You will be given a separate consent form for part 2 of the study. 
 
Induction Therapy 
Cycles 1, 2 
Stem Cell Collection 
Induction Therapy 
Cycles 3,4,5 
Surgery to remove 
tumor 
Induction Therapy 
Cycle 6 
Off Study Therapy  
Your tumor grows 
or spreads during 
treatment 
Disease stays the 
same or gets better 
Go on to  
Part 2 of Study* 


 
 
ANBL0532 
Page 135 
 
Induction Chemotherapy 
This treatment uses chemotherapy to make the tumor as small as possible, hopefully allowing it 
to be removed.  All patients will begin treatment with the Induction phase of chemotherapy, 
which is divided into six 3-week cycles. There are three different drug combinations used during 
the six cycles. Cycles 1 and 2 will use the new combination of cyclophosphamide and 
topotecan.  Cycles 3 and 5 use the anti-cancer drugs etoposide and cisplatin.  Cycles 4 and 6 
use the anti-cancer drugs vincristine, cyclophosphamide, and doxorubicin and the drugs 
MESNA. MESNA is given to help protect the bladder from potential damaging effects of 
cyclophosphamide. The drugs used Cycles 3, 4, 5 and 6 are standard drugs used for the 
treatment of high risk neuroblastoma study. Cycles of chemotherapy will be given approximately 
every 21 days.  An additional drug referred as the myeloid growth factor (eg: filgrastim (G-CSF)) 
is given after the chemotherapy. It helps start the production of white blood cells (infection 
fighting cells) and will help your body recover from treatment. Any myeloid growth factor may be 
given after chemotherapy for induction cycles 1 and 3-6 whereas only filgrastim (G-CSF) 
(granulocyte colony stimulating factor) has to be specifically given after cycle 2. 
 
Methods for Giving Drugs 
Your doctor will recommend the placement of a tube, or catheter, into a large vein in the chest 
or neck during a short operation as the standard way to give chemotherapy into a vein. This 
tube is called a central line.  You will be given medication to help you sleep during this 
procedure and pain medication afterwards to help you stay comfortable. The central line is used 
to give chemotherapy drugs and to take small amounts of blood for testing during treatment. A 
central line will be used to give chemotherapy even if you do not participate in this study.  The 
risks associated with central lines will be explained to you by your surgeon.  You will be given a 
separate informed consent form to read and sign prior to having a central line inserted.   
 
You may also receive one of your medications as an injection under the skin.   
 
Schedule and Methods of Giving Chemotherapy 
A schedule of how and when the drugs will be given during the Induction phase of therapy is 
listed below. 
 
Various methods will be used to give drugs:.  
PO - Drug is given by tablet or liquid swallowed through the mouth (PO). 
IV - Drug is given using a needle or tubing inserted into a vein. It can be given by IV push over 
several minutes or by infusion over minutes or hours 
SUBQ - Drug is given by injecting a needle into the tissue just under the skin (SUBQ shot) 
 
Most drugs on this study will be given using a needle or tubing inserted into a vein (IV). 
 
 


 
 
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CALENDAR FOR THERAPY  
 
INDUCTION (Total of 6 cycles; one cycle given every 3 weeks (21 days) 
Drug 
Method 
Schedule 
 
 
 Day 
1 
2 
3 
4 
5 
    6-21 
Cycle 1 
 
 
 
 
 
 
 
 
Cyclophosphamide 
IV infusion for 30 minutes 
 
X 
X 
X 
X 
X 
 
Topotecan 
IV infusion for 30 minutes 
 
X 
X 
X 
X 
X 
   
Myeloid growth factor  Depends on the agent used 
         
 
 
 
 
   X 
 
 
Day
1 
2 
3 
4 
5 
    6-21 
Cycle 2 
 
 
 
 
 
 
 
 
Cyclophosphamide 
IV infusion for 30 minutes 
 
X 
X 
X 
X 
X 
 
Topotecan 
IV infusion for 30 minutes 
 
X 
X 
X 
X 
X 
   
Filgrastim (G-CSF) 
Sub Q (or) IV                       
         
 
 
 
 
   X 
Cycles 3 and 5: 
 
Day
1 
2 
3 
4 
5 
6-21 
Cisplatin 
IV infusion for 1 hour 
 
X 
X 
X 
X 
 
 
Etoposide 
IV infusion for 1 hour 
 
X 
X 
X 
 
 
 
Myeloid growth factor  Depends on the agent used 
 
 
 
 
 
X 
 
Cycles 4, 6: 
 
Day
1 
2 
3 
4 
5 
6-21 
Cyclophosphamide 
IV infusion for 6 hours 
 
X 
X 
 
 
 
 
MESNA  
IV infusion prior to each 
cyclophosphamide dose 
and at 4 and 8 hours after 
each cyclophosphamide 
dose.    
 
X 
X 
 
 
 
 
Doxorubicin  
IV infusion for 24 hours 
 
X 
X 
X 
 
 
 
Vincristine 
IV infusion for 1-2 minutes 
 
X 
X 
X 
 
 
 
Myeloid growth factor  Depends on the agent used 
 
 
 
 
 
X 
 
 
 
Stem Cell Harvest 
After the second cycle of Induction is finished, your stem cells will be collected using a 
procedure called apheresis.  During apheresis, your blood is collected into a machine that filters 
out the stem cells and the filtered blood is returned to your body.  This procedure may need to 
be done several times to collect enough stem cells for the Consolidation phase of therapy. This 
procedure will be performed at [local institution]. The stem cells will be frozen and stored until 
needed for the Consolidation phase of therapy. 
 
The risks of Stem Cell Harvests can be found in Attachment #2.   
 
Surgery 
After the fifth cycle of Induction, you will have surgery to remove as much remaining tumor as 
possible.  The surgeon will talk to you about your surgery and any possible risks involved with 
the surgery.  
 
Additional Medicines 
You may get some extra medications, like antibiotics, to help fight infection.  Other medications 
may be given to lessen the side effects of chemotherapy.  These medicines are part of standard 
care. 
 


 
 
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Additional optional research studies 
 
We would like to collect additional blood to learn more about how chemotherapy drugs are 
broken down in your body, to see if certain genes (genes direct the activities of cells) will affect 
whether you experience bad effects after chemotherapy, whether your immune system is able 
to find neuroblastoma tumor cells and to test new methods for finding tumor cells. We will obtain 
all blood specimens through your central venous catheter.  We will try to collect additional blood 
when you are already having blood drawn for routine purposes.   
 
We would like to use any leftover portions of your bone marrow or stem cells that are not 
needed to treat you to carry out special biology research studies to learn more about 
neuroblastoma. These studies will test new methods for finding tumor cells.  
 
Blood tests 
Before starting treatment, we would like to take additional blood (20 mL = 4 teaspoons) to see if 
your immune cells can recognize neuroblastoma tumors.   
 
Before starting treatment, we would like to take additional blood (10 ml = 2 tsp) to look at how 
certain genes (genes direct the activities of cells) may effect whether you have side effects after 
chemotherapy. 
 
During Cycle 1 and Cycle 2 of Induction therapy we would like to take additional blood (4 ml = 
just less than 1 teaspoon) to study how topotecan is broken down by your body.   
 
Before starting Induction therapy and at the end of Induction therapy, we would like to collect 
additional blood (4 mL = just less than 1 teaspoon) to test new methods of finding 
neuroblastoma. 
 
Bone marrow Tests 
 
We would also like to take 5 mL (1 tsp) of extra bone marrow at diagnosis and at the end of 
induction and to take 0.5 mL (1/10 of a tsp) after Cycle 2 of Induction to study new methods of 
finding tumor cells. This bone marrow will be taken when we are normally taking a sample to 
see how you are responding to therapy.  The extra bone marrow will be shipped to a central lab 
for storage.   
 
Peripheral Blood Stem Cell Tests 
We would also like to obtain 1 mL (1/4 tsp) of stem cells that you do not need for your treatment 
to store for future research.  These stem cells will be collected during your standard stem cell 
collection and will be shipped to a central lab for storage.   
You and your physicians will not get the results of these blood, bone marrow and stem cell 
tests.. You will not benefit from allowing us to perform these extra studies. We will try to take the 
blood samples when we are already taking blood for standard therapy.  The blood will be taken 
from your central line and will not require extra blood draws.  You can request that we stop 
collecting these specimens at any time during your treatment.  You will continue to get treatment 
on the study whether or not you allow us to collect these additional samples. 
Please read each sentence below and think about your choice. After reading each sentence, 
choose "Yes" or "No" then add your initials and date after your answer.  No matter what you 
decide to do, it will not affect your care.  If you have any questions, please talk to your doctor 
or nurse, or call our research review board at IRB's phone number included in this consent. 


 
 
ANBL0532 
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I agree to have additional blood obtained for research purposes (to test for immune cells that 
recognize neuroblastoma). 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
I agree to have additional blood obtained for research purposes (to test if certain genes are 
associated with side effects). 
 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
I agree to have additional blood obtained for research purposes (to test how topotecan is broken 
down). 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
I agree to have additional blood obtained for research purposes (to find new ways to detect 
neuroblastoma). 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
I agree to have additional bone marrow obtained for research purposes (to find new ways to 
detect neuroblastoma) 
 
 
Yes ______ 
 
No _______ 
 
 
 
Initials______ 
 
 
I agree to have extra peripheral blood stem cells used for research purposes (to find new ways 
to detect neuroblastoma) 
 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
 
HOW LONG WILL I BE ON THIS STUDY? 
 
The first part of the treatment takes about 5 months.  As long as your tumor doesn't get worse, 
you will be offered the option to continue on Part 2 of this clinical trial once you have completed 
Induction therapy. You will need to get more therapy for neuroblastoma whether or not you take 
part in Part 2.  
 
We will continue to collect some medical information about how you are doing for 10 years after 
you enter the study. Keeping in touch with you and checking on how your health is every year 
for a while after you complete treatment helps us understand the long-term effects of the study.  
 
Your doctor or the study doctor may decide to take you off this study for the following reasons: 
 
 
he/she believes that it is your best interest 
 
your disease comes back during treatment 
 
you had side effects from the treatment that are considered too severe 


 
 
ANBL0532 
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 
new information becomes available that shows that another treatment would be better for 
you 
 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the study doctor and your regular doctor first. 
 
 
WHAT ARE THE RISKS OF THE STUDY AND HOW ARE THE RISKS DIFFERENT FROM 
TREATMENT? 
 
Treatment Risks 
All people who get cancer treatment are at risk of having side effects. In addition to killing tumor 
cells, cancer chemotherapy can damage normal tissue and produce side effects. Side effects 
are usually reversible when the medication is stopped but occasionally persist and cause 
serious complications. A person can die from these and other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be given to 
prevent or decrease nausea and vomiting. Hair loss is usually temporary but on very rare 
occasions it may be permanent. Some chemotherapy may lead to sterility.  Sterility is the 
inability to have children. There is also the possibility that a second cancer may develop years 
later as a result of the chemotherapy.  The risks of the individual drugs given as standard 
treatment are listed on the tables in Attachment #1.  Side effects can be increased when 
chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of blood 
cells resulting in anemia, increased chance of infection, and bleeding tendency. Low blood 
counts are described in your Family Handbook for Children with Cancer. You will be taught 
more about caring for your child when his or her blood counts are low.  
 
There is a risk that the treatment plan will not cure the cancer or that the cancer can go away 
after the treatment and then come back at a later date.  
 
Reproductive risks: 
Because the drugs and/or radiation therapy in this study can affect a developing fetus (unborn 
baby in the womb), you should not become pregnant or father a baby while on this study. Ask 
about counseling and more information about preventing pregnancy. The administration of 
chemotherapy described may cause infertility (being less able to produce a viable egg or sperm) 
or sterility (being unable to produce a viable egg or sperm). We will talk to males who have 
reached puberty about sperm banking. 
 
For Women: 
The treatment on this study can affect an unborn child. You should not become pregnant or 
breast feed your baby while being treated on this study. If you are sexually active and are at risk 
of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex. The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study. You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctor about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation. If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor. If you 


 
 
ANBL0532 
Page 140 
become pregnant during the research study, please tell the investigator and your doctor 
immediately. 
 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctor about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage sperm. You should not father a child while on this 
study as the treatment may indirectly affect an unborn child. If you are sexually active and are at 
risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex. The investigator will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study. You will have 
to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctor about the length of time you need to 
avoid pregnancy or abstain. Natural family planning and the rhythm method will not be 
permissible means of avoiding pregnancy during study participation. If you have questions 
about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor. If your partner becomes pregnant during the research study, please tell the investigator 
and your doctor immediately. 
 
 
Risks of Study 
The use of the topotecan/cyclophosphamide combination may lead to increased side effects 
compared to standard chemotherapy.   
 
The use of topotecan/cyclophosphamide may not work as well as the current standard 
treatment.  
 
In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
 
 
 
Risks and side effects related to cyclophosphamide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Loss of appetite 
 
Nausea  
 
Vomiting 
 
Fewer white blood cells 
in the blood. 
○ 
A low number of 
white blood cells 
may make it easier 
to get infections. 
 
Hair loss 
 
Decreased ability of the 
body to fight infection  
 
Absence  or decrease in 
the number of  sperm  
which may be temporary 
or permanent which may 
decrease the ability to 
 Abnormal hormone 
function which may lower 
the level of salt in the 
blood  
 Abdominal pain 
 Diarrhea 
 Fewer red blood cells 
and platelets in the blood 
○ 
A low number of red 
blood cells may make 
you feel tired and 
weak. 
○ 
A low number of 
platelets may cause 
you to bruise and 
bleed more easily. 
 Bleeding and 
 
Heart muscle damage which 
may occur with very high 
doses and which may be 
fatal 
 
Abnormal heart rhythms 
 
Damage and scarring of lung 
tissue which may make you 
short of breath 
 
A new cancer or leukemia 
resulting from this 
treatment. 
 
Damage or scarring of 
urinary bladder tissue 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 


 
 
ANBL0532 
Page 141 
have children 
 
 
inflammation of the 
urinary bladder 
 Absence  or decrease 
monthly periods which 
may be temporary or 
permanent and which 
may decrease the ability 
to have children 
 Temporary blurred vision 
 Nasal stuffiness with IV 
infusions 
 Skin rash 
 Darkening of areas of the 
skin and finger nails 
 Slow healing of wounds 
 Infections  
rate chills and fever 
 
Infertility which is the 
inability to have children 
 
 
 
Risks and side effects related to topotecan include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Diarrhea  
 
Nausea 
 
Vomiting 
 
Constipation 
 
Fewer white blood cells, 
red blood cells and 
platelets in the blood. 
o A low number of 
white blood cells can 
make it easier to get 
infections 
o A low number of red 
blood cells can make 
you feel tired and 
weak 
o A low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
Fever including fever 
with a low white blood 
cell count which could 
indicate infection and 
may require 
hospitalization and 
treatment with 
antibiotics 
 
Pain which may be in 
your abdomen, back or 
bones 
 
A feeling of weakness 
and/or tiredness 
 
Loss of appetite 
 
Elevation in the blood of 
certain enzymes or 
bilirubin found in the 
liver which could 
indicate liver irritation or 
damage 
 
Headache 
 
Rash, hives, itching or a 
red bumpy rash 
 
A mild lowering of the 
blood pressure which 
usually does not require 
treatment 
 
Inflammation and/or 
sores in the mouth, 
throat and/or esophagus 
 
An infection in the blood 
which will require 
admission to the hospital 
and treatment with 
antibiotics 
 
Numbness and tingling 
in the fingers and toes 
 
Small amount of blood 
and/or protein in the 
urine or an elevation in 
blood creatinine which 
may indicate mild kidney 
damage 
 
Shortness of breath 
 
Muscle or joint aches 
 
Severe allergic reaction 
which can be life 
threatening with 
shortness of breath, low 
blood pressure and a 
rapid heart rate 
 
Severe allergic reaction 
which can be life 
threatening with rapid 
build-up of fluid under 
the skin, in the lining of 
the intestine and 
possibly in the throat or 
swelling of the tongue 
which could make it 
difficult to breath. 
 
Bleeding into the tumor 
which may cause 
damage depending on 
the location of the tumor 


 
 
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 
Temporary hair loss 
 
and pains 
 
Chest pain 
 
Shaking chills 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
We hope that you will get personal medical benefit from participation in this clinical trial, but we 
cannot be sure that will happen. These potential benefits could include better chance of a cure 
or less side effects. 
 
We expect that the information learned from this study will benefit other patients in the future.  
 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
 
 
Current standard therapy even if you do not take part in the study. Standard therapy 
is described on page 2.   
 
 
Taking part in another study 
 
You are encouraged to discuss these options with your regular doctor as well as other trusted 
personal and family advisors. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
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. Information about 
the certificate is attached at end of this consent. 
 
Organizations that may inspect and/or copy your research records for quality assurance 
and data analysis include groups such as: 
 
 
The Children's Oncology Group 
 
Representatives of the National Cancer Institute (NCI), Food and Drug Administration 
(FDA), and other U.S. and international governmental regulatory agencies involved in 
overseeing research  
 
The Institutional Review Board (IRB) of this hospital 
 
Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute 
 
 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance company. Please ask 
about any expected added costs or insurance problems. Staff will be able to assist you with this.  


 
 
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You or your insurance company will not be charged for research studies performed on blood, 
bone marrow or stem cells. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. However by signing this form, you are not giving up any legal rights to 
seek to obtain compensation for injury. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
There are no plans to pay you for taking part in this study.  If this study includes providing 
specimens to the researcher, there is no intention or plan for you to profit from any new 
products developed from research done on your specimens. 
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary.  You may leave the study at any time. Refusing to take 
part in the study, or leaving the study will not result in any penalty or loss of benefits to which 
you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies institutions 
if changes must be made to the study. Members of COG meet twice a year to evaluate results 
of treatment and to plan new treatments.  
 
During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years after treatment for all people on the 
study is completed.   
 
 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or a research-related problem, or if you think you have been 
injured, you may contact Dr. XXXX or your doctor at XXXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call  XXXX IRB Administrator at (XXXX 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX 
 
WHERE CAN I GET MORE INFORMATION? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources. 
 


 
 
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If you are in the United States, you may call the NCI's Cancer Information Service at: 
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/ 
 
Visit the COG Web site at http://www.curesearch.org 
 
Information about long term follow-up after cancer treatment can be found at 
http://www.survivorshipguidelines.org/ 
 
A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
 
SIGNATURE 
I have been given a copy of all _____ [insert total number of pages] pages of this form.  
The form includes three (3) attachments. 
 
 
I agree to take part in this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
IRB# 
IRB Approved: 
 


 
 
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Attachment #1 
Risks of individuals drugs given as standard treatment for Neuroblastoma 
 
Risks and side effects related to cisplatin include those which are: 
Likely 
Less Likely
Rare But Serious
 
Nausea and vomiting  
 
fewer red blood cells and 
white blood cells and 
platelets in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and weak 
o 
a low number of white 
blood cells can make it 
easier to get infections 
o 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Abnormal levels of 
magnesium in the body 
which may require that you 
take extra magnesium by 
mouth or in the vein  
 
Loss of appetite 
 
Damage to the ear causing 
difficulty in hearing high 
pitched sounds 
 
Temporary and mild 
increases in levels of 
certain chemicals in the 
blood because the kidney 
is not working as well as 
normal 
 Abnormal levels of certain 
salts in the body like 
sodium, calcium, 
potassium and phosphate 
 Metallic taste 
 Rash 
 Numbness and tingling in 
the fingers and toes 
 Temporary changes in 
vision 
 Damage to the ear causing 
hearing loss, balance 
problems and ringing in 
the ears 
 Elevation in the blood of 
certain enzymes found in 
the liver which may 
indicate liver irritation or 
damage. 
  Inflammation and 
discomfort in the vein 
through which the 
medicine was given 
 Damage to the skin may 
occur if the medication 
leaks from the vein 
 
 Allergic reactions which 
may be severe and life-
threatening, causing 
difficulty in breathing, 
rapid heart rate, facial 
swelling and or a drop in 
blood pressure 
 Damage to the kidney 
which may be 
permanent 
 Deafness 
 Seizures 
 Damage to the vision 
which could lead to 
blurred vision, blue-
green color blindness 
and to loss of vision 
which usually goes 
away after stopping the 
drug. 
 Decrease in muscle and 
nerve reflexes that may 
affect normal functions 
such as walking 
 Leukemia later in life 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
ANBL0532 
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Risks and side effects related to doxorubicin include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea 
 
Vomiting 
 
Temporary hair loss 
 
Pink or red color to 
urine, sweat, tears, 
saliva 
 
Fewer white blood cells, 
red blood cells and 
platelets in the blood. 
○ 
A low number of red 
blood cells can make 
you feel tired and 
weak 
○ 
A low number of 
white blood cells can 
make it easier to get 
infections 
○ 
A low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
Slight damage to the 
heart muscle that is 
unlikely to have any 
noticeable effects on 
your heart function 
 
 Inflammation and/or sores 
in the mouth (and/or throat 
and /or esophagus, the 
tube that leads from the 
mouth to the stomach) that 
may make swallowing 
difficult and are painful 
(painful mouth sores) 
 Damage to the heart 
muscle which may make 
you tired, weak, feel short 
of breath, and retain fluid 
 Facial Flushing 
 Fever/chills 
 Hives 
 High levels of uric acid in 
the blood which could 
damage the kidneys 
 Dark discoloration of the 
hands, feet and under the 
fingernails with possible 
separation of the nail from 
the nail bed. 
 Damage to the skin if the 
medication leaks from a 
vein 
 Thickening and hardening 
of the veins through which 
the medication is given 
 Reddening reaction of the 
vein through which the 
drug is given. 
 Elevation in the blood of 
certain enzymes found in 
the liver which may 
indicate liver irritation or 
damage. 
 Tearing and inflammation 
of the eyes 
 Loss of appetite 
 Redness and burning at 
sites which have received 
radiation in the past  
 Diarrhea 
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure and a rapid heart 
rate  
 
Ulceration of the lower 
intestinal tract 
 
An irregular heart beat 
which can be life-
threatening 
 
Severe damage to the heart 
muscle which may lead to 
severe heart failure 
 
A new cancer or leukemia 
resulting from this 
treatment. 
 
 
The risk of heart damage may be greater in very young children than in older ones 
 
 
 
 
 
 
 
 


 
 
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Risks and side effects related to etoposide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea and vomiting 
 
Hair Loss 
 
A feeling of weakness or 
tiredness 
 
fewer red and white 
blood cells and platelets 
in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and 
weak 
o 
a low number of 
white blood cells can 
make it easier to get 
infections 
o 
a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
 
 
Loss of appetite 
 
Decreased blood 
pressure during the 
infusion which may 
require treatment 
 
rashes 
 
Diarrhea 
 
Pain in the abdomen 
 
Mouth sores 
 
Tingling sensation or 
loss of sensation in 
fingers or toes 
 
A feeling of  extreme 
tiredness or weakness 
 
The finger or toe nails 
may loosen from their 
nail beds 
 
Inflammation of the vein 
through which the 
medication was given 
 
Chest pain 
 
Damage to the liver 
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure, rapid heart rate 
chills and fever 
 
A new cancer or leukemia 
resulting from this 
treatment 
 
Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes 
 
Absence  or decrease 
monthly periods which 
may be temporary or 
permanent and which may 
decrease the ability to 
have children 
 
Damage to the heart 
muscle which may make 
you feel tired, weak, feel 
short of breath, and retain 
fluid 
 
 
 
 
Risks and side effects related to myeloid growth factors (filgrastim (G-CSF) or pegfilgrastim) 
include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Aching or pain in the 
bones 
 
 
Pain, redness, itching, 
and hardening of the 
skin and bruising at the 
site of the injection 
 
Headache 
 
Higher than normal 
levels of liver enzymes 
in the blood which may 
indicate liver irritation 
or damage 
 
Increase of uric acid in 
the blood 
 
A low number of 
platelets in the blood 
which may cause you 
to bruise and bleed 
more easily 
 
Low fever 
 
Enlargement of the 
spleen (an organ in the 
abdomen/belly which 
stores blood cells) 
 
Allergic reactions which 
can be life threatening 
with shortness of 
breath, low blood 
pressure, rapid heart 
rate, hives, itching, and 
facial swelling.  
 
Serious allergic reaction 
which can be life 
threatening with rapid 
build-up of fluid under 
the skin, in the lining of 
the intestine, and 
possibly in the throat or 
swelling of the tongue 
which could make it 
difficult to breath2 
 
If you are known to have 
sickle cell disease, 
filgrastim or 
pegfilgrastim may cause 
a sickle cell crisis. 


 
 
ANBL0532 
Page 148 
which may cause pain 
in the abdomen or left 
shoulder 
 
Higher than normal 
white blood count 
 
Skin condition marked 
by fever and painful 
skin lesions that 
appear mainly on the 
face, neck, back and 
arms  
 
Rash or worsening of 
rash1 
 
Inflammation of blood 
vessels in the skin 
leading to a raised 
purple rash and 
bruising has been seen 
mainly in patient who 
are treated for a long 
time1 
 
Overall reddening with 
feelings of warmth2 
 
 
 
Severe damage to the 
spleen (an organ in the 
abdomen/belly which 
stores blood cells) 
which could lead to pain 
and loss of blood into 
the abdomen (belly) and 
maybe life threatening 
 
Difficulty breathing and 
lung damage that may 
be due to the white 
blood cells that are 
stimulated by filgrastim 
or pegfilgrastim 
traveling to the lungs 
when they are inflamed 
or infected. 
 
A blood disorder or 
leukemia that has only 
been seen in patients 
with certain immune 
disorders who are 
treated for a very long 
time1 
 
1 Reported with filgrastim 
2 Reported with pegfilgrastim 
 
Risks and side effects related to mesna IV include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
 
Nausea. 
 
Vomiting 
 
Stomach pain. 
 
Headache. 
 
Pain in arms, legs and 
joints. 
 
Tired feeling. 
 
Rash. 
 
Temporary low blood 
pressure. 
 
Diarrhea. 
 
Fever 
 
Facial flushing with red 
cheeks 
 
Nervousness 
 
Dizziness 
 
Confusion 
 
Swelling around the 
eyes 
 
Coughing 
 
Rapid heart rate 
 
Severe allergic reaction 
which can be life 
threatening with 
shortness of breath, low 
blood pressure, rapid 
heart rate chills and 
fever 
 
 


 
 
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Page 149 
 
 
Risks and side effects related to vincristine include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Hair loss 
 
Reversible nerve 
problem that may affect 
the way you walk or the 
feelings in your fingers 
or toes 
 
Constipation 
 Jaw pain 
 Headache 
 Muscle weakness 
 Pain and bloating in your 
abdomen 
 Numbness and tingling 
 Wrist or foot drop 
 Drooping eyelids 
 Double vision, difficulty 
seeing at night 
 Hoarseness of your voice 
 Difficulty sweating 
 Abnormal walk with foot 
slapping 
 Difficulty with urination 
or increase desire to 
urinate 
 Dizziness and low blood 
pressure when you stand 
 Abnormal hormone 
function which may lower 
the level of salt in the 
blood 
 A mild drop in white 
blood cells, red blood 
cells and platelets in the 
blood 
o 
a low number of red 
blood cells can make 
you feel tired and 
weak 
o 
a low number of 
white blood cells can 
make it easier to get 
infections 
o 
a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
Complete stoppage of 
your intestinal activity 
which can result in 
intestinal blockage 
 
If the drug leaks out of 
the vein when being 
administered it will 
cause damage to nearby 
tissue 
 
Seizures 
 
Vocal cord paralysis 
 
Difficulty breathing 
 
Inability to walk 
 
Decreased ability to 
hear clearly 
 
Damage to the nerve to 
the eye (optic nerve) 
leading to decreased 
vision and possible 
blindness 
 
In combination with 
other chemotherapy 
drugs: damage to the 
liver which can lead to 
inflammation and/or 
scarring which could 
lead to a yellow 
appearing skin, and fluid 
collection in the 
abdomen (belly) which 
makes it look larger  
 
 


 
 
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Attachment #2 
Peripheral Blood Stem Cell Harvesting Risks  
 
 
Peripheral Blood Stem Cell Harvesting  
These procedures are usually safe. Side effects that can occur during PBSC collection include 
nausea, vomiting, fainting or dizziness, seizures, skin rash, hives, flushing (redness and 
warmness of the skin, usually the face), blood loss, and infection. Tingling of the lips, muscle 
cramping and, very rarely, changes in the heart rhythm can occur. These can be prevented or 
made milder by giving calcium supplements, either by mouth or IV. Very rarely, (less than 1 in 
1,000 procedures), clotting may occur in the apheresis machine or in a patient and is potentially 
life-threatening. To reduce the risk of clotting, you will be given a drug called ACD (acid-citrate-
dextrose). This drug may increase the risk of bleeding and may cause temporary tingling of the 
lips and limbs, muscle cramping, seizures, or changes in the heart rhythm. 
 


 
 
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Attachment #3 
Certificate of Confidentiality Information 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the 
federal government, which will help us protect the privacy of our research subjects.  The 
Certificate protects against the involuntary release of information about subjects 
collected during the course of our covered studies.  The researchers involved in the 
studies cannot be forced to disclose the identity or any information collected in the study 
in any legal proceedings at the federal, state, or local level, regardless of whether they 
are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain 
circumstances.  For example, if the subject or his/her guardian requests the release of 
information in writing, the Certificate does not protect against that voluntary disclosure.  
Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA 
request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will 
not protect against the required reporting by hospital staff of information on suspected 
child abuse, reportable communicable diseases, and/or possible threat of harm to self 
or others. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH  
 
 
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed. (Institutions 
should attempt to use sections of this document which are in bold type in their entirety.) Editorial 
changes to these sections may be made as long as they do not change information or intent. If 
the local IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they must be justified in writing by the investigator and approved by the 
IRB.  
 
ANBL0532, Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation 
Therapy for High-Risk Neuroblastoma:  
 
PART 2 A: CONSENT FOR PATIENTS RANDOMIZED TO CONSOLIDATION THERAPY 
 
Consolidation and Maintenance Phases of Therapy for High Risk Neuroblastoma 
(Please note that this consent MUST be signed before the patient proceeds for consolidation 
therapy) 
 
When the word “you” appears in this consent form, it refers to you or your son or daughter; “we” 
means the doctors and other staff. 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY? 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you. 
 
The Children's Oncology Group (COG) is carrying out this study. COG is an international 
research group that conducts clinical trials for children with cancer at more than 200 hospitals in 
the United States, Canada, Australia, New Zealand, the Netherlands, and Switzerland. It is 
common medical practice to treat children with cancer on research studies like this one. 
 
You are being asked to take part in this study because you have high risk neuroblastoma and 
you have participated in Part 1 of this study. Neuroblastoma is a type of cancer.  You have the 
type of neuroblastoma that is called High Risk because your tumor has spread from where it 
started from or because your type of tumor is harder to treat.   
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard treatment for High Risk neuroblastoma and this clinical 
trial. Please take your time to make your decision about taking part in this clinical trial.  You may 
discuss your decision with your friends and family.  You can also discuss it with your health care 
team.  We encourage you to include your child in the discussion and decision to the extent that 
she or he is able to understand and take part.  If you have any questions, you can ask your 
study doctor for more explanation.  
 
WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE? 
The treatment for neuroblastoma includes 3 parts (phases) of therapy called Induction, 
Consolidation and Maintenance.  During Induction therapy anti-cancer drugs (chemotherapy) 


 
 
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and surgery are used to kill and remove as much tumor as possible.  Blood stem cells are 
collected during the Induction phase of therapy.  After collection the blood stem cells are frozen 
and stored to be used during Consolidation phase of treatment.  Blood stem cells are the cells 
that create new blood cells, such as red blood cells, white blood cells, and platelets. Blood stem 
cells can be collected from the blood by using a machine that can separate out the part of blood 
that has stem cells and then return the remaining blood back to the patient.  You have already 
received this part of therapy. 
 
During the Consolidation phase of treatment extremely high doses of chemotherapy are given to 
better kill any remaining neuroblastoma cells. It is standard therapy to give one cycle of this 
extremely high dose chemotherapy. The high doses of chemotherapy destroy healthy bone 
marrow. Bone marrow is the soft tissue in the hollow of flat bones of the body that produces new 
blood cells.  The peripheral blood stem cells that were stored during the Induction phase of 
treatment are given back to the patient after the high dose Consolidation chemotherapy.  These 
stems cells allow the bone marrow to return to normal so that new blood cells can be made. 
This type of therapy is called a Hematopoietic Stem Cell Transplant. Once the patient has 
healed from the effects of high doses of chemotherapy, radiation therapy is given to the first 
place the tumor was found and to any additional places where the tumor was found after 
Induction therapy.   
 
During the third phase of therapy, Maintenance, an oral drug, called cis-retinoic acid (Accutane) 
is given. 
 
WHY IS THIS STUDY BEING DONE? 
The main goal of this research study is to find out if using 2 cycles of high dose 
Consolidation chemotherapy, instead of 1 cycle, will decrease the chance that the 
neuroblastoma will grow back after therapy.  In this study, you will get either 2 cycles of high 
dose Consolidation chemotherapy or 1 cycle of high dose Consolidation chemotherapy.  It is 
standard to give only one cycle of high dose Consolidation chemotherapy.  Smaller clinical trials 
have studied the safety of giving 2 cycles of high dose Consolidation chemotherapy to treat high 
risk neuroblastoma.  We do not know whether using 2 cycles of Consolidation chemotherapy 
will be better for treatment of high risk neuroblastoma. 
 
Tandem stem cell transplant for children with neuroblastoma is experimental. 
 
This research study will also find out if patients whose tumor did not disappear with initial 
induction therapy will need a higher dose of radiation therapy.   
 
This study is being done because more than half of the patients with high risk neuroblastoma 
will not be cured of their disease.   
 
The treatment is described in two separate consent forms.  You have already read the first 
consent form (Part 1) and completed Part 1 of treatment. We are now presenting Part 2 (the 
second consent form) of the study. The second consent (Part 2) will discuss the Consolidation 
and Maintenance phases of therapy.   
 
 
During this part of the study, we will: 
 
Compare the effects, good and/or bad, of using 2 cycles of high dose Consolidation 
chemotherapy with 1 cycle of high dose Consolidation chemotherapy on children with 
high risk neuroblastoma to find out which is better. 
 
Study whether a higher dose of radiation, given only to patients with tumor remaining 


 
 
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after induction therapy, will decrease the chance that tumor will grow back.   
 
Study whether your immune system (blood cells that help fight infection) can produce 
cells that can recognize and kill neuroblastoma.   
 
Study whether new tests can be used to find small amounts of neuroblastoma cells. 
 
Study how cis-retinoic acid (Accutane) is broken down by your body and study whether 
your genes (genes direct activities of cells) effect how you respond to cis-retinoic acid 
therapy. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 664 subjects will take part in this study. The study will last about 3-4 years.   
 
WHAT WILL HAPPEN ON THIS STUDY? 
 
Random Assignment 
 
If you participate in this part of the study you will be given one of 2 different treatment plans. The 
treatment plan you get is decided by a process called randomization. Randomization means 
that the treatment is assigned based on chance. It is a lot like flipping a coin, except that it is 
done by computer to make sure that there are about the same number of people on each 
treatment plan of the study.  You or your doctor can not choose what treatment you will have.  
 
Treatment Plan 
The treatment plan involves cancer fighting medicine called chemotherapy plus radiation 
therapy.  The treatment on this part of the clinical trial takes about 9-11 months. It is divided into 
2 stages.  
 
The two different treatment plans are the same except for some differences during the 
Consolidation phase of therapy. The rest of the treatment that is given is standard therapy for 
people with high risk neuroblastoma.  
 
The two treatment arms are as follows: 
 
A:  Single Myeloablative Consolidation Therapy 
 
B:  Tandem Myeloablative Consolidation Therapy 
 
Myeloablative therapy means that you will receive very high doses of chemotherapy that 
will destroy bone marrow cells. Stem cells are given back after the chemotherapy to 
replace the bone marrow cells that were destroyed. 
 
You will receive consolidation treatment after you have finished induction therapy and signed 
this consent.  
 
Randomization 
 
After you have finished induction therapy and signed this consent, you will be randomized to 
receive either a single (one cycle) of extremely high dose chemotherapy (Single Myeloablative 
Consolidation Therapy) or tandem (two cycles) of extremely high dose chemotherapy (Tandem 
Myeloablative Consolidation Therapy).  
 The rest of the Consolidation therapy and Maintenance therapy will be the same in both groups 
of patients.  
 


 
 
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Diagram of treatment 
 
A diagram of part 2 of the treatment can be seen below. 
                                       
Randomized 
Consolidation Therapy 
Treatment A 
1 Cycle of High Dose 
Chemotherapy
Treatment B 
1st Cycle of High Dose 
Chemotherapy
 
Stem Cell Transplant 
 
Rest Period 
4 weeks
 
Radiation Therapy 
 
Maintenance Therapy 
(6 cycles) 
 
Stem Cell Transplant 
Rest Period 
6 weeks 
 
Stem Cell Transplant 
Rest Period 
4 weeks 
Radiation Therapy 
 
Maintenance Therapy 
(6 cycles) 
Treatment B 
2nd Cycle of High Dose 
Chemotherapy
Off Therapy 
Off Therapy 
Completion of Induction 
Therapy 


 
 
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Treatment Plan Tables 
 
The following drug therapies compare standard consolidation chemotherapy and stem cell 
transplant to the experimental tandem consolidation chemotherapy and transplant.    
 
Various methods will be used to give drugs:.  
PO - Drug is given by tablet or liquid swallowed through the mouth (PO). 
IV - Drug is given using a needle or tubing inserted into a vein. It can be given by IV push over 
several minutes or by infusion over minutes or hours 
SUBQ - Drug is given by injecting a needle into the tissue just under the skin (SUBQ shot) 
 
Most drugs on this study will be given using a needle or tubing inserted into a vein (IV). 
 
Treatment for participants who are on treatment plan A 
 
After you finish induction therapy, you will get one cycle of very high dose chemotherapy and a 
hematopoietic stem cell transplant. The transplant will begin with treatment with very high doses 
of the chemotherapy drugs carboplatin, etoposide and melphalan. Etoposide and carboplatin 
are given as a continuous infusion for 4 consecutive days. The drug melphalan is given as a 
daily dose for 3 days. After the high dose chemotherapy treatment, your stored stem cells will 
be given IV (through the central line). These stem cells were collected from you during the 
induction phase of therapy and frozen.  This is called a Hematopoietic Stem Cell Transplant.  
You will be given filgrastim (GCSF) starting on the same day you receive your stem cells and 
continuing until your white blood cells have returned to a safe number, usually about 2 weeks. 
 
Drug  
How the drug will be given 
Days  
Carboplatin 
IV over 24 hours 
-7,-6,-5,-4 
Etoposide 
IV over 24 hours 
-7,-6,-5,-4 
Melphalan 
IV over 15-30 minutes  
-7,-6,-5 
Blood Stem Cells 
IV 
 0 
Filgrastim (GCSF) 
SUBQ (or) IV 
 0-14 
 
Treatment for participants who are on treatment plan B 
 
After completion of induction therapy, you will begin the first of the two cycles of very high dose 
chemotherapy and hematopoietic stem cell transplant. The first transplant will begin with 
treatment with very high doses of the chemotherapy drugs thiotepa and cyclophosphamide 
given IV over 6 total days. After the high dose chemotherapy treatment, some of your stored 
stem cells will be given IV (through the central line). These stem cells were previously collected 
from you during the induction phase and frozen.  You will be given filgrastim (GCSF) starting on 
the same day you get your stem cells and you will continue to get filgrastim (GCSF) until your 
white blood cells have returned to a safe number, usually about 2 weeks. 
 
Drug  
How the drug will be given 
Days  
Thiotepa 
IV over 2 hours 
-7,-6,-5 
Cyclophosphamide 
IV over 1 hour 
-5,-4,-3,-2 
Mesna 
IV over 15 minutes  
-5,-4,-3,-2 
Blood Stem Cells  
IV 
 0 
GCSF 
SUBQ (or) IV 
 0-14 
 


 
 
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Between 6-10 weeks from the start of the first treatment a second cycle of very high dose 
treatment is given. The treatment includes the drugs etoposide and carboplatin, which are given 
as a continuous infusion for 4 consecutive days. The drug melphalan is also given as a daily 
dose for 3 days during this treatment. After this second high dose chemotherapy treatment, 
some of your remaining stored stem cells will be given back to you. You will be given the same 
care as the first transplant. You will be given filgrastim (GCSF) starting on the same day you get 
your stem cells and you will continue to get  filgrastim (GCSF)  until your white blood cells have 
returned to a safe number, usually about 2 weeks. 
 
 
Drug  
How the drug will be given 
Days  
Carboplatin 
IV over 24 hours 
-7,-6,-5,-4 
Etoposide 
IV over 24 hours 
-7,-6,-5,-4 
Melphalan 
IV over 15-30 minutes 
-7,-6,-5 
Blood Stem Cells 
IV 
 0 
 Filgrastim (GCSF) 
SUBQ (or) IV 
 0-14 
 
 
Radiation Therapy 
 
It is standard to give radiation treatment to the area of the main tumor and to areas that still 
showed signs of active disease at the end of Induction phase of treatment.  Radiation therapy 
will begin after you have gotten better from the immediate side effects of the high doses of 
chemotherapy. If you are randomized to arm B (2 cycles of consolidation chemotherapy) you 
will get radiation therapy after you have recovered from the 2nd transplant. Radiation therapy 
usually starts about a month after the transplant.  The radiation therapy doctors will discuss this 
with you in more detail. The radiation is given in one short session each day, for a period of 
about 3- 4 weeks. Radiation to the stomach may cause nausea and vomiting, and often causes 
the blood counts to drop temporarily, which may require treatment with filgrastim (GCSF) or 
transfusions (give you blood). Other risks are discussed below. 
 
You will get a higher dose of radiation treatment if x-ray tests performed at the end of Induction 
therapy still show tumor (a lump).  The higher dose of radiation will only be given to the area 
where tumor is present.  This higher dose of radiation is experimental.  We are studying whether 
this higher dose of radiation will decrease the risk of tumor growing back.   
 
MAINTENANCE PHASE OF THERAPY 
Maintenance therapy will begin after you have recovered from effects of radiation therapy.  The 
use of an immune therapy that targets neuroblastoma (a medicine called chimeric 14.18 
antibody) combined with the prior standard therapy of cis-Retinoic acid (Accutane) has recently 
been shown to improve survival for children with high risk neuroblastoma.  Chimeric 14.18 
antibody is only available to patients with high risk neuroblastoma by enrolling onto another 
clinical trial.  It is strongly encouraged that you speak with your physician about receiving 
chimeric 14.18 therapy.  If you are not able to get ch14.18 therapy or choose not to get it, then 
you will get cis-Retinoic acid (Accutane) therapy alone.  Cis-Retinoic acid is given by mouth, 
twice daily for 2 weeks, followed by two weeks without the drug. This cycle will be repeated 6 
times for a total of 6 months of treatment. 
 
 
Standard Medical Tests 


 
 
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Before treatment on this study begins, and while receiving treatment, you will have a series of 
standard medical tests: 
 
 
Physical exam 
 
Blood Tests 
 
Bone marrow tests 
 
Tests of vision and hearing  
 
Urine tests 
 
Various scans (x-ray tests to see 
where the tumor is in your body) 
 
Tests of kidney function 
 
Tests of lung and heart function 
 
Hearing tests 
 
Dental exams 
 
Research study tests and procedures 
 
The following tests will be done because you are part of this study. These tests are not part of 
standard care. 
 
Some copies of the scans (x-rays) used to make the diagnosis of your disease and to see how 
your tumor responded to therapy will be sent to a central review center as part of COG quality 
control. 
 
We would like to collect additional blood to see if certain genes (genes direct the activities of 
cells) will effect whether you experience bad effects after chemotherapy, to see if your immune 
system is able to recognize neuroblastoma tumor cells and to test new methods for finding 
tumor cells. We will get all blood specimens through your central venous catheter.  We will try to 
get these additional blood samples when you are already having blood drawn for routine 
purposes.   
 
We would like to use any leftover portions of your bone marrow that is not needed to treat you to 
carry out special biology research studies to learn more about neuroblastoma. These studies 
will test new methods for finding tumor cells.  
 
Blood tests 
Before starting cis-retinoic acid (Accutane) treatment, we would like to take additional blood (20 
ml = 4 teaspoons) to see if your immune cells can recognize neuroblastoma tumors.   
 
After you have received the first 14 days of cis-retinoic acid, we would like to take additional 
blood (5 mL = 1 tsp) to look at how certain genes (genes direct the activities of cells) may affect 
whether you have side effects. 
 
At the end of Consolidation phase of therapy (after completing radiation therapy) and at the end 
of Maintenance therapy, we would like to obtain additional blood (2 ml = 1/2 teaspoon) to test 
new methods of finding neuroblastoma. 
 
Bone marrow tests 
We would also like to take 0.5 ml (1/10 tsp) of extra bone marrow at the end of Consolidation 
therapy and at the end of Maintenance therapy to study new methods of finding tumor cells.  
This bone marrow will be taken when we are normally taking a sample to see how you are 
responding to therapy.  The extra bone marrow will be shipped to a central lab for storage.   


 
 
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You and your physicians will not be given the results of these blood and bone marrow tests. You 
will not benefit from allowing us to perform these extra studies. We will try to take the blood 
samples when we are already taking blood for standard therapy.  The blood will be taken from 
your central line and will not require an extra blood draw.  You can ask that we stop collecting 
these specimens at any time during your treatment.  You will continue to get treatment on the 
study whether or not you allow us to collect these additional samples. 
 
Please read each sentence below and think about your choice. After reading each sentence, 
choose "Yes" or "No" then add your initials and date after your answer.  No matter what you 
decide to do, it will not affect your care.  If you have any questions, please talk to your doctor 
or nurse, or call our research review board at IRB's phone number included in this consent. 
 
 
I agree to the have additional bone marrow obtained for research purposes (to find new ways to 
detect neuroblastoma). 
 
 
Yes ______ 
 
No  _______  
 
Initials______ 
 
 
I agree to have additional blood obtained for research purposes (to test for immune cells that 
recognize neuroblastoma). 
 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
I agree to have additional blood obtained for research purposes (to find new ways to detect 
neuroblastoma). 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
I agree to have additional blood obtained for research purposes (to test how cis-RA is broken 
down). 
  
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
HOW LONG WILL I BE ON THIS STUDY? 
 
The Consolidation phase of therapy takes about 2 - 3 months (Arm A) or about 4 - 5 months 
(Arm B).  The Maintenance phase of therapy will last an additional 6 months.   
 
We will continue to collect some medical information about how you are doing for 10 years after 
you enter the study. Keeping in touch with you and checking on how your health is every year 
for a while after you complete treatment helps us understand the long-term effects of the study.  
 
Your doctor or the study doctor may decide to take you off this study for the following reasons: 
 
he/she believes that it is your best interest 
 
your disease comes back during treatment 
 
you experiences side effects from the treatment that are considered too severe 


 
 
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 
new information becomes available that shows that another treatment would be better for 
you 
 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the study doctor and your regular doctor first. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Treatment Risks 
All people who have cancer treatment are at risk of having side effects. In addition to killing 
tumor cells, cancer chemotherapy can damage normal tissue and produce side effects. Side 
effects are usually reversible when the medication is stopped but occasionally persist and cause 
serious complications. A person can die from these and other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be given to 
prevent or decrease nausea and vomiting. Hair loss is usually temporary but on very rare 
occasions it may be permanent. Some chemotherapy may lead to sterility.  Sterility means that 
you will not be able to have children. There is also the possibility that a second cancer may 
develop years later as a result of the chemotherapy.  The risks of the individual drugs given as 
standard treatment are listed on the tables in Attachment #1. Side effects can be increased 
when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of blood 
cells resulting in anemia, increased chance of infection, and bleeding tendency. Low blood 
counts are described in your Family Handbook for Children with Cancer. The high doses of 
chemotherapy used during the Consolidation phase of treatment will cause very severe lowering 
of the blood cell numbers.  You will be at risk to develop a life-threatening infection and bleeding 
following the very high doses of chemotherapy. To limit the risk of infection, your child will 
remain in a special hospital room until blood counts return to safe levels. Your stem cells that 
were previously collected and stored will be used to help your body make new blood cells.   
 
It is possible that it will take a very long time for your blood cells to be made.  This can happen if 
the stem cells were injured in your body even before they were removed or if the stem cells are 
injured during the collection, freezing or thawing processes.  If this happens, you will have a 
high chance that you will develop a severe infection and/or bleeding. This is very unlikely to 
happen, but would almost certainly be fatal.  Even after your body makes blood cells after the 
transplant, your ability to fight infection will be low for weeks to months after the transplant is 
complete.  You will be more likely to develop an infection in the months after transplant, 
especially from viruses. 
 
There is also a small risk of severe organ damage, especially to liver and kidney, with an even 
smaller risk to the heart and lungs. Though rare, the kidney damage can be severe enough to 
require dialysis. The liver damage can also be severe, resulting in jaundice and, occasionally, 
complete failure of the liver to function. This damage may be reversible or irreversible, and if 
irreversible, the liver failure would be fatal.  
 
There is a chance that the stem cells may contain tumor cells. These cells could result in the 
tumor coming back. 
 
These problems alone or in combination may be severe enough to be life-threatening. The 
purpose of using stem cells is to decrease the chance that these problems will happen. Your 


 
 
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doctor will also give you antibiotic and blood transfusions to decrease risk for infection or 
bleeding.   
 
Months or years after treatment other side effects may appear.  
 
We know that the chemotherapy drugs cyclophosphamide, melphalan and etoposide 
can cause leukemia.  
 
Radiation therapy may cause bone cancers or other kinds of sarcomas.  
 
Cyclophosphamide and melphalan will cause damage to the sexual glands. As a 
result, if you are a boy, you will almost certainly not be able to have biologically 
related children, and, if you are girl, you are likely to need hormones or other 
interventions to have children. 
Reproductive risks: 
It is unknown what effect(s) these treatments may have on an unborn child. As the drugs 
and/or radiation therapy in this study can affect a developing fetus (unborn baby in the womb), 
you should not become pregnant or father a baby while on this study. For this reason, if you 
are of child-bearing age, you will be asked to practice an effective method of birth control 
while participating on this study. The use of Isotretinoin can cause birth defects to 
unborn children if taken during pregnancy. Ask about counseling and more information 
about preventing pregnancy. Having the chemotherapy described may cause infertility (being 
less able to produce a viable egg or sperm) or sterility (being unable to produce a viable egg or 
sperm). We will talk to males who have reached puberty about sperm banking. 
 
For Women: 
The treatment on this study can affect an unborn child. You should not become pregnant or 
breast feed your baby while being treated on this study. If you are sexually active and are at risk 
of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex. The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study. You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctor about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation. If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor. If you 
become pregnant during the research study, please tell the investigator and your doctor 
immediately. 
 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctor about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage sperm. You should not father a child while on this 
study as the treatment may indirectly affect an unborn child. If you are sexually active and are at 
risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex. The investigator will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study. You will have 
to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctor about the length of time you need to 
avoid pregnancy or abstain. Natural family planning and the rhythm method will not be 


 
 
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permissible means of avoiding pregnancy during study participation. If you have questions 
about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor. If your partner becomes pregnant during the research study, please tell the investigator 
and your doctor immediately. 
 
There is a risk that the treatment plan will not cure the cancer or that the cancer can go away 
after the treatment and then come back at a later date.  
 
Risks of Study 
Tandem transplants are experimental.  We have over 10 years of experience with tandem 
transplant, but we are still learning about the risks that happen after this type of treatment.  The 
side effects described above may be increased if you have tandem (2 cycles) of high dose 
Consolidation chemotherapy.    
 
If you receive the tandem therapy (2 cycles) you will receive an additional cycle of high dose 
Consolidation chemotherapy, cyclophosphamide and thiotepa.  These drugs are often used for 
high dose Consolidation chemotherapy. You will receive them together, as the additional cycle 
of high dose Consolidation chemotherapy.   
 
You may get a higher dose of radiation if you still had tumor remaining after finishing the 
Induction phase of treatment.  For most patients, the area receiving the additional radiation dose 
will be small.  However, it is possible that the use of higher doses of radiation may be more 
likely to cause the side effects of radiation that are described in Attachment #2.    
 
Please see the attachment at the end of the consent (Attachment #2) for more information 
regarding the risks associated with radiation therapy and Peripheral Blood Stem Cell Harvesting 
and Reinfusion.  
 
Information may also be found in the COG Family Handbook  
 
For more information about risks and side effects, ask your child’s study doctor. 
 
In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
 
Your physician will be checking closely to see if any of these side effects are occurring. Routine 
physical exams and laboratory tests will be done to monitor the effects of treatment. Side effects 
usually disappear after the treatment is completed.  
 
Treatment on this study may have risks we don't know about. We may stop this treatment if 
we learn of serious, unexpected risks. We will explain the effects of stopping, and we will offer 
other treatments. 
 
Risks and side effects related to the thiotepa include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea  
 
Vomiting 
 
Loss of appetite 
 
A 
feeling 
of 
extreme 
tiredness or weakness 
 
Fewer white blood cells, 
 
Pain at the injection site 
 
Dizziness 
 
Headache 
 
Blurred vision 
 
Hives, skin rash 
 
Wheezing 
 
Severe allergic 
reaction which can 
be life threatening 
with shortness of 
breath, low blood 
pressure and a 


 
 
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red blood cells and 
platelets in the blood. 
○ A low number of red 
blood cells can make 
you feel tired and weak. 
○ A low number of white 
blood cells can make it 
easier to get infections. 
○ A low number of 
platelets causes you to 
bruise and bleed 
 
Absence  or decrease in 
the number of  sperm  
which may be temporary 
or permanent which may 
decrease the ability to 
have children 
 
Absence or decrease in 
monthly 
periods 
and 
could affect your ability to 
become pregnant 
 
With High Doses used before 
marrow transplants:  
 
Inflammation and/or sores 
in the mouth, throat 
and/or esophagus (the 
passage between the 
throat and stomach) 
 
Sudden high fever 
 
Pain in the abdomen 
 
Difficulty emptying the 
bladder 
 
Feeling the urgency to 
urinate or pain on 
urination 
 
Hair loss 
 
Inflammation and 
reddening of the eye 
 
Inflammation of the skin 
where the drug comes 
into contact with the skin
 
With High Doses used 
before marrow transplants:  
 
Inappropriate behavior  
 
Confusion 
 
Drowsiness 
 
Elevation in the blood of 
certain enzymes and/or 
bilirubin found in the 
liver 
 
Bronze discoloration or 
darkening of the skin 
rapid heart rate 
 
Swelling and 
tightening of the 
throat which can 
cause difficulty 
with breathing 
 
A new cancer or 
leukemia resulting 
from this treatment 
 
 
 


 
 
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Risks and side effects related to cyclophosphamide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Loss of appetite 
 
Nausea  
 
Vomiting 
 
Fewer white blood cells 
in the blood. 
○ 
A low number of 
white blood cells 
may make it easier 
to get infections. 
 
Hair loss 
 
Decreased ability of the 
body to fight infection  
 
Absence  or decrease in 
the number of  sperm  
which may be temporary 
or permanent which may 
decrease the ability to 
have children 
 
 
 Abnormal hormone 
function which may lower 
the level of salt in the 
blood  
 Abdominal pain 
 Diarrhea 
 Fewer red blood cells 
and platelets in the blood 
○ 
A low number of red 
blood cells may make 
you feel tired and 
weak. 
○ 
A low number of 
platelets may cause 
you to bruise and 
bleed more easily. 
 Bleeding and 
inflammation of the 
urinary bladder 
 Absence  or decrease 
monthly periods which 
may be temporary or 
permanent and which 
may decrease the ability 
to have children 
 Temporary blurred vision 
 Nasal stuffiness with IV 
infusions 
 Skin rash 
 Darkening of areas of the 
skin and finger nails 
 Slow healing of wounds 
 Infections  
 
Heart muscle damage which 
may occur with very high 
doses and which may be 
fatal 
 
Abnormal heart rhythms 
 
Damage and scarring of lung 
tissue which may make you 
short of breath 
 
A new cancer or leukemia 
resulting from this 
treatment. 
 
Damage or scarring of 
urinary bladder tissue 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate chills and fever 
 
Infertility which is the 
inability to have children 
 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
This experimental treatment may have benefits. This experimental treatment may turn out to be 
better at treating neuroblastoma than treatments we have used in the past. Unfortunately, there 
is no guarantee. We may find out that this treatment is not better. 
 
It is hoped that the information learned from this study may help future patients with high-risk 
neuroblastoma. 
 


 
 
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WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
 
Current standard therapy even if you do not take part in the study. 
 
Other stem cell transplant therapies.  
 
More treatment with standard doses of chemotherapy 
 
No further chemotherapy but just radiation therapy and cis-retinoinc acid therapy. 
 
No further therapy.   
 
You are encouraged to discuss these options with your regular doctor as well as other trusted 
personal and family advisors.  
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
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. Information about 
the certificate is attached at end of this consent. 
 
Organizations that may inspect and/or copy your research records for quality assurance 
and data analysis include groups such as: 
 
 
The Children's Oncology Group 
 
Representatives of the National Cancer Institute (NCI), Food and Drug Administration 
(FDA), and other U.S. and international governmental regulatory agencies involved in 
overseeing research  
 
The Institutional Review Board (IRB) of this hospital 
 
Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute 
 
 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance company. Please ask 
about any expected added costs or insurance problems. Staff will be able to assist you with this.  
You or your insurance company will not be charged for research studies performed on blood or 
bone marrow. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to pay you in 
the event of injury. However by signing this form, you are not giving up any legal rights to seek 
to payment for injury. 


 
 
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You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
There are no plans to pay you for taking part in this study.  If this study includes providing 
specimens to the researcher, there are no plans for you to profit from any new products 
developed from research done on your specimens 
 
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary.  You may leave the study at any time. Refusing to take 
part in the study, or leaving the study will not result in any penalty or loss of benefits to which 
you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies institutions 
if changes must be made to the study. Members of COG meet twice a year to evaluate results 
of treatment and to plan new treatments.  
 
During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years after treatment for all people on the 
study is completed.   
 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or a research-related problem, or if you think you have been 
injured, you may contact Dr. XXXX or your doctor at XXXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX IRB Administrator at (XXXX 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX 
 
WHERE CAN I GET MORE INFORMATION? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
 
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 


 
 
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Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/ 
 
Visit the COG Web site at http://www.curesearch.org 
 
Information about long term follow-up after cancer treatment can be found at 
http://www.survivorshipguidelines.org/ 
 
A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
 
SIGNATURE 
I have been given a copy of all _____ [insert total number of pages] pages of this form.  
The form includes three (3) attachments. 
 
 
I agree to take part in this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
IRB# 
IRB Approved: 
 
 


 
 
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Attachment #1 
Risks of Chemotherapy Drugs Used  
 
Risks and side effects related to carboplatin include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea and vomiting  
 
fewer red blood cells and 
white blood cells and 
platelets in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and weak 
o 
a low number of white 
blood cells can make it 
easier to get infections 
o 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Abnormal levels of certain 
salts in the body like 
sodium and potassium 
 
 Allergic reactions (can be 
severe and life-threatening 
causing difficulty in 
breathing and or a drop in 
blood pressure) 
 Rash 
 Metallic taste 
 Numbness and tingling in 
the fingers and toes 
 Hair loss 
 Constipation or diarrhea 
 Pain in your abdomen 
 Temporary changes in 
vision 
 Damage to the ear causing 
hearing and balance 
problems 
 A 
feeling 
of 
weakness 
and/or tiredness 
 Inflammation and/or sores 
in the mouth (and/or throat 
and /or esophagus, the 
tube that leads from the 
mouth to the stomach) 
that may make swallowing 
difficult and are painful 
(painful mouth sores) 
 Damage to the liver   
 Damage to the kidney  
 Leukemia later in life 
 
 
 
 


 
 
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Risks and side effects related to etoposide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea and vomiting 
 
Hair Loss 
 
A feeling of weakness or 
tiredness 
 
fewer red and white 
blood cells and platelets 
in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and 
weak 
o 
a low number of 
white blood cells can 
make it easier to get 
infections 
o 
a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
 
 
Loss of appetite 
 
Decreased blood 
pressure during the 
infusion which may 
require treatment 
 
rashes 
 
Diarrhea 
 
Pain in the abdomen 
 
Mouth sores 
 
Tingling sensation or 
loss of sensation in 
fingers or toes 
 
A feeling of  extreme 
tiredness or weakness 
 
The finger or toe nails 
may loosen from their 
nail beds 
 
Inflammation of the vein 
through which the 
medication was given 
 
Chest pain 
 
Damage to the liver 
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure, rapid heart rate, 
chills and fever 
 
A new cancer or leukemia 
resulting from this 
treatment 
 
Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes 
 
Absence  or decrease 
monthly periods which 
may be temporary or 
permanent and which may 
decrease the ability to 
have children 
 
Damage to the heart 
muscle which may make 
you feel tired, weak, feel 
short of breath, and retain 
fluid 
 
 
Risks and side effects related to isotretinoin (Accutane) include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Dryness of  your 
skin and mucous 
membranes  
 
Dry, cracked and 
bleeding lips 
 
An increased 
tendency to sun 
burn 
 
Bloody nose from 
dry membranes of 
the nose 
 
Aches and pains in 
the joints  
 
Back pain 
 
Elevation of the 
fats in your blood 
 
Increase in calcium 
in your blood 
which may require 
decreasing the 
dose 
 Rash and itching 
 Headache 
 Increase in cholesterol and a 
decrease in the good fat in 
the blood 
 Red eyes 
 Elevation in the blood of 
certain enzymes found in the 
liver which may mean liver 
irritation or damage 
 Fewer red blood cells and 
white blood cells and 
platelets in the blood  
o a low number of red blood 
cells can make you feel 
tired and weak 
o a low number of white 
blood cells can make it 
easier to get infections 
o a low number of platelets 
causes you to bruise and 
 
Severe allergic reaction 
which can be life 
threatening with 
shortness of breath, low 
blood pressure, rapid 
heart rate, chills and 
fever 
 
Irritation of the small 
airways in your lungs 
that can make you 
cough and wheeze 
 
An allergic reaction in 
the blood vessels of the 
skin which turn the skin 
red, inflamed and  
bumpy and which may 
lead to skin breakdown 
 
A severe lowering of the 
white blood count which 
can make you very 
susceptible to infections 


 
 
ANBL0532 
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 
An increase in a 
laboratory test on 
your blood that 
may measure some 
non specified 
inflammation 
which may or may 
not be of any 
importance 
bleed more easily 
 
Too many platelets in the 
blood 
 
Loss or thinning of hair 
 
Appetite disturbances 
causing you not to feel 
hungry or to feel unusually 
hungry 
 
Weight loss 
 
Increase in blood sugar 
levels 
 
A darkening or lightening 
of your skin 
 
Finger and toe nail changes 
including breaking or 
splitting more easily 
 The sudden appearance of 
little yellow raised bumps 
on the skin usually 
because the cholesterol in 
the blood is too high 
(xanthomas) 
 
Dizziness 
 
Difficulty falling asleep or 
staying asleep and strange 
dreams 
 
A feeling of tiredness or 
not feeling well 
 
Nervousness 
 
Numbness and tingling in 
the fingers and toes 
 
Difficulty hearing clearly or 
a ringing in the ears 
 
Changes in vision including 
more difficulty seeing at 
night, blurred vision, 
changes in color vision, 
pain or squinting in bright 
light, and cataract 
formation 
 
Fluid retention 
 
Chest pain 
 
Inflammation of the gums 
 
A dry throat which could 
lead to a change in your 
voice and more throat 
infections 
 
Slowed growth 
 
Irregular periods 
which could be life 
threatening  
 
Convulsions 
 
Brain swelling that can 
give you symptoms of 
severe headache, 
nausea and vomiting, 
and changes to your 
vision including 
blurriness and pressure 
behind the eyes 
 
Life threatening or fatal 
changes in moods have 
occurred including 
severe depression or 
feelings of suicide and 
feelings of 
aggressiveness and 
violent behavior   
 
Thinning of the bone 
(osteoporosis) which 
could lead to weakness 
of the bone, bone 
fractures or delay in 
healing of fractures 
 
Inflammation of the 
pancreas which can lead 
to severe abdominal 
pain and in some very 
rare cases can be fatal 
 
Damage to the muscle 
which can release a 
protein that can cause 
severe damage to the 
kidneys 
 
Inflammation of the 
intestinal tract which 
can result in diarrhea 
and bleeding 
 
This drug can cause 
severe birth defects in a 
developing fetus, if you 
are capable of becoming 
pregnant or of child 
bearing age, you must 
practice 2 forms of 
reliable birth control, 
sign the Patient 
Information/Informed 
Consent form(s), have 


 
 
ANBL0532 
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 
Mild kidney damage which 
could lead to blood or 
protein in the urine or renal 
stones 
 
Extra bone growth along 
the spine and a tendency 
for calcium deposits in the 
tendons and ligaments 
where they attach to the 
bone which can lead to 
pain or stiffness and 
arthritis of the back and 
tendonitis 
regular pregnancy tests, 
be able to keep 
appointments and agree 
to follow the iPLEDGE 
program steps (a special 
program required by the 
manufacturers and 
approved by the Food 
and Drug Administration 
(FDA) which your doctor 
will explain to you). 
 
 
 


 
 
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Risks and side effects related to melphalan include those which are: 
Likely 
Less Likely 
Rare But serious 
 
Loss of Appetite 
 
Nausea and/or vomiting 
 
Low levels of salt in the 
blood which may need to 
be treated (usually 
associated with high 
doses) 
 
Diarrhea 
 
Inflammation and/or 
sores in the mouth 
(and/or throat and /or 
esophagus, the tube that 
leads from the mouth to 
the stomach) that may 
make swallowing difficult 
and are painful (painful 
mouth sores) 
 
Temporary hair loss 
 
Fewer white blood cells, 
red blood cells and 
platelets in the blood  
o    a low number of 
white blood cells 
can make it easier 
to get infections 
o    a low number of red 
blood cells can 
make you feel tired 
and weak 
o     a low number of 
platelets causes 
you to bruise and 
bleed more easily 
 
 
Absence of menstrual 
cycles (periods) and 
damage to the ovaries 
that may decrease the 
ability to have children 
in the future 
 
Absence or decrease in 
the number of sperm  
which may be 
temporary or 
permanent which may 
decrease the ability to 
have children 
 
Inability to have 
children (infertility)   
 
Sweating 
 
Itching 
 
Low blood pressure  
 
Abnormal heart rate 
(usually associated 
with high doses) 
 
Damage to the skin if 
the medication leaks 
from the vein 
 
Increase in the blood of 
certain enzymes or 
bilirubin (a substance 
that comes from the 
liver breaking down 
waste products) which 
could indicate liver 
irritation or damage 
 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate, chills and fever 
 
Seizures 
 
Damage to the liver which 
can lead to inflammation 
and/or scarring which could 
lead to a yellow appearing 
skin, and fluid collection in 
the abdomen (belly) which 
makes it look larger 
 
Severe damage to the bone 
marrow which could lead to 
low numbers of white blood 
cells, red blood cells and 
platelets and could be 
permanent 
 
Sudden damage to the red 
blood cells (hemolytic 
anemia) which could cause a 
rapid decrease in the 
number of red blood cells 
such that you would be tired 
and weak and feel short of 
breath and may require a 
blood transfusion 
 
Inflammation and/or scarring 
of the lungs that can lead to 
fluid in the lungs and affect 
your ability to breath and the 
levels of oxygen in your 
blood making you short of 
breath 
 
A new cancer or leukemia 
resulting from this treatment 
 
 
 
 
 


 
 
ANBL0532 
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Risks and side effects related to myeloid growth factors (filgrastim (G-CSF) or pegfilgrastim) 
include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Aching or pain in the 
bones 
 
 
Pain, redness, itching, 
and hardening of the 
skin and bruising at the 
site of the injection 
 
Headache 
 
Higher than normal 
levels of liver enzymes 
in the blood which may 
indicate liver irritation 
or damage 
 
Increase of uric acid in 
the blood 
 
A low number of 
platelets in the blood 
which may cause you 
to bruise and bleed 
more easily 
 
Low fever 
 
Enlargement of the 
spleen (an organ in the 
abdomen/belly which 
stores blood cells) 
which may cause pain 
in the abdomen or left 
shoulder 
 
Higher than normal 
white blood count 
 
Skin condition marked 
by fever and painful 
skin lesions that 
appear mainly on the 
face, neck, back and 
arms  
 
Rash or worsening of 
rash1 
 
Inflammation of blood 
vessels in the skin 
leading to a raised 
purple rash and 
bruising has been seen 
mainly in patient who 
are treated for a long 
time1 
 
Overall reddening with 
feelings of warmth2 
 
 
 
Allergic reactions which 
can be life threatening 
with shortness of 
breath, low blood 
pressure, rapid heart 
rate, hives, itching, and 
facial swelling.  
 
Serious allergic reaction 
which can be life 
threatening with rapid 
build-up of fluid under 
the skin, in the lining of 
the intestine, and 
possibly in the throat or 
swelling of the tongue 
which could make it 
difficult to breath2 
 
If you are known to have 
sickle cell disease, 
filgrastim or 
pegfilgrastim may cause 
a sickle cell crisis. 
 
Severe damage to the 
spleen (an organ in the 
abdomen/belly which 
stores blood cells) 
which could lead to pain 
and loss of blood into 
the abdomen (belly) and 
maybe life threatening 
 
Difficulty breathing and 
lung damage that may 
be due to the white 
blood cells that are 
stimulated by filgrastim 
or pegfilgrastim 
traveling to the lungs 
when they are inflamed 
or infected. 
 
A blood disorder or 
leukemia that has only 
been seen in patients 
with certain immune 
disorders who are 
treated for a very long 
time1 
 
1 Reported with filgrastim 
2 Reported with pegfilgrastim 
 
 
 
 


 
 
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Risks and side effects related to mesna include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
 
Nausea. 
 
Vomiting 
 
Stomach pain. 
 
Headache. 
 
Pain in arms, legs and 
joints. 
 
Tired feeling. 
 
Rash. 
 
Temporary low blood 
pressure. 
 
Diarrhea. 
 
Fever 
 
Facial flushing with red 
cheeks 
 
Nervousness 
 
Dizziness 
 
Confusion 
 
Swelling around the 
eyes 
 
Coughing 
 
Rapid heart rate 
 
Severe allergic 
reaction which can 
be life threatening 
with shortness of 
breath, low blood 
pressure, rapid heart 
rate chills and fever 
 
 
 


 
 
ANBL0532 
Page 175 
 
 
 
Attachment #2 
Risks of Radiation Therapy and Peripheral Blood Stem Cell Harvesting and Reinfusion 
 
Radiation Therapy Risks 
The risks of radiation therapy depend on the parts of the body being treated. Some possible 
risks are described below, but you should talk to your child’s doctor to see which apply to your 
child. Radiation therapy can cause nausea, vomiting, diarrhea, red or dry skin, low blood counts, 
hair loss (permanent or temporary), jaw pain and swelling, temporary weakness or loss of 
sensation. Some patients have a week or two of low grade fever and sleepiness can occur six to 
eight weeks after radiation therapy is done. Damage to body organs such as the brain, eyes, 
heart, lung, liver, and kidneys can occur. Radiation therapy can also cause abnormal bone 
growth. There is also a small chance that radiation can cause another type of tumor years later. 
 
Peripheral Blood Stem Cell Harvesting and Reinfusion 
These procedures are usually safe. Side effects that can occur during PBSC collection include 
nausea, vomiting, fainting or dizziness, seizures, skin rash, hives, flushing (redness and 
warmness of the skin, usually the face), blood loss, and infection. Tingling of the lips, muscle 
cramping and, very rarely, changes in the heart rhythm can occur. These can be prevented or 
made milder by giving calcium supplements, either by mouth or IV. Very rarely, (less than 1 in 
1,000 procedures), clotting may occur in the apheresis machine or in a patient and is potentially 
life-threatening. To reduce the risk of clotting, you will be given a drug called ACD (acid-citrate-
dextrose). This drug may increase the risk of bleeding and may cause temporary tingling of the 
lips and limbs, muscle cramping, seizures, or changes in the heart rhythm. 
 
 
The risks associated with infusing the cells back into your body include dark urine, nausea, 
vomiting, fever, chills, and high blood pressure. All of these are temporary and go away after the 
infusion is done. As with any procedure, there may be side effects we do not expect. 
 


 
 
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Attachment #3 
Certificate of Confidentiality Information 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the 
federal government, which will help us protect the privacy of our research subjects.  The 
Certificate protects against the involuntary release of information about subjects 
collected during the course of our covered studies.  The researchers involved in the 
studies cannot be forced to disclose the identity or any information collected in the study 
in any legal proceedings at the federal, state, or local level, regardless of whether they 
are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain 
circumstances.  For example, if the subject or his/her guardian requests the release of 
information in writing, the Certificate does not protect against that voluntary disclosure.  
Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA 
request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will 
not protect against the required reporting by hospital staff of information on suspected 
child abuse, reportable communicable diseases, and/or possible threat of harm to self 
or others. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SAMPLE INFORMED CONSENT / PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH  
 
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed. (Institutions 
should attempt to use sections of this document which are in bold type in their entirety.) Editorial 
changes to these sections may be made as long as they do not change information or intent. If 
the local IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they must be justified in writing by the investigator and approved by the 
IRB.  
 
ANBL0532, Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation 
Therapy for High-Risk Neuroblastoma:  
 
PART 2 B: CONSENT FOR PATIENTS TO BE NON-RANDOMLY ASSIGNED TO SINGLE 
MYELOABLATIVE CONSOLIDATION THERAPY 
 
Consolidation and Maintenance Phases of Therapy for High Risk Neuroblastoma (Please 
note that this consent MUST be signed before the patient proceeds for consolidation therapy) 
 
When the word “you” appears in this consent form, it refers to you or your son or daughter; “we” 
means the doctors and other staff. 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY? 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you. 
 
The Children's Oncology Group (COG) is carrying out this study. COG is an international 
research group that conducts clinical trials for children with cancer at more than 200 hospitals in 
the United States, Canada, Australia, New Zealand, the Netherlands, and Switzerland. It is 
common medical practice to treat children with cancer on research studies like this one. 
 
You are being asked to take part in this study because you have high risk neuroblastoma and 
you have participated in Part 1 of this study. Neuroblastoma is a type of cancer.  You have the 
type of neuroblastoma that is called High Risk because your tumor has spread from where it 
started from or because your type of tumor is harder to treat.   
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard treatment for High Risk neuroblastoma and this clinical 
trial. Please take your time to make your decision about taking part in this clinical trial.  You may 
discuss your decision with your friends and family.  You can also discuss it with your health care 
team.  We encourage you to include your child in the discussion and decision to the extent that 
she or he is able to understand and take part.  If you have any questions, you can ask your 
study doctor for more explanation.  
 
WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE? 
The treatment for neuroblastoma includes 3 parts (phases) of therapy called Induction, 
Consolidation and Maintenance. During Induction therapy anti-cancer drugs (chemotherapy) 
and surgery are used to kill and remove as much tumor as possible.  Blood stem cells are 
collected during the Induction phase of therapy.  After collection the blood stem cells are frozen 


 
 
ANBL0532 
Page 178 
and stored to be used during Consolidation phase of treatment.  Blood stem cells are the cells 
that create new blood cells, such as red blood cells, white blood cells, and platelets. Blood stem 
cells can be collected from the blood by using a machine that can separate out the part of blood 
that has stem cells and then return the remaining blood back to the patient.  You have already 
received this part of therapy. 
 
During the Consolidation phase of treatment extremely high doses of chemotherapy are given to 
better kill any remaining neuroblastoma cells. It is standard therapy to give one cycle of this 
extremely high dose chemotherapy. The high doses of chemotherapy destroy healthy bone 
marrow. Bone marrow is the soft tissue in the hollow of flat bones of the body that produces new 
blood cells.  The peripheral blood stem cells that were stored during the Induction phase of 
treatment are given back to the patient after the high dose Consolidation chemotherapy.  These 
stems cells allow the bone marrow to return to normal so that new blood cells can be made. 
This type of therapy is called a Hematopoietic Stem Cell Transplant. Once the patient has 
healed from the effects of high doses of chemotherapy, radiation therapy is given to the first 
place the tumor was found and to any additional places where the tumor was found after 
Induction therapy.   
 
During the third phase of therapy, Maintenance, an oral drug, called cis-retinoic acid (Accutane) 
is given. 
 
WHY IS THIS STUDY BEING DONE? 
 
Most of the patients enrolled on this study have very high risk neuroblastoma.  The main 
goal of this study applies to them. That goal is to find out if using 2 cycles of high dose 
Consolidation chemotherapy, instead of 1 cycle, will decrease the chance that the 
neuroblastoma will grow back after therapy.  However, some types of high risk 
neuroblastoma have a lower risk of having tumor grow back. 
 
These types of neuroblastoma are described as being in one of two groups.  These groups are: 
 
Patients who are between the ages of 12 and 18 months at diagnosis of neuroblastoma.  
Their neuroblastoma tumor has spread to distant sites (stage 4), does not have 
increased levels of the MYCN gene, but does have other high risk biologic 
characteristics. 
 
Patients who are greater than 18 months of age at diagnosis of neuroblastoma.  Their 
neuroblastoma tumor has spread locally (stage 3), does not have increased levels of the 
MYCN gene but does have other high risk biologic characteristics. 
 
Very few patients with high risk neuroblastoma (about 5-10%) have these types of 
neuroblastoma.  Previous clinical trials have not always used high dose Consolidation 
chemotherapy to treat these types of high risk neuroblastoma. We need to learn more about the 
best way to treat this smaller group.  We want to evaluate how patients in this group respond to 
treatment after 1 cycle of high dose Consolidation therapy.   
 
This research study will also find out if patients whose tumor did not disappear with initial 
induction therapy will need a higher dose of radiation therapy.   
 
The treatment is described in two separate consent forms.  You have already read the first 
consent form (Part 1) and completed Part 1 of treatment. We are now presenting Part 2 (the 
second consent form) of the study. The second consent (Part 2) will discuss the Consolidation 
and Maintenance phases of therapy.   
 
 


 
 
ANBL0532 
Page 179 
During this part of the study, we will: 
 
Find out if patients with high-risk neuroblastoma who have a lower risk of the tumor 
coming back can be treated with 1 cycle of high dose Consolidation chemotherapy. 
 
Study whether a higher dose of radiation, given only to patients with tumor remaining 
after induction therapy, will decrease the chance that tumor will grow back.   
 
Study whether your immune system (blood cells that help fight infection) can produce 
cells that can recognize and kill neuroblastoma.   
 
Study whether new tests can be used to find small amounts of neuroblastoma cells. 
 
Study how cis-retinoic acid (Accutane) is broken down by your body and study 
whether your genes (genes direct activities of cells) effect how you respond to cis-
retinoic acid therapy. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 664 subjects will take part in this study. The study will last about 3-4 years.   
 
WHAT WILL HAPPEN ON THIS STUDY? 
If you participate in this part of the study you will be given the following treatment plan.  
 
Treatment Plan 
The treatment plan involves cancer fighting medicine called chemotherapy plus radiation 
therapy.  The treatment on this part of the clinical trial takes about 9 months.  
 
Myeloablative therapy means that you will receive very high doses of chemotherapy that 
will destroy normal bone marrow cells. 
 
You will receive consolidation treatment after you have finished induction therapy and signed 
this consent.  
 


 
 
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Page 180 
 
Diagram of treatment 
 
A diagram of part 2 of the treatment can be seen below.   
 
 
                                     
Treatment A 
1 Cycle of High Dose 
Chemotherapy
 
Stem Cell Transplant 
 
Rest Period 
4 weeks
 
Radiation Therapy 
 
Maintenance Therapy 
(6 cycles) 
Off Therapy 
Non-Randomized 
Consolidation Therapy 
Completion of Induction 
Therapy 


 
 
ANBL0532 
Page 181 
 
Treatment Plan Tables 
The following drug therapies will be used for Single Myeloablative Consolidation.    
 
Various methods will be used to give drugs:  
PO - Drug is given by tablet or liquid swallowed through the mouth (PO). 
IV - Drug is given using a needle or tubing inserted into a vein. It can be given by IV push over 
several minutes or by infusion over minutes or hours 
SUBQ - Drug is given by injecting a needle into the tissue just under the skin (SUBQ shot) 
 
Most drugs on this study will be given using a needle or tubing inserted into a vein (IV). 
 
Treatment  
 
After you finish induction therapy, you will get one cycle of very high dose chemotherapy and a 
hematopoietic stem cell transplant. The transplant will begin with treatment with very high doses 
of the chemotherapy drugs carboplatin, etoposide and melphalan. Etoposide and carboplatin 
are given as a continuous infusion for 4 consecutive days. The drug melphalan is given as a 
daily dose for 3 days. After the high dose chemotherapy treatment, your stored stem cells will 
be given IV (through the central line). These stem cells were collected from you during the 
induction phase of therapy and frozen.  This is called a Hematopoietic Stem Cell Transplant.  
You will be given filgrastim (GCSF) starting on the same day you receive your stem cells and 
continuing until your white blood cells have returned to a safe number, usually about 2 weeks. 
 
Drug  
How the drug will be given 
Days  
Carboplatin 
IV over 24 hours 
-7,-6,-5,-4 
Etoposide 
IV over 24 hours 
-7,-6,-5,-4 
Melphalan 
IV over 15-30 minutes  
-7,-6,-5 
Blood Stem Cells 
IV 
 0 
Filgrastim (GCSF) 
SUBQ (or) IV 
 0-14 
 
Radiation Therapy 
It is standard to give radiation treatment to the area of the main tumor and to areas that still 
showed signs of active disease at the end of Induction phase of treatment.  Radiation therapy 
will begin after you have gotten better from the immediate side effects of the high doses of 
chemotherapy. Radiation therapy usually starts about a month after the transplant.  The 
radiation therapy doctors will discuss this with you in more detail. The radiation is given in one 
short session each day, for a period of up to 3 weeks. Radiation to the stomach may cause 
nausea and vomiting, and often causes the blood counts to drop temporarily, which may require 
treatment with filgrastim (GCSF) or transfusions (give you blood). Other risks are discussed 
below. 
 
You will get a higher dose of radiation treatment if x-ray tests performed at the end of Induction 
therapy still show tumor (a lump).  The higher dose of radiation will only be given to the area 
where tumor is present.  This higher dose of radiation is experimental.  We are studying whether 
this higher dose of radiation will decrease the risk of tumor growing back.   


 
 
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MAINTENANCE PHASE OF THERAPY 
Maintenance therapy will begin after you have recovered from effects of radiation therapy.  The 
use of an immune therapy that targets neuroblastoma (a medicine called chimeric 14.18 
antibody) combined with the prior standard therapy of cis-Retinoic acid (Accutane) has recently 
been shown to improve survival for children with high risk neuroblastoma.  Chimeric 14.18 
antibody is only available to patients with high risk neuroblastoma by enrolling onto another 
clinical trial.  It is strongly encouraged that you speak with your physician about receiving 
chimeric 14.18 therapy.  If you are not able to get ch14.18 therapy or choose not to get it, then 
you will get cis-Retinoic acid (Accutane) therapy alone.  Cis-Retinoic acid is given by mouth, 
twice daily for 2 weeks, followed by two weeks without the drug. This cycle will be repeated 6 
times for a total of 6 months of treatment. 
 
 
Standard Medical Tests 
Before treatment on this study begins, and while receiving treatment, you will have a series of 
standard medical tests: 
 
Physical exam 
 
Blood Tests 
 
Bone marrow tests 
 
Tests of vision and hearing  
 
Urine tests 
 
Various scans (x-ray tests to see 
where the tumor is in your body) 
 
Tests of kidney function 
 
Tests of lung and heart function 
 
Hearing tests 
 
Dental exams 
 
Research study tests and procedures 
The following tests will be done because you are part of this study. These tests are not part of 
standard care. 
 
Some copies of the scans (x-rays) used to make the diagnosis of your disease and to see how 
your tumor responded to therapy will be sent to a central review center as part of COG quality 
control. 
 
We would like to collect additional blood to see if certain genes (genes direct the activities of 
cells) will effect whether you experience bad effects after chemotherapy, to see if your immune 
system is able to recognize neuroblastoma tumor cells and to test new methods for finding 
tumor cells. We will get all blood specimens through your central venous catheter.  We will try to 
get these additional blood samples when you are already having blood drawn for routine 
purposes.   
 
We would like to use any leftover portions of your bone marrow that is not needed to treat you to 
carry out special biology research studies to learn more about neuroblastoma. These studies 
will test new methods for finding tumor cells.  
 
Blood tests 
Before starting cis-retinoic acid (Accutane) treatment, we would like to take additional blood (20 
ml = 4 teaspoons) to see if your immune cells can recognize neuroblastoma tumors.   
 
After you have received the first 14 days of cis-retinoic acid, we would like to take additional 
blood (5 mL = 1 tsp) to look at how certain genes (genes direct the activities of cells) may affect 
whether you have side effects. 
 


 
 
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At the end of Consolidation phase of therapy (after completing radiation therapy) and at the end 
of Maintenance therapy, we would like to obtain additional blood (2 ml = 1/2 teaspoon) to test 
new methods of finding neuroblastoma. 
 
Bone marrow tests 
We would also like to take 0.5 ml (1/10 tsp) of extra bone marrow at the end of Consolidation 
therapy and at the end of Maintenance therapy to study new methods of finding tumor cells.  
This bone marrow will be taken when we are normally taking a sample to see how you are 
responding to therapy.  The extra bone marrow will be shipped to a central lab for storage.   
 
 
 
 
You and your physicians will not be given the results of these blood and bone marrow tests. You 
will not benefit from allowing us to perform these extra studies. We will try to take the blood 
samples when we are already taking blood for standard therapy.  The blood will be taken from 
your central line and will not require an extra blood draw.  You can ask that we stop collecting 
these specimens at any time during your treatment.  You will continue to get treatment on the 
study whether or not you allow us to collect these additional samples. 
 
Please read each sentence below and think about your choice. After reading each sentence, 
choose "Yes" or "No" then add your initials and date after your answer.  No matter what you 
decide to do, it will not affect your care.  If you have any questions, please talk to your doctor 
or nurse, or call our research review board at IRB's phone number included in this consent. 
 
I agree to the have additional bone marrow obtained for research purposes (to find new ways to 
detect neuroblastoma). 
 
Yes ______ 
 
No  _______  
 
Initials______ 
 
 
I agree to have additional blood obtained for research purposes (to test for immune cells that 
recognize neuroblastoma). 
 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
I agree to have additional blood obtained for research purposes (to find new ways to detect 
neuroblastoma). 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
I agree to have additional blood obtained for research purposes (to test how cis-RA is broken 
down). 
 
 
Yes ______ 
 
No _________ 
 
 
Initials _______ 
 
 
HOW LONG WILL I BE ON THIS STUDY? 
 


 
 
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The Consolidation phase of therapy takes about 2 - 3 months.  The Maintenance phase of 
therapy will last an additional 6 months.   
 
We will continue to collect some medical information about how you are doing for 10 years after 
you enter the study. Keeping in touch with you and checking on how your health is every year 
for a while after you complete treatment helps us understand the long-term effects of the study.  
 
 
Your doctor or the study doctor may decide to take you off this study for the following reasons: 
 
he/she believes that it is your best interest 
 
your disease comes back during treatment 
 
you experiences side effects from the treatment that are considered too severe 
 
new information becomes available that shows that another treatment would be better for 
you 
 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the study doctor and your regular doctor first. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Treatment Risks 
All people who have cancer treatment are at risk of having side effects. In addition to killing 
tumor cells, cancer chemotherapy can damage normal tissue and produce side effects. Side 
effects are usually reversible when the medication is stopped but occasionally persist and cause 
serious complications. A person can die from these and other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be given to 
prevent or decrease nausea and vomiting. Hair loss is usually temporary but on very rare 
occasions it may be permanent. Some chemotherapy may lead to sterility.  Sterility means that 
you will not be able to have children. There is also the possibility that a second cancer may 
develop years later as a result of the chemotherapy.  The risks of the individual drugs given as 
standard treatment are listed on the tables in Attachment #1. Side effects can be increased 
when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of blood 
cells resulting in anemia, increased chance of infection, and bleeding tendency. Low blood 
counts are described in your Family Handbook for Children with Cancer. The high doses of 
chemotherapy used during the Consolidation phase of treatment will cause very severe lowering 
of the blood cell numbers.  You will be at risk to develop a life-threatening infection and bleeding 
following the very high doses of chemotherapy. To limit the risk of infection, your child will 
remain in a special hospital room until blood counts return to safe levels. Your stem cells that 
were previously collected and stored will be used to help your body make new blood cells.   
 
It is possible that it will take a very long time for your blood cells to be made.  This can happen if 
the stem cells were injured in your body even before they were removed or if the stem cells are 
injured during the collection, freezing or thawing processes.  If this happens, you will have a 
high chance that you will develop a severe infection and/or bleeding. This is very unlikely to 
happen, but would almost certainly be fatal.  Even after your body makes blood cells after the 
transplant, your ability to fight infection will be low for weeks to months after the transplant is 
complete.  You will be more likely to develop an infection in the months after transplant, 
especially from viruses. 
 


 
 
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There is also a small risk of severe organ damage, especially to liver and kidney, with an even 
smaller risk to the heart and lungs. Though rare, the kidney damage can be severe enough to 
require dialysis. The liver damage can also be severe, resulting in jaundice and, occasionally, 
complete failure of the liver to function. This damage may be reversible or irreversible, and if 
irreversible, the liver failure would be fatal.  
 
There is a chance that the stem cells may contain tumor cells. These cells could result in the 
tumor coming back. 
 
These problems alone or in combination may be severe enough to be life-threatening. The 
purpose of using stem cells is to decrease the chance that these problems will happen. Your 
doctor will also give you antibiotic and blood transfusions to decrease risk for infection or 
bleeding.   
 
 
Months or years after treatment other side effects may appear.  
 
We know that the chemotherapy drugs cyclophosphamide, melphalan and etoposide 
can cause leukemia.  
 
Radiation therapy may cause bone cancers or other kinds of sarcomas.  
 
Cyclophosphamide and melphalan will cause damage to the sexual glands. As a 
result, if you are a boy, you will almost certainly not be able to have biologically 
related children, and, if you are girl, you are likely to need hormones or other 
interventions to have children. 
 
Reproductive risks: 
It is unknown what effect(s) these treatments may have on an unborn child. As the drugs 
and/or radiation therapy in this study can affect a developing fetus (unborn baby in the womb), 
you should not become pregnant or father a baby while on this study. For this reason, if you 
are of child-bearing age, you will be asked to practice an effective method of birth control 
while participating on this study. The use of Isotretinoin can cause birth defects to 
unborn children if taken during pregnancy. 
 
Ask about counseling and more information about preventing pregnancy. Having the 
chemotherapy described may cause infertility (being less able to produce a viable egg or sperm) 
or sterility (being unable to produce a viable egg or sperm). We will talk to males who have 
reached puberty about sperm banking. 
 
For Women: 
The treatment on this study can affect an unborn child. You should not become pregnant or 
breast feed your baby while being treated on this study. If you are sexually active and are at risk 
of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex. The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study. You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctor about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation. If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor. If you 
become pregnant during the research study, please tell the investigator and your doctor 
immediately. 
 


 
 
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If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctor about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage sperm. You should not father a child while on this 
study as the treatment may indirectly affect an unborn child. If you are sexually active and are at 
risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex. The investigator will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study. You will have 
to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctor about the length of time you need to 
avoid pregnancy or abstain.  
 
Natural family planning and the rhythm method will not be permissible means of avoiding 
pregnancy during study participation. If you have questions about this or want to change your 
method to avoid pregnancy during therapy, please ask your doctor. If your partner becomes 
pregnant during the research study, please tell the investigator and your doctor immediately. 
 
There is a risk that the treatment plan will not cure the cancer or that the cancer can go away 
after the treatment and then come back at a later date.  
 
Risks of Study 
The side effects of high dose chemotherapy are more severe than the side effects of standard 
doses of chemotherapy. 
 
You may get a higher dose of radiation if you still had tumor remaining after finishing the 
Induction phase of treatment.  For most patients, the area receiving the additional radiation dose 
will be small.  However, it is possible that the use of higher doses of radiation may be more 
likely to cause the side effects of radiation that are described in Attachment #2.    
 
Please see the attachment at the end of the consent (Attachment #2) for more information 
regarding the risks associated with radiation therapy and Peripheral Blood Stem Cell Harvesting 
and Reinfusion.  
 
Information may also be found in the COG Family Handbook  
 
For more information about risks and side effects, ask your child’s study doctor. 
 
In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
 
Your physician will be checking closely to see if any of these side effects are occurring. Routine 
physical exams and laboratory tests will be done to monitor the effects of treatment. Side effects 
usually disappear after the treatment is completed.  
 
Treatment on this study may have risks we don't know about. We may stop this treatment if 
we learn of serious, unexpected risks. We will explain the effects of stopping, and we will offer 
other treatments. 


 
 
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ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
This experimental treatment may have benefits. This experimental treatment may turn out to be 
better at treating neuroblastoma than treatments we have used in the past. Unfortunately, there 
is no guarantee. We may find out that this treatment is not better. 
 
It is hoped that the information learned from this study may help future patients with high-risk 
neuroblastoma. 
 
 
 
 
WHAT OTHER OPTIONS ARE THERE? 
Instead of being in this study, you have these options: 
 
Current standard therapy even if you do not take part in the study. 
 
Other stem cell transplant therapies.  
 
More treatment with standard doses of chemotherapy 
 
No further chemotherapy but just radiation therapy and cis-retinoinc acid therapy. 
 
No further therapy.   
 
You are encouraged to discuss these options with your regular doctor as well as other trusted 
personal and family advisors.  
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
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. Information about 
the certificate is attached at end of this consent. 
 
Organizations that may inspect and/or copy your research records for quality assurance 
and data analysis include groups such as: 
 
 
The Children's Oncology Group 
 
Representatives of the National Cancer Institute (NCI), Food and Drug Administration 
(FDA), and other U.S. and international governmental regulatory agencies involved in 
overseeing research  
 
The Institutional Review Board (IRB) of this hospital 
 
Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute 
 
WHAT ARE THE COSTS? 
Taking part in this study may lead to added costs to you or your insurance company. Please ask 
about any expected added costs or insurance problems. Staff will be able to assist you with this.  
You or your insurance company will not be charged for research studies performed on blood or 
bone marrow. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to pay you in 
the event of injury. However by signing this form, you are not giving up any legal rights to seek 
to payment for injury. 
 


 
 
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You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
There are no plans to pay you for taking part in this study.  If this study includes providing 
specimens to the researcher, there are no plans for you to profit from any new products 
developed from research done on your specimens 
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
Taking part in this study is voluntary.  You may leave the study at any time. Refusing to take 
part in the study, or leaving the study will not result in any penalty or loss of benefits to which 
you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies institutions 
if changes must be made to the study. Members of COG meet twice a year to evaluate results 
of treatment and to plan new treatments.  
 
During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years after treatment for all people on the 
study is completed.   
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related problem, or if you think you have been 
injured, you may contact Dr. XXXX or your doctor at XXXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call  XXXX IRB Administrator at (XXXX 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX 
 
WHERE CAN I GET MORE INFORMATION? 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/ 
 
Visit the COG Web site at http://www.curesearch.org 
 
Information about long term follow-up after cancer treatment can be found at 
http://www.survivorshipguidelines.org/ 
 


 
 
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A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
SIGNATURE 
I have been given a copy of all _____ [insert total number of pages] pages of this form.  
The form includes three (3) attachments. 
 
 
I agree to take part in this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
IRB# 
IRB Approved: 
 
 


 
 
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Attachment #1 
Risks of Chemotherapy Drugs Used  
 
Risks and side effects related to carboplatin include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea and vomiting  
 
fewer red blood cells and 
white blood cells and 
platelets in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and weak 
o 
a low number of white 
blood cells can make it 
easier to get infections 
o 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Abnormal levels of certain 
salts in the body like 
sodium and potassium 
 
 Allergic reactions (can be 
severe and life-threatening 
causing difficulty in 
breathing and or a drop in 
blood pressure) 
 Rash 
 Metallic taste 
 Numbness and tingling in 
the fingers and toes 
 Hair loss 
 Constipation or diarrhea 
 Pain in your abdomen 
 Temporary changes in 
vision 
 Damage to the ear causing 
hearing and balance 
problems 
 A 
feeling 
of 
weakness 
and/or tiredness 
 Inflammation and/or sores 
in the mouth (and/or throat 
and /or esophagus, the 
tube that leads from the 
mouth to the stomach) 
that may make swallowing 
difficult and are painful 
(painful mouth sores) 
 Damage to the liver   
 Damage to the kidney  
 Leukemia later in life 
 
 
 
 


 
 
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Risks and side effects related to etoposide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Nausea and vomiting 
 
Hair Loss 
 
A feeling of weakness or 
tiredness 
 
fewer red and white 
blood cells and platelets 
in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and 
weak 
o 
a low number of 
white blood cells can 
make it easier to get 
infections 
o 
a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
 
 
Loss of appetite 
 
Decreased blood 
pressure during the 
infusion which may 
require treatment 
 
rashes 
 
Diarrhea 
 
Pain in the abdomen 
 
Mouth sores 
 
Tingling sensation or 
loss of sensation in 
fingers or toes 
 
A feeling of  extreme 
tiredness or weakness 
 
The finger or toe nails 
may loosen from their 
nail beds 
 
Inflammation of the vein 
through which the 
medication was given 
 
Chest pain 
 
Damage to the liver 
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure, rapid heart rate, 
chills and fever 
 
A new cancer or leukemia 
resulting from this 
treatment 
 
Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes 
 
Absence  or decrease 
monthly periods which 
may be temporary or 
permanent and which may 
decrease the ability to 
have children 
 
Damage to the heart 
muscle which may make 
you feel tired, weak, feel 
short of breath, and retain 
fluid 
 
 
 
 
Risks and side effects related to isotretinoin (Accutane) include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Dryness of  your 
skin and mucous 
membranes  
 
Dry, cracked and 
bleeding lips 
 
An increased 
tendency to sun 
burn 
 
Bloody nose from 
dry membranes of 
the nose 
 
Aches and pains in 
the joints  
 
Back pain 
 
Elevation of the 
fats in your blood 
 
Increase in calcium 
in your blood 
which may require 
 Rash and itching 
 Headache 
 Increase in cholesterol and a 
decrease in the good fat in 
the blood 
 Red eyes 
 Elevation in the blood of 
certain enzymes found in the 
liver which may mean liver 
irritation or damage 
 Fewer red blood cells and 
white blood cells and 
platelets in the blood  
o a low number of red blood 
cells can make you feel 
tired and weak 
o a low number of white 
blood cells can make it 
easier to get infections 
 
Severe allergic reaction 
which can be life 
threatening with 
shortness of breath, low 
blood pressure, rapid 
heart rate, chills and 
fever 
 
Irritation of the small 
airways in your lungs 
that can make you 
cough and wheeze 
 
An allergic reaction in 
the blood vessels of the 
skin which turn the skin 
red, inflamed and  
bumpy and which may 
lead to skin breakdown 
 
A severe lowering of the 
white blood count which 


 
 
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decreasing the 
dose 
 
An increase in a 
laboratory test on 
your blood that 
may measure some 
non specified 
inflammation 
which may or may 
not be of any 
importance 
o a low number of platelets 
causes you to bruise and 
bleed more easily 
 
Too many platelets in the 
blood 
 
Loss or thinning of hair 
 
Appetite disturbances 
causing you not to feel 
hungry or to feel unusually 
hungry 
 
Weight loss 
 
Increase in blood sugar 
levels 
 
A darkening or lightening 
of your skin 
 
Finger and toe nail changes 
including breaking or 
splitting more easily 
 The sudden appearance of 
little yellow raised bumps 
on the skin usually 
because the cholesterol in 
the blood is too high 
(xanthomas) 
 
Dizziness 
 
Difficulty falling asleep or 
staying asleep and strange 
dreams 
 
A feeling of tiredness or 
not feeling well 
 
Nervousness 
 
Numbness and tingling in 
the fingers and toes 
 
Difficulty hearing clearly or 
a ringing in the ears 
 
Changes in vision including 
more difficulty seeing at 
night, blurred vision, 
changes in color vision, 
pain or squinting in bright 
light, and cataract 
formation 
 
Fluid retention 
 
Chest pain 
 
Inflammation of the gums 
 
A dry throat which could 
lead to a change in your 
voice and more throat 
infections 
can make you very 
susceptible to infections 
which could be life 
threatening  
 
Convulsions 
 
Brain swelling that can 
give you symptoms of 
severe headache, 
nausea and vomiting, 
and changes to your 
vision including 
blurriness and pressure 
behind the eyes 
 
Life threatening or fatal 
changes in moods have 
occurred including 
severe depression or 
feelings of suicide and 
feelings of 
aggressiveness and 
violent behavior   
 
Thinning of the bone 
(osteoporosis) which 
could lead to weakness 
of the bone, bone 
fractures or delay in 
healing of fractures 
 
Inflammation of the 
pancreas which can lead 
to severe abdominal 
pain and in some very 
rare cases can be fatal 
 
Damage to the muscle 
which can release a 
protein that can cause 
severe damage to the 
kidneys 
 
Inflammation of the 
intestinal tract which 
can result in diarrhea 
and bleeding 
 
This drug can cause 
severe birth defects in a 
developing fetus, if you 
are capable of becoming 
pregnant or of child 
bearing age, you must 
practice 2 forms of 
reliable birth control, 
sign the Patient 


 
 
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Page 193 
 
Slowed growth 
 
Irregular periods 
 
Mild kidney damage which 
could lead to blood or 
protein in the urine or renal 
stones 
 
Extra bone growth along 
the spine and a tendency 
for calcium deposits in the 
tendons and ligaments 
where they attach to the 
bone which can lead to 
pain or stiffness and 
arthritis of the back and 
tendonitis 
Information/Informed 
Consent form(s), have 
regular pregnancy tests, 
be able to keep 
appointments and agree 
to follow the iPLEDGE 
program steps (a special 
program required by the 
manufacturers and 
approved by the Food 
and Drug Administration 
(FDA) which your doctor 
will explain to you). 
 
 
 


 
 
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Page 194 
 
Risks and side effects related to melphalan include those which are: 
Likely 
Less Likely 
Rare But serious 
 
Loss of Appetite 
 
Nausea and/or vomiting 
 
Low levels of salt in the 
blood which may need to 
be treated (usually 
associated with high 
doses) 
 
Diarrhea 
 
Inflammation and/or 
sores in the mouth 
(and/or throat and /or 
esophagus, the tube that 
leads from the mouth to 
the stomach) that may 
make swallowing difficult 
and are painful (painful 
mouth sores) 
 
Temporary hair loss 
 
Fewer white blood cells, 
red blood cells and 
platelets in the blood  
o    a low number of 
white blood cells 
can make it easier 
to get infections 
o    a low number of red 
blood cells can 
make you feel tired 
and weak 
o     a low number of 
platelets causes 
you to bruise and 
bleed more easily 
 
 
Absence of menstrual 
cycles (periods) and 
damage to the ovaries 
that may decrease the 
ability to have children 
in the future 
 
Absence or decrease in 
the number of sperm  
which may be 
temporary or 
permanent which may 
decrease the ability to 
have children 
 
Inability to have 
children (infertility)   
 
Sweating 
 
Itching 
 
Low blood pressure  
 
Abnormal heart rate 
(usually associated 
with high doses) 
 
Damage to the skin if 
the medication leaks 
from the vein 
 
Increase in the blood of 
certain enzymes or 
bilirubin (a substance 
that comes from the 
liver breaking down 
waste products) which 
could indicate liver 
irritation or damage 
 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate, chills and fever 
 
Seizures 
 
Damage to the liver which 
can lead to inflammation 
and/or scarring which could 
lead to a yellow appearing 
skin, and fluid collection in 
the abdomen (belly) which 
makes it look larger 
 
Severe damage to the bone 
marrow which could lead to 
low numbers of white blood 
cells, red blood cells and 
platelets and could be 
permanent 
 
Sudden damage to the red 
blood cells (hemolytic 
anemia) which could cause a 
rapid decrease in the 
number of red blood cells 
such that you would be tired 
and weak and feel short of 
breath and may require a 
blood transfusion 
 
Inflammation and/or scarring 
of the lungs that can lead to 
fluid in the lungs and affect 
your ability to breath and the 
levels of oxygen in your 
blood making you short of 
breath 
 
A new cancer or leukemia 
resulting from this treatment 
 
 
 
 
 


 
 
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Risks and side effects related to myeloid growth factors (filgrastim (G-CSF) or pegfilgrastim) 
include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Aching or pain in the 
bones 
 
 
Pain, redness, itching, 
and hardening of the 
skin and bruising at the 
site of the injection 
 
Headache 
 
Higher than normal 
levels of liver enzymes 
in the blood which may 
indicate liver irritation 
or damage 
 
Increase of uric acid in 
the blood 
 
A low number of 
platelets in the blood 
which may cause you 
to bruise and bleed 
more easily 
 
Low fever 
 
Enlargement of the 
spleen (an organ in the 
abdomen/belly which 
stores blood cells) 
which may cause pain 
in the abdomen or left 
shoulder 
 
Higher than normal 
white blood count 
 
Skin condition marked 
by fever and painful 
skin lesions that 
appear mainly on the 
face, neck, back and 
arms  
 
Rash or worsening of 
rash1 
 
Inflammation of blood 
vessels in the skin 
leading to a raised 
purple rash and 
bruising has been seen 
mainly in patient who 
are treated for a long 
time1 
 
Overall reddening with 
feelings of warmth2 
 
 
 
Allergic reactions which 
can be life threatening 
with shortness of 
breath, low blood 
pressure, rapid heart 
rate, hives, itching, and 
facial swelling.  
 
Serious allergic reaction 
which can be life 
threatening with rapid 
build-up of fluid under 
the skin, in the lining of 
the intestine, and 
possibly in the throat or 
swelling of the tongue 
which could make it 
difficult to breath2 
 
If you are known to have 
sickle cell disease, 
filgrastim or 
pegfilgrastim may cause 
a sickle cell crisis. 
 
Severe damage to the 
spleen (an organ in the 
abdomen/belly which 
stores blood cells) 
which could lead to pain 
and loss of blood into 
the abdomen (belly) and 
maybe life threatening 
 
Difficulty breathing and 
lung damage that may 
be due to the white 
blood cells that are 
stimulated by filgrastim 
or pegfilgrastim 
traveling to the lungs 
when they are inflamed 
or infected. 
 
A blood disorder or 
leukemia that has only 
been seen in patients 
with certain immune 
disorders who are 
treated for a very long 
time1 
 
1 Reported with filgrastim 
2 Reported with pegfilgrastim 
 
 
 
 


 
 
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Attachment #2 
Risks of Radiation Therapy and Peripheral Blood Stem Cell Harvesting and Reinfusion 
 
Radiation Therapy Risks 
The risks of radiation therapy depend on the parts of the body being treated. Some possible 
risks are described below, but you should talk to your child’s doctor to see which apply to your 
child. Radiation therapy can cause nausea, vomiting, diarrhea, red or dry skin, low blood counts, 
hair loss (permanent or temporary), jaw pain and swelling, temporary weakness or loss of 
sensation. Some patients have a week or two of low grade fever and sleepiness can occur six to 
eight weeks after radiation therapy is done. Damage to body organs such as the brain, eyes, 
heart, lung, liver, and kidneys can occur. Radiation therapy can also cause abnormal bone 
growth. There is also a small chance that radiation can cause another type of tumor years later. 
 
Peripheral Blood Stem Cell Harvesting and Reinfusion 
These procedures are usually safe. Side effects that can occur during PBSC collection include 
nausea, vomiting, fainting or dizziness, seizures, skin rash, hives, flushing (redness and 
warmness of the skin, usually the face), blood loss, and infection. Tingling of the lips, muscle 
cramping and, very rarely, changes in the heart rhythm can occur. These can be prevented or 
made milder by giving calcium supplements, either by mouth or IV. Very rarely, (less than 1 in 
1,000 procedures), clotting may occur in the apheresis machine or in a patient and is potentially 
life-threatening. To reduce the risk of clotting, you will be given a drug called ACD (acid-citrate-
dextrose). This drug may increase the risk of bleeding and may cause temporary tingling of the 
lips and limbs, muscle cramping, seizures, or changes in the heart rhythm. 
 
 
The risks associated with infusing the cells back into your body include dark urine, nausea, 
vomiting, fever, chills, and high blood pressure. All of these are temporary and go away after the 
infusion is done. As with any procedure, there may be side effects we do not expect. 
 


 
 
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Attachment #3 
Certificate of Confidentiality Information 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the 
federal government, which will help us protect the privacy of our research subjects.  The 
Certificate protects against the involuntary release of information about subjects 
collected during the course of our covered studies.  The researchers involved in the 
studies cannot be forced to disclose the identity or any information collected in the study 
in any legal proceedings at the federal, state, or local level, regardless of whether they 
are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain 
circumstances.  For example, if the subject or his/her guardian requests the release of 
information in writing, the Certificate does not protect against that voluntary disclosure.  
Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA 
request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will 
not protect against the required reporting by hospital staff of information on suspected 
child abuse, reportable communicable diseases, and/or possible threat of harm to self 
or others.