A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma
Phase: PHASE3
Conditions: Localized Extraskeletal Ewing Sarcoma, Peripheral Primitive Neuroectodermal Tumor of Bone, Peripheral Primitive Neuroectodermal Tumor of Soft Tissues
Sponsor: Children's Oncology Group

AEWS1031 
CHILDREN’S ONCOLOGY GROUP 
AEWS1031 
A Phase III Randomized Trial of Adding Vincristine-topotecan-cyclophosphamide to 
Standard Chemotherapy in Initial Treatment of Non-metastatic Ewing Sarcoma 
A Groupwide Phase III Study 
This study is supported by the NCI Cancer Trials Support Unit (CTSU) (See page # 2) 
Endorsing Cooperative Groups 
Group name   
 
Radiation Therapy Oncology Group (RTOG) 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN 
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org 
Version Date: 
03/04/16 
Activated: 
11/22/10 
Closed:            07/17/17
Amendment: 
#2 
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AEWS1031 
 
 
 
 
 
Institutions not aligned with COG will participate through the CTSU mechanism as outlined 
below and detailed in Appendix III- CTSU Participation Procedures. 
 
• 
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU members’ side of the website located at https://www.ctsu.org 
 
• 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
participation procedures (Appendix III) for specific instructions and documents to be submitted.  
• 
Patient enrollments will be conducted by the CTSU. Refer to Appendix III for specific instructions 
and forms to be submitted. 
 
• 
Data management will be performed by COG. Case report forms (with the exception of patient 
enrollment forms), clinical reports, and transmittals must be sent to COG unless otherwise 
directed by the protocol. Do not submit study data or case report forms to the CTSU Data 
Operations. Do not copy the CTSU on data submissions.  
 
• 
Data query and delinquency reports will be available for viewing on the COG website. Query 
responses and delinquent data will be handled with COG via the SADD (Schedule and Delinquent 
Data) system. Sites should check this system regularly to view their site’s information. Do not copy 
the CTSU Data Operations on any forms. Each site should have a designated CTSU Administrator 
and Data Administrator and must keep their CTEP IAM account contact information current. This 
will ensure timely communication between the clinical site and the COG data center. 
 
 
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AEWS1031 
TABLE OF CONTENTS 
SECTION 
PAGE 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Objective 
11 
1.2 
Correlative Science Objectives 
11 
2.0 
BACKGROUND 
12 
2.1 
Rationale for cyclophosphamide, topotecan and vincristine in Ewing sarcoma 
12 
2.2 
Rationale for weekly vincristine schedule 
13 
2.3 
Dexrazoxane cardioprotection 
13 
2.4 
Rationale for timing intensification 
13 
2.5 
Feasibility of administration of VDC-IE-VTC on a interval compressed schedule 
14 
2.6 
Biologic prognostic factors 
14 
2.7 
Tumor size and histologic response as prognostic Factors 
14 
2.8 
Impact of local therapy decisions on local control 
15 
2.9 
Radiologic Response and prognosis 
16 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
17 
3.1 
Study Enrollment 
17 
3.2 
Patient Criteria 
18 
4.0 
TREATMENT PROGRAM 
21 
4.1 
Overview of Treatment plan 
21 
4.2 
Concomitant Medications 
24 
4.3 
General Approach to Primary Tumor Treatment (Local Control) 
25 
4.4 
Chemotherapy Administration Schedule 
27 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
57 
5.1 
Slow Blood Count Recovery 
57 
5.2 
Renal Toxicity 
57 
5.3 
Cardiac Toxicity 
58 
5.4 
Neurological Toxicity 
59 
5.5 
Mucositis 
59 
5.6 
Hematuria or Hemorrhagic Cystitis 
60 
5.7 
Hepatotoxicity 
60 
5.8 
Dermatologic Toxicity 
61 
5.9 
Any Other Grade 3 or 4 Toxicities 
61 
5.10 
Allergy to Etoposide 
61 
6.0 
DRUG INFORMATION 
61 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
61 
7.1 
Required/Recommended Clinical, Laboratory and Disease Evaluations 
62 
7.2 
Follow-up 
63 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
64 
8.1 
Criteria for Removal from Protocol Therapy 
64 
8.2 
Off Study Criteria 
64 
9.0 
STATISTICAL CONSIDERATIONS 
64 
9.1 
Patient Accrual and Expected Outcome and Expected Duration of Trial 
64 
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9.2 
Statistical Analysis Methods 
65 
9.3 
Gender and Minority Accrual Estimates 
70 
10.0 
EVALUATION CRITERIA 
70 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
70 
10.2 
Response Criteria for Patients with Solid Tumors 
70 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
73 
11.1 
Purpose 
73 
11.2 
Determination of Reporting Requirements 
73 
11.3 
Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway 73 
11.4 
Routine Adverse Event Reporting 
74 
12.0 
RECORDS AND REPORTING 
74 
12.1 
CDUS 
75 
13.0 
SURGICAL GUIDELINES 
75 
13.1 
Surgical Guidelines for Biopsy 
75 
13.2 
Surgical Guidelines for Consideration of Amputation at Diagnosis 
76 
13.3 
Surgical Guidelines for Primary Bone Lesions 
76 
13.4 
Anatomic Guidelines for Resectability 
77 
13.5 
Reporting 
82 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
82 
14.1 
Biopsy Pathology Procedures 
82 
14.2 
Molecular and Cytogenetic Studies for Initial Diagnosis 
83 
14.3 
Specimen From Surgical Resection 
83 
14.4 
Pathology Review Requirements 
84 
14.5 
Consultation 
85 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
85 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
85 
16.1 
Primary site imaging 
86 
16.2 
Metastatic site imaging 
86 
16.3 
Required and Recommended Imaging 
86 
16.4 
Technical Guidelines 
88 
16.5 
Submitting Imaging for Central Review 
88 
17.0 
RADIATION THERAPY GUIDELINES 
89 
17.1 
General Guidelines 
89 
17.2 
Indications for Radiation Therapy 
90 
17.3 
Timing of Radiotherapy 
90 
17.4 
Emergency Radiation Therapy 
91 
17.5 
Equipment and Methods of Delivery and Verification 
91 
17.6 
Target Volumes 
92 
17.7 
Target Dose 
96 
17.8 
Treatment Technique 
98 
17.9 
Organs at Risk 
100 
17.10 Dose Calculations and Reporting 
101 
17.11 Quality Assurance Documentation 
101 
17.12 Definition of Minor and Major Deviations 
104 
APPENDIX I: 
GUIDELINES FOR OPTIONAL FDG-PET IMAGING  
105 
APPENDIX II: 
YOUTH INFORMATION SHEETS 
109 
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APPENDIX III 
CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION 
PROCEDURES 
111 
REFERENCES 
115 
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For Group Operations (GOC) and  
AGENT  
 
NSC#   
IND# 
Statistics and Data Center (SDC) contacts see: 
Vincristine 
 
NSC #67574 
Exempt 
http://members.childrensoncologygroup.org 
Doxorubicin 
 
NSC #123127  
Exempt 
Telephone: 
(626) 447-0064 
Cyclophosphamide 
NSC #26271  
Exempt 
 
Topotecan 
 
NSC #609699 
Exempt 
 
Ifosfamide 
 
NSC #109724 
Exempt 
 
Etoposide 
 
NSC #141540  
Exempt 
 
Mesna  
 
NSC #113891 
Exempt 
 
Dexrazoxane 
 
NSC# 169780  
Exempt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 14.4.3 FOR SPECIMEN SHIPPING ADDRESSES 
 
 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
 
ABSTRACT 
 
 
Intergroup Ewing sarcoma study INT-0091 (CCG 7881, POG 8850) demonstrated that a regimen of 
alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide was superior to 
vincristine-doxorubicin-cyclophosphamide alone. AEWS0031 has demonstrated interval compression to 
be superior to standard timing. The five drug alternating combination using interval compression should be 
considered the North American standard therapy for localized Ewing sarcoma. Cyclophosphamide with 
topotecan has been demonstrated to be active in patients with recurrent and metastatic Ewing sarcoma. 
Vincristine has been shown to be synergistic with topotecan in xenograft models of rhabdomyosarcoma. 
This randomized Phase 3 trial will test the efficacy of adding vincristine-topotecan-cyclophosphamide to 
the interval compressed 5 drug backbone. 
 
This study will also assess initial tumor volume, histologic response to induction chemotherapy and 
response measured by FDG-PET as prognostic factors for event free survival in patients with non-metastatic 
Ewing sarcoma. 
  
 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
  
 
RANDOMIZATION AT STUDY ENTRY  
to 
REGIMEN A or REGIMEN B 
 
INDUCTION 
 
6 Cycles(12 weeks) 
Regimen A: VDC1200/IE 
Regimen B: VTC250/IE/VDC1200  
LOCAL CONTROL THERAPY 
 
(May involve surgery and/or XRT. 
If radiation is used, it will be given 
with Consolidation therapy) 
 
EVALUATIONS 
• 
Progressive disease (local progression 
or disease detected at new sites) or 
• 
Biopsy positive residual disease after 
all local control measures completed 
OFF PROTOCOL 
THERAPY 
CONSOLIDATION 
11 Cycles (22 weeks) 
Regimen A: VDC1200/IE/VC1200 
Regimen B: VTC250/IE/VDC1200  
 
VDC1200: vincristine-doxorubicin-cyclophosphamide1200 mg 
IE: 
ifosfamide-etoposide 
VTC250: vincristine-topotecan-cyclophosphamide250 mg 
VC1200: 
vincristine-cyclophosphamide1200 mg 
XRT: 
radiation therapy 
 
EVALUATIONS 
After Local Control 
 
Progressive disease 
(local progression or disease 
detected at new sites) 
OFF PROTOCOL 
THERAPY 
END OF PROTOCOL 
THERAPY 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objective 
Test the effect of the combination of vincristine, cyclophosphamide and topotecan added to the standard 5-
drug chemotherapy interval compressed backbone on event-free and overall survival in children and young 
adults with Ewing sarcoma. 
 
1.2 
Correlative Science Objectives 
 
1.2.1 
Evaluate initial volumetric tumor size as a prognostic factor for event free survival (EFS) in patients with 
localized Ewing tumors. 
 
1.2.2 
Evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors. 
 
1.2.3 
Continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via 
encouraging concurrent enrollment on a Ewing sarcoma specimen collection study. 
 
1.2.4 
Evaluate imaging response by FDG-positron emission tomography (PET) as a prognostic factor for EFS. 
 
1.2.5 
Evaluate the effects of the type of local therapy on EFS and overall survival. 
 
1.2.6 
Evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients 
with localized Ewing tumors. 
 
1.2.7 
Evaluate the effect of local therapy modality (surgery, radiotherapy or a combination) as well as the type 
of surgical reconstruction on musculoskeletal complications. 
 
 
 
 
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2.0 
BACKGROUND  
Intergroup Ewing sarcoma study INT-0091 (CCG 7881, POG 8850) demonstrated that a regimen of 
alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide was superior to 
vincristine-doxorubicin- cyclophosphamide alone. Dactinomycin was substituted for doxorubicin once a 
cumulative doxorubicin dose of 375 mg/m2 had been given. Patients received 17 courses of chemotherapy. 
Among the 398 patients with non-metastatic disease the mean five year event free survival in the 
experimental therapy group was 69% ± 3% (198 patients) as compared with 54% ± 4% (200 patients) in 
the standard therapy group.1 The five drug alternating combination (without dactinomycin) became the 
North American standard therapy for Ewing sarcoma. The 5-year event-free survival (EFS) and overall 
survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% 
to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with 
the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 
63.9% to 75%).2 
 
The recently completed study for initially localized Ewing sarcoma, AEWS0031, tested dose intensification 
of all agents by interval compression. The compressed arm was demonstrated to be superior to the standard 
arm in event free survival: 76% versus 65% at 4 years (p=0.029), and overall survival: 91% versus 85% at 
4 years (p=0.026).3 This study established the five drug alternating chemotherapy combination using 
interval compression as the standard therapy for localized Ewing sarcoma. 
 
The European collaborative study Euro-Ewing 99 uses six cycles of 4 drug induction (vincristine- 
ifosfamide-doxorubicin-etoposide or VIDE) based on results of EICESS 92 and UK ET-2 which 
demonstrated the importance of ifosfamide in induction. After induction therapy, the study includes two 
randomized comparisons: for patients with localized disease and a good response (< 10% viable tumor after 
VIDE), continuation therapy with either vincristine-dactinomycin with cyclophosphamide (VAC) versus 
ifosfamide (VAI); for patients with large tumors (>200 mL) or poor response (>10% viable tumor after 
VIDE) VAI versus Busulfan-Melphalan megatherapy. 
 
Another strategy to potentially improve outcome for these patients would be the addition of new active drug 
combinations.  
 
2.1 
Rationale for cyclophosphamide, topotecan and vincristine in Ewing sarcoma 
Cyclophosphamide in combination with topotecan has been studied in the pediatric Phase I setting, 
establishing a recommended dose of cyclophosphamide (250 mg/m2/dose) followed by topotecan 
(0.75 mg/m2/dose), each given as a 30-minute infusion, daily for 5 days, followed by G-CSF on Day 6. The 
Pediatric Oncology Group Phase II study showed activity in recurrent or refractory rhabdomyosarcoma, 
neuroblastoma and Ewing sarcoma. Responses were reported in 6/17 patients with Ewing sarcoma. 
Hematopoietic toxicities were common but only 11% of 307 courses were associated with Grade 3 or 4 
infection.4 Non-hematologic toxicities were rare. Additional experience in the window setting in patients 
with Ewing sarcoma that was metastatic at initial diagnosis (P9457) yielded 21 PR (57%), 15 SD and only 
1 PD of 37 evaluable patients treated with one (the patient with PD) or two cycles of topotecan-
cyclophosphamide. Again, the predominant toxicity was hematologic. Non-hematopoietic toxicities were 
rare. Recently reported data from Germany confirm a similar response rate in patients with recurrent Ewing 
sarcoma. Forty-four patients (37 in first relapse) received a median of 3 courses. Responses were observed 
in 18/44 (41%) including 5 CR and 13 PR.5 
 
In xenografts representing rhabdomyosarcoma, neuroblastoma and brain tumors, the combination of 
topotecan and vincristine has greater than additive activity. The schedule used was topotecan IV daily for 
5 days and vincristine IV every 7 days.6 The combination of vincristine, topotecan and cyclophosphamide 
has been tolerable in the rhabdomyosarcoma intermediate risk study (D9803) and in patients with metastatic 
rhabdomyosarcoma7 
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The combination of topotecan-cyclophosphamide with weekly vincristine is therefore a good candidate for 
testing in previously untreated patients with localized Ewing sarcoma. 
 
2.2 
Rationale for weekly vincristine schedule 
The single agent activity of vincristine in Ewing sarcoma has been estimated at 50%.8 Vincristine has been 
used in a once every 21- 28 day schedule in Ewing sarcoma with VDC and VAC courses in previous Ewing 
study group protocols. This is in contrast to the once every 7 day scheduling used in other tumors such as 
Wilms tumor and rhabdomyosarcoma. Specific information regarding the effect of vincristine scheduling 
in Ewing sarcoma is lacking. However, a study of 7 versus 21-day intervals in human rhabdomyosarcoma 
xenografts demonstrated clear superiority of every 7 day administration.9 The xenograft study of vincristine 
with topotecan also includes every 7-day dosing of vincristine.6 In order to maximize the effectiveness of 
vincristine, and appropriately parallel the xenograft model of vincristine-topotecan synergy, it is proposed 
to use vincristine in a weekly schedule during VDC and VTC courses in this study. 
 
2.3 
Dexrazoxane cardioprotection 
Long term cardiotoxicity is a recognized complication of anthracycline-based chemotherapy. Clinical 
cardiotoxicity has been reported in up to 3% of patients treated for Ewing sarcoma.10 Dexrazoxane has been 
shown to provide short- and medium-term protection from cardiotoxicity induced by anthracyclines in 
children with acute lymphoblastic leukemia11 as well as pediatric sarcomas.12,13 Dexrazoxane has also been 
included in pediatric trials for Hodgkin lymphoma, T cell ALL and osteosarcoma. The agent has been well 
tolerated, although there have been reported increases in neutropenia and neutropenic enteropathy in some 
series. Possible tumor protection was reported in one adult breast tumor study although the response rate in 
the control arm appeared to be unusually high.14 Tumor protection has not been demonstrated in other 
studies including pediatric trials using dexrazoxane.15 In adults, decreased cardiotoxicity has been observed 
when dexrazoxane has been used with later anthracycline containing courses.16 Based on this it has been 
recommended that dexrazoxane be considered in adults receiving more than 300 mg/m² doxorubicin-based 
therapy.17 No similar recommendations exist for pediatric oncology. We propose the addition of 
dexrazoxane to doxorubicin containing courses above a 225 mg/m² cumulative dose. Long term clinical 
toxicity will be evaluated in comparison to previous Ewing studies which have used the same agents and 
the same total doxorubicin dose. 
 
In order to facilitate the use of dexrazoxane, doxorubicin will be administered as short, 15 minute infusions, 
rather than the 48- hour infusion used in CCG7942/POG 9354 and AEWS0031. Short infusion doxorubicin 
has been previously used in INT0091 (POG8850/CCG7881). The similar event free survivals for patients 
with non-metastatic Ewing tumors on the INT0091 and CCG7942/POG9354 suggest the use of short 
infusion will not affect EFS. Continuous infusion doxorubicin was initially reported as being associated 
with less cardiotoxicity.18,19 However, recent publications suggest no benefit.20-22 In addition patients 
receiving doxorubicin by continuous infusion as part of treatment for osteosarcoma on CCG7921/POG9351 
were reported to have more mucositis than those who received divided bolus doses on the previous 
intergroup study. The use of short infusion/bolus doxorubicin will also decrease the hospitalization time 
necessary with 48-hour infusion doxorubicin. 
 
2.4 
Rationale for timing intensification 
Dose intensification by escalating drug doses is limited by the toxicities of the agents used. The advantage 
of dose intensification via interval compression is that it provides a means of increasing the dose intensity 
of all drugs, without apparent increases in toxicity. Decreasing the chemotherapy interval from three weeks 
to two provides 33% dose intensification. Though this does not seem a huge increase, it may be 
therapeutically significant. This therapeutic effect and feasibility has been demonstrated in several adult 
breast and lung cancer studies.23-28 
 
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COG AEWS0031 (which closed to patient accrual in August 2005) investigated interval compression of 
the 5-drug combination vs. standard chemotherapy for localized Ewing sarcoma and showed comparable 
toxicity between both treatment regimens. Five hundred and sixty four eligible patients were randomized 
between the experimental every-2-week regimen and the standard every-3-week regimen. Preliminary 
results of this study reveal that patients treated with the experimental interval compressed 5-drug alternating 
combination had a superior EFS (4 year EFS: 76 vs. 65%, p=0.029) and OS (4 year OS: 91 vs. 85%, p= 
0.026) when compared to the standard 5-drug alternating combination administered every 3 weeks.3 On the 
basis of this, the five drug alternating combination with interval compression has become the North 
American standard therapy for localized Ewing sarcoma.  
 
2.5 
Feasibility of administration of VDC-IE-VTC on a interval compressed schedule 
The feasibility of administering the vincristine-topotecan-cyclophosphamide in combination with the five 
drug standard chemotherapy was tested in AEWS07P1. This study demonstrated that interval compression 
was possible with the mean time from start of therapy to surgery (after 6 cycles of chemotherapy) was 14.7 
weeks. The mean time from start of therapy to the chemotherapy prior to local therapy was 12.62 weeks as 
compared to 11.5 weeks for subjects on AEWS0031 who were receiving the 5 drug standard combination. 
Toxicity appeared to be otherwise acceptable. It is suggested that this degree of interval compression 
demonstrated is acceptable for proceeding to test this combination in a phase 3 setting.29  
 
2.6 
Biologic prognostic factors 
Biologic prognostic factors are being investigated as part of companion specimen studies. Investigation of 
these biologic factors will continue in parallel to AEWS1031, through enrollment on the current Ewing 
sarcoma biology study such as AEWS07B1 or on any successor biology study.  
 
2.7 
Tumor size and histologic response as prognostic Factors 
The most prognostic risk factor in Ewing sarcoma is the presence of metastatic disease. In patients with 
localized disease at diagnosis, both initial tumor size and histologic response have been evaluated as risk 
factors. In patients treated according to CESS 86, 177/263 (67%) had tumors >100 mL and had a 10 yr EFS 
0.51 as compared with 0.61 for patients with tumors <100 mL.30 Sixty-nine of 118 (58%) patients treated 
on INT-0091 had tumors >100 mL and had a 5 yr EFS 0.6 as compared with 0.81 in patients with tumors 
<100 mL.31 In patients treated according to CESS 86, 85/228 (37%) had tumors >200 mL and had a 10 yr 
EFS 0.36 as compared with 0.63 for patients with tumors < 200 mL.30 Forty-one of 118 (35%) patients 
treated on INT-0091 had tumors >200 mL and had a 5 yr EFS 0.47 as compared with 0.8 in patients with 
tumors <200 mL.31 Current data from EuroEwing 99 (AEWS0331), in which volumes are being used for 
treatment stratification suggest that about 50% (482/986) are >200 mL. The results of the recently 
completed CCG9354/POG7942 combined with the results from INT-0091 confirm these findings. One 
hundred seventeen of 381 (117/381) patients had tumors 200 mL or more in volume and had a 5 year EFS 
0.55 as compared with patients having tumors < 200 mL who had an EFS 0.78. Although tumor volumes 
may be estimated as ellipses or cylinders, volume estimation as 200mL or more based on approximating 
tumor volume as an ellipse defined by three perpendicular tumor diameters (volume in mm3= π /6 (d1·d2·d3) 
was the best discriminator of outcome. The calculations to derive the estimates of tumor volume were 
performed centrally, based on tumor dimensions supplied by the institution.31 
 
Although data is accumulating regarding the prognostic value of tumor size for EFS, data regarding the 
influence of tumor volume and local control (LC) are mixed. In a recent report of patients with pelvic 
tumors treated on INT-0091, tumor size did not correlate with LC.32 This is in contrast to a previous 
prospective study from St Jude Children’s Research Hospital suggesting improved local control for tumors 
< 8cm (90% vs 52%, p = 0.054). A retrospective update of the St. Jude experience focusing only on patients 
treated with definitive radiotherapy confirmed an association between tumor size and LC. LC for tumors 
<8cm was 89%, in contrast to only 54% in the larger tumors (p=.002).33 The majority of data evaluating 
the association between tumor size and local control in Ewing tumor has used 8cm as a cut- point for risk 
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determination, with tumors larger than 8cm in maximal diameter being at higher risk for local recurrence.34 
In the CESS studies, size > 100mL was associated with increased risk of local recurrence in definitive 
radiotherapy patients, but not in patients who received surgery as a component of local therapy.35  
 
CESS 86 data demonstrated 10 year EFS 0.64 in patients with a good histologic response and 0.38 in 
patients with a poor response.30 INT-0091 data suggests a 5 year EFS 0.56 if some viable tumor is present 
and 0.79 where no viable tumor is found.31 It should be noted that patients treated on INT 0091 received 
4 courses of chemotherapy prior to local therapy while patients receiving therapy on this trial will receive 
6 cycles, as do patients receiving treatment on EuroEwing 99 (AEWS0331). This increase in treatment prior 
to local therapy may increase the proportion of patients having a good histologic response and change the 
utility of this response as prognostic factor for EFS.  
 
Local control outcomes based on histologic response have been retrospectively reported based on outcomes 
in the (EI) CESS-Studies. In patients with wide surgical margins and favorable histologic response, only 
1% experienced local relapse. Even with wide margins, 12% experienced local relapse with a poor 
histologic response, which was improved to 6% in the patients who received post-operative radiotherapy. 
Post-operative radiation was recommended for patients with narrow margins or poor histologic response 
but not always administered. LC was similar in patients with or without post-operative radiation after 
marginal resections (6%). However, patients who received post-operative radiotherapy were more likely to 
have a poor histologic response.36 
 
Confirmation of these findings may allow future development of risk based treatment for patients with 
localized Ewing sarcoma. 
 
2.8 
Impact of local therapy decisions on local control 
Although surgery is the preferred local therapy in patients with Ewing family tumors, there remain a 
significant portion of patients treated on COG studies who receive radiotherapy for local control either 
definitively (20%), or adjuvantly (15%) (Krailo, personal communication). Generally, definitive 
radiotherapy patients tend to have large axial tumors and complete surgical resection is felt to be impossible 
or associated with significant morbidity. However, improvements in surgical techniques have allowed 
previously unresectable tumors to be potentially resectable. A recent COG report of patients treated on INT-
0091 suggests local control rates of 80-90% even for pelvic tumors, a historically poor-prognostic site, 
regardless of local therapy modality utilized. Although not significant, combined surgery and radiotherapy 
was associated with the lowest rates of local relapse (10.5% surgery + RT vs 25% for either surgery or RT 
alone).32 These results mirror the local recurrence outcomes in the entire cohort of patients which was only 
2% for patients receiving combined modality treatment (versus 5% for surgery and 9% for radiotherapy 
alone, p= NS).2 Combined modality treatment has been favored in European studies with 63% of patients 
treated on EICESS 92 receiving combined surgery and radiation, and 19% and 18% receiving surgery or 
radiotherapy alone, respectively. This aggressive treatment strategy resulted in 95% LC for patients 
receiving surgery as a component of local therapy, compared to 75% for those receiving RT alone.36  
 
Prospective, randomized data in adults with soft tissue sarcomas has demonstrated superiority of pre-
operative RT over post-operative RT in terms of better local control, improved survival and smaller 
radiotherapy field sizes.37 Thus, in patients with Ewing sarcoma felt to be at high risk for requiring adjuvant 
radiotherapy, there may be a role for pre-operative radiotherapy to allow for a lower-dose and more limited 
radiotherapy volume. In addition, if combined modality treatment is necessary, treating the intact tumor 
generally allows a more favorable geometry because normal tissues are displaced by the tumor. Post-
operatively, adjacent normal structures, such as lung in the thorax and small bowel in the pelvis, are in 
closer proximity to the radiation target and thus receive higher radiation doses. The goal of pre-operative 
radiotherapy would be primarily to minimize morbidity in patients requiring combined modality therapy as 
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well as to improve the likelihood of necrosis at the margin thus preventing the need for a high-dose boost 
after surgery. The objective of preoperative radiotherapy is not to make an inoperable tumor operable. 
 
There is little information regarding musculoskeletal complications related to type of local therapy 
(radiation versus surgery) and to type of surgical reconstruction when surgery is used as local control. In 
addition, the durability of local therapy modalities has not been well described. Failures may occur 
throughout the first decade. Surgical revisions may be required either as a result of fracture or dysfunction 
(usually loosening) or early vascular compromise.38 Single institution reports suggest surgical revisions 
may be required in 25% of patients.39 Although not possible to study long term outcomes within the context 
of this trial there is an opportunity to follow functional outcomes throughout study follow-up at 5 years post 
closure of the study to accrual. One report in adults suggests a revision rate of 17% for endoprostheses at 5 
years40 supporting the usefulness of this length of follow-up. Functional limitations or pain may be present. 
Although contemporary clinical trials have emphasized EFS and OS outcomes, better information regarding 
functional outcomes may influence early decisions regarding local therapy choices.  
 
2.9 
Radiologic Response and prognosis 
 
2.9.1 
Initial Staging And Prognosis 
Presence of metastasis is the strongest prognostic factor in Ewing sarcoma. Conventional staging has 
generally included plain radiographs, MRI and CT of the primary site, CT of the chest, and bone 
scintography. More recently, functional imaging such as FDG-PET have been increasingly available, and 
appear more sensitive at detecting metastatic disease.41 A recent prospective, multi-institutional study 
compared effectiveness of conventional imaging modalities with that of PET in pediatric sarcoma patients 
in terms of tumor staging and treatment planning. FDG-PET was superior in detection of lymph node 
metastasis (sensitivity, 95% vs 25%) and osseous metastasis (sensitivity, 90% vs 57%). The sensitivity 
difference for detecting osseous metastasis was more significant in Ewing sarcoma, (sensitivity, 88% vs 
37%). Treatment was modified in 30% of patients based on the additional data obtained from FDG PET. A 
study by Kniesl in Ewing and osteosarcoma patients revealed similar results. For Ewing sarcoma, FDG 
PET detected osseous metastases not evident on bone scintography in 18% of cases which resulted in 
modification of treatment strategy.42 
 
2.9.2 
Imaging Response And Prognosis 
The correlation of imaging response and EFS has not been completely evaluated in pediatric patients 
receiving treatment for Ewing tumor. The response in bone is difficult to evaluate using traditional 
radiologic tools. Response, in terms of disappearance of the soft tissue component has been evaluated only 
in small numbers of patients.43 The radiology committee has recommended MRI, bone scan and functional 
imaging (thallium or FDG PET) as appropriate investigations at diagnosis and prior to local therapy, surgery 
or radiation. A small series using FDG PET in evaluation of a variety of non-bone sarcomas suggests this 
modality may be a useful predictor of histologic response and EFS.44 Standardized uptake value (SUV) 
both prior to treatment and the change between pre-treatment and pre-local therapy were found to be 
important in prognosis. In a small series of Ewing sarcoma family tumors, FDG PET at diagnosis (SUV1) 
and at the time of local therapy (SUV2) was evaluated to assess the correlation with histologic response at 
the time of surgery as well as EFS. In this report SUV2 was correlated with histologic response in 68% of 
patients and was strongly correlated with EFS regardless of initial SUV. EFS at 4 years for patients with an 
SUV2 < 2.5 was 72%, compared to only 27% for patients with an SUV2 ≥ 2.5 (p.01).45 
 
Functional imaging response (PET) and radiologic response may aid in prognostic stratification of patients 
with localized Ewing sarcoma and allow development of future risk based treatment strategies. In addition, 
future local control decisions may also be individualized as to guiding surgical resection, the utility of pre-
operative or post-operative radiotherapy, and modified radiotherapy volumes based on local control 
correlations with functional imaging response. 
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3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment  
 
3.1.1 
Patient Registration  
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This number is 
obtained via the eRDE system once authorization for the release of protected health information (PHI) has 
been obtained. The COG patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help.  
 
In order for an institution to maintain COG membership requirements, every newly diagnosed patient needs to 
be offered participation in ACCRN07, Protocol for the Enrollment on the Official COG Registry, The 
Childhood Cancer Research Network (CCRN). 
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be 
assigned only one BPC number per COG Patient ID. For additional information about the labeling of specimens 
please refer to the Pathology and/or Biology Guidelines in this protocol.  
 
3.1.2 
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. 
 
3.1.3 
Patient Registration 
Prior to study enrollment, all patients must have been registered via the eRDE system into the COG Cancer 
Registry (Diagnosis/Registry). The patient registration application is available 24 hours a day, 7 days a 
week. 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. 
 
3.1.4 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study 
enrollment is accomplished by going to the Enrollment application in the eRDE system. If you have 
problems with enrollment, refer to online help in the Applications area of the COG website. 
 
3.1.5 
Timing 
Study enrollment must take place prior to beginning protocol therapy. The date protocol therapy is projected 
to start must be no later than five (5) calendar days after enrollment. All clinical and laboratory studies to 
determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated in the 
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eligibility section below. All staging scans to evaluate for metastatic disease need to be done within 4 weeks 
of enrollment and adequate preoperative imaging of the primary site is required prior to unplanned 
excisions. Patients must be enrolled within 8 weeks (56 days) of diagnostic biopsy. 
 
 
3.1.6 
Inclusion of Women and Minorities  
Both men and women of all races and ethnic groups are eligible for this study. To allow non-English speaking 
patients to participate in the study, bilingual health care services will be provided in the appropriate language. 
 
3.1.7 
Randomization 
Randomization will take place at the time a patient is enrolled on study. Patients will be assigned to either 
Regimen A (vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide) or Regimen B 
(vincristine/topotecan/cyclophosphamide, 
ifosfamide/etoposide 
and 
vincristine/doxorubicin/ 
cyclophosphamide). Randomization will be stratified according to age and primary tumor site. Age will be 
stratified as: (a) seventeen years or less at age at diagnosis; or (b) eighteen years of age or greater at 
diagnosis. Primary site will be stratified as: (a) pelvic primary; or (b) non-pelvic primary (c) extra-osseous 
site. 
 
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 
Age less than or equal to 50 years.  
 
Note:  
• 
Patients of age 0-15 years are to be enrolled by pediatric oncology services. Infants and small 
children are eligible for this study, however, the treating physicians and family must be prepared 
to deliver adequate local control as required in this study. 
• 
Patients of age 16-50 years can be enrolled by both pediatric and adult oncology services. 
 
3.2.2 
Diagnosis  
Patients with newly diagnosed, biopsy confirmed, extracranial, non-metastatic Ewing sarcoma or PNET of 
bone or soft tissue are eligible for this study. 
Note: 
• 
For the purpose of this study, chest wall tumors with ipsilateral pleural effusions, ipsilateral positive 
pleural fluid cytology or ipsilateral pleural based secondary tumor nodules will be considered 
localized disease. 
• 
Patients with regional node involvement, based on clinical suspicion confirmed by pathologic 
documentation are considered to be non-metastatic.  
• 
Patients with discontinuous osseous lesions within the same bone are considered to be non-
metastatic. 
• 
See Section 3.2.6 for the protocol definition of pulmonary metastatic disease. 
• 
 
• 
Tumors arising in the bony skull (extra-dural) are considered to be extracranial.  
 
3.2.3 
Pathologic Criteria 
Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by institutional pathologist. 
(Note: Refer to Section 14.0 for details of microscopy, immunohistochemistry, and molecular and 
cytogenetic studies.) 
 
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3.2.4 
Prior Therapy 
No prior chemotherapy or radiation therapy is allowed. Patients should only have had a biopsy of the 
primary tumor without an attempt at complete or partial resection. Patients will still be eligible if unplanned 
excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery. (Note: 
Refer to Section 4.1 for details on unplanned excision.) 
 
3.2.5 
Organ Function Requirements:  
 
3.2.5.1 Adequate renal function defined as: 
- 
Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or 
- 
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.  
  
 
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3.2.5.2 Adequate liver function defined as: 
 
- 
Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and 
 
- 
SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. 
 
3.2.5.3 Adequate cardiac function defined as: 
 
- 
Shortening fraction of ≥ 27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by radionuclide angiogram. 
 
EXCLUSION CRITERIA 
 
3.2.6  Patients must have no evidence of metastatic disease 
Metastatic disease: 
• 
Are lesions which are discontinuous from the primary tumor, are not regional lymph nodes and do 
not share a body cavity with the primary tumor. If there is any doubt whether lesions are metastatic, 
a biopsy of those lesions should be taken. 
• 
Skeletal lesions in adjacent bones (trans-articular). See Section 4.1 
• 
Contralateral pleural effusion and contralateral pleural nodules. 
• 
Distant lymph node involvement.  
• 
Patients with pulmonary nodules are considered to have metastatic disease if the patient has: 
o Solitary nodule >0.5 cm or multiple nodules of > 0.3 cm unless biopsied and negative for 
Ewings 
o Biopsies of solitary nodule ≤ 0.5 cm or multiple nodules ≤ 0.3 cm are not required but if 
performed and positive indicate metastatic disease. 
 
 
3.2.7 
Patients whose tumors arise in the dural and intra-dural soft tissues of the cranium and spine are 
not eligible. 
 
3.2.8 
Microscopy 
Patients with pathologic diagnoses other than Ewing sarcoma as defined in Section 14.0 will be excluded. 
 
3.2.9 
Second Malignant Neoplasms 
Patients diagnosed with Ewing Sarcoma as a second malignant neoplasm are not eligible if they have 
received chemotherapy or radiation for the treatment of their primary malignancy. 
 
3.2.10 Pregnancy and breast feeding  
Pregnant women will not be entered on this study as fetal toxicities and teratogenic effects have been noted for 
several of the study drugs. Pregnancy tests must be obtained in female patients who are post-menarchal. 
Lactating females may not participate unless they have agreed not to breastfeed their infants. Males or 
females of reproductive potential may not participate unless they have agreed to use an effective 
contraceptive method for the duration of the study treatment.  
 
3.2.11 Regulatory Criteria 
 
3.2.11.1 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.11.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
 
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4.0 
TREATMENT PROGRAM 
 
 
 
 
 
 
 
 
4.1 
Overview of Treatment plan 
Please note: Patients should not have planned or unplanned surgical resections prior to chemotherapy. If a 
patient has a (presumably small) soft tissue mass that was not expected to be malignant and was resected 
with negative margins, no further local therapy will be required, provided the primary tumor was not 
violated at the time of surgery and the cuff of normal tissue surrounding the soft tissue tumor was at least 
2 cm wide on all surfaces. In the case of Ewing tumor within an encapsulated organ, no additional local 
treatment is required if the capsule was not breached by the tumor or violated at the time of surgery. If the 
primary tumor was violated at the time of surgery, prior to the initiation of chemotherapy or margins as 
defined in this paragraph are inadequate, then further local therapy (surgery, radiation or both) at the time 
of local control must be delivered. In this case the initial procedure would be considered a large biopsy. For 
osseous (“skip”) lesions within the same bone involved by the primary tumor, the intervening “normal” 
area should be included in the local control treatment plan.  
 
 
4.1.1 
Protocol therapy will consist of Induction, Local control and Consolidation therapy. Local therapy planning 
with a surgical and radiation oncology team should be initiated at the time of diagnosis, to ensure 
appropriate imaging is obtained for surgical or radiotherapy treatment planning.  
 
Protocol therapy must begin only after study enrollment and randomization. All patients, whether in 
Regimen A or Regimen B will receive a total of 17 cycles of chemotherapy; each cycle will be of 2 weeks 
duration. Induction consists of 6 cycles (12 weeks) of chemotherapy and will be delivered prior to local 
control therapy which may involve surgery and/or radiation therapy. Consolidation therapy will consist of 
11 cycles (22 weeks) of chemotherapy.  
 
 
4.1.1.1 
Local control will take place once patients have recovered from Induction chemotherapy. If surgery is the 
primary local control, it should be scheduled at the time of recovery from the sixth cycle of Induction 
chemotherapy- usually at chronological Week 13. When surgery is performed, the next cycle of 
chemotherapy should be given as soon as possible post-operatively. This is usually possible one to two 
weeks later. The passing of more than 6 weeks between chemotherapy cycles for reasons other than severe 
chemotherapy toxicity should be avoided. 
 
4.1.1.2 
For patients who will have radiation alone or will be given radiation pre-operatively, Consolidation 
chemotherapy should be initiated concurrently with the radiation therapy, upon recovery from Induction 
chemotherapy. Administration of vinCRIStine-topotecan-cyclophosphamide and ifosfamide-etoposide 
chemotherapy concurrently with radiation is allowed. Radiation may begin concurrently or immediately 
after Cycle 1 Consolidation 1(VDC) in Regimen A. Otherwise, DOXOrubicin should not be given during 
radiation treatment. 
 
If radiation therapy is to follow surgery, radiation therapy should be scheduled to start as soon as recovery 
from surgery permits. The objective of preoperative radiotherapy should not be an attempt to make an 
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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inoperable tumor operable. Patients who are to be treated with planned lower dose (36 Gy) radiation 
followed by planned excision should be treated with radiation during Weeks 1 through 4 of Consolidation, 
and then proceed onto surgical resection of the tumor as soon as possible (ideally within 2 weeks). If post-
operative radiotherapy boost is required, radiation therapy should be scheduled to start as soon as recovery 
from surgery permits. Following surgery, the next cycle of chemotherapy should be given as soon as 
possible post-operatively: this can be given concurrently with boost radiotherapy if necessary. The passing 
of more than 6 weeks between chemotherapy cycles for reasons other than severe chemotherapy toxicity 
should be avoided.  
 
See Section 4.3 for detailed information about local control and Section 4.4 for the drug administration 
schedule and criteria to start chemotherapy cycles. 
 
4.1.1.3 
Evaluations will occur prior to local therapy, post Cycle 5 Consolidation and at the end of therapy. See 
Sections 7.1 and 16.0 for details.  
 
4.1.1.4 
 
Blood count criteria for start of cycle are ANC ≥ 750/µL and platelet count ≥75,000/µL post nadir. The 
ANC often falls after discontinuing myeloid growth factor support. If the ANC has risen to ≥ 750/µL after 
the nadir but then falls the next cycle should be given despite ANC <750/µL. 
  
 
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4.1.2 
Treatment schema 
 
Regimen A  
 
INDUCTION 
 
CONSOLIDATION 
Cycle 
Week 
Drugs  
Cycle 
Week 
Drugs  
 
1 
1 
VDC1200 
1 
 
1 
VD%C1200 
2 
V 
2 
V 
2 
3 
IE 
2 
3 
IE 
4 
 
4 
 
3 
5 
VDC1200 
3 
5 
IE 
6 
V 
6 
 
4 
7 
IE 
4 
7 
VC1200 
8 
 
8 
V 
5 
9 
VDC1200 
5 
9 
VD%C1200 
10 
V 
10 
V 
6 
11 
IE 
6 
11 
IE 
12 
 
12 
 
Evaluations 
Local Control 
13 
 
7 
13 
VC1200 
14 
14 
V 
V=VinCRIStine  
C1200=Cyclophosphamide1200 mg 
I=Ifosfamide 
E=Etoposide 
D=DOXOrubicin  
 
NOTES:  
 If radiation is the primary local control measure or will 
be 
given 
pre-operatively 
then 
consolidation 
chemotherapy should be initiated concurrently with the 
radiation therapy, i.e. both radiation and consolidation 
Cycle 1 should start at the same time. 
 
%- Dexrazoxane 375 mg/m² (or 12.5mg/kg if <10kg or 
< 1yo) will be administered ONLY in the 4th and 5th 
VDC cycles (Cycles 1 and 5 of Consolidation), on Days 
1 and 2 prior to DOXOrubicin. 
 
Myeloid growth factor support between cycles is 
required for interval compression (GM-CSF excluded). 
 
8 
15 
IE 
16 
 
9 
17 
VC1200 
18 
V 
10 
19 
IE 
20 
 
11 
21 
VC1200 
22 
V 
End of Therapy 
 
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Regimen B 
 
INDUCTION 
 
CONSOLIDATION 
Cycle 
Week 
Drugs  
Cycle 
Week 
Drugs  
 
1 
1 
VTC250 
1 
 
1 
VTC250 
2 
V 
2 
V 
2 
3 
IE 
2 
3 
IE 
4 
 
4 
 
3 
5 
VDC1200 
3 
5 
IE 
6 
V 
6 
 
4 
7 
IE 
4 
7 
VTC250 
8 
 
8 
V 
5 
9 
VTC250 
5 
9 
VDC1200 
10 
V 
10 
V 
6 
11 
VDC1200 
6 
11 
IE 
12 
V 
12 
 
Evaluations 
Local Control 
13 
 
7 
13 
VD%C1200 
14 
14 
V 
V=VinCRIStine T=TOPOtecan 
C1200=Cyclophosphamide1200 mg C250=Cyclophosphamide250 mg 
D=DOXOrubicin    I=Ifosfamide     E=Etoposide      
 
NOTES:  
 If radiation is the primary local control measure or will be 
given pre-operatively then consolidation chemotherapy should 
be initiated concurrently with the radiation therapy, i.e. both 
radiation and consolidation Cycle 1 should start at the same 
time. 
 
%- Dexrazoxane 375 mg/m² or 12.5mg/kg if <10kg or < 1yo 
will be administered ONLY in the 4th and 5th VDC cycles 
(Cycles 7 and 10 of Consolidation), on Days 1 and 2 prior to 
DOXOrubicin. 
 
Myeloid growth factor support between cycles is required for 
interval compression (GM-CSF excluded). 
8 
15 
VTC250 
16 
V 
9 
17 
IE 
18 
 
10 
19 
VD%C1200 
20 
V 
11 
21 
IE 
22 
 
 
End of Therapy 
 
 
4.2 
Concomitant Medications 
 
4.2.1 
No other cancer chemotherapy or immunomodulating agents (including steroids unless used as an 
antiemetic) will be used. 
 
4.2.2 
Clinically significant drug interactions have been reported when using vinCRIStine with strong 
CYP450 3A4 inhibitors and inducers. Selected strong inhibitors of cytochrome P450 3A4 include azole 
antifungals (such as fluconazole, voriconazole, itraconazole, ketoconazole) and strong inducers include 
drug such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John’s wort. These drugs should 
be avoided with vinCRIStine.  
 
The clinical outcome and significance of CYP450 interactions with cyclophosphamide, DOXOrubicin, 
etoposide and ifosfamide are less clear. CYP450 3A4 stimulators or inhibitors should be avoided or used 
with great caution. Aprepitant also interacts with CYP3A4 and should be used with caution with etoposide, 
ifosfamide, or vinCRIStine chemotherapy. 
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A more complete list of drugs that are metabolized by cytochrome P450 isoform is available via the link 
below. Drug names are hyperlinks to specific journal references: 
http://medicine.iupui.edu/clinpharm/ddis 
 
4.2.3 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to 
be used as necessary. For COG Supportive Care Guidelines see  
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
 
4.3 
General Approach to Primary Tumor Treatment (Local Control) 
This study requires definitive treatment of the primary tumor with complete surgical excision, a 
combination of surgical excision and radiation therapy for microscopic residual disease, or full-dose 
radiation therapy. A multidisciplinary approach to primary tumor treatment involving the oncologist, the 
radiation oncologist, and the surgeon is indispensable, and planning should begin immediately upon 
diagnosis. The guiding principle for local control should be to eradicate the primary tumor and avoid local 
recurrence with the least amount of functional loss. This will require careful consultation between the 
orthopedic or surgical oncologist and the radiation oncologist.  
 
Recent experience indicates that most patients will be treated with surgical excision alone or surgical 
excision preceded or followed by radiation therapy.  
 
4.3.1 
Primary Tumor Treatment Modalities 
 
4.3.1.1 Surgery 
Surgical excision should be considered for all tumors which respond to Induction chemotherapy. Surgery 
is the local therapy modality of choice if the lesion can be resected with negative margins and a reasonable 
functional result. If surgical expertise is not available at a given institution, it is strongly suggested that 
consultation be made with an experienced orthopedic or surgical oncologist at another institution. Patients 
with unresectable lesions or inadequate margins after surgery will receive radiation therapy.  
 
The aim of surgery is to achieve a wide (R0) surgical excision which leaves a clear margin of normal tissue 
surrounding the lesion. Patients treated with neo-adjuvant chemotherapy having complete resections (R0) 
with a clear margin (defined as no viable tumor at the cut surface) will not require radiation therapy. 
Currently there is no reliable way to assess tumor responsiveness non-invasively. Therefore, in most cases, 
a wide cuff of normal tissue will surround the tumor consistent with the planned reconstruction. In rare 
cases, the margin may be closer if an important structure such as a major growth plate, a joint or a structure 
such as the acetabulum can be preserved. A marginal (R1) excision leaves inflammatory tissue containing 
residual tumor cells. The pathologic margin is microscopic. The patient requires post operative radiation 
therapy. Patients who have excisional biopsy of the tumor as a first procedure before the administration of 
chemotherapy require at least a 2 cm cuff of normal tissue completely surrounding the tumor to be 
considered a clear margin. In cases where the normal uninvolved tissue is less than 2 cm thick, the procedure 
will be considered as a large biopsy and additional surgery or radiation therapy will be required after the 
completion of induction chemotherapy. For encapsulated organs, complete excision of the organ prior to 
chemotherapy where the tumor has not been violated at the time of surgery and the capsule not breached 
by the tumor will be considered to have had adequate local therapy and no additional surgery and/or 
radiation is necessary. 
 
Intralesional or debulking (R2) operations leaves gross residual tumor. This type of surgical procedure is 
never indicated. Recovery from complicated surgical procedures will delay the resumption of 
chemotherapy. Since gross residual tumor remains, the patient will require full dose radiation therapy (the 
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same dose as if no surgical procedure was performed). Radiation will be less effective in the hypoxic post 
surgical bed and the radiation field size will be larger than if surgery was not attempted. 
 
For details on the surgical approach to the biopsy and excision, see Section 13.0. 
 
4.3.1.2 Margins 
At the time of resection, the surgeon should mark all margins and orient the specimen at the operative field, 
so that margin evaluation is precise. Narrow margins are unavoidable in some areas. In these situations, the 
surgeon should take a number of separate biopsies of the “normal” tissue around the margins of resection 
and these should be marked and submitted separately for pathologic review. Communication with the 
pathologist is mandatory to assure accuracy of margin examination. Consideration should be given to 
having the pathologist inspect the specimen in the operating theatre to help with orientation. The tumor 
should not be bisected or cut into separate specimens prior to this discussion.  
 
The aim of surgery is to achieve a wide (R0) surgical excision which leaves a clear margin of normal tissue 
surrounding the lesion. Patients with complete resections (R0) after neo-adjuvant chemotherapy with a clear 
margin (defined as no viable tumor at the cut surface) will not require radiation therapy. In most instances 
this will be normal non-reactive tissue. In some instances when resected tumors have greater than 90% 
overall necrosis, the tissue at the margin may be bland scar or loose fibrous tissue. This will be considered 
a clear margin and no postoperative radiation therapy will be required. If specimens with greater than 90% 
overall necrosis have inflammatory tissue or coagulative tumor necrosis at the margin, (the cytoarchitecture 
of the tumor cells is preserved) the margin will be considered microscopically positive and require post 
operative radiation therapy. If the tumor specimen has less than 90% overall necrosis, the cut surface of the 
resected tumor must be normal non-reactive tissue in order to be considered pathologically negative. If the 
tumor is completely resected prior to administration of chemotherapy, the cuff of surrounding normal tissue 
must be at least 2 cm wide on all surfaces, otherwise additional local therapy will be needed following 
induction chemotherapy. 
 
4.3.1.3 Surgery plus Radiation Therapy 
Most patients will have either surgery alone, surgery with radiation therapy for positive microscopic 
margins, or radiation therapy alone. While avoiding radiation completely with a wide (R0) excision 
decreases the risk of secondary sarcoma for example, a combined approach appears to be a reasonable 
alternative. Patients with apparently resectable tumors in some select sites such as pelvis, chest wall, axial 
tumors etc. can have a higher risk of positive microscopic margins following surgery and many orthopedic 
and surgical oncologists prefer to combine surgery with pre-operative radiation. In these cases, 36 Gy of 
radiation therapy may be considered prior to resection. The objective of preoperative radiotherapy should 
not be an attempt to make an inoperable tumor operable. This low dose should only be given when complete 
surgical excision is planned within 2 weeks following the completion of the last dose of radiation. If a 
possible outcome of surgery is an intralesional excision (R2), pre-operative radiotherapy as mandated in 
this study is not indicated. This approach may result in considerable delays in chemotherapy: thus the 
benefits must be weighed against risk in each patient. The final decision regarding the best treatment is 
dependent on patient and tumor characteristics and is left to the consultants at the patient’s hospital center. 
 
When surgery is done first, followed by radiation therapy, surgery should occur as soon as possible after 
recovery from Induction Cycle 6 chemotherapy and radiation therapy should begin as soon as feasible 
thereafter usually within 2 weeks. 
 
 
 
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Patients with microscopic residual disease after planned pre-operative radiation therapy will receive 
additional radiation (see Sections 17.2 and 17.7.2.1).  
 
For details on the surgical approach to the biopsy and excision, see Section 13.0. For details on radiotherapy, 
see Section 17.0. 
 
4.3.1.4 Radiation Therapy Only 
Candidates for radiotherapy alone will include patients with bulky lesions in surgically difficult sites such 
as the spine, skull and periacetabular pelvis, patients with a poor response to induction chemotherapy, or 
those patients in whom surgery would result in unacceptable functional results. Sites which, if removed, 
would result in significant impairment of function include the skull, facial bones, vertebrae and pelvic bones 
about the acetabulum. In some cases, resection even in these sites may be feasible in combination with 
radiation therapy, and decisions regarding a specific patient must be individualized. 
 
Patients who are to be treated with radiotherapy alone should be treated with radiotherapy at the start of 
Consolidation, once recovered from Induction chemotherapy. For details on radiotherapy, see Section 17.0. 
 
4.4 
Chemotherapy Administration Schedule 
Note: See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusion. As applicable, also see the 
CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
4.4.1 
Administration Schedules for Regimen A 
 
4.4.1.1 Administration Schedule for Induction (Weeks 1-12) for Regimen A  
Criteria to start Induction: ANC ≥ 750/µL and platelets ≥ 75,000/µL (without transfusion). 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without 
transfusion). The ANC often falls after discontinuing myeloid growth factor support. If the ANC has risen 
to ≥ 750/µL after the nadir but then falls the next cycle should be given despite ANC < 750/µL. If a cycle 
of chemotherapy is delayed due to toxicity, see Section 5.0 for criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age or weighing less than 10 kilograms, chemotherapy should 
be calculated by weight rather than by surface area. Dose/kilogram = dose/meter2 divided by 30. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day 1 of Weeks 1, 2, 5, 6, 9 and 10. 
Dose: 1.5 mg/m2/dose. (Maximum dose is 2 mg.) For patients < 10 kg or < 1 year old, the dose is 
0.05 mg/kg/dose. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the statement 
“Do not remove covering until moment of injection. For intravenous use only - Fatal if given by other 
routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. VinCRIStine is 
available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI, Marqibo®). The 
conventional and liposomal formulations are NOT interchangeable. 
 
 
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DOXOrubicin: IV push/infusion over 1-15 minutes. Short infusion times may be lengthened slightly 
(and up to 60 minutes) if institutional policies mandate. 
 
Days: 1 and 2 of Weeks 1, 5 and 9. 
Dose: 37.5 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 1.25 mg/kg/dose. 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that DOXOrubicin be administered 
through the tubing of rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between DAUNOrubicin and 
DOXOrubicin. DOXOrubicin is available in a liposomal formulation. The conventional and liposomal 
formulations are NOT interchangeable. 
 
Cyclophosphamide: IV over 30-60 minutes 
Day 1 of Weeks 1, 5 and 9 
Dose is 1,200 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic 
solution) or further diluted.  
 
Mesna must be administered in conjunction with cyclophosphamide (see below). Hydrate per institutional 
guidelines 
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days 1-5 of Weeks 3, 7 and 11. 
Dose: 1,800 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 60 mg/kg/dose. 
Mesna must be administered in conjunction with ifosfamide (see below). 
 
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. May use diuretics 
(eg, furosemide) to increase urine output. Consider adding potassium and magnesium to prevent electrolyte 
deficiencies.  
 
Mesna with Cyclophosphamide 
Administer mesna by IV infusion or IV/PO on Day 1 of Weeks 1, 5 and 9. 
Total IV Dose: 720 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 24 mg/kg/day. 
 
Mesna with Ifosfamide 
Administer mesna by IV infusion or IV/PO on Days 1-5 of Weeks 3, 7 and 11. 
Total IV Dose: 1,080 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 36 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 60% of the daily 
ifosfamide/cyclophosphamide dose. Mesna can be administered in 3 divided doses by short infusion over 
15 to 30 minutes. The initial bolus dose of mesna may be administered 15 minutes before or at the same 
time as the ifosfamide/cyclophosphamide dose; subsequent doses are given 4 and 8 hours after the start of 
ifosfamide/cyclophosphamide).  
For example: if the oxazaphosphorine dose is 1,000 mg, then the total daily mesna dose is 600 mg; 200 mg 
of mesna will be given 15 minutes before or with the oxazaphosphorine dose (Hour 0) and 2 boluses of 
200 mg each will be given at Hours 4 and 8. 
 
 
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This total daily dose of mesna can also be administered as IV continuous infusion (CI). The continuous 
infusion should be started 15-30 minutes before or at the same time as ifosfamide/cyclophosphamide and 
finished no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide infusion.  
For example: if the ifosfamide/cyclophosphamide dose is 1,000 mg, then the total daily mesna dose is 
600 mg; the 600 mg mesna continuous infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours after the end of the 
ifosfamide/cyclophosphamide infusion. If ifosfamide/cyclophosphamide is administered over 1 hour and 
mesna is started 30 minutes before the oxazaphosphorine infusion, the total mesna infusion will last at least 
9 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna may receive the last TWO 
bolus doses (originally at Hours 4 and 8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral 
doses will be administered at Hours 2 and 6. 
 
For example: if the oxazaphosphorine dose is 1,000 mg, then 200 mg of mesna will be given IV 15 minutes 
before or with the oxazaphosphorine dose (Hour 0) and the TWO oral doses of 400 mg each will be given 
at Hours 2 and 6. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute mesna parental solution 
before oral administration. The solution can be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit 
juices (grape, apple, tomato and orange) or plain or chocolate milk. The most palatable is chilled grape 
juice. Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be rounded up to nearest 
200 mg. Administer doses on a schedule as determined by timing of cyclophosphamide/ifosfamide 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days 1-5 of Weeks 3, 7 and 11. 
Dose: 100 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if hypotension occurs. The 
use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes of D5W 
due to potential development of hyponatremia. 
 
Growth Factor Support 46-52 
Begin myeloid growth factor support at least 24-36 hours after the last dose of chemotherapy. If given daily 
then continue a minimum of 7 days and until ANC ≥ 750/µL post nadir and discontinue at least 24 hours 
prior to next cycle of chemotherapy. If given daily, growth factor administration is to be continued in weeks 
where vinCRIStine is given alone, without regard to vinCRIStine administration.  
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
The therapy delivery maps for Induction are provided in the following three pages. Local control will follow 
Induction. (see Section 4.3 for details). See Section 7.1 for observations prior to Local Control. See Section 
16.0 for imaging pre- and post- Local Control. Details of Consolidation chemotherapy for Regimen A are 
provided in Section 4.4.1.2 
 
 
 
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Induction for Regimen A (Weeks 1-12) 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 1 and 2 (Weeks 1-4); a VDC cycle followed by an IE cycle. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
 
Criteria to start each cycle: ANC ≥ 750/µL and platelets ≥ 75,000/µL (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 2 should be given 
despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 min$ 
1.5 mg/m2/dose OR 0.05 mg/kg/dose for 
pt < 10 kg or <1 yo 
1 and 8 
$- Or infusion via minibag as per institutional 
policy.  
Maximum dose: 2 mg. See Section 4.4.1.1. 
a. History and physical 
exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, 
ALT, 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
 
* See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion 
over 1-15 mins& 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg or < 1 yo  
1 and 2 
&- Short infusion times may be lengthened slightly 
(up to 60 minutes) if institutional policies mandate. 
See Section 4.4.1.1 for details. 
Cyclophosphamide 
(CPM) 
IV over 30-60 mins  
1200 mg/m2/dose OR 40 mg/kg/dose 
for pt < 10 kg or < 1 yo 
1 
See Section 4.4.1.1 for details. 
Mesna (MESNA)  
IV or IV/PO 
See Section 4.4.1.1 
1 
Administer with CPM, see Section 4.4.1.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or < 1 yo  
15 - 19 
See Section 4.4.1.1 for details. 
Mesna (MESNA)  
IV or IV/PO 
See Section 4.4.1.1 
15 - 19 
Administer with IFOS, see Section 4.4.1.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 3.3 mg/kg/dose for 
pt < 10 kg or <1 yo  
15 - 19 
Slow rate of administration if hypotension occurs. 
See Section 4.4.1.1 for details. 
 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA__________m2  
 
 Cycle 2: Ht__________cm  
Wt__________kg  
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DOXO 
____mg 
CPM 
____mg 
MESNA (with CPM) 
______________mg/day% 
IFOS 
_____mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
_____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
1 
_____mg 
_____mg 
_____mg 
_____________mg/day% 
 
 
 
a, b, c, d,  
 
 
 
2 
 
_____mg 
 
 
 
 
 
 
 
 
 
3-4# 
Growth factor used: ____________ Dose: _____     
Date of first dose: ___________  
Date of last dose: ____________ 
 
 
 
2 
8 
_____mg 
 
 
 
 
 
 
d 
 
 
 
14 
 
 
 
 
 
 
 
d* 
 
 
3 
15 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
a, b, c, d 
 
 
 
16 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
17 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
18 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
19 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
20-21# 
Growth factor used: __________________  Dose: ___________ 
Date of first dose: ___________  
Date of last dose: ____________ 
 
 
 
4 
22 
 
 
 
 
 
 
 
d 
 
 
 
28 
 
 
 
 
 
 
 
d* 
 
% Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.1.  
The therapy delivery map for Induction continues on the next 2 pages.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 1 of 3 
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AEWS1031 
 
 
Induction for Regimen A Continued 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 3 and 4 (Weeks 5-8); a VDC cycle followed by an IE cycle. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 3 and 
4 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
29 and 36 
$-Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg. See Section 
4.4.1.1. 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT,  
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion 
over 1-15 mins& 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg or <1 yo  
29  and  30 
&- Short infusion times may be lengthened 
slightly (up to 60 minutes) if institutional 
policies mandate. See Section 4.4.1.1 for details. 
Cyclophosphamide 
(CPM)  
IV over 30-60 mins  1200 mg/m2/dose OR 40 mg/kg/dose for 
pt < 10 kg or <1 yo 
29 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.1 
29 
Administer with CPM, see Section 4.4.1.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
43-47 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.1 
43-47 
Administer with IFOS, see Section 4.4.1.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 3.3 mg/kg/dose for 
pt < 10 kg or <1 yo 
43-47 
Slow rate of administration if hypotension 
occurs. See Section 4.4.1.1 for details. 
 
 
Cycle 3 : Ht__________cm Wt__________kg  
BSA__________m2  
 
 
Cycle 4: Ht__________cm Wt__________kg  
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DOXO 
____mg 
CPM 
____mg 
MESNA (with CPM) 
__________mg/day% 
IFOS 
_____mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
_____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
5 
29 
_____mg 
_____mg 
_____mg 
_____________mg/day% 
 
 
 
a, b, c, d 
 
 
 
30 
 
_____mg 
 
 
 
 
 
 
 
 
 
31-32# 
Growth factor used: _____________________   Dose: ________  
Date of first dose: ___________ Date of last dose: ____________ 
 
 
6 
36 
_____mg 
 
 
 
 
 
 
d 
 
 
 
42 
 
 
 
 
 
 
 
d* 
 
 
7 
43 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
a, b, c, d 
 
 
 
44 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
45 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
46 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
47 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
48-49# 
Growth factor used: ______________________  Dose: __________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
8 
50 
 
 
 
 
 
 
 
d 
 
 
 
56 
 
 
 
 
 
 
 
d* 
 
% Enter total daily dose as mg/day by CI or intermittent infusion; 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.1.  
 
The therapy delivery map for Induction continues on the next page. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 2 of 3 
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AEWS1031 
 
 
Induction for Regimen A Continued 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 5 and 6 (Weeks 9-12); a VDC cycle followed by an IE cycle. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 5 and 
6 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or < 1 yo 
57 and 64 
$-Or infusion via minibag as per institutional 
policy.  
Maximum dose: 2 mg. See Section 4.4.1.1 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT, 
c. Urinalysis 
d. CBC, Plt, Diff* 
e. ECG and ECHO or MUGA 
 
 *See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins& 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg or < 1 yo 
57 and 58 
&- Short infusion times may be lengthened 
slightly (up to 60 minutes) if institutional 
policies mandate. See Section 4.4.1.1 for details. 
Cyclophosphamide 
(CPM)  
IV over 30-60 mins  
1200 mg/m2/dose OR 40 mg/kg/dose for 
pt < 10 kg or < 1 yo  
57 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.1 
57 
Administer with CPM, see Section 4.4.1.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or < 1 yo  
71-75 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.1 
71-75 
Administer with IFOS, see Section 4.4.1.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 3.3 mg/kg/dose for 
pt < 10 kg or < 1 yo 
71-75 
Slow rate of administration if hypotension 
occurs. See Section 4.4.1.1 for details. 
 
 
Cycle 5: Ht __________cm Wt __________kg  
BSA__________m2  
 
 
Cycle 6: Ht __________cm Wt __________kg  
BSA__________m2 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DOXO 
____mg 
CPM 
____mg 
MESNA (with CPM) 
_______________mg/day% 
IFOS 
_____mg 
MESNA (with IFOS) 
_________________mg/day% 
ETOP 
_____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
9 
57 
_____mg 
_____mg 
_____mg 
_______________mg/day% 
 
 
 
a, b, c, d, e 
 
 
 
58 
 
_____mg 
 
 
 
 
 
 
 
 
 
59-60# 
Growth factor used: _________________ Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
_____mg 
 
 
 
 
 
 
d 
 
 
 
70 
 
 
 
 
 
 
 
d* 
 
 
11 
71 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
a, b, c, d 
 
 
 
72 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
73 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
74 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
75 
 
 
 
 
_______mg 
_______________mg/day% 
_______mg 
 
 
 
 
76-77# 
Growth factor used: ________________  Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
12 
78 
 
 
 
 
 
 
 
d 
 
 
 
84 
Local Control will follow Induction therapy. See Section 4.3 for Local Control options. See Section 7.1 for observations prior to Local Control. 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion; 
 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.1 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guideline 
Page 3 of 3 
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AEWS1031 
 
 
 
4.4.1.2 Administration Schedule for Consolidation Therapy (Weeks 1-22) for Regimen A 
Ensure adequate time for healing following surgical local control. Consolidation will not begin until 
2 weeks post-operatively. For patients receiving radiation therapy for local control, radiation therapy should 
begin concomitantly with Week 1 of consolidation therapy. DOXOrubicin may be administered 
concurrently with radiation therapy only at Week 1 of consolidation chemotherapy. 
 
Criteria to start Consolidation: ANC ≥ 750/µL and platelet ≥ 75,000/µL post nadir (without transfusion).  
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without 
transfusion).The ANC often falls after discontinuing myeloid growth factor support. If the ANC has risen 
to ≥ 750/µL after the nadir but then falls the next cycle should be given despite ANC < 750/µL. If a cycle 
of chemotherapy is delayed due to toxicity, see Section 5.0 for criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age or weighing less than 10 kilograms, chemotherapy should 
be calculated by weight rather than by surface area. Dose/kilogram = dose/meter2 divided by 30. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day 1 of Weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21 and 22. 
Dose: 1.5 mg/m2/dose (Maximum dose is 2 mg). For patients < 10 kg or < 1 year old, the dose is 
0.05 mg/kg/dose. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the statement 
“Do not remove covering until moment of injection. For intravenous use only - Fatal if given by other 
routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. VinCRIStine is 
available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI, Marqibo®).  The 
conventional and liposomal formulations are NOT interchangeable. 
 
DOXOrubicin: IV push/infusion over 1-15 minutes  
Days: 1 and 2 of Weeks 1 and 9 
Dose: 37.5 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 1.25 mg/kg/dose. 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that DOXOrubicin be administered 
through the tubing of rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between DAUNOrubicin and 
DOXOrubicin. DOXOrubicin is available in a liposomal formulation. The conventional and liposomal 
formulations are NOT interchangeable. 
 
Dexrazoxane: Slow IV Push (eg, over 5-15 minutes) given immediately prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1 and 9. 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of DOXOrubicin). For patients < 10 kg or 
< 1 year old, the dose is 12.5 mg/kg/dose. 
Note: Administer the DOXOrubicin after completing the infusion of dexrazoxane but within 30 minutes of 
beginning the dexrazoxane infusion.  
 
Cyclophosphamide: IV over 30-60 minutes 
Day 1 of Weeks 1, 7, 9, 13, 17 and 21 
Dose: 1,200 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 40 mg/kg/dose. 
Version date: 03/04/16 
 
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AEWS1031 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic 
solution) or further diluted.  
 
Mesna must be administered in conjunction with Cyclophosphamide (see below). 
Hydrate per institutional guidelines 
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days 1-5 of Weeks 3, 5, 11, 15 and 19 
Dose: 1,800 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 60 mg/kg/dose. 
Mesna must be administered in conjunction with IFOS (see below). 
 
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. May use diuretics 
(eg, furosemide) to increase urine output. Consider adding potassium and magnesium to prevent electrolyte 
deficiencies.  
 
Mesna with cyclophosphamide 
Administer mesna by IV infusion or IV/PO on Day 1 of Weeks 1, 7, 9, 13, 17 and 21 
Total IV Dose: 720 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 24 mg/kg/day. 
 
Mesna with ifosfamide 
Administer mesna by IV infusion or IV/PO on Days 1-5 of Weeks 3, 5, 11, 15 and 19 
Total IV Dose: 1,080 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 36 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 60% of the daily 
ifosfamide/cyclophosphamide dose. Mesna can be administered in 3 divided doses by short infusion over 
15 to 30 minutes. The initial bolus dose of mesna may be administered 15 minutes before or at the same 
time as the ifosfamide/cyclophosphamide dose; subsequent doses are given 4 and 8 hours after the start of 
ifosfamide/cyclophosphamide).  
For example: if the oxazaphosphorine dose is 1,000 mg, then the total daily mesna dose is 600 mg; 200 mg 
of mesna will be given 15 minutes before or with the oxazaphosphorine dose (Hour 0) and 2 boluses of 
200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion 
should be started 15-30 minutes before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide infusion.  
For example: if the ifosfamide/cyclophosphamide dose is 1,000 mg, then the total daily mesna dose is 
600 mg; the 600 mg mesna continuous infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours after the end of the 
ifosfamide/cyclophosphamide infusion. If ifosfamide/cyclophosphamide is administered over 1 hour and 
mesna is started 30 minutes before the oxazaphosphorine infusion, the total mesna infusion will last at least 
9 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna may receive the last TWO 
bolus doses (originally at Hours 4 and 8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral 
doses will be administered at Hours 2 and 6. 
For example: if the oxazaphosphorine dose is 1,000 mg, then 200 mg of mesna will be given IV 15 minutes 
before or with the oxazaphosphorine dose (Hour 0) and the TWO oral doses of 400 mg each will be given 
at Hours 2 and 6. 
Version date: 03/04/16 
 
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AEWS1031 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute mesna parental solution 
before oral administration. The solution can be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit 
juices (grape, apple, tomato and orange) or plain or chocolate milk. The most palatable is chilled grape 
juice. Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be rounded up to nearest 
200 mg. Administer doses on a schedule as determined by timing of cyclophosphamide/ifosfamide 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days 1-5 of Weeks 3, 5, 11, 15 and 19 
Dose: 100 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if hypotension occurs. The 
use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes of D5W 
due to potential development of hyponatremia. 
 
Growth Factor Support 
Begin myeloid growth factor support at least 24-36 hours after the last dose of chemotherapy. If given daily 
then continue a minimum of 7 days and until ANC ≥ 750/µL post nadir and discontinue at least 24 hours 
prior to next cycle of chemotherapy. If given daily, growth factor administration is to be continued in weeks 
where vinCRIStine is given alone, without regard to vinCRIStine administration. 
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
 
See Section 5.0 for Dose Modifications based on toxicities. 
The therapy delivery maps for Consolidation are provided on the following 6 pages. See Section 7.1 for 
observations required at end of therapy. 
Version date: 03/04/16 
 
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AEWS1031 
 
 
Consolidation Chemotherapy for Regimen A 
 
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycle 1 (Weeks 1 and 2) of Consolidation chemotherapy  
 
____________________________Patient name or initials 
 
____________________________ 
DOB   
 
Begin Consolidation when ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). Myeloid growth factor support should be stopped a minimum of 
24 hours prior to the administration of a chemotherapy cycle. If radiation is the primary local control measure or will be given pre-operatively then consolidation chemotherapy 
should be initiated concurrently with the radiation therapy, i.e. both radiation and n Cycle 1 Consolidation should start at the same time. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg 
or <1 yo 
1 and 8 
$-Or infusion via minibag as per institutional 
policy.  
Maximum dose: 2 mg. See Section 4.4.1.2. 
a. History and Physical Exam 
b. Electrolytes, creatinine, bicarbonate, 
phosphorus, calcium, bilirubin, AST, 
ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
e Imaging per Section 16.0 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push  
(eg, over 5-15 min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 10 kg 
or <1 yo 
1 and 2 
Administer immediately prior to DOXO. The 
combined infusion time for DXRZ + DOXO 
should be ≤ 30 min. See Section 4.4.1.2. 
DOXOrubicin 
(DOXO) 
IV push over  
1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg 
or <1 yo 
1 and 2 
See Section 4.4.1.2 for details.  
Cyclophosphamide 
(CPM) 
IV over 30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or 
<1 yo 
1 
See Section 4.4.1.2. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
1 
Administer with CPM, see Section 4.4.1.2 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA_________m2 
 
%-Enter total daily dose as mg/day by CI or intermittent infusion; 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
The therapy delivery map for Consolidation continues on the next page.  
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DXRZ 
____mg 
DOXO 
___mg 
CPM 
_____mg 
MESNA (with CPM) 
_________________mg/day% 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
1 
_________mg 
_________mg 
_________mg 
_______mg 
_________________mg/day% 
a, b, c, d, e* 
 
 
 
 
2 
 
_________mg 
_________mg 
 
 
 
 
 
 
 
3-4# 
Growth factor used: _______________ Dose: ________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
2 
8 
_________mg 
 
 
 
 
d 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
d* 
 
Page 1 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
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AEWS1031 
Consolidation Chemotherapy for Regimen A  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 2 and 3 (Weeks 3 - 6) of Consolidation chemotherapy 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 2 and 3 
should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next cycle.  
 
Cycle 2: Ht__________cm Wt__________kg  
BSA______m2  
 
 
Cycle 3: Ht__________cm     Wt__________kg 
BSA__________m2 
 
% Enter total daily dose as mg/day by CI or intermittent infusion; 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2.  
The therapy delivery map for Consolidation continues on the next page. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
15–19 and 
29-33 
See Section 4.4.1.2 for details. 
a. History and physical exam 
b. Electrolytes, creatinine, bicarbonate, 
phosphorus, calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
* See Section 7.1 for details. 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE  
Mesna 
(MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
15–19 and 
29-33 
Administer with IFOS, see Section 
4.4.1.2. 
Etoposide 
(ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 3.3 mg/kg/dose 
for pt < 10 kg or <1 yo 
15–19 and 
29-33 
Slow rate of administration if 
hypotension occurs. See Section 
4.4.1.2. 
Date Due 
Date 
Given 
Week 
Day 
IFOS 
_________mg 
MESNA (with IFOS) 
__________________mg/day% 
ETOP 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
3 
15 
_________mg 
__________________mg/day% 
________mg 
a, b, c, d 
 
 
 
 
16 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
17 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
18 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
19 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
20-21# 
Growth factor used: ________________ Dose: ________    Date of first dose: ___________ 
 Date of last dose: ____________ 
 
 
4 
22 
 
 
 
d 
 
 
 
 
28 
 
 
 
d* 
 
 
 
5 
29 
_________mg 
__________________mg/day% 
________mg 
a, b, c, d 
 
 
 
 
30 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
31 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
32 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
33 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
34-35# 
Growth factor used: ________________ Dose: _________    Date of first dose: ___________  
Date of last dose: ____________ 
 
 
6 
36 
 
 
 
d 
 
 
 
 
42 
 
 
 
d* 
 
Page 2 of 6 
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AEWS1031 
 
Consolidation Chemotherapy for Regimen A  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 4 and 5 (Weeks 7-10) of Consolidation chemotherapy 
 
 ____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 4 and 5 
should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next cycle. 
Cycle 4: Ht__________cm Wt__________kg  
BSA______m2  
 
 
Cycle 5: Ht__________cm     Wt__________kg 
BSA__________m2 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
_____mg 
CPM 
____mg 
MESNA (with CPM) 
_________________mg/day% 
DXRZ 
_____mg 
DOXO 
_____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
7 
43 
_____mg 
_____mg 
_________________mg/day% 
 
 
a, b, c, d 
 
 
 
 
44-45# 
Growth factor used: ________ Dose: _____ 
Date of first dose: ___________ Date of last dose: : __________ 
 
 
8 
50 
_____mg 
 
 
 
 
d 
 
 
 
 
56 
 
 
 
 
 
d* 
 
 
 
9 
57 
_____mg 
_____mg 
_________________mg/day% 
_____mg 
_____mg 
a, b, c, d, e 
 
 
 
 
58 
 
 
 
_____mg 
_____mg 
 
 
 
 
 
59-60# 
Growth factor used: ____________ Dose: _____   Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
_____mg 
 
 
 
 
d 
 
 
 
 
70 
 
 
 
 
 
d*, f 
 
% Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
 
43, 50, 57 
and 64 
$-Or infusion via minibag as per 
institutional policy. Maximum dose: 
2 mg. See Section 4.4.1.2. 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT, 
c. Urinalysis 
d. CBC, Plt, Diff* 
e. ECG and ECHO or MUGA* 
f. Imaging per Section 16.0 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Cyclophosphamide 
(CPM) 
IV over 
30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo 
43 and 57 
See Section 4.4.1.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
43 and 57 
Administer with CPM, see Section 
4.4.1.2 
 
Dexrazoxane 
(DXRZ) 
Slow IV push  
(eg, over 5 15min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 10 kg or <1 yo 
57 and 58 
Administer immediately prior to DOXO. 
The combined infusion time for DXRZ+ 
DOXO should be ≤ 30 min. See Section 
4.4.1.2 
DOXOrubicin 
(DOXO) 
IV push 
over 1-15 mins 
 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg or <1 yo 
57 and 58 
See Section 4.4.1.2 for details. 
Page 3 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
Page 38 

 
 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
 
AEWS1031 
Consolidation Chemotherapy for Regimen A  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 6 and 7 (Weeks 11-14) of Consolidation chemotherapy. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 6 and 
7 should be given despite ANC < 750/µL Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
71-75 
See Section 4.4.1.2 for hydration 
guidelines. 
a. History and physical  
exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, calcium, 
bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
71-75 
Administer with IFOS, see Section 4.4.1.2 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 3.3 mg/kg/dose for 
pt < 10 kg or <1 yo 
71-75 
Slow rate of administration if hypotension 
occurs. 
VinCRIStine 
(VCR) 
IV push over 1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
85 and 92 
$-Or infusion via minibag as per 
institutional policy.  
Maximum dose: 2 mg See Section 4.4.1.2 
Cyclophosphamide 
(CPM) 
IV over 30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo 
85 
See Section 4.4.1.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
85 
Administer with CPM, see Section 4.4.1.2 
Cycle 6: Ht __________cm Wt __________kg  
BSA______m2  
 
 
Cycle 7: Ht __________cm Wt __________kg BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
_____mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
____mg 
VCR 
_____mg 
CPM1200 
_____mg 
MESNA (with CPM) 
______________mg/day% 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
11 
71 
_____mg 
______________mg/day% 
_____mg 
 
 
 
a, b, c, d 
 
 
 
72 
_____mg 
______________mg/day% 
_____mg 
 
 
 
 
 
 
 
73 
_____mg 
______________mg/day% 
_____mg 
 
 
 
 
 
 
 
74 
_____mg 
______________mg/day% 
_____mg 
 
 
 
 
 
 
 
75 
_____mg 
______________mg/day% 
_____mg 
 
 
 
 
 
 
 
76-77# 
Growth factor used: ______________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________ 
 
 
12 
78 
 
 
 
 
 
 
d 
 
 
 
84 
 
 
 
 
 
 
d* 
 
 
13 
85 
 
 
 
_____mg 
_____mg 
_______________mg/day% 
a, b, c, d 
 
 
 
86-87# 
Growth factor used: ______________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________ 
 
 
14 
92 
 
 
 
_____mg 
 
 
d 
 
 
 
98 
 
 
 
 
 
 
d* 
 
 
%-Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2 
The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 4 of 6 
Page 5 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
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 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
 
AEWS1031 
Consolidation Chemotherapy for Regimen A  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 8 and 9 (Weeks 15-18) of Consolidation chemotherapy. 
 
 ____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 8 and 9 
should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg OR <1 yo 
99-103 
See Section 4.4.1.2 for details. 
a. History and physical  
exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, calcium, 
bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
99-103 
Administer with IFOS, see Section 
4.4.1.2 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 3.3 mg/kg/dose for pt 
< 10 kg OR <1 yo 
99-103 
Slow rate of administration if 
hypotension occurs. 
VinCRIStine 
(VCR) 
IV push over 1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg OR <1 yo 
113 and 120 
$-Or infusion via minibag as per 
institutional policy. Maximum dose: 
2 mg. See Section 4.4.1.2 for details. 
Cyclophosphamide 
(CPM) 
IV over 30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg OR <1 yo 
113 
See Section 4.4.1.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
113 
Administer with CPM, see Section 
4.4.1.2 
Cycle 8: Ht__________cm Wt__________kg  
BSA______m2  
 
 
Cycle 9: Ht__________cm   
Wt__________kg BSA__________m2 
 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
__________mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
_________mg 
VCR 
_________mg 
CPM 
___________mg 
MESNA (with CPM) 
_______________mg/day% 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
15 
99 
__________mg 
______________mg/day% 
_________mg 
 
 
 
a, b, c, d 
 
 
 
100 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
 
101 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
 
102 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
 
103 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
 
104-105# 
Growth factor used: __________________ Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
16 
106 
 
 
 
 
 
 
d 
 
 
 
112 
 
 
 
 
 
 
d* 
 
 
17 
113 
 
 
 
_________mg 
___________mg 
_______________mg/day% 
a, b, c, d 
 
 
 
114-115# 
Growth factor used: ___________________ Dose: ________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
18 
120 
 
 
 
_________mg 
 
 
d 
 
 
 
126 
 
 
 
 
 
 
d* 
%-Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
 
The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Version date: 03/04/16 
 
 
 
 
 
 
Page 40 

 
 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
 
AEWS1031 
Consolidation Chemotherapy for Regimen A  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This therapy delivery map relates to Cycles 10 and 11 (Weeks 19-22) of Consolidation chemotherapy. 
 
 ____________________________ 
Patient name or initials 
____________________________ 
DOB 
 Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 10 and 11 
should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg OR <1 yo 
127-131 
See Section 4.4.1.2 for details.. 
a. History and physical  
exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
127-131 
Administer with IFOS, see Section 4.4.1.2 
Etoposide (ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 3.3 mg/kg/dose for 
pt < 10 kg OR <1 yo 
127-131 
Slow rate of administration if hypotension occurs. 
See Section 4.4.1.2 
VinCRIStine 
(VCR) 
IV push over  
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg OR <1 yo 
 
141 and 
148 
$-Or infusion via minibag as per institutional 
policy.  
Maximum dose: 2 mg. See Section 4.4.1.2. 
Cyclophosphamide 
(CPM) 
IV over  
30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg OR <1 yo 
141 
See Section 4.4.1.2 for further details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.1.2 
141 
Administer with CPM, see Section 4.4.1.2 
 
Cycle 10: Ht__________cm Wt__________kg  
BSA______m2 
 
 
 Cycle 11: Ht__________cm   
Wt__________kgBSA__________m2 
 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
________mg 
MESNA (with IFOS) 
_______________mg/day% 
ETOP 
______mg 
VCR 
_____mg 
CPM 
______mg 
MESNA (with CPM) 
______________mg/day% 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
19 
127 
________mg 
______________mg/day% 
______mg 
 
 
 
a, b, c, d 
 
 
 
128 
________mg 
______________mg/day% 
______mg 
 
 
 
 
 
 
 
129 
________mg 
______________mg/day% 
______mg 
 
 
 
 
 
 
 
130 
________mg 
______________mg/day% 
______mg 
 
 
 
 
 
 
 
131 
________mg 
______________mg/day% 
______mg 
 
 
 
 
 
 
 
132-133# 
Growth factor used: ______________ Dose: _______   Date of first dose: ___________ Date of last dose: ____________ 
 
 
20 
134 
 
 
 
 
 
 
d 
 
 
 
140 
 
 
 
 
 
 
d* 
 
 
21 
141 
 
 
 
_____mg 
______mg 
______________mg/day% 
a, b, c, d  
 
 
 
142-143# 
Growth factor used: ______________ Dose: _______    Date of first dose: ___________ Date of last dose: ____________ 
 
 
22 
148 
 
 
 
_____mg 
 
 
d 
 
 
 
154 
End of Therapy. See Section 7.1 and Section 16.0 for required observations and imaging at end of therapy 
 
%-Enter total daily dose as mg/day by CI or intermittent infusion; 
  #- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
Page 6 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
Page 41 

 
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AEWS1031 
4.4.2 
Administration Schedules for Regimen B 
 
4.4.2.1 Administration Schedule for Induction Therapy (Weeks 1-12) 
Criteria to start Induction: ANC ≥ 750/µL and platelets ≥ 75,000/µL (without transfusion). 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without 
transfusion). The ANC often falls after discontinuing myeloid growth factor support. If the ANC has risen 
to ≥ 750/µL after the nadir but then falls the next cycle should be given despite ANC < 750/µL. If a cycle 
of chemotherapy is delayed due to toxicity, see Section 5.0 for criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age or weighing less than 10 kilograms, chemotherapy should 
be calculated by weight rather than by surface area. Dose/kilogram = dose/meter2 divided by 30. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day 1 of Weeks 1, 2, 5, 6, 9, 10, 11 and 12. 
Dose: 1.5 mg/m2/dose (Maximum dose is 2 mg). For patients < 10 kg or < 1 year old, the dose is 
0.05 mg/kg/dose.  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the statement 
“Do not remove covering until moment of injection. For intravenous use only- Fatal if given by other 
routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. VinCRIStine is 
available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI, Marqibo®). The 
conventional and liposomal formulations are NOT interchangeable. 
 
Topotecan: IV, infuse the diluted solution over 30 minutes 
Days 1-5 of Weeks 1 and 9. 
Dose: 0.75 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 0.025 mg/kg/dose. 
 
Cyclophosphamide 
Note that the VDC and the VTC combinations involve a different dose of CPM. 
 
C250 – dose administered during cycles of VTC: IV over 15-30 minutes 
Days 1-5 of Weeks 1 and 9. 
C250 dose is 250 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 8.3 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic 
solution) or further diluted.  
Hydrate per institutional guidelines 
 
C1200 – dose administered during cycles of VDC: IV over 30-60 minutes 
Day 1 of Weeks 5 and 11. 
C1200 dose is 1,200 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic 
solution) or further diluted.  
Mesna must be administered in conjunction with C1200 (see below). 
Hydrate per institutional guidelines 
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days 1-5 of Weeks 3 and 7. 
Dose: 1,800 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 60 mg/kg/dose. 
Mesna must be administered in conjunction with IFOS (see below). 
Version date: 03/04/16 
 
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AEWS1031 
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. May use diuretics 
(eg, furosemide) to increase urine output. Consider adding potassium and magnesium to prevent electrolyte 
deficiencies.  
 
Mesna with IFOS 
Administer mesna by IV infusion or IV/PO on Days 1-5 of Weeks 3 and 7. 
Total IV Dose: 1,080 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 36 mg/kg/day. 
 
Mesna with C1200 
Administer mesna by IV infusion or IV/PO on Day 1 of Weeks 5 and 11. 
Total IV Dose: 720 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 24 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 60% of the daily 
ifosfamide/cyclophosphamide dose. Mesna can be administered in 3 divided doses by short infusion over 
15 to 30 minutes. The initial bolus dose of mesna may be administered 15 minutes before or at the same 
time as the ifosfamide/cyclophosphamide dose; subsequent doses are given 4 and 8 hours after the start of 
ifosfamide/cyclophosphamide).  
For example: if the oxazaphosphorine dose is 1,000 mg, then the total daily mesna dose is 600 mg; 200 mg 
of mesna will be given 15 minutes before or with the oxazaphosphorine dose (Hour 0) and 2 boluses of 
200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion 
should be started 15-30 minutes before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide infusion.  
For example: if the ifosfamide/cyclophosphamide dose is 1,000 mg, then the total daily mesna dose is 
600 mg; the 600 mg mesna continuous infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours after the end of the 
ifosfamide/cyclophosphamide infusion. If ifosfamide/cyclophosphamide is administered over 1 hour and 
mesna is started 30 minutes before the oxazaphosphorine infusion, the total mesna infusion will last at least 
9 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna may receive the last TWO 
bolus doses (originally at Hours 4 and 8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral 
doses will be administered at Hours 2 and 6. 
For example: if the oxazaphosphorine dose is 1,000 mg, then 200 mg of mesna will be given IV 15 minutes 
before or with the oxazaphosphorine dose (Hour 0) and the TWO oral doses of 400 mg each will be given 
at Hours 2 and 6. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute mesna parental solution 
before oral administration. The solution can be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit 
juices (grape, apple, tomato and orange) or plain or chocolate milk. The most palatable is chilled grape 
juice. Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be rounded up to nearest 
200 mg. Administer doses on a schedule as determined by timing of cyclophosphamide/ifosfamide 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
Version date: 03/04/16 
 
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AEWS1031 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days 1-5 of Weeks 3 and 7. 
Dose: 100 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if hypotension occurs The 
use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes of D5W 
due to potential development of hyponatremia. 
 
DOXOrubicin: IV push/infusion over 1-15 minutes. Short infusion times may be lengthened slightly 
(and up to 60 minutes) if institutional policies mandate. 
Days 1 and 2 of Weeks 5 and 11. 
Dose: 37.5 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 1.25 mg/kg/dose. 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that DOXOrubicin be administered 
through the tubing of rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between DAUNOrubicin and 
DOXOrubicin. DOXOrubicin is available in a liposomal formulation. The conventional and liposomal 
formulations are NOT interchangeable. 
 
Growth Factor Support 
Begin myeloid growth factor support 24-36 hours after the last dose of chemotherapy. If given daily then 
continue a minimum of 7 days and until ANC ≥ 750/µL post nadir and discontinue at least 24 hours prior 
to next cycle of chemotherapy. If given daily, growth factor administration is to be continued in weeks 
where vinCRIStine is given alone, without regard to vinCRIStine administration. 
Note: Use of GM-GCSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
The therapy delivery maps for Induction are provided on the following 4 pages. Local control will follow 
Induction (see Section 4.3 for details). See Section 7.1 for observations prior to Local Control. See Section 
16.0 for imaging pre- and post- Local Control. Details of Consolidation chemotherapy for Regimen B are 
provided in Section 4.4.2.2. 
 
 
Version date: 03/04/16 
 
Page 44 

 
 
 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
 
AEWS1031 
 
 
Induction for Regimen B 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 1 and 2 (Weeks 1-4): a VTC250 cycle followed by an IE cycle. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
 
Criteria to start each cycle: ANC ≥ 750/µL and platelets ≥ 75,000/µL (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycle 2 should be given despite 
ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push 
over 1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
 
1 and 8 
$-Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.2.1 for 
further details. 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Topotecan (TOPO) 
IV over  
30 min 
0.75 mg/m2/dose OR 
0.025 mg/kg/dose for pt < 10 kg or <1 yo 
1 - 5 
See Section 4.4.2.1 
Cyclophosphamide 
(CPM250) 
IV over  
15-30 min 
250 mg/m2/dose OR 
8.3 mg/kg/dose for pt < 10 kg or <1 yo 
1 - 5 
See Section 4.4.2.1. 
Ifosfamide (IFOS) 
IV over 1 
hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
15 - 19 
See Section 4.4.2.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.1 
15 - 19 
Administer with IFOS, see Section 4.4.2.1 
Etoposide (ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt < 10 kg or <1 yo 
15 - 19 
Slow rate of administration if hypotension occurs. 
See Section 4.4.2.1 
 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA______m2  
 
 
 
Cycle 2: Ht__________cm     Wt__________kg 
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
TOPO 
_____mg 
CPM250 
____mg 
IFOS 
______mg 
MESNA (with IFOS) 
__________mg/day% 
ETOP 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
1 
_____mg 
______mg 
_____mg 
 
 
 
a, b, c, d 
 
 
 
 
2 
 
______mg 
_____mg 
 
 
 
 
 
 
 
 
3 
 
______mg 
_____mg 
 
 
 
 
 
 
 
 
4 
 
______mg 
_____mg 
 
 
 
 
 
 
 
 
5 
 
______mg 
_____mg 
 
 
 
 
 
 
 
 
6-7# 
Growth factor used: ______________ Dose: _______   Date of first dose: ___________ Date of last dose: ____________ 
 
 
2 
8 
_____mg 
 
 
 
 
 
d 
 
 
 
 
14 
 
 
 
 
 
 
d* 
 
 
 
3 
15 
 
 
 
________mg 
_____________mg/day% 
_______mg 
a, b, c, d 
 
 
 
 
16 
 
 
 
________mg 
_____________mg/day% 
_______mg 
 
 
 
 
 
17 
 
 
 
________mg 
_____________mg/day% 
_______mg 
 
 
 
 
 
18 
 
 
 
________mg 
_____________mg/day% 
_______mg 
 
 
 
 
 
19 
 
 
 
________mg 
_____________mg/day% 
_______mg 
 
 
 
 
 
20-21# 
Growth factor used: ______________ Dose: _______   Date of first dose: ___________ Date of last dose: ____________ 
 
 
4 
22 
 
 
 
 
 
 
d 
 
 
 
 
28 
 
 
 
 
 
 
d* 
 
%- Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.1. 
The therapy delivery maps for Induction continue on the next 2 pages. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 1 of 3 
Version date: 03/04/16 
 
 
 
 
 
 
 
Page 45 

 
 
 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
 
AEWS1031 
 
Induction for Regimen B 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 3 and 4 (Weeks 5-8): a VDC1200 cycle followed by an IE cycle. 
 
 ____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls,  
Cycles 3 and 4 should  be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
29 and 36 
$-Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.2.1 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV 
push/infusion 
over 1-15 min& 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg or <1 yo 
29 and 30 
&- Short infusion times may be lengthened slightly 
(up to 60 minutes) if institutional policies mandate. 
See Section 4.4.2.1. 
Cyclophosphamide 
(CPM1200) 
IV over  
30-60 min 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo 
29 
See Section 4.4.2.1 for further details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.1 
29 
Administer with CPM, see Section 4.4.2.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
43 - 47 
See Section 4.4.2.1 for further details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.1 
43 - 47 
Administer with IFOS, see Section 4.4.2.1 
Etoposide (ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt < 10 kg or <1 yo 
43 - 47 
Slow rate of administration if hypotension occurs. 
See Section 4.4.2.1. 
 
 
Cycle 3: Ht __________cm Wt __________kg  
BSA______m2  
 
 
 
Cycle 4: Ht __________cm     Wt __________kg 
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
DOXO 
____mg 
CPM1200 
____mg 
MESNA (with CPM1200) 
_____________mg/day% 
IFOS 
______mg 
MESNA (with IFOS) 
__________________mg/day% 
ETOP 
______mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
5 
29 
_____mg 
_____mg 
_____mg 
______________mg/day% 
 
 
 
a, b, c, d 
 
 
 
30 
 
_____mg 
 
 
 
 
 
 
 
 
 
31-32# 
Growth factor used: ________________ Dose: _________     Date of first dose: ____________ Date of last dose: ____________ 
 
 
 
6 
36 
_____mg 
 
 
 
 
 
 
d 
 
 
 
42 
 
 
 
 
 
 
 
d* 
 
 
7 
43 
 
 
 
 
_______mg 
_________________mg/day% 
_______mg 
a, b, c, d 
 
 
 
44 
 
 
 
 
_______mg 
_________________mg/day% 
_______mg 
 
 
 
 
45 
 
 
 
 
_______mg 
_________________mg/day% 
_______mg 
 
 
 
 
46 
 
 
 
 
_______mg 
_________________mg/day% 
_______mg 
 
 
 
 
47 
 
 
 
 
_______mg 
_________________mg/day% 
_______mg 
 
 
 
 
48-49# 
Growth factor used: ________________ Dose: __________    Date of first dose: ____________ Date of last dose: ____________ 
 
 
 
8 
50 
 
 
 
 
 
 
 
d 
 
 
 
56 
 
 
 
 
 
 
 
d* 
%- Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.1. 
The therapy delivery maps for Induction continue on the next page. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 2 of 3 
Version date: 03/04/16 
 
 
 
 
 
 
 
Page 46 

 
 
 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
 
AEWS1031 
 
Induction for Regimen B 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 5 and 6 (Weeks 9-12): a VTC250 cycle followed by a VDC1200 cycle. 
 
 ____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µLand platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls,  
Cycles 5 and 6 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over  
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
57, 64, 71 
and 78 
$-Or infusion via minibag as per 
institutional policy.  
Maximum dose: 2 mg. See Section 4.4.2.1  
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, calcium, 
bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Topotecan (TOPO) 
IV over 30 min 
0.75 mg/m2/dose OR 
0.025 mg/kg/dose for pt < 10 kg or <1 
yo 
57 - 61 
See Section 4.4.2.1 
Cyclophosphamide 
(CPM250) 
IV over  
15-30 min  
250 mg/m2/dose OR 
8.3 mg/kg/dose for pt < 10 kg or <1 yo 
57 - 61 
See Section 4.4.2.1 for r details. 
DOXOrubicin 
(DOXO) 
IV 
push/infusion 
over 1-15 min& 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 10 kg or <1 yo 
71 and 72 
&- Short infusion times may be lengthened 
slightly (up to 60 minutes) if institutional 
policies mandate. See Section 4.4.2.1. 
Cyclophosphamide 
(CPM1200) 
IV over  
30-60 min 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo  
71 
See Section 4.4.2.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.1. 
 
71 
Administer with CPM1200, see Section 
4.4.2.1. 
 
 
Cycle 5: Ht__________cm Wt__________kg  
BSA______m2  
 
 
 
Cycle 6: Ht__________cm     Wt__________kg 
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
TOPO 
____mg 
CPM250 
____mg 
DOXO 
____mg 
CPM1200 
_______mg 
MESNA (with CPM1200) 
_________________mg/day% 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
9 
57 
_____mg 
_____mg 
_____mg 
 
 
 
a, b, c, d 
 
 
 
 
58 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
59 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
60 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
61 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
62-63# 
Growth factor used: ____________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
_____mg 
 
 
 
 
 
d 
 
 
 
 
70 
 
 
 
 
 
 
d* 
 
 
 
11 
71 
_____mg 
 
 
_____mg 
________mg 
_________________mg/day% 
a, b, c, d,  
 
 
 
 
72 
 
 
 
_____mg 
 
 
 
 
 
 
 
73-74# 
Growth factor used: ____________ Dose: _____     Date of first dose: ___________ Date of last dose: ____________ 
 
 
12 
78 
_____mg 
 
 
 
 
 
d 
 
 
 
 
 
84 
Local Control will follow Induction therapy. See Section 4.3 for Local Control options. See Section 7.1 for observations prior to Local Control. 
%- Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.1. 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
Page 3 of 3 
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4.4.2.2 Administration Schedule for Consolidation Therapy (Weeks 1-22) for Regimen B 
Ensure adequate time for healing following surgical local control. 
 
Criteria to start Consolidation: ANC ≥ 750/µL and platelet ≥ 75,000/µL post nadir (without transfusion). 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet ≥ 75,000/µL post nadir (without transfusion). 
The ANC often falls after discontinuing myeloid growth factor support. If the ANC has risen to ≥ 750/µL 
after the nadir but then falls the next cycle should be given despite ANC < 750/µL. If a cycle of 
chemotherapy is delayed due to toxicity, see Section 5.0 for criteria to resume chemotherapy. For patients 
receiving radiation therapy for local control, radiation therapy should begin concomitantly with Week 1 of 
consolidation therapy. DOXOrubicin should not be administered concurrently with radiation therapy. 
 
Note: for children less than 1 year of age or weighing less than 10 kilograms, chemotherapy should 
be calculated by weight rather than by surface area. Dose/kilogram = dose/meter2 divided by 30. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day 1 of Weeks 1, 2, 7-10, 13-16, 19 and 20. 
Dose: 1.5 mg/m2/dose. (Maximum dose is 2 mg.) For patients < 10 kg or < 1 year old, the dose is 
0.05 mg/kg/dose.  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the statement 
“Do not remove covering until moment of injection. For intravenous use only- Fatal if given by other 
routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. VinCRIStine is 
available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI, Marqibo®). The 
conventional and liposomal formulations are NOT interchangeable. 
 
Topotecan: IV, infuse the diluted solution over 30 minutes 
Days 1-5 of Weeks 1, 7 and 15. 
Dose: 0.75 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 0.025 mg/kg/dose. 
 
Cyclophosphamide: 
Note that the VDC and the VTC combinations involve a different dose of CPM. 
 
C250 – dose administered during cycles of VTC: IV over 15-30 minutes 
Days 1-5 of Weeks 1, 7 and 15. 
C250 dose is 250 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 8.3 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic 
solution) or further diluted.  
Hydrate per institutional guidelines 
 
C1200 – dose administered during cycles of VDC: IV over 30-60 minutes 
Day 1 of Weeks 9, 13 and 19. 
C1200 dose is 1200 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to avoid hypotonic 
solution) or further diluted.  
Mesna must be administered in conjunction with C1200 (see below). 
Hydrate per institutional guidelines 
 
 
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Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days 1-5 of Weeks 3, 5, 11, 17, and 21. 
Dose: 1800 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 60 mg/kg/dose. 
Mesna must be administered in conjunction with IFOS (see below). 
 
Suggested hydration: Administer 3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. May use diuretics 
(eg, furosemide) to increase urine output. Consider adding potassium and magnesium to prevent electrolyte 
deficiencies.  
 
Mesna with IFOS 
Administer mesna by IV infusion or IV/PO on Days 1-5 of Weeks 3, 5, 11, 17, and 21. 
Total IV Dose: 1080 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 36 mg/kg/day. 
 
Mesna with C1200 
Administer mesna by IV infusion or IV/PO on Day 1 of Weeks 9, 13 and 19. 
Total IV Dose: 720 mg/m2/day. For patients < 10 kg or < 1 year old, the IV dose is 24 mg/kg/day. 
 
Mesna with C250  
Mesna is not required with C250 containing cycles but may be used at investigator discretion. Initial Dose 
if required: 150 mg/m2/day. For patients <10 kg or < 1 year old, the IV dose is 5 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 60% of the daily 
ifosfamide/cyclophosphamide dose. Mesna can be administered in 3 divided doses by short infusion over 
15 to 30 minutes. The initial bolus dose of mesna may be administered 15 minutes before or at the same 
time as the ifosfamide/cyclophosphamide dose; subsequent doses are given 4 and 8 hours after the start of 
ifosfamide/cyclophosphamide).  
For example: if the oxazaphosphorine dose is 1,000 mg, then the total daily mesna dose is 600 mg; 200 mg 
of mesna will be given 15 minutes before or with the oxazaphosphorine dose (Hour 0) and 2 boluses of 
200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion 
should be started 15-30 minutes before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide infusion.  
For example: if the ifosfamide/cyclophosphamide dose is 1,000 mg, then the total daily mesna dose is 
600 mg; the 600 mg mesna continuous infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours after the end of the 
ifosfamide/cyclophosphamide infusion. If ifosfamide/cyclophosphamide is administered over 1 hour and 
mesna is started 30 minutes before the oxazaphosphorine infusion, the total mesna infusion will last at least 
9 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna may receive the last TWO 
bolus doses (originally at Hours 4 and 8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral 
doses will be administered at Hours 2 and 6. 
For example: if the oxazaphosphorine dose is 1,000 mg, then 200 mg of mesna will be given IV 15 minutes 
before or with the oxazaphosphorine dose (Hour 0) and the TWO oral doses of 400 mg each will be given 
at Hours 2 and 6. 
 
Version date: 03/04/16 
 
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AEWS1031 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute mesna parental solution 
before oral administration. The solution can be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit 
juices (grape, apple, tomato and orange) or plain or chocolate milk. The most palatable is chilled grape 
juice. Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be rounded up to nearest 
200 mg. Administer doses on a schedule as determined by timing of cyclophosphamide/ifosfamide 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days 1-5 of Weeks 3, 5, 11, 17, and 21. 
Dose: 100 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if hypotension occurs. The 
use of an in-line filter during the infusion is suggested. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes of D5W 
due to potential development of hyponatremia. 
 
Dexrazoxane: Slow IV Push (eg, over 5-15 minutes) given immediately prior to DOXOrubicin 
Days 1 and 2 of Weeks 13 and 19. 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of DOXOrubicin). For patients < 10 kg or 
< 1 year old, the dose is 12.5 mg/kg/dose. 
Note: Administer the DOXOrubicin after completing the infusion of dexrazoxane but within 30 minutes of 
beginning the dexrazoxane infusion.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes. Short infusion times may be lengthened slightly 
(and up to 60 minutes) if institutional policies mandate. 
Days 1 and 2 of Weeks 9, 13* and 19*. 
Dose: 37.5 mg/m2/dose. For patients < 10 kg or < 1 year old, the dose is 1.25 mg/kg/dose. 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that DOXOrubicin be administered 
through the tubing of rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
Note: * Administration must not exceed 15 minutes for Weeks 13 and 19 where dexrazoxane is 
administered immediately prior to DOXOrubicin doses. Longer infusions must not be used when 
DOXOrubicin is administered post-dexrazoxane. 
 
Special precautions: Medication errors have occurred due to confusion between DAUNOrubicin and 
DOXOrubicin. DOXOrubicin is available in a liposomal formulation. The conventional and liposomal 
formulations are NOT interchangeable. 
 
Growth Factor Support 
Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. If given 
daily then continue a minimum of 7 days and until ANC ≥ 750/µL post nadir and discontinue at least 
24 hours prior to next cycle of chemotherapy. If given daily, growth factor administration is to be continued 
in weeks where vinCRIStine is given alone, without regard to vinCRIStine administration. 
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
The therapy delivery maps for Consolidation are provided on the following 6 pages. See Section 7.1 for 
observations required at end of therapy. 
 
Version date: 03/04/16 
 
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AEWS1031 
Consolidation Chemotherapy for Regimen B 
 
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
 
This page relates to Cycle 1 (Weeks 1 and 2) of Consolidation chemotherapy 
 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
 
Begin Consolidation when ANC ≥ 750/µL and platelets ≥ 75,000/µL (without transfusion). Myeloid growth factor support should be stopped a minimum of 24 
hours prior to the administration of a chemotherapy cycle. If radiation is the primary local control measure or will be given pre-operatively then consolidation chemotherapy 
should be initiated concurrently with the radiation therapy, i.e. both radiation and Cycle 1 Consolidation should start at the same time. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
 
1 and 8 
$-Or infusion via minibag as 
per institutional policy.  
Maximum dose: 2 mg. See 
Section 4.4.2.2  
a. History and Physical Exam 
b. Electrolytes, creatinine, bicarbonate, 
phosphorus, calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
e. Imaging per Section 16.0 
 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Topotecan (TOPO) 
IV over  
30 min 
0.75 mg/m2/dose OR 
0.025 mg/kg/dose for pt < 10 kg or <1 yo 
1 - 5 
 
Cyclophosphamide 
(CPM250) 
IV over  
15-30 min  
250 mg/m2/dose or 
8.3  mg/kg/dose for pt < 10 kg or <1 yo 
 
1 - 5 
See Section 4.4.2.2 
 
 
 
 
 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA______m2       
 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
________mg 
TOPO 
________mg 
CPM250 
________mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
1 
1 
_________mg 
_________mg 
_________mg 
a, b, c, d, e* 
 
 
 
 
2 
 
_________mg 
_________mg 
 
 
 
 
 
3 
 
_________mg 
_________mg 
 
 
 
 
 
4 
 
_________mg 
_________mg 
 
 
 
 
 
5 
 
_________mg 
_________mg 
 
 
 
 
 
6-7# 
Growth factor used: _______________ Dose: ___________     Date of first dose: ___________ Date of last dose: ____________ 
 
 
2 
8 
_________mg 
 
 
d 
 
 
 
 
14 
 
 
 
d* 
 
 
# Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2 
The therapy delivery maps for Consolidation continue on the next 5 pages. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
  
 
Page 1 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
Page 51 

 
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AEWS1031 
Consolidation Chemotherapy for Regimen B  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 2 and 3 (Weeks 3 - 6) of Consolidation chemotherapy 
 
 ____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If the ANC has risen to >750//µL after nadir, but then falls Cycles 2 
and 3 should be given despite ANC < 750//µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over  
1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
15–19 and 
29-33 
See Section 4.4.2.2 details. 
a. History and physical exam 
b. Electrolytes, creatinine, bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
Mesna 
(MESNA) 
IV or IV/PO 
See Section 4.4.2.2. 
15–19 and 
29-33 
Administer with IFOS, see 
Section 4.4.2.2. 
Etoposide 
(ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt < 10 kg or <1 yo 
15–19 and 
29-33 
Slow rate of administration if 
hypotension occurs. See Section 
4.4.2.2. 
 
 
Cycle 2: Ht __________cm Wt __________kg  
BSA______m2  
 
 
Cycle 3: Ht __________cm     Wt __________kg BSA__________m2 
 
Date Due 
Date 
Given 
Week 
Day 
IFOS 
________mg 
MESNA (with IFOS) 
_____________________mg/day% 
ETOP 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
3 
15 
_________mg 
_____________________mg/day% 
________mg 
a, b, c, d 
 
 
 
 
16 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
17 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
18 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
19 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
20-21# 
Growth factor used: ______________ Dose: ________      Date of first dose: ___________ Date of last dose: ____________ 
 
 
4 
22 
 
 
 
d 
 
 
 
 
28 
 
 
 
d* 
 
 
 
5 
29 
_________mg 
_____________________mg/day% 
________mg 
a, b, c, d 
 
 
 
 
30 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
31 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
32 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
33 
_________mg 
_____________________mg/day% 
________mg 
 
 
 
 
 
34-35# 
Growth factor used: _______________ Dose: ________     Date of first dose: ___________ Date of last dose: ____________ 
 
 
6 
36 
 
 
 
d 
 
 
 
 
42 
 
 
 
d* 
 
%- Enter total daily dose as mg/day by CI or intermittent infusion; 
#-Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2 
The therapy delivery maps for Consolidation continue on the next 4 pages. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
 
Page 2 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
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AEWS1031 
Consolidation Chemotherapy for Regimen B 
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 4 and 5 (Weeks 7 - 10) of Consolidation chemotherapy 
____________________________ 
Patient name or initials 
____________________________DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If the ANC has risen to >750//µL after nadir, but then falls Cycles 4 and 
5 should be given despite ANC < 750//µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
43, 50, 57 
and 64 
$-Or infusion via minibag as per institutional 
policy.  
Maximum dose: 2 mg. See Section 4.4.2.2. 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
e. ECG and ECHO or MUGA 
f. Imaging per Section 16.0 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Topotecan (TOPO) 
IV over 
30 min 
0.75 mg/m2/dose OR 
0.025 mg/kg/dose for pt < 10 kg or <1 yo 
43 - 47 
 
Cyclophosphamide 
(CPM250) 
IV over  
15-30 min 
250 mg/m2/dose OR 
8.3 mg/kg/dose for pt < 10 kg or <1 yo 
43 - 47 
See Section 4.4.2.2.  
DOXOrubicin 
(DOXO) 
IV 
push/infusion 
over 1-15min& 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for patients < 10 kg or <1 yo 
57 and 58 
&- Short infusion times may be lengthened 
slightly (up to 60 minutes) if institutional 
policies mandate. See Section 4.4.2.2 
Cyclophosphamide 
(CPM1200) 
IV over 30-
60 min 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo 
 
57 
See Section 4.4.2.2  
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.2 
57 
Administer with CPM1200, see Section 4.4.2.2 
 
 
Cycle 4: Ht __________cm Wt __________kg  
BSA______m2  
 
 
Cycle 5: Ht __________cm     Wt __________kg BSA__________m2 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
____mg 
TOPO 
____mg 
CPM250 
____mg 
DOXO 
_____mg 
CPM1200 
_____mg 
MESNA (with CPM1200) 
_________________mg/day% 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
7 
43 
_____mg 
_____mg 
_____mg 
 
 
 
a, b, c, d 
 
 
 
 
44 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
45 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
46 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
47 
 
_____mg 
_____mg 
 
 
 
 
 
 
 
 
48-49# 
Growth factor used: ______________ Dose: _______   Date of first dose: ___________ Date of last dose: ____________ 
 
 
8 
50 
_____mg 
 
 
 
 
 
d 
 
 
 
 
56 
 
 
 
 
 
 
d* 
 
 
 
9 
57 
_____mg 
 
 
______mg 
______mg 
_________________mg/day% 
a, b, c, d, e 
 
 
 
 
58 
 
 
 
______mg 
 
 
 
 
 
 
 
59-60# 
Growth factor used: _______________ Dose: _______    Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
_____mg 
 
 
 
 
 
d 
 
 
 
 
70 
 
 
 
 
 
 
d*, f 
 
%- Enter total daily dose as mg/day by CI or intermittent infusion; 
#- Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2 
The therapy delivery maps for Consolidation continue on the next 3 pages. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 3 of 6 
Version date: 03/04/16 
 
 
 
 
 
 
Page 53 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
AEWS1031 
Consolidation Chemotherapy for Regimen B  
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 6 and 7 (Weeks 11 - 14) of Consolidation chemotherapy 
____________________________ 
Patient name or initials 
____________________________ 
DOB   
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls,  
Cycles 6 and 7 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
71-75 
See Section 4.4.2.2 for details. 
a. History and physical 
 exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, 
ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for 
details. 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.2 
71-75 
Administer with IFOS, see Section 4.4.2.2 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt < 10 kg or <1 yo  
71-75 
Slow rate of administration if hypotension occurs. See 
Section 4.4.2.2 
VinCRIStine 
(VCR) 
IV push over 
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
85 and 92 
$-Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.2.2. 
Dexrazoxane 
(DXRZ) 
Slow IV push  
(eg, over 5-15 min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 10 kg or <1 yo 
85 and 86 
Administer immediately prior to DOXO. Combined 
infusion time for DXRZ + DOXO should be ≤ 30 min. 
See Section 4.4.2.2 
DOXOrubicin 
(DOXO) 
IV push over  
1-15 min  
37.5 mg/m2/dose OR 1.25 mg/kg/dose 
for patients < 10 kg or <1 yo 
85 and 86 
See Section 4.4.2.2 
Cyclophosphamide 
(CPM1200) 
IV over 30-60 min 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo 
85 
See Section 4.4.2.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.2 
85 
Administer with CPM1200, see Section 4.4.2.2. 
Cycle 6: Ht __________cm Wt __________kg  
BSA______m2  
 
 
Cycle 7: Ht __________cm     Wt __________kg 
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
_______mg 
MESNA (with IFOS) 
_____________mg/day% 
ETOP 
__________mg 
VCR 
______mg 
DXRZ 
______mg 
DOXO 
______mg 
CPM1200 
_____mg 
MESNA (with 
CPM1200) 
____________mg/day% 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
11 
71 
_______mg 
_____________mg/day% 
__________mg 
 
 
 
 
 
a, b, c, d 
 
 
 
72 
_______mg 
_____________mg/day% 
__________mg 
 
 
 
 
 
 
 
 
 
73 
_______mg 
_____________mg/day% 
__________mg 
 
 
 
 
 
 
 
 
 
74 
_______mg 
_____________mg/day% 
__________mg 
 
 
 
 
 
 
 
 
 
75 
_______mg 
_____________mg/day% 
__________mg 
 
 
 
 
 
 
 
 
 
76-77# 
Growth factor used: ______________ Dose: ________     Date of first dose: ___________ Date of last dose: ____________ 
 
 
 
12 
78 
 
 
 
 
 
 
 
 
d 
 
 
 
84 
 
 
 
 
 
 
 
 
d* 
 
 
13 
85 
 
 
 
______mg 
______mg 
______mg 
_____mg 
____________mg/day% 
a, b, c, d,  
 
 
 
86 
 
 
 
 
______mg 
______mg 
 
 
 
 
 
 
87-88# 
Growth factor used: ______________ Dose: _________     Date of first dose: ___________ Date of last dose: ____________ 
 
 
 
14 
92 
 
 
 
______mg 
 
 
 
 
d 
 
 
 
98 
 
 
 
 
 
 
 
 
d* 
%- Enter total daily dose as mg/day by CI or intermittent infusion; *Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2 
The therapy delivery maps for Consolidation continue on the next 2 pages. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 4 of 6 
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Consolidation Chemotherapy for Regimen B 
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 8 and 9 (Weeks 15 - 18) of Consolidation chemotherapy 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls,  
Cycles 8 and 9 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over  
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
99 and 
106 
$-or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg. See Section 
4.4.2.2. 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, calcium, 
bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
 
* See Section 7.1 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Topotecan (TOPO) 
IV over 30 
min 
0.75 mg/m2/dose OR 
0.025 mg/kg/dose for pt < 10 kg or <1 yo 
99-103 
 
Cyclophosphamide 
(CPM250) 
IV over  
15-30 min 
250 mg/m2/dose OR 
8.3 mg/kg/dose for pt < 10 kg or <1 yo 
99-103 
See Section 4.4.2.2. 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
113-117 
See Section 4.4.2.2 for details.  
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.2 
113-117 
Administer with IFOS, see Section 4.4.2.2. 
Etoposide (ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt < 10 kg or <1 yo 
113-117 
Slow rate of administration if hypotension occurs. 
See Section 4.4.2.2. 
 
Cycle 8: Ht __________cm Wt __________kg  
BSA______m2  
 
 
 
Cycle 9: Ht __________cm     Wt__________kgBSA__________m2 
 
Date Due 
Date Given 
Week 
Day 
VCR 
_______mg 
TOPO 
_____mg 
CPM250 
_____mg 
IFOS 
_______mg 
MESNA (with IFOS) 
_____________mg/day% 
ETOP 
_______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
15 
99 
_______mg 
_____mg 
______mg 
 
 
 
a, b, c, d 
 
 
 
 
100 
 
_____mg 
______mg 
 
 
 
 
 
 
 
 
101 
 
_____mg 
______mg 
 
 
 
 
 
 
 
 
102 
 
_____mg 
______mg 
 
 
 
 
 
 
 
 
103 
 
_____mg 
______mg 
 
 
 
 
 
 
 
 
104-105# 
Growth factor used: _______________ Dose: ________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
16 
106 
_______mg 
 
 
 
 
 
d 
 
 
 
 
112 
 
 
 
 
 
 
d* 
 
 
 
17 
113 
 
 
 
_______mg 
______________mg/day% 
_______mg 
a, b, c, d 
 
 
 
 
114 
 
 
 
_______mg 
______________mg/day% 
_______mg 
 
 
 
 
 
115 
 
 
 
_______mg 
______________mg/day% 
_______mg 
 
 
 
 
 
116 
 
 
 
_______mg 
______________mg/day% 
_______mg 
 
 
 
 
 
117 
 
 
 
_______mg 
______________mg/day% 
_______mg 
 
 
 
 
 
118-119# 
Growth factor used: _______________ Dose: ________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
18 
120 
 
 
 
 
 
 
d 
 
 
 
 
126 
 
 
 
 
 
 
d* 
 
%-Enter total daily dose as mg/day by CI or intermittent infusion; 
#-Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2. 
The therapy delivery map for Consolidation continues on the next page. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE
Page 5 of 6 
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AEWS1031 
 
Consolidation Chemotherapy for Regimen B 
Consolidation Chemotherapy consists of 11 two-week cycles (154 days in total). 
This Therapy Delivery Map is on 6 pages.  
This page relates to Cycles 10 and 11 (Weeks 19 - 22) of Consolidation chemotherapy 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start each cycle: ANC ≥ 750/µLand platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 10 
and 11 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over  
1 min$ 
1.5 mg/m2/dose OR 
0.05 mg/kg/dose for pt < 10 kg or <1 yo 
127 and 
134 
$-Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.2.2. 
a. History and physical exam 
b. Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium, bilirubin, AST, ALT 
c. Urinalysis 
d. CBC, Plt, Diff* 
e. ECG and ECHO or MUGA 
 
*See Section 7.1 for details.  
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push  
(eg, over 5-15 min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 10 kg or <1 yo 
127 and 
128 
Administer immediately prior to DOXO. The combined 
infusion time for DXRZ + DOXO should be ≤ 30 min.  
DOXOrubicin 
(DOXO) 
IV push 
over 1-15 min  
37.5 mg/m2/dose OR 1.25 mg/kg/dose 
for pt < 10 kg or <1 yo 
127 and 
128 
See Section 4.4.2.2. 
Cyclophosphamide 
(CPM1200) 
IV over 30-60 min 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 10 kg or <1 yo 
127 
See Section 4.4.2.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.2 
127 
Administer with CPM1200, see Section 4.4.2.2. 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 10 kg or <1 yo 
141-145 
See Section 4.4.2.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
See Section 4.4.2.2 
141-145 
Administer with IFOS, see Section 4.4.2.2. 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt < 10 kg or <1 yo 
141-145 
Slow rate of administration if hypotension occurs.  
Cycle 10: Ht __________cm Wt __________kg  
BSA______m2  
 
 
 
Cycle 11: Ht __________cm     Wt __________kg BSA__________m2 
 
Date Due 
Date 
Given 
Wee
k 
Day 
VCR 
_______mg 
DEXRA 
______mg 
DOXO 
_____mg 
CPM1200 
_______mg 
MESNA (with CPM1200) 
_____________mg/day% 
IFOS 
______mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
_____mg 
Studies 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
19 
127 
_______mg 
______mg 
_____mg 
_______mg 
_____________mg/day% 
 
 
 
a, b, c, d, e 
 
 
 
128 
 
______mg 
_____mg 
 
 
 
 
 
 
 
 
 
129-130# 
Growth factor used: ____________  
Dose: _______     Date of first dose: ___________ 
 Date of last dose: ____________ 
 
 
 
20 
134 
_______mg 
 
 
 
 
 
 
 
d 
 
 
 
140 
 
 
 
 
 
 
 
 
d* 
 
 
21 
141 
 
 
 
 
 
______mg 
______________mg/day% 
_____mg 
a, b, c, d 
 
 
 
142 
 
 
 
 
 
______mg 
______________mg/day% 
_____mg 
 
 
 
 
143 
 
 
 
 
 
______mg 
______________mg/day% 
_____mg 
 
 
 
 
144 
 
 
 
 
 
______mg 
______________mg/day% 
_____mg 
 
 
 
 
145 
 
 
 
 
 
______mg 
______________mg/day% 
_____mg 
 
 
 
 
146-147# 
Growth factor used: ____________  
Dose: ________     Date of first dose: ___________  
Date of last dose: ____________ 
 
 
 
22 
148 
 
 
 
 
 
 
 
 
d 
 
 
 
154 
End of Therapy. See Section 7.1 and Section 16.0 for required observations and imaging at end of therapy 
% Enter total daily dose as mg/day by CI or intermittent infusion; 
#-Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE. 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Slow Blood Count Recovery 
Recovery of absolute neutrophil count to ≥750/µL, and platelet count to ≥75,000/µL is required at the start 
of each myelosuppressive cycle. The ANC often falls after discontinuing myeloid growth factor support. If 
the ANC has risen to ≥ 750/µL after the nadir but then falls the next cycle can be given despite ANC 
<750/µL. If a cycle is delayed for more than 7 days, the next time the chemotherapy combination causing 
the delay is administered doses of myelosuppressive agents should be reduced by 25%. If cycles are still 
delayed, a further 25% reduction in dose may be made for a total of 50% reduction. Re-escalation should 
be attempted if subsequent cycles do not result in treatment delay. If a particular cycle is delayed for more 
than 14 days, the administered doses of the myelosuppressive agents for the following cycle of 
chemotherapy should be decreased by 25%. Doses may be re-escalated as tolerated for subsequent cycles. 
Only vinCRIStine is not considered myelosuppressive. Vincristine doses at weeks where vincristine is 
given alone should be given regardless of blood counts.  
 
5.2 
Renal Toxicity 
 
5.2.1 
Ifosfamide  
Renal toxicity is the primary, long-term dose-limiting side effect of ifosfamide. Available information 
indicates that the renal injury produced by ifosfamide may be permanent, and in some cases progressive. 
Renal irradiation, young age (< 3 years of age), and absence of one kidney are risk factors for severe renal 
toxicity. The elements below define incomplete and significant Fanconi’s syndrome for the purposes of this 
study. In the event a patient appears to have evidence of Fanconi’s syndrome, the investigator may consider 
evaluation as detailed below and consider modifying therapy as detailed below. 
 
Elements of Fanconi Syndrome include: 
1. Renal phosphorus wasting with hypophosphatemia. (serum phosphate <2.5 mg/dL= 0.8 mmol/L). 
2. Renal bicarbonate wasting with acidosis (Bicarbonate <16). 
3. Renal potassium wasting with hypokalemia (< 3.0 mEq/L). 
4. 1+ glycosuria with serum glucose < 150 mg/dL. 
5. Proteinuria: a ratio of urine protein: urine creatinine > 0.2 occurring in the absence of significant 
malnutrition and acidosis due to sepsis/infection.  
 
Incomplete Fanconi Syndrome, with only one or a few of these elements, is common. Over time, these 
abnormalities may resolve, remain static, or progress. 
 
For the purposes of this study, significant Fanconi Syndrome will be defined as: 
1. GFR is < 50 mL/min/1.73 m2, not due to other causes such as aminoglycoside toxicity, amphotericin 
B, etc., in the presence of mineral/electrolyte wasting, OR 
2. The GFR is any level, but there is significant evidence of persistent Renal Tubular Acidosis (RTA) as 
evidenced by serum bicarbonate less than 16 mmol/L and serum phosphate ≤ 2 mg/dL (or 
< 0.6 mmol/L) without supplementation on measurements taken before the next ifosfamide cycle. 
 
Modify therapy as follows: 
Delete ifosfamide from all subsequent cycles and substitute cyclophosphamide 440 mg/m2 per day or 
15 mg/kg/day for those < 10 kg or < 1 year old with mesna uroprotection (60% of the 
cyclophosphamide dose =265 mg/m2/day or 9 mg/kg/day for those < 10 kg or < 1 year old) for 5 days 
to be given together with 5 days of etoposide. This schedule of fractionated cyclophosphamide has 
previously been used in National Wilms Tumor Trial V, Regimen I. 
 
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5.2.2 
Etoposide 
If Grade 2 or greater renal toxicity (creatinine > 1.5 X ULN) occurs, nephrotoxic agents should be 
discontinued, chemotherapy held and renal function tests repeated in one week. If toxicity persists a GFR 
or creatinine clearance should be obtained. The following initial dose modification should be considered 
based on measured creatinine clearance: for CrCl > 50 mL/min/1.73 m2 give full dose, for CrCl of 15-
50 mL/min/1.73m2 give 75% of the dose (a 25% dose reduction). Etoposide should be held if 
CrCl < 15 mL/min/1.73m2. 
 
5.2.3 
Cyclophosphamide 
If Grade 2 or greater renal toxicity (creatinine >1.5 X ULN) occurs, nephrotoxic agents should be 
discontinued. Cyclophosphamide, since it is subject to renal clearance, should be held and renal function 
repeated in one week. If estimated creatinine clearance (eGFR) drops by ≥ 33% (1/3) from the eGFR 
at study baseline or if the eGFR drops into the abnormal range, cyclophosphamide will require dose 
modifications. Prior to dose adjustment the local investigator should confirm the subject was well-
hydrated when renal chemistries were obtained and a validated 24-hour creatinine clearance or a 
radionuclide GFR should be obtained.  
 
The following initial dose modification should be instituted:  
 
Renal function 
Cyclophosphamide dose 
If drop in eGFR < 33% AND CrCl > 40 mL/min/1.73m2 
Full dose 
If drop in eGFR > 33% BUT CrCl > 40 mL/min/1.73m2 
90% dose 
If drop in eGFR > 33% BUT CrCl < 40 but > 10 mL/min/1.73m2 
50% dose 
If CrCL < 10 mL/min/1.73m² 
Withhold until toxicity resolves 
 
5.2.4 
Topotecan 
If Grade 2 or greater renal toxicity (creatinine >1.5 X ULN) occurs, nephrotoxic agents should be 
discontinued, chemotherapy held and renal function tests repeated in one week. If toxicity persists a GFR 
or creatinine clearance should be obtained. The following initial dose modification should be considered 
based on measured creatinine clearance: for CrCl > 40 mL/min/1.73 m2 give full dose, for CrCl of 20-
40 mL/min/1.73 m2 give 50% of the dose (a 50% dose reduction). Topotecan should be held if CrCL 
<20 mL/min/1.73 m2 
 
5.3 
Cardiac Toxicity 
 
5.3.1 
Monitoring 
Electrocardiogram for evaluation of QTc and echocardiogram with determination of shortening fraction or 
MUGA (radionuclide angiogram) for ejection fraction is to be obtained before treatment, prior to 3rd and 
5th doxorubicin containing cycle, and at the completion of therapy. Use the same test each time for 
consistency in evaluation. 
 
5.3.2 
Abnormalities 
If prolongation of the QTc interval (> 0.48 sec), a decrease in the ejection fraction to < 50%, or a decrease 
of the left ventricular shortening fraction to < 27%, the doxorubicin-containing chemotherapy should be 
postponed 1 week, any existing electrolyte or micronutrient deficiencies corrected and the tests repeated. If 
the abnormalities persist, doxorubicin should be PERMANENTLY DISCONTINUED. Substitute 
dactinomycin 0.045 mg/kg/day (max dose 2.5 mg) for 1 day, IV slow push on Day 1 only of the VDC cycle. 
The dactinomycin containing chemotherapy courses should be administered on a 21 day cycle (and not 14 
days) since interval compression is not possible when dactinomycin is administered. No changes in 
doxorubicin dosing is recommended for an asymptomatic decrease in cardiac ejection or shortening fraction 
provided they remain at or above 50% and 27% respectively. 
 
 
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5.4 
Neurological Toxicity 
Neurological toxicity can result from two of the agents used in this study, vincristine and ifosfamide. 
 
5.4.1 
Vincristine Neuropathy 
Vincristine neurotoxicity may occur more frequently on this trial as a result of the increased exposure 
to vincristine. 
 
Grade 1 and 2 neurotoxicity requires no dose modification. For Grades 3 and 4 (interfering with activities 
of daily living) hold until symptoms decrease to Grade 1 (present on exam/testing but not symptomatic) or 
less and resume at 50% dose. Increases to 75% and full dose should be considered at the start of each 
vincristine containing cycle based on patient’s symptoms.  
 
Anticipate autonomic neuropathy resulting in constipation. Laxatives and/or stool softeners should be used 
preemptively during vincristine containing cycles. If severe paralytic ileus occurs vincristine should be 
stopped until normal bowel movements are re-established and then resumed at 50% dose. Mild to moderate 
constipation (< 4 days) is not an indication for interrupting vincristine. 
 
5.4.2 
Ifosfamide Neurotoxicity 
This is an organic brain syndrome that ranges from mild confusion and disorientation to seizures, ataxia, 
and coma. It may be aggravated by impaired renal function. It usually, but does not always, resolve 
spontaneously, and it may or may not recur with subsequent doses. If symptoms are mild and transient cycle 
may continue with strict avoidance of potentially aggravating co-administered medications such as 
sedatives and anticholinergic drugs. If Grade 4 neurotoxicity occurs during ifosfamide administration, 
investigators may consider administration of methylene blue. Patients who have experienced mild 
symptoms (≤ Grade 2) may receive ifosfamide in subsequent cycles. If neurotoxicity > Grade 2 occurs or 
symptoms are prolonged, delete ifosfamide from all subsequent cycles and substitute cyclophosphamide 
440 mg/m2 per day with mesna uroprotection for 5 days, with 5 days of etoposide. This schedule of 
fractionated cyclophosphamide has previously been used in National Wilms Tumor Trial V, Regimen I. 
 
5.5 
Mucositis 
 
A few simple remedies for mucositis are available, and all should be pursued before doses are reduced. The 
incidence and severity of mucositis have been related to degree of pre-existing mucosal disease and oral 
hygiene. Good mouth care, including use of mouth rinses such as 0.12% chlorhexidine gluconate should be 
considered. Medications include the following: 
 
Glutamine: Oral swish-and-swallow glutamine suspension at 2 gram/m2 swish-and-swallow twice daily 
has been shown to reduce the severity and duration of mucositis associated with chemotherapy and 
radiotherapy in a randomized controlled trial.  
 
Sucralfate: Though its effectiveness is controversial, sucralfate suspension 1 gram/10 mL (40-
80 mg/kg/day, max 1 gram per dose) swish-and-swallow q.i.d. may reduce the symptoms or severity 
of mucositis from chemotherapy and radiation therapy. 
 
Chemotherapy doses should not be reduced for mucositis unless all supportive care remedies outlined above 
have been exhausted. 
 
For Grade 3 or 4 mucositis (mouth or throat pain interfering with ability to hydrate or aliment adequately 
or diarrhea resulting in incontinence and interfering with daily activities) which persists more than 15 days 
after a vincristine-doxorubicin-cyclophosphamide cycle, and is unresponsive to the measures described, 
decrease the doxorubicin dose by 25% in subsequent cycles. Do not decrease the doses of the other drugs.  
 
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For Grade 3 or 4 mucositis which persists more than 15 days after an ifosfamide-etoposide cycle, reduce 
both the ifosfamide and etoposide doses by 25% in subsequent cycles. Re-escalation should be attempted 
if mucosal toxicity > Grade 2 does not recur. 
 
For Grade 3 or 4 mucositis which persists more than 15 days after a vincristine-topotecan-
cyclophosphamide cycle, reduce the topotecan dose by 25% in subsequent cycles. Re-escalation should be 
attempted if mucosal toxicity > Grade 2 does not recur. 
 
5.6 
Hematuria or Hemorrhagic Cystitis 
5.6.1 
Microscopic Hematuria 
For treatment modifications, microscopic hematuria is a count defined as > 50 RBCs/HPF without visible 
blood in the urine. 
 
For transient microscopic hematuria (no more than 2 abnormal urinalyses on 2 separate days during a cycle 
of therapy), do not modify the cyclophosphamide/ifosfamide dose. Administer with increased hydration 
(3500-4000 mL/m2/day) 
using 
a 
total 
daily 
mesna 
dose 
equal 
to 
60% 
of 
the 
daily 
cyclophosphamide/ifosfamide dose as a continuous infusion over at least 9 hrs. For example, if the full 
cyclophosphamide dose is 1200 mg, then administer at least 720 mg of mesna by continuous infusion. 
 
For persistent microscopic hematuria (more than 2 abnormal urinalyses during a cycle of therapy), do not 
modify 
the 
cyclophosphamide/etoposide 
dose. 
Administer 
with 
increased 
hydration 
(3500-4000 mL/m2/day) 
using 
a 
total 
daily 
mesna 
dose 
equal to 
100% 
of 
the 
daily 
cyclophosphamide/ifosfamide dose as a continuous infusion over at least 9 hrs. 
 
5.6.2 
Gross Hematuria 
Gross hematuria is defined as visible blood in the urine. 
 
All episodes of gross hematuria should be evaluated in conjunction with a pediatric surgical consult. Further 
testing, such as cystoscopy, urine culture, excretory urogram, and voiding cystogram should be considered 
based on good clinical judgment. 
 
For transient gross hematuria (only 1 episode, which clears to less than gross hematuria) during or following 
a cycle of therapy, hold cyclophosphamide/ifosfamide until hematuria clears. When hematuria clears, restart 
at 50% of the previous cyclophosphamide/ifosfamide dose. Use hydration of 3500-4000 mL/m2/day and 
mesna at 100% of the cyclophosphamide/ifosfamide dose as a continuous infusion over 24 hrs/day. The 
cyclophosphamide/ifosfamide dose may be escalated back to 100% if tolerated. 
 
For persistent gross hematuria after completion of a cycle of therapy, hold subsequent 
cyclophosphamide/ifosfamide doses until the urine clears to less than gross hematuria. Reinstitute 
cyclophosphamide/ifosfamide at 50% of the initial dose, with hydration of 3500-4000 mL/m2/day and 
the mesna at 100% of the cyclophosphamide/ifosfamide dose given as a continuous infusion over 
24 hours. If this regimen is tolerated, the cyclophosphamide/ifosfamide dose may be escalated back to the 
original dose (100%). For persistent or recurrent gross hematuria on the mesna continuous infusion 
regimen, discontinue cyclophosphamide/ifosfamide. 
 
5.7 
Hepatotoxicity 
Hepatotoxicity is not expected to occur frequently on this study and if observed, causes should be 
investigated. However, abnormal liver function may be associated with increased vincristine and 
doxorubicin toxicity. Dose adjustments for vincristine, doxorubicin and etoposide should be made based 
on the level of direct bilirubin. Vincristine doses omitted due to toxicity will not be replaced. 
 
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Hepatotoxicity 
Vincristine adjustment 
Doxorubicin adjustment 
Etoposide adjustment 
Grade 1  
(Direct bilirubin < 1.5 X 
ULN) 
 
Full Dose 
 
Full Dose 
 
Full Dose  
 
Grade 2 
(Direct bilirubin 1.5-3 X 
ULN) 
Delay 1 week. 
Full dose if resolved to 
Grade 1 or less. 
50% if still Grade 2. 
Delay 1 week. Full dose if 
resolved to Grade 1 or less.  
50% if still Grade 2 
Delay 1 week. Full dose if 
resolved to Grade 1 or 
less.  
50% if still Grade 2. 
Grade 3,4 
 
Delay 1 week or until 
resolved to Grade 1 
Delay 1 week or until 
resolved to Grade 1 
Delay 1 week or until 
resolved to Grade 1 
 
5.8 
Dermatologic Toxicity 
 
5.8.1 
Nails 
Patients receiving compressed chemotherapy may slough their fingernails. This is painless and reversible, 
and no countermeasures are indicated. 
 
5.8.2 
Palms and Soles 
A few patients may experience painful inflammation and desquamation of the palms and soles, more often 
after ifosfamide-etoposide cycles. If this occurs, allow a 21-day interval in the next cycle, and attempt a 14-
day cycle again subsequently. 
 
5.9 
Any Other Grade 3 or 4 Toxicities 
Delay therapy until toxicity has resolved to Grade 1. Dose reduction of 25% may be considered at 
investigator’s discretion. Attempts should be made to re-escalate dose if toxicity does not recur. 
 
5.10 
Allergy to Etoposide 
Pre-medication (such as diphenhydramine, +/- ranitidine and +/- hydrocortisone) and slowing of the rate of 
infusion with etoposide can be tried. Substitution with etoposide phosphate should be considered if a patient 
develops a reaction that would put him/her at risk if further etoposide were given. Etoposide phosphate may 
be substituted for etoposide with pre-medication and administered given at the same dose and rate.  
 
 
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. 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise note below.  
 
 
 
 
 
 
 
 
  
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 
(except where explicitly prohibited within the protocol). 
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7.1 
Required/Recommended Clinical, Laboratory and Disease Evaluations 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below. 
 
 
1 
Obtain prior to each cycle. 
2 
Obtain on Day 1 and 8 of each cycle. Obtain blood counts every Monday, Wednesday and Friday (or 3 other non-consecutive 
days per week) after Day 12, until the criteria for starting the next cycle are satisfied  
3 
Preferably pre-biopsy.  
4 
Obtain within 4 weeks prior to primary tumor treatment (local control). 
5 
Functional imaging with FDG- PET is recommended, if available at the institution. For patients having PET- SUVmax will be 
reported and images submitted (see Section 16.1) 
6 
Obtain for bone tumors of extremity and pelvic sites at study entry. 
7 
Note that MRI may not be interpretable if the patient has undergone resection of the primary bony site of disease with placement 
of a massive metallic prosthesis. Imaging of the primary site may be limited to plain radiographs. CT scan with contrast may 
be considered in place of MRI for post local control and end of therapy evaluation. For chest wall primaries –MRI is strongly 
encouraged to visualize soft tissue extent but not required. If MRI is not performed, the chest wall primary site should be 
adequately imaged by CT.  
8 
MRI for patients having surgery as primary control may be done anytime between surgery and recovery from Consolidation 
Cycle 5. For patients receiving radiation as primary control obtain MRI at the end of Consolidation therapy.  
9 
CT Scan of the chest should use spiral technique (if available) with a single breathhold, for patients able to cooperate.  
10 Electrocardiogram for evaluation of QTc and echocardiogram with determination of shortening fraction or MUGA 
(radionuclide angiogram) for ejection fraction is to be obtained prior to 3rd and 5th doxorubicin containing cycle. Use the same 
test each time for consistency in evaluation. 
11 Pregnancy test required prior to study enrollment for females of childbearing potential only. 
12 Regular assessment should include range of motion, limb length assessment, gait and pain assessment. 
 
$ 
Unilateral bone marrow aspirate and biopsy is sufficient from the contralateral side for pelvic tumors that involve the ilium. 
# 
See Section 16.0 for complete details of the required imaging and also recommended imaging. 
 
This table only includes evaluations necessary to answer the primary and other aims. Obtain other studies as 
indicated for good clinical care.  
Observation 
Study Entry 
During 
Chemotherapy 
Prior to Local 
Control 
Post Local Control 
and post Cycle 5 
Consolidation 
Off protocol 
therapy/End 
of Therapy 
History and Physical Exam 
X 
X1 
X 
 
X 
Biopsy 
X 
 
 
 
 
Electrolytes, creatinine, bicarbonate, 
phosphorus, calcium, bilirubin, AST, ALT 
X 
X1 
 
 
 
LDH 
X 
Recommended 
 
 
 
 
Performance Status 
X 
 
 
 
 
Urinalysis 
X 
X1 
X 
 
 
CBC, Plt, Diff.  
X 
X2 
X  
 
 
Bilateral Bone Marrow Biopsy and Aspirate 
X$ 
 
 
 
 
Whole Body Bone Scintigraphy 
X3 
 
X4 
 
X# 
PET Scan (See Section 16.0)5 
X  
Recommended 
 
X4 
Recommended 
 
X# 
Radiograph (2 views of primary site)6 
X 
 
X4 
 
X# 
X# 
MRI with gadolinium (primary site)7 
X3 
 
X4 
 
X8, # 
X# 
CT Scan of Chest9 
X 
 
X4 
 
X #  
X# 
Chest X-Ray (PA and Lateral) 
X 
Recommended 
 
 
 
 
ECG and ECHO or MUGA 
X 
X10 
 
 
X 
Pregnancy test11 
X 
 
 
 
 
Orthopedic functional assessment12 
 
 
 
 
X 
Recommended 
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AEWS1031 
 
7.2 
Follow-up  
General follow-up should occur as per local institutional standards and as appropriate for individual patient care and known long term toxicities of 
agents received. Refer to COG Late Effects Guidelines for recommended post treatment follow-up at: http://www.survivorshipguidelines.org/.  
 
7.2.1 
Suggested Observations Following Completion of Protocol Therapy 
 
Observation 
3  
Months 
6  
Months 
9  
Months 
1 
Year 
1.25 
Years 
1.5 
Years 
1.75 
Years 
2 
Years 
2.25 
Years 
2.5 
Years 
2.75 
Years 
3 
Years 
3.5 
Years 
4 
Years 
4.5 
Years 
5 
Years 
History and Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with diff, platelet 
count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest Radiograph 
(PA and Lateral) 
 
CT Chest4 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Radiograph 1 
(Primary site) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
MRI or CT 2 
(Primary Site) 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Whole Body Bone 
Scintigraphy3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDG- PET 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrolytes, creatinine, 
bicarbonate, phosphorus, 
calcium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram or MUGA 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
1 
Obtain for bone tumors of extremity and pelvic sites at study entry 
2 
Obtain for non-bony, soft tissue tumor not readily assessed by physical examination or abnormal symptoms or abnormal imaging. 
3 
Recommended only in case of abnormal symptoms or abnormal imaging 
4 
Recommended if previous abnormalities, abnormal chest X-ray or symptoms 
 
7.2.2 
Relapse 
Biopsy confirmation of suspected recurrence is recommended in most cases. In case of local relapse, metastatic work-up is required for confirmation 
of extent of recurrence. 
 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
 
a) 
Progressive disease. 
b) 
Disease detected at new sites 
c) 
Biopsy positive residual disease after all local control measures completed 
d) 
Refusal of further protocol therapy by patient/parent/guardian. 
e) 
Completion of planned therapy. 
f) 
Physician determines it is in patient’s best interest. 
g) 
Development of a second malignant neoplasm. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below). Follow-up data will be required unless consent was withdrawn. 
 
8.2 
Off Study Criteria 
 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) 
Withdrawal of consent for any further data submission. 
e) 
Tenth anniversary of the date the patient was enrolled on the study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Patient Accrual and Expected Outcome and Expected Duration of Trial 
 
Based on past studies, COG institutions will enroll approximately 140 patients with localized Ewing 
Sarcoma annually. The sample size calculations are based on the model of Barthel et al.53  
 
The aggregate EFS outcome of AEWS0031 current to March 2008 is summarized in the table below: 
Time Since Enrollment (Years) 
Estimated Aggregate Event-Free 
Survival 
95% Confidence Interval 
1 
0.94 
0.92-0.96 
2 
0.81 
0.78-0.84 
3 
0.75 
0.71-0.79 
4 
0.73 
0.68-0.76 
5 
0.70 
0.65-0.75 
 
Patients will be enrolled for 54 months (4.5 years) and the last patient enrolled will be followed for an 
additional 1 year. This will provide approximately 630 patients with at least 1 year of follow-up for the last 
patient enrolled. We anticipate we will require at most 693 patients to account for a maximum ineligibility 
rate of 10%. The statistical characteristics associated with this design are provided below. 
 
Randomization will be stratified according to age and primary tumor site. Age will be stratified as: (1) 
seventeen years or less at age at diagnosis; or (2) eighteen years of age or greater at diagnosis. Primary site 
will be stratified as: (1) pelvic primary; (2) non-pelvic primary; or (3) extra-osseous site.  
 
 
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9.2 
Statistical Analysis Methods 
 
9.2.1 
Primary Outcome Comparisons 
The primary endpoint will be event free survival (EFS). This is defined as the time from study enrollment 
to disease progression, appearance of disease at sites considered previously uninvolved, diagnosis of a 
second malignant neoplasm, death or last patient contact, whichever occurs first. Disease progression, 
appearance of disease at sites considered previously uninvolved, diagnosis of a second malignant neoplasm 
and death are considered analytic events for the purposes of comparing the two regimens with respect to 
EFS. In all other cases, the patient will be considered censored at last contact. 
 
The endpoint for the comparison between the two regimens to address aim 1.2.1 will be survival from study 
enrollment. Survival is defined as the time from study enrollment to death or last patient contact, whichever 
occurs first. Death, regardless of cause, is considered an event for the purposes of comparing the two 
regimens with respect to survival. In all other cases, the patient will be considered censored at last contact. 
 
The therapy containing topotecan will be considered the experimental regimen. This regimen has increased 
intensity when compared with the intensively timed non-VTC therapy (‘standard therapy’) used in this 
protocol. The experimental regimen will be identified as the one to carry forward only if that regimen 
reduces the risk for EFS-event significantly using a 1-sided test of size 0.05. Patients will be enrolled for 
4.5 years and followed for an additional 1 year. This will provide approximately 630 patients with at least 
1 year of follow-up for the last patient enrolled. With these accrual characteristics, we will be able to detect 
an increase from 70% to 80% long-term EFS with approximately 80% power. This corresponds to a relative 
hazard rate of 0.63 for a proportional hazards model for EFS. The primary analysis will include all eligible 
patients and outcome will be assigned to the patient’s randomized regimen. 
 
9.2.2 
Interim Monitoring 
We will monitor for emerging differences between the randomized treatments using the Lan and DeMets 
spending function approach. The test statistic used for this for interim monitoring will be: 
 
 
{
}
ln Hazard Ratiofor EFS-event for Experimental: Standard Therapy
Estimated VarianceoftheHazard Ratio
 
 
Where the hazard ration is estimated from a proportional hazards regression stratified according to the 
factors by which randomization is stratified. The spending function will be α(t)=αt2. We will monitor for 
differences in EFS across the regimens at the times shown below. The projected expected information times 
are presented in the tables as well.  
 
Monitoring Time (Years 
Since Study Opening) 
Expected 
Information 
Time 
Lower 
Monitoring 
Boundary 
Cumulative α 
2 
0.21 
-2.85 
0.0022 
3 
0.43 
-2.41 
0.0071 
4 
0.65 
-2.13 
0.021 
5.5 (Final Analysis) 
1.0 
-1.74 
0.05 
 
At each of the monitoring times above, we will calculate the conditional probability the log-rank test 
statistic will exceed 1.74 in absolute value at the projected final analysis time of the study. The model used 
for the EFS-failure time for all patients who have not experienced an EFS event by the time of analysis will 
be that associated with outcome table quoted above for those randomized to the experimental regimen and 
will be 
( )
( )
0.63
Standard
S t
S
t
=



, viz., the alternative as specified in Section 9.2. If the conditional 
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probability of rejection of the null hypothesis is less than 5% at any monitoring time, the study will be 
identified for possible closure of accrual. 
 
Monitoring the Incidence of Second Malignant Neoplasms 
At the time of the next two planned interim monitoring occurrences, which will occur at 43% and 65% of 
the expected information, the aggregated SMN sub-distribution for AEWS1031 will be compared with the 
aggregated SMN sub-distribution for AEWS0031 using the methods proposed by Fine and Gray.54 If the 
one-sided p-value is 0.05 or less for the test H0: the relative sub-distribution hazard ratio (SHR) for SMN 
for AEWS1031 relative to AEWS0031 is 1 v. the alternative hypothesis H1: the relative sub-distribution 
hazard ratio (SHR) for SMN for AEWS1031 relative to AEWS0031 is greater than 1, AEWS1031 will be 
considered for possible modification, including termination of enrollment to AEWS1031.  
 
The dataset for AEWS0031 will be taken to be that used for the publication Womer RB, West DC, Krailo 
MD, Dickman PS, Pawel BR, Grier E, Marcus K, Sailer S, Healey JH, Dormans JP and Weiss AR 
Randomized Controlled Trial of Interval-Compressed Chemotherapy for the Treatment of Localized Ewing 
Sarcoma: A Report From the Children's Oncology Group. J Clin Oncol 30: 4148-54. The cumulative 
incidences of SMN for the two regimens that comprised AEWS0031 were very similar and, therefore, the 
aggregate cohort for AEWS0031 is an appropriate comparator for AEWS1031. 
 
9.2.3 
Outcome Comparisons for Correlative Science Objectives 
The relative risk for death and the naïve p-value associated with the null hypothesis H0: relative risk for 
death is 1 will be estimated using the stratified partial likelihood for the relative risk regression model 
accounting for the factors used to stratify randomization at the time full information is obtained for the EFS 
comparison. The survival analysis comparison will be conducted again once the observed number of death-
events reaches the expected number of EFS-events under the primary null hypothesis. 
 
Event free survival after local control will be the endpoint for the analysis of the prognostic effect of 
histological response. Only patients who received surgery as part of local control will be considered for that 
endpoint, as described below. Event free survival after local control will be the endpoint for the analysis of 
the prognostic effect of PET-determined response. All patients who receive local control therapy, regardless 
of the modalities employed, will be considered for this analysis. Methods for censored survival data, 
including but not limited to log-rank comparisons and proportional hazards regression modeling will be 
used to assess prognostic significance. 
 
Assessment of the Prognostic Significance of Tumor Volume at Study Enrollment: At enrollment, patients 
should have three tumor dimensions available, either by CT or MRI. Tumor volume will be calculated 
centrally using three perpendicular tumor dimensions according to the formula:  
 
3
3
1
2
1
2
3
4
0.52
3 2 2 2
d
d d
Volumeinmm
d d d
π
=
=
 
The same formula will be used for all tumor shapes. 
 
Tumor volume will be calculated according to the formula above from tumor measurements provided by 
institutional investigators. Event-free survival will be used as the outcome measure. Data from INT-0091 
indicated that the relative risk for EFS-event associated with tumors 200 ml or greater compared with 
tumors 199 ml or less is between two and three. The probabilities of identifying tumors of at least 200 ml 
as associated with increased risk using a two sided log-rank test of size 0.05 as a function of the percent of 
patients for whom measurements can be obtained are described below. For the table below, we assume 
conservatively that 35% of patients will have tumors of 200 ml or greater in estimated volume. The long-
term EFS for patients with small tumors is assumed to be 80%, the target EFS for the experimental therapy. 
We plan to conduct the analysis concurrently with the final analysis for the primary study aim. 
 
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Probability of Identifying Tumors of 200 ml or Greater At Enrollment as Associated with Poor Prognosis 
As a Function of Percent of Patients With Three Tumor Dimensions Available and Relative Risk Associated 
with ‘Large’ Tumor Volume 
 
Percent of Patients For Whom Tumor Volume Can Be Determined 
Relative Risk 
50 
60 
70 
80 
1.5 
0.42 
0.49 
0.55 
0.60 
2.0 
0.89 
0.94 
0.97 
0.98 
2.5 
0.99 
>0.99 
>0.99 
>0.99 
 
 
Assessment of the Prognostic Significance of Necrosis Grading after ‘Induction’ Chemotherapy: Extent of 
tumor necrosis will be obtained at time of local therapy for patients who have surgical resection of their 
tumor. The necrosis grading will be correlated with risk for EFS-event. All patients who receive surgery as 
the only local control modality will be considered for this outcome. Also, patients who receive surgery and 
radiation therapy as local control therapy will be considered for this analysis, provided the radiation therapy 
has occurred after surgery. Event-free survival post local control will be used as the outcome measure. Data 
from INT-0154 indicates approximately 60% of patients will be included in this cohort of patients. The 
primary analysis will be to segregate patients into two groups according to ‘good’ necrosis grading (less 
than 10% viable tumor in the resection specimen) and ‘standard’ necrosis grading (10% or more viable 
tumor in the resection specimen). The long-term EFS for patients with good necrosis grading is assumed to 
be 80%, the target EFS for the experimental therapy. The probabilities of identifying patients with 
‘standard’ necrosis grading as associated with increased risk using a two sided log-rank test of size 0.05 as 
a function of the percent of patients with ‘standard’ necrosis grading and its associated relative risk are 
described below.  
 
Probability of Identifying Patients with ‘Standard’ Necrosis Grading as Having Poor Prognosis As a 
Function of Percent of Patients With ‘Standard’ Necrosis Grading and Relative Risk Associated with 
‘Standard’ Necrosis Grading 
 
 
Percent of Patients with ‘Good’ Necrosis Grading 
Relative Risk 
60 
50 
40 
30 
1.5 
0.48 
0.49 
0.46 
0.40 
2.0 
0.94 
0.94 
0.91 
0.86 
2.5 
>0.99 
>0.99 
>0.99 
0.99 
 
Assessment of the Prognostic Significance of Radiological Response by Positron Emission Tomography 
(PET) and Disappearance of Soft Tissue Mass: Radiological data prior to treatment and prior to local 
therapy, including disappearance of soft tissue mass and PET characteristics (SUV prior to treatment and 
prior to local control therapy) will be collected and correlated with risk for EFS-event. Radiological 
response of soft tissue component of mass to induction chemotherapy will be obtained from institutional 
reports. 
 
Institutions using clinical PET scanning as functional imaging in evaluation and response to treatment will 
be asked to submit data at start of therapy and prior to local treatment (prior to Week 13) as part of the 
patients scheduled evaluation. This will be an optional element and PET scanning will not be required for 
study entry. However, it is recognized as an acceptable evaluation tool being used by many institutions at 
this time and is expected to increase in use over the upcoming years. Guidelines for image acquisition and 
processing, as developed by ACRIN will be included for institutional use. Institutionally reported SUV 
values will be used. Electronic copies of images will be reviewed centrally for study purposes by study 
imaging representative. An interim evaluation of this objective will be performed and this objective deleted 
if it appears futile. 
 
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All patients who survive event free to the time of local control will be considered for this outcome. Event-
free survival post local control will be used as the outcome measure. Data from INT-0154 indicate 
approximately 95% of patients will have conventional imaging study data available for the assessment of 
radiological response to induction therapy. We posit the long-term post-local-control EFS in the CR group 
of patients will be 80%. The primary analysis will be to segregate patients into two groups according to 
complete v. not complete soft tissue response. The probabilities of identifying patients with CR as 
associated with decreased risk for EFS-event when compared with patients with less-than-CR using a two 
sided log-rank test of size 0.05 as a function of the percent of patients with standard response and its 
associated relative risk are described below.  
 
Probability of Identifying Patients with Less than CR as Having Poor Prognosis As a Function of Percent 
of Patients With Less than CR and Relative Risk Associated with Less than CR Radiographic Response 
 
 
Percent of Patients with Less than CR Radiographic Response 
Relative Risk 
40 
50 
60 
70 
1.5 
0.48 
0.49 
0.46 
0.40 
2.0 
0.94 
0.94 
0.91 
0.86 
2.5 
>0.99 
>0.99 
>0.99 
0.99 
 
Not all institutions will comply with the guidelines for PET because of availability of the requisite 
equipment or funding issues. We will monitor the number of patients who participate in the PET analysis 
each time an interim monitoring report is prepared. If there is evidence that significantly fewer than 34% 
of all patients enrolled will participate in the PET evaluation, that component of the trial will be considered 
for termination. If 34% of patients participate in the PET investigation (approximately 214 patients total), 
the power to detect an increase in risk for event associated with ‘standard’ response under a ‘favorable’ 
statistical configuration (50% of patients have a ‘standard’ response and the relative risk associated with a 
‘standard’ response is 2.5) will be 0.95. 
 
The analysis of the prognostic impact of SUVmax derived from PET scanning done at enrollment will be 
assessed on EFS and an analysis of the prognostic impact of SUVmax derived from PET scanning done prior 
to the local control phase will be carried out on EFS post local control therapy. The study population will 
be divided into two groups based on amount of uptake (high versus standard, generally as above v. at or 
below the median SUVmax). These groups will be compared using the log-rank test. The expected statistical 
properties of this strategy are similar to those given in the tables given above. 
 
Assessment of the Prognostic Significance of Type of Local Control Therapy on Risk for EFS-Event: All 
patients who survive event-free to the time of local control will be considered for this outcome. Event-free 
survival post local control will be used as the outcome measure. Data from INT-0154 indicate 
approximately 95% of patients will complete induction therapy. The primary analysis will be to segregate 
patients into three groups according to surgery only v. radiation therapy only v. surgery and radiation 
therapy as local control measures. Data from AEWS0031 indicate this will occur in the ratio of 
approximately 0.50:0.20:0.30. An omnibus log-rank test of size 0.05 will be used to assess whether there 
are differences associated with local control modality. Since site of tumor is related to both risk for EFS 
event and type of local control modality employed, the analysis will be stratified according to primary site 
of tumor as pelvis v. bone but not pelvis v. extra-osseous site. The analysis for this study goal will be 
conducted at the time of the analysis for the primary study aim. The probability the omnibus test of equality 
of risk across types of local control, as a function of the relative risks associated with each local control 
type, is provided below. The long-term EFS associated with the surgery-only group is assumed to be 80%. 
  
 
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Probability of Identifying A Pattern of Risk Significantly Different than Equal Risk Across Local Modality 
Types as a Function of the True Relative Risks of EFS-Event 
 
Scenario Number 
Type of Local Control 
Relative Risk for EFS-Event 
Power 
1 
Surgery Only 
1 
0.968 
Radiation Therapy Only 
2 
Surgery Plus Radiation 
Therapy 
2 
2 
Surgery Only 
1 
0.9189 
Radiation Therapy Only 
1.5 
Surgery Plus Radiation 
Therapy 
2 
3 
Surgery Only 
1 
0.507 
Radiation Therapy Only 
1.5 
Surgery Plus Radiation 
Therapy 
1.5 
 
Evaluate the effect of local therapy modality (surgery, radiotherapy or a combination) as well as the type 
of surgical reconstruction on musculoskeletal complications: Any CTCAE version 4.0 Grade 2 or higher 
musculoskeletal events, or surgery required to treat a complication of local therapy that occur within three 
months of the date of the first local control procedure will be considered a musculoskeletal event (ME). 
Any patient who experiences a ME at any time during the three months following completion of local 
control therapy or does not experience an ME and completes three months of post-local-control therapy 
follow-up will be considered in the analysis of this outcome measure. The proportion of patients who 
experience any ME will be compared across the three regimens using logistic regression where the p-value 
to indicate a statistically significant relationship will be 0.05. Size of tumor at the time of local control may 
be a strong confounding variable, as it is related to the approach to local therapy and may be related to the 
occurrence of ME after surgery. The logistic analysis will be adjusted for size of the tumor after enrollment 
but before the first local control modality is executed. Both the longest dimension and size relative to initial 
measurement will be employed. 
 
As with the analysis of risk of EFS-event according to local control type, we expect 95% of patients enrolled 
will contribute to the analysis of ME. The proportion of patients who will receive surgery only as local 
control therapy and who will experience an ME has not been investigated to date. The power characteristics 
of the proposed test of proportions is presented below using various ME rates associated with the types of 
local control considered.  
 
Probability of Identifying A Pattern of Risk for ME Significantly Different From That of Equal Risk Across 
Local Modality Types as a Function of the True Probabilities of ME 
 
Scenario Number 
Type of Local Control 
Relative Risk for EFS-
Event 
Power 
1 
Surgery Only 
0.10 
0.787 
Radiation Therapy Only 
0.15 
Surgery Plus Radiation Therapy 
0.20 
2 
Surgery Only 
0.20 
0.93 
Radiation Therapy Only 
0.30 
Surgery Plus Radiation Therapy 
0.35 
3 
Surgery Only 
0.10 
0.904 
Radiation Therapy Only 
0.20 
Surgery Plus Radiation Therapy 
0.20 
 
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9.3 
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 
28 
34 
62 
Not Hispanic or Latino 
289 
342 
631 
Ethnic Category: Total of all subjects 
317 
376 
*693 
Racial Category 
 
American Indian or Alaskan Native 
3 
3 
6 
Asian 
8 
7 
15 
Black or African American 
8 
12 
20 
Native Hawaiian or other Pacific Islander 
7 
2 
9 
White 
291 
352 
643 
Racial Category: Total of all subjects 
317 
376 
*693 
* These totals must agree 
 
This distribution was derived from AEWS0031. 
 
 
10.0 
EVALUATION CRITERIA  
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Additionally, toxicities are 
to be reported on the appropriate data collection forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE v4.0 as 
referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to version 5.0). 
 
10.2 
Response Criteria for Patients with Solid Tumors 
This study will use three dimensional measurements of the primary tumor rather than single dimension as 
used in RECIST. Regional nodal disease if present will be evaluated by single dimension measurement. 
The value of 3D volume measurement has already been substantiated in several studies.55-57 In addition, 
bone tumors, which will constitute the majority of tumors on this trial, are considered non-measurable 
according to RECIST guidelines. The evaluation of response in multiple lesions as outlined in RECIST will 
not apply as this study is limited to patients with localized disease only.  
 
10.2.1 Primary Tumor Measurement 
 
10.2.1.1 Technical guidelines for cross-sectional imaging computed tomography (CT)  
1.  All CT scans should be done with technical factors using the lowest radiation exposure possible 
(ALARA principle). 
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2. CT slice thickness should be 5mm or less. 
3. The diameter of a "measurable" mass should be at least twice the reconstructed slice thickness. 
Smaller masses are considered detectable, but will be counted as "non-measurable." 
4. Edge-enhanced lung windows, liver, and bone windows should be photographed, if recorded in 
hard copies. Digital images are submitted either electronically or in CD using DICOM format. 
 
10.2.1.2 Magnetic resonance imaging (MRI) 
1. Axial images and at least one additional plane are acquired. At least two pulse sequences, such as 
T1, T2, STIR, or FLAIR-weighted, or in-phase/out-of-phase images are obtained. Post-contrast 
images are obtained if appropriate. Measurements should be made using the same sequence best 
showing the tumor in follow up for comparisons. 
2. Only axial images will be used for measurement. The cranio-caudal diameter is represented by the 
distance between the most cranial and caudal slice positions plus one slice thickness (or [slice 
thickness + gap] x number of slices showing the tumor minus one gap distance). 
 
10.2.1.3 The primary tumor will be measured in the largest anterior-posterior, transverse and longitudinal 
dimensions. Reporting of these three dimensions will be required. These dimensions will be used for 
central estimation of tumor volume using the formula for a prolate ellipsoid: volume in mm3= π /6 · (d1·d2·d3) 
= (AP x transverse x longitudinal) x 0.5. Measurements should be obtained as described in the figure below. 
 
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
 
 
10.2.2 Response of the Primary tumor 
 
Based on previously published data correlating tridimensional measurements to bi-directional and 
unidirectional measurements the following response criteria for the primary tumor will be used58: 
  
 
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Complete Response (CR): Complete disappearance of the tumor. 
 
Partial Response (PR): At least 64% decrease in volume compared to the baseline. 
 
Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest 
measurement obtained since the beginning of therapy. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest disease measurement since the treatment started. 
 
10.2.3 Local-regional Lymph Node Disease  
 
Pathologic lymph nodes: Other than the primary tumor the only other lesions that will be followed 
radiographically are local-regional lymph nodes in which tumor involvement has been biopsy proven. 
Lymph nodes that can be accurately measured in the axial plane (do not use the longitudinal dimension, 
even though it may be the largest diameter) and whose longest diameter in the axial plane is ≥ 1.0 cm will 
be considered to be pathologic and will be followed. The local investigator will identify up to a total of 5 
pathologic lymph nodes. If there are more than 5 total pathologic lymph nodes, then those that are the most 
easily measured and amenable to reliable, reproducible, follow-up measurement should be chosen. The 
nodes must be measured in 2 planes; the longest diameter and the axis perpendicular to it. 
 
Serial measurements of lesions are to be done with CT or MRI.  The same method of assessment is to be 
used to characterize each identified and reported lymph node at baseline and during follow-up. 
 
10.2.4 Response of pathologic lymph nodes:  
The response of lymph nodes will be based on the report of an international workshop to standardize 
response criteria for non-Hodgkin’s lymphomas.59 
 
Complete Response:  
1)  All nodes measure < 1.0 cm OR 
2)  All lymph nodes with 1.5cm maximal transverse diameter must decrease to less than 
1.5 cm, and all nodes 1.1-1.5 cm in maximal transverse diameter before treatment must 
decrease to 1.0 cm or less OR  
3)  More than 75% decrease in the sum of the products of the two dimensions for each 
node (SPD) 
 
Partial Response:  
At least 50% decrease in SPD  
 
Stable Disease:  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as a 
reference the smallest disease measurement since the treatment started  
 
Progressive Disease: 
At least 50% increase from nadir in the SPD   
 
10.2.5 Overall response assessment 
The overall response assessment takes into account response in the primary tumor, associated pathologic 
lymph nodes, and the appearance of new lesions, where applicable, according to the criteria described in 
the table below. The overall response assessment is shown in the last column, and depends on the 
assessments of the primary tumor, adenopathy and new lesions in the preceding columns. 
 
 
 
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Primary tumor 
Lymph nodes 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
PR/SD 
No 
PR 
PR 
PR/SD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Any* 
PD 
Any 
PD 
Any* 
PD 
Any 
Any 
Yes* 
PD 
 
*Solitary, small (< 1cm) and osseous sites of suspected new disease should be biopsied 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents.  
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of the adverse event 
including the grade (severity); 2) the relationship to the study therapy (attribution); and 3) the prior 
experience (expectedness) of the adverse event. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source. In some cases an agent obtained commercially may be used for indications not included in the 
package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even in 
these cases, the agent is still considered to be a commercial agent and the procedures described below 
should be followed. 
 
Determine the prior experience Expected events are those that have been previously identified as resulting 
from administration of the agent. An adverse event is considered unexpected, for reporting purposes only, 
when either the type of event or the severity of the event is not listed in:  
 
• 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group posted 
on the COG website; or 
• 
the drug package insert. 
 
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 front of this protocol immediately following the Study Committee roster. 
 
• 
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. 
 
 
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CTCAE term (AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting 
and are located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment 
areas should have access to a copy of the CTCAE 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who have NOT received 
any doses of an investigational agent on this study. 
 
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. 
 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment with 
investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial neoplasm is not 
considered a secondary malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via AdEERS. Three options 
are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy   
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy 
 
11.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on the COG case 
report forms and do not affect the requirements for AdEERS 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. All events requiring AdEERS 
reporting also need to be reported on the AE CRF. In addition, for this study, routine reporting will include: 
 
• 
Grade 2 and higher musculoskeletal adverse events occurring within 3 months of completion of 
local therapy. 
 
 
• 
 
12.0 
RECORDS AND REPORTING 
 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
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Any tumor that involves bone or is in contact with bone is classified as and should be reported as an osseous 
primary. All others should be reported as extra-osseous primaries. 
 
12.1 
CDUS 
 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be 
submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 
31. This is not a responsibility of institutions participating in this trial. 
 
 
13.0 
SURGICAL GUIDELINES 
 
 
 
COG member institutions are encouraged to enroll patients on a specimen collection study (such as 
AEWS07B1 or on any successor biology study). Surgeons, treating team and pathologists should review 
specimen requirements for tissue collection and handling for that study if applicable prior to biopsy and 
definitive surgery. 
 
13.1 
Surgical Guidelines for Biopsy 
 
13.1.1 Technique 
Open, incisional biopsy of the primary is recommended to allow procurement of enough tissue for all 
biologic studies. A move to performing open biopsy may be against the current practice in many institutions 
where a needle biopsy provides adequate tissue for diagnosis. Biologic studies are becoming increasingly 
important and may lead to changes in therapeutic approach. Multiple passes with a needle may not provide 
enough aggregate tissue for all of the studies currently done. A minimum of 1 cubic centimeter of tissue is 
required for special studies. An additional amount of fresh tissue must be obtained for diagnostic studies. 
Most children require a general anesthetic for needle biopsy, and often a venous access device can be 
inserted at the time of biopsy. Changing the practice to doing open biopsies therefore should not result in 
increased morbidity for the patients. 
 
In most instances the diagnosis can be made from the surrounding involved soft tissues avoiding the need 
for obtaining bone. Creation of a bone defect during biopsy significantly weakens the bone thus increasing 
the risk of pathologic fracture. This risk is markedly increased if radiotherapy is later given as the definitive 
local therapy. A bone biopsy will also preclude the possibility of performing a frozen section to determine 
the adequacy of material for diagnosis. 
 
13.1.2 Specimen Quality 
Biopsy material should be sent to pathology in a fresh state in normal saline or tissue culture medium. 
Tissue from Ewing sarcomas are often necrotic, therefore intra-operative frozen section or touch 
preparations should be done to be certain that the tissue obtained is adequate and sufficient for diagnosis. 
It is strongly recommended that adequate tissue be obtained for biologic studies.  
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly 
prohibited within the protocol).  
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13.1.3 Specimen Quantity and Handling 
Proper handling of biopsy tissue requires knowledge of the objectives to be studied. A minimum of 3-5 
grams of fresh, viable, non-necrotic tumor tissue should be sent immediately to the Pathology Department. 
Material must be obtained for multiple analyses (routine histopathology, cytology, touch preparations, 
electron microscopy, tissue culture, flow cytometry, cytogenetics, etc.) to permit full evaluation for 
diagnosis and cancer biology studies. 
 
 
13.1.4 Therapeutic Considerations 
Future surgical excision and radiation therapy must be borne in mind during the biopsy. Principles of biopsy 
should be followed. Imaging, in particular MRI, should be obtained prior to biopsy. These include: 
longitudinal incisions, the ability to remove the biopsy tract with the lesion at the time of surgical excision, 
avoidance of neurovascular structures and a direct route to the tumor through muscles rather than retracting 
them. If appropriate management of the tumor requires a compartmental resection, one should be able to 
proceed after biopsy and neoadjuvant chemotherapy without significantly extending the margins beyond 
those previously planned. If one is unfamiliar with the suspected extension of the lesion and the three 
dimensional compartmental anatomy of the extremity, a simple error on incision orientation and placement 
or injudicious exposure of a major neurovascular structure could result in the need for amputation. 
Postoperative hematoma formation can render a previously resectable lesion unresectable. Techniques that 
will diminish the likelihood of hematoma formation and dissection could include the use of a tourniquet 
(after gravity exsanguination), thrombogenic agents (activated thrombin, Oxygel, Avitene), and a 
hemostatic subarticular closure. The tourniquet if used at all should be deflated prior to closure in order to 
assure absolute hemostasis. Anatomic structures and planes dissected by hematoma should be considered 
contaminated and may have to be included in the subsequent definitive surgical margins. If a drain is left 
in place, it should exit in line with the longitudinal biopsy incision and close to the margin of the incision. 
 
13.1.5 Regional Lymph Node Evaluation for Soft Tissue Tumors 
Clinical and imaging evaluation of regional lymph nodes should be performed before therapy begins. 
Pathologic evaluation of clinically suspicious nodes should be performed. Regional node sampling in the 
absence of clinical or radiographic abnormality is not necessary, except in soft tissue primary tumors, which 
may prove to be rhabdomyosarcomas on detailed pathologic evaluation. Regional node debulking or 
resection is not recommended. Open biopsy of the involved node is recommended, but needle biopsy or 
fine needle aspiration may be appropriate based on the surgeon’s judgment and pathologist’s 
recommendations. Sentinel node techniques may be used if lymph node sampling is planned. 
 
13.2 
Surgical Guidelines for Consideration of Amputation at Diagnosis 
While the role of amputation in the management of the extremity primary in Ewing sarcoma is 
controversial, in certain clinical situations amputation may be the best alternative. In compliance with the 
objectives of the study, if necessary, amputation should be done after the completion of neo-adjuvant 
chemotherapy. In the case of pathologic fracture, in most instances it is preferable to attempt to splint, cast 
or brace the extremity for the induction neo-adjuvant phase of chemotherapy before resorting to amputation. 
Large destructive lower extremity lesions in children less than the age of 10, where considerable limb length 
inequality will be anticipated, may be the best managed by amputation. Consultation with an experienced 
orthopedic or surgical oncologist is encouraged, because newer methods of limb length equalization, the 
use of growth plate sparing operations (especially for diaphyseal lesions) and “expandable” prosthesis may 
make amputation unnecessary.  
 
13.3 
Surgical Guidelines for Primary Bone Lesions 
 
13.3.1 
Tumors arising in the extremities are usually situated in recognized anatomical compartments.60,61 Utilizing 
standard radiographic techniques (e.g., plain films, bone scan, MRI and at times CT or CT angiography), 
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the precise anatomic location of the lesion should be defined prior to biopsy and the studies repeated prior 
to resection. In some institutions, where available, a PET scan is indicated for evaluation. Furthermore, the 
extent of the lesions is usually dramatically reduced following induction chemotherapy, making lesions 
which are huge at diagnosis smaller and more “resectable” after chemotherapy. A surgical staging system 
for extremity musculoskeletal sarcomas which incorporates histopathological grading has been extensively 
tested and devised, whereby the histologic grade (high or low) and the extent of the disease (compartments 
involved, presence or absence of metastases) can be linked to the type of surgical procedure.62,63 The 
procedures are defined based upon the margins they achieve relative to the tumor and its pseudocapsule. In 
the setting of pre-operative chemotherapy the aim of surgery should generally be to achieve a wide (R0) 
surgical margin of normal tissue around the lesion. The second surgical margin that may be acceptable is a 
marginal (R1) excision. In this surgery there are microscopically positive cells at the cut surface of the 
tumor which remain in the patient and must be treated by radiotherapy. The histologic response of the tumor 
to chemotherapy is also important but there is no means of making this assessment prior to resection.  
 
For the purpose of this study, viable tumor at the cut surface of the specimen is considered a positive margin 
and requires radiotherapy. The plane of dissection should be through non-inflamed, non-edematous tissue 
to avoid leaving tumor cells in this tumor reactive zone.  
 
Pre-resection consultation with a radiation oncologist is recommended, even if it seems less likely a wide 
excision with a clear margin will be achieved. If a lesion is considered inoperable, that is, gross residual 
tumor would be left behind (an intralesional R2 excision), surgery should not be attempted. A partially 
removed tumor leaves the patient with a worse situation since full dose radiotherapy will be needed. The 
field size will be considerably larger since all of the surgical wound would have to be irradiated rather than 
the original tumor volume with a small margin. The post surgery tumor bed will be more anoxic rendering 
radiation less effective.  
 
13.3.2 Patient Eligibility 
Having completed the initial phase of chemotherapy, the effect of induction chemotherapy on the primary 
lesion will be evaluated by plain radiographs, bone scan, MRI and PET scan where available. It is 
recommended that all patients with a good clinical/radiologic response be considered for surgical resection 
with negative margins (i.e., “de-bulking” R2 excision is not an acceptable term or procedure). If initial surgical 
excision is elected, using the criteria defined below, the procedure should be performed following recovery 
from Week 12 Induction chemotherapy and prior to Consolidation therapy.  
 
 
13.4 
Anatomic Guidelines for Resectability 
The choice of local treatment will be left to the treating physicians, and may include: radiation alone, 
radiation followed by resection, resection followed by radiation, or surgical resection alone. The trend for 
local management of Ewing sarcoma has changed recently toward surgical resection whenever possible for 
non-metastatic disease. The guidelines for determining “resectability” and “adequate margins” are still 
being defined and require considerable judgement on the part of the entire treatment team. In general, the 
goal should be to remove the entire tumor and involved bone with a cuff of normal tissue around the tumor 
(a wide excision). Since the response of Ewing sarcoma/PNET to preoperative chemotherapy is usually 
dramatic, the soft tissue extent of the tumor is frequently much less than at diagnosis. The exact thickness 
of the “cuff” of normal tissue oncologically "safe" (with respect to local recurrence) is not known, and 
probably depends upon the type of tissue forming the cuff. Fascia, periosteum and intermuscular septae are 
good barriers to tumor spread. On the other hand, fat and muscle are relatively poor barriers and require a 
thicker cuff. If margins are deemed "positive" after review of the treatment team (see Section 4.3.1.2), or if 
there is intra-operative tumor spill or cut through, then post-operative radiotherapy is indicated. Otherwise 
wide surgical resection alone is the goal when feasible. 
 
 
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At the end of Consolidation chemotherapy, the treatment team should review residual masses and consider 
surgical resection. If definitive radiation is to be used first, followed by "late" consideration of surgery, the 
delayed surgery should be done after the end of chemotherapy. The decision about whether a given patient 
is "resectable" should be made by the treatment team which should include an experienced 
orthopedic/surgical oncologist, radiation oncologist and oncologist. Consideration must be given at each 
site to the neurovascular structures, uninvolved muscles, the adjacent joint(s) and the growth centers. Not 
every tumor is resectable, nor should this necessarily be a goal. Experience and wisdom are needed to make 
this decision for an individual patient. Some specific guidelines by site are as follows: 
 
13.4.1 Tibia 
Proximal tibial lesions must be evaluated for the status of the adjacent knee joint. If it is free of tumor 
involvement an intra-articular resection may be employed, followed by reconstruction in using osteo-articular 
allografts or metallic prostheses. An estimation of growth remaining should be made and plans for limb length 
equalization considered. Lesions with joint involvement will require an extra-articular resection and 
reconstruction with an arthrodesis or metallic prosthesis or rotationplasty. 
 
Tibial lesions of the diaphysis may be treated by resection and diaphyseal reconstruction using allograft 
bone, autografts or metallic spacers. If it is possible to preserve the joint and growth plates at either end, 
near normal function can be expected. The posterior neurovascular bundle is often protected by the deep 
posterior compartment muscles. 
 
Distal tibial lesions (supramalleolar) are probably best managed by below knee amputation. Rarely are 
lesions suitable for resection and intercalary reconstruction or ankle arthrodesis. 
 
13.4.2 Femur 
Proximal femoral lesions may be resected if there has been a good response to induction chemotherapy. At 
times it is possible to preserve the femoral head and neck and perform an intercalary reconstruction. If an 
intra-articular resection is necessary, reconstruction with a metallic prosthesis, or allograft-prosthesis 
composite is indicated. Extra-articular resections can be achieved if the joint is involved and reconstruction 
carried out by means of an arthrodesis using allograft and/or autograft bone, or at times a modified total hip 
replacement or rotationplasty. 
 
Diaphyseal lesions are frequently resectable using the vastus intermedius as a muscle cuff around the tumor. 
Intercalary reconstructions with allograft, autografts or - metallic spacers are possible with good functional 
results if the adjacent joints and growth plates are possible to preserve. As in the tibia, if a growth plate 
must be sacrificed to achieve an adequate margin, plans should be considered for limb length equalization 
after the completion of the drug protocol. 
 
Distal femoral lesions may be resected either as an intra-articular procedure or an extra-articular procedure 
(depending upon the analysis of the staging studies with regard to joint involvement) if the neurovascular 
bundle is free. Intra-articular resections can be reconstructed with osteoarticular allograft or metallic 
prostheses, whereas extra-articular resections will require arthrodesis, metallic prostheses or allograft 
prosthesis composites. In skeletally immature patients less than age of 10, or in those with strong athletic 
inclinations, a rotationplasty may be considered. 
 
13.4.3 Bones of the Hands and Feet 
Lesions involving the digits, metacarpals, and metatarsals may be managed by ray amputation or resection, 
depending upon the degree of soft tissue and joint involvement following induction chemotherapy. If 
surgically managed, the aim should be for complete resection with negative margins. Selected lesions may 
be managed by radiotherapy. Large destructive lesions of the hind portion of the foot may not be suited for 
either radiation or resection. Below-knee amputation is frequently the treatment of choice for these sites. 
 
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13.4.4 Fibula 
The proximal fibula can be resected if the response to induction chemotherapy is good. Soft tissue 
involvement noted at operation may be more extensive than that anticipated by pre-operative staging 
studies, therefore one should plan to take a wide cuff of tissue around the lesion. Extra-articular excision of 
the proximal tibial fibular joint can be done if there is epiphyseal involvement. MRI is the best imaging 
study from which to judge the extent of bony and soft tissue involvement. Reconstruction is not necessary 
as long as the distal 6-8 cm of fibula near the ankle can be preserved. The peroneal nerve may need to be 
sacrificed, but a posterior tibial tendon transfer or ankle foot orthosis compensates for its loss reasonably 
well. In some cases the soft tissue extent mandates that the toe and foot extensor muscles be removed with 
the tumor.  
 
Lesions involving the distal fibula may also be resected. Ideally, the lateral malleolus should be preserved, 
but if it is resected, adequate ankle function can be achieved by soft tissue reconstruction long term, bracing 
or, at times, an ankle arthrodesis. Occasionally a reconstruction is done with the uninvolved proximal 
fibular moved distally. 
 
13.4.5 Ankle Region 
For lesions located in the distal tibia, calcaneus and hindfoot a below knee amputation at the classical level 
is usually the best alternative (radiotherapy may be an alternative). Very small lesions might be managed 
by resection, but these are extremely unusual. 
 
13.4.6 Pelvis 
The pelvis is one of the most difficult areas for surgical resection, yet it is the site where removal of residual 
bulk disease may have the greatest impact relative to local control and survival. All pelvic lesions should 
be carefully studied by MRI with or without CT (and, at times CT or MR angiography) at the completion 
of induction chemotherapy to decide if a resection is possible. Smaller lesions limited to the iliac wing, 
ischium or pubis, with good response, should be resected. Lesions which are more extensive or have a 
poorer response to chemotherapy may become resectable after radiation, and one should consider at the 
completion of consolidation chemotherapy. Surgical complication rates are high particularly when they 
follow high dose radiotherapy. Delays in resumption of chemotherapy may contribute to the poor prognosis 
of pelvic Ewing tumors. Radiotherapy planning can be difficult due to the proximity to vital organs such as 
bowel and bladder. During surgery expandable spacers can sometimes be inserted which when inflated can 
help push bladder and bowel out of the way. Ovaries can occasionally be transplanted out of the radiation 
field.  
 
Lesions in the periacetabular area require careful consideration. There are no good reconstruction options 
for a resection at this site, but the therapeutic gain from resection of disease may outweigh sacrifice of some 
function. The decision will be individualized and require consultation with an experienced Orthopedic 
oncologist and radiotherapist, and full discussion of the local management options with the patient and his 
or her family. Possible reconstruction options include allografts (with or without hip joint prostheses), 
metallic implants, or arthrodesis (ilio-femoral or ischio-femoral). At times, amputation or leaving the hip 
flail with an internal hemipelvectomy or a saddle prosthesis may be the best options. 
 
Pelvic lesions which cross the sacroiliac joint to reach the sacrum also require careful consideration. Most 
of these lesions will be managed by radiation alone. The ability to perform a resection will depend upon 
the extent of the lesion within the sacrum and the expected neurologic deficits (including possible loss of 
bowel and bladder function) which would remain following a resection. A combined radiotherapy/surgical 
approach may be appropriate if the improvement in disease control outweighs the functional loss.  
 
The role of hemipelvectomy for large "unresectable" lesions of the pelvis is unclear. In most instances it is 
to be avoided unless it is the only means feasible to achieve adequate control in a non-metastatic patient. 
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13.4.7 Spine 
Patients with symptoms of spinal cord compression should be considered for emergency radiotherapy (see 
Section 17.4). In many cases chemotherapy will relieve the cord compression and destabilizing 
laminectomies should be avoided. Surgical resection of primary lesions arising in the vertebrae may be 
indicated when the lesions are localized and there has been a good response to induction chemotherapy. 
There are a variety of spine implants and bone grafts that are available for reconstruction following wide 
excision. Consultation could be made with a local orthopaedic spine surgeon. Radiation dose is limited at 
this site due to the sensitivity of the spinal cord. Special techniques can be used such as proton therapy (see 
Section 17.0), for protection of spinal cord and adjacent structures. The final decision regarding local 
management is ideally made after the response to induction chemotherapy is assessed. It is expected that 
patients with vertebral and/or paraspinal tumors will most likely require radiation therapy. Before 
attempting local control with surgery only, the plan should be discussed with the treatment team. 
 
13.4.8 Ribs 
Initial resection is strongly discouraged. Patients should receive Induction chemotherapy prior to 
resection. Defining the extent of the rib involvement is difficult due to the curvature of the chest wall. MRI 
is the best modality for documenting extent around the curvature of the chest. Consideration can be made 
to marking the extent of involvement by a metallic marker inserted at the margins with pre-operative CT. 
The rib with a cuff of surrounding normal tissue should be resected en bloc. Generally the resection has 
included one normal rib above and one below the lesion. The depth of the resection should include at least 
the full thickness of the musculoskeletal chest wall with pleura, and wide resection of any areas of 
attachment to underlying lung parenchyma, pericardium or diaphragm. More conservative procedures may 
also yield good oncologic results and eliminate a need of chest wall reconstruction. Half of the 
circumference of the uninvolved rib above and below can be excised with all of the soft tissues on the 
adjacent upper and lower ribs. Limiting factors for effective resection are lesions encroaching on vertebrae, 
great vessels, and brachial plexus. 
 
Primary radiotherapy is an alternative to resection if resection is unreasonable, and post-operative 
radiotherapy is indicated if the margins are microscopic. If gross residual tumor is the expected outcome 
surgery should not be attempted.  
 
13.4.9 Scapula 
Lesions presenting in the body of the scapula which do not invade the chest wall or glenoid can be resected 
without significant impairment of shoulder function. Primary lesions which involve the glenoid are possible 
to resect but reconstruction options are limited and there will be some loss of function (shoulder abduction 
active rotation strength). If the arm and brachial plexus can be preserved, resection may be attempted, even 
if it requires total scapulectomy. Reconstruction options include soft tissue repairs and fascial or artificial 
ligament slings to stabilize the proximal humerus to the chest wall. Metallic prostheses for the scapula and 
allografts have been attempted, but the functional results are as yet not well established. 
 
 
13.4.10 Sternum and Medial One-fifth of Clavicle 
Most lesions of this site are resectable if there is a reasonable response to pre-operative chemotherapy, but 
there is risk to the underlying normal structures in this area. Great care must be exercised regarding the 
heart, great vessels, trachea, esophagus, pleura and nerves. No reconstruction is necessary. 
 
13.4.11 Clavicle (Lateral four-fifths) 
A surgical resection should be considered unless this is precluded by the extent of the soft tissue 
involvement. The clavicle can be readily resected without appreciable loss of function. 
 
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13.4.12 Humerus 
The proximal one third of the humerus may be resected in either an intra or extra-articular fashion, along 
with surrounding soft tissues (deltoid). A reduction in abduction arc and power is almost a certainty. 
Reconstructions employing allografts or vascularized fibula grafts for arthrodeses (extra-articular resections 
including the deltoid and rotator cuff) or as osteoarticular implants (if the rotator cuff can be preserved at 
time of an intra-articular resection), or employing metallic implants are possible. 
 
The diaphyseal region of the humerus frequently lends itself to resection if the adjacent shoulder and elbow 
joint can be preserved and the neurovascular structures are free. Reconstruction of the intercalary defect 
with allograft or VFG autograft bone, or metallic implants are possible and offer good excellent functional 
results. 
 
The distal humerus (elbow) is a rare site of occurrence, and decisions relative to resection will depend on 
the size of the lesion and its relationship to the adjacent neurovascular structures. Reconstructions at this 
site are not commonly performed and require innovation depending upon the exact clinical situation. 
Radiotherapy may be a superior option at this site. 
 
13.4.13 Radius and Ulna 
Small lesions localized to one of the two bones may be considered for resection if there has been a good 
response to chemotherapy. Lesions which lend themselves to intercalary resections of one of the bones are 
ideal, as are lesions of the distal ulna which can be sacrificed without reconstruction. The distal radius can 
be resected as well, and reconstructed with auto- or allografts to re-create the radiocarpal joint or to establish 
an arthrodesis. Radiotherapy is an alternative.  
 
 
13.4.14 Wrist 
Fortunately, tumors arising in the small bones of the carpus are rare. Small well-localized lesions may be 
managed by radiation or resection; however, a below elbow amputation may be required. 
 
13.4.15  Skull and Mandible 
Tumors in these locations are beyond the scope of these guidelines. Consultation with a surgical oncologist 
or neurosurgeon experienced in tumors of these sites should be made. Resections are sometimes feasible, 
again with the aim of complete tumor excision with negative margins, but radiotherapy is usually required 
alone or as an adjunct for tumors in these locations. 
 
13.4.16  Soft Tissue Ewing/PNET 
In general, soft tissue lesions should be staged and treated along the same guidelines as those for bone 
tumors. If a patient has a (presumably small) soft tissue mass that was not expected to be malignant and 
was resected with negative margins no further local therapy will be required provided the primary tumor 
was not violated at the time of surgery and the cuff of normal tissue surrounding the soft tissue tumor was 
at least 2 cm wide on all surfaces. In the case of Ewing tumor within an encapsulated organ, margins are 
negative if the capsule was not surgically violated or breached by the tumor. If the primary tumor was 
violated at the time of surgery prior to the initiation of chemotherapy, then further local therapy (surgery, 
radiation or both) at the time of local control must be delivered. In this case the initial procedure would be 
considered a large biopsy. At the completion of induction chemotherapy, the patients should be re-staged 
with plain radiographs of the primary site, MRI, total body bone scan, and a chest CT and PET scan. 
 
In most cases an enbloc resection of the lesion, the biopsy tract and a cuff of normal tissue surrounding the 
lesion en bloc should be attempted. If the lesion is adjacent to a major neurovascular structure or bone, it 
may be helpful to precede the resection with radiotherapy. It is not necessary to resect the entire muscle 
compartment of involvement if the staging studies indicate lesser involvement, but in all cases the goal 
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should be to achieve a wide or marginal excision as defined by Enneking.62,63 Once transected a muscle is 
non-functional so generous margins of the muscle can be removed with the tumor. 
 
If the adjacent bone is clearly involved by tumor, treatment principles for bone tumors should be employed. 
In most cases, lesions adjacent to bone with no recognizable involvement by CT or MRI can be resected 
without removing the bone; periosteum should be taken as a margin in these cases. When postoperative 
radiation therapy is required the denuded bone is more susceptible to late pathologic fracture. 
 
Major nerves should be preserved when feasible. If they are directly involved by tumor, a combined 
radiotherapy and surgical approach or radiation alone may be necessary. Similar guidelines apply to major 
vascular structures, but resection with vascular reconstruction is an alternative for involved vessels. 
 
Most major muscle groups can be sacrificed without much loss in function. Local muscle transfers to restore 
function, achieve soft tissue coverage or to prevent dead space are sometimes necessary either at the time 
of resection or at completion of therapy. Some surgeons recommend tendon transfers at the time of 
resection. 
 
13.5 
Reporting 
The surgical checklist and AEWS1031 Local Control Checklist must be completed by the surgeon within one 
month of the definitive surgical procedure.  
 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
Central pathology retrospective review of definitive resection margins (post-chemotherapy) will be done. 
Submission of materials must be done within two months from the time of diagnostic biopsy and any surgical 
procedure done on study. COG member institutions are also encouraged to enroll patients on a Ewing sarcoma 
specimen collection study, such as AEWS07B1 or on any successor biology study. Please see the specimen 
collection study for directions for specimen preparation and shipment. 
 
14.1 
Biopsy Pathology Procedures  
Gross 
Surgeons should be encouraged to send fresh tissue in all biopsy and resection procedures. 
 
Every effort should be made to obtain viable, undistorted tissue for study. Fixation and processing in a manner 
with which the laboratory routinely obtains good results (e.g., 10% neutral buffered formalin) is satisfactory. 
Whenever the amount of tissue is sufficient, fresh and frozen tissue should be obtained for cytogenetics and 
diagnostic biologic studies. A 1 mm slice from the cut surface of the tumor should be placed in buffered 
glutaraldehyde or other electron microscopy (EM) fixative when sufficient tissue is present and saved or 
processed for electron microscopy. Touch preparations should be made for cytologic screening. Institutions are 
strongly encouraged to perform cytogenetics on fresh specimens when sufficient tissue is available and when 
this service is available. 
 
Microscopy 
The tumor must have a light microscopic appearance (by hematoxylin and eosin staining) consistent with 
a Ewing family tumor (Ewing sarcoma/peripheral primitive neuroectodermal tumor) of bone or soft tissue. 
In addition, there should be no immunohistochemical or ultrastructural evidence suggesting lymphoma or 
another sarcoma such as rhabdomyosarcoma. Patients with esthesioneuroblastoma will be ineligible. 
 
Immunohistochemistry 
In addition to routine H&E staining, it is recommended that institutional pathologists perform 
immunohistochemistry (IHC) using a panel of antibodies to aid in the diagnosis and exclude entities other than 
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Ewing sarcoma/PNET. A suggested panel would include CD99 (MIC2, 12E7, O13) to support a diagnosis of 
Ewing sarcoma/PNET, myogenic markers such as desmin, muscle-specific actin, myogenin and MyoD1) to 
rule out rhabdomyosarcoma; antibodies for detecting lymphoid antigens (CD45, TdT and additional B and T 
cell markers), as well as any exclusionary antibodies as indicated by a particular case. While CD99 (MIC2; 
12E7, O13) positivity suggests Ewing sarcoma/PNET, CD99 positivity alone is not sufficient for a diagnosis 
of Ewing sarcoma/PNET, as lymphomas, synovial sarcoma, and alveolar rhabdomyosarcoma, among other 
tumors, may express this antigen. 
 
Electron Microscopy 
It is recommended that tissue should be saved for electron microscopy, and ultrastructural evaluation should 
be performed whenever necessary for diagnosis. 
 
 
14.2 
Molecular and Cytogenetic Studies for Initial Diagnosis 
 
14.2.1 Molecular studies 
The most common cytogenetic abnormalities in EWS/PNET include t(11;22) and t(21;22); other, less common 
translocations have also been described. It is strongly recommended that tissue be obtained for molecular 
biologic study of these and other abnormalities by reverse transcriptase polymerase chain reaction (RT-PCR) 
and/or fluorescence in situ hybridization (FISH) using probes for the involved regions of chromosomes 11, 21, 
and 22. Evidence of a EWS rearrangement consistent with a Ewing family tumor may be used as supporting 
evidence for a Ewing sarcoma/PNET diagnosis. 
 
14.2.2 Cytogenetic Studies 
If sufficient tumor is available after submission of tumor for molecular studies, it is suggested that tumor 
cytogenetics be done at the home institution, if available. Fresh, sterile, unfixed tumor tissue should be 
submitted as specified by the local institution's cytogenetic laboratory. 
 
14.3 
Specimen From Surgical Resection  
Gross: Resection margins must be marked with India ink or other color indicator. Description of the 
specimen, including measurements, should be recorded. Gross assessment of the completeness of resection 
should be made. A specimen radiograph (when facilities are available) should be made prior to taking 
sections. A single slice through the largest axis of the tumor should be fixed, decalcified if necessary, and 
entirely submitted for processing, with the location of blocks clearly marked on a photograph or diagram 
of the gross specimen. These sections will then be used for assessment of histologic response to 
chemotherapy. Additional sections of primary tumor, extraosseous tumor, any grossly or radiographically 
abnormal areas and margins of bone and/or soft tissue should be obtained. If viable tumor is grossly 
recognizable, obtain tissue for cytogenetics, flow cytometry, biologic studies, and EM as described in 
Section 14.1. 
 
 
14.3.1 Surgical margins  
Completeness of resection and the status of the margins should be assessed. A positive margin will be any 
margin in which either viable tumor or tumor displaying coagulative necrosis is present at the inked surface. 
The presence of bland scar or loose fibrous tissue, in the absence of coagulative tumoral necrosis at the margin 
(where the cytoarchitecture of tumor cells is preserved) will not be considered as a positive margin, provided 
that there is 90% or greater overall tumor necrosis In tumors with less than 90% overall necrosis, the presence 
of abnormal fibrosis or reactive inflammatory tissue at the margin (indicative of treated tumor bed) will be 
considered as a positive margin. The distance of the tumor from the margins should be measured in millimeters, 
and positive margins should be described as going through a solid nodule of viable tumor, going through 
individual viable infiltrating tumor cells, or going through necrotic tumor.  
 
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In patients where surgical resection precedes neo-adjuvant therapy the cuff of normal tissue surrounding the 
soft tissue tumor should be least 2 cm wide on all surfaces. In the case of Ewing tumor within an 
encapsulated organ, margins are negative if the capsule was not surgically violated or breached by the 
tumor. 
 
14.3.2 Histologic Response 
Following definitive surgery the tumor should be examined to determine “histologic response”. Since the effect 
of the preoperative chemotherapy may not be uniform throughout the tumor, adequate sampling as described 
in Section 14.3 is required to grade the histologic response accurately. The institutional pathologist should 
assess the tumor’s pathologic response as follows: 
 
- 
No viable tumor in specimen 
- 
Viable tumor cells present, occupying < 10% of the original tumor bed 
- 
Viable tumor occupies ≥ 10% of the original tumor bed 
 
Unlike osteosarcoma, Ewing sarcoma does not produce a stromal framework, and as a result in some post-
treatment specimens, tumor volume decreases significantly, complicating efforts to assess percentage 
necrosis.64 In addition, many Ewing sarcomas have marked necrosis at diagnosis, prior to treatment. In general, 
post-treatment specimens that contain only isolated individual viable tumor cells would correspond with a 
response of < 10% viable tumor cells present and post- treatment specimens with larger nodules or sheets of 
viable tumor would correspond to a response of ≥ 10% viable tumor cells present. 
 
 
14.4 
Pathology Review Requirements 
The following material must be submitted to the COG Biopathology Center (BPC) (see address below) 
within 2 months of diagnostic biopsy and subsequent surgical procedures. Dr. Bruce Pawel, MD and Dr. 
Atif Ahmed, M.B.B.S are the COG reviewers for AEWS1031 specimens. Do NOT send specimens directly 
to them. Send all specimens to the Biopathology Center as specified below. 
 
14.4.1 Biopsy 
Required materials for central review, within 2 months of initial diagnostic biopsy are: 
• 
2 representative H & E stained slides from the diagnostic biopsy with tumor 
• 
A copy of the institutional pathology report(s) 
• 
A copy of the institutional surgical report 
• 
Specimen Transmittal Form 
 
It is the responsibility of the Principal Investigator at the institution to ensure that the pathologist is informed 
of each patient enrolled on AEWS1031 and to request that patients’ materials be forwarded to the 
Biopathology Center. The Biopathology Center and the review pathologist will not request materials. 
 
14.4.2 Resection/Amputation 
Required materials for central review, within 2 months of the surgical resection/amputation are: 
• 
Two blocks representing the closest margins from the resection specimen should be selected. From 
both blocks, 2 H&E stained slides and 5 unstained slides should be submitted. In specimens where 
there is no evidence of residual tumor or fibrosis or inflammation (the entire specimen composed 
of histologically unremarkable tissue), blocks and slides do not have to be submitted for central 
review. 
• 
Grid diagram of resection specimen (MAP) denoting location of blocks obtained. 
 
• 
A copy of the institutional pathology report(s) which includes measurement of the tumor in 2 
dimensions, percent necrosis and margins of excision (mm) 
• 
A copy of the institutional surgical report 
• 
Institutional Radiology Report(s)] 
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• 
Photograph of the gross specimen (if available). 
• 
Completed AEWS1031 Pathology checklist 
 
It is the responsibility of the Principal Investigator enrolling a patient on this trial to request from the 
submitting pathologist that s/he send the appropriate set of forms, local pathology report including the 
schematic block map, and specimens to the Biopathology Center. 
 
14.4.3 Pathology Review Specimen Shipment 
Pathology review materials can be shipped by regular mail or using your own courier account. 
 
Please label pathology review materials with patient’s COG Patient ID Number and the surgical pathology 
identification (SPID) number and block number from the corresponding pathology report. 
Send specimens to: 
Biopathology Center 
(Attn: Pathology Review AEWS1031) 
Nationwide Children’s Hospital 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2894 
FAX: (614) 722-2897 
For questions call: (800) 347-2486 
*The room number is required. Packages not listing the room number will be denied and returned to the sender. 
 
14.5 
Consultation 
If a consultation for a difficult case is desired this would be on a consultation basis only and a fee may 
be charged. If a consultation is desired, the institution should send pathology materials (all slides, a 
block or unstained slides, and surgical pathology report) to the consultant of their choice. Ship 
consultation materials using your own courier account. 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
Please note that materials sent to the reviewers for consultation will not be included in the Biopathology 
Center’s Institutional Performance Monitoring System. The consultation is separate from a study 
submission. 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
This protocol does not include correlative biology studies. However, COG member institutions are strongly 
encouraged to collect tumor specimens by enrolling patients onto one of the Ewing sarcoma biology studies 
for banking (such as AEWS07B1 or on any successor biology study). 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
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16.1 
Primary site imaging  
MRI is the preferred method of primary site imaging prior to treatment and prior to local therapy. Plain 
radiographs of primary site should also be obtained. 
 
Functional imaging with FDG-PET is recommended prior to treatment and prior to local therapy. If FDG-
PET is used SUVmax at those two time points will be reported by local institution and electronic copies of 
scan (PET and CT/MRI of involved area) as well as reports will be submitted to QARC for imaging 
committee review (see Section 16.5). 
 
16.1.1 
The primary tumor must be measured and reported in three dimensions prior to therapy and prior to local 
therapy. The three largest perpendicular measurements will be measured and reported in RDE. See Section 
10.2.1.3. 
 
16.2 
Metastatic site imaging  
Total body bone scan, chest CT, and imaging of selected regional nodal sites by MRI or CT are required to 
exclude metastatic disease. Functional imaging with FDG-PET is strongly recommended as it has increased 
sensitivity for detection of osseous and lymphatic metastasis. Patients with metastatic disease at diagnosis, 
other than regional nodal spread, are not eligible for enrollment. 
 
16.3 
Required and Recommended Imaging 
All imaging studies are required unless otherwise noted. 
 
16.3.1 At Presentation and Prior to Local Control 
 
Site 
Anatomic Imaging 
Functional Imaging 
Timing 
Primary  
Frontal and lateral 
radiographs 
 
Required at presentation and prior to local 
control for bone tumors of extremity and pelvic 
sites at study entry* 
Primary  
MRI with gadolinium 
 
 
Required at presentation and prior to local 
control* 
Chest 
CT 
 
Required at presentation and prior to local 
control* 
Chest 
Frontal and lateral 
radiographs 
 
Recommended at presentation only 
Whole body 
 
MDP bone scintigraphy  Required at presentation and prior to local 
control* 
Whole body 
 
FDG-PET 
Strongly recommended at presentation. 
Recommended prior to local control*, 
particularly if primary bone tumor positive on 
prior PET and negative on bone scintigraphy. 
*- The pre-local control image should be obtained within 4 weeks of local control 
  
 
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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16.3.2 Surveillance on Consolidation Chemotherapy and End of Therapy Evaluations 
 
Site 
Anatomic Imaging 
Functional 
Imaging 
Timing 
Primary  
Frontal and lateral 
radiographs 
 
Required for bone tumors of extremity and pelvic 
sites at study entry – After Cycle 5 consolidation 
and at end of cytotoxic chemotherapy  
Chest 
CT 
 
Required – After Cycle 5 consolidation and at 
end of cytotoxic chemotherapy 
Whole body 
 
MDP bone 
scintigraphy  
At end of cytotoxic chemotherapy (unless bone 
scintigraphy negative and FDG-PET positive at 
presentation)  
Perform sooner if symptoms or abnormal 
imaging (and surgical or other intervention 
contemplated AND primary tumor positive on 
prior bone scintigraphy) 
Whole body 
 
FDG-PET  
Required – At end of cytotoxic chemotherapy if 
bone scintigraphy negative and FDG-PET 
positive on prior imaging 
Recommended – At end of cytotoxic 
chemotherapy (unless bone scintigraphy 
positive and FDG-PET negative at presentation)  
Perform sooner if symptoms or abnormal 
imaging (and surgical or other intervention 
contemplated AND positive on prior FDG-PET) 
Primary  
MRI with gadolinium 
or CT scan with IV 
contrast  
 
Recommended if symptoms or abnormal 
imaging (and surgical intervention or radiation 
therapy contemplated) 
 
16.3.3 Recommended Surveillance Post-Chemotherapy 
 
Site 
Anatomic Imaging 
Functional 
Imaging 
Timing 
Primary 
Frontal and lateral 
radiographs 
 
Obtain for bone tumors of extremity and 
pelvic sites at study entry: 
q 3 months x 8, then 
q 6 months x 6, then 
q 12 months x 5 
Chest 
Frontal and lateral 
radiographs 
 
q 3 months x 8, then 
q 6 months x 6, then 
q 12 months x 5 
Chest 
CT 
 
If abnormal chest radiographs 
Primary 
MRI with gadolinium or 
CT scan with IV contrast 
 
If symptoms or abnormal imaging (and 
surgical or other intervention contemplated) 
Whole body 
 
MDP bone 
scintigraphy  
 
If symptoms or abnormal imaging (and 
primary tumor positive on prior bone 
scintigraphy AND surgical or other 
intervention contemplated) 
Whole body 
 
FDG-PET  
 
If symptoms or abnormal imaging (and 
primary tumor positive on prior FDG-PET 
AND surgical or other intervention 
contemplated) 
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16.4 
Technical Guidelines 
 
16.4.1 CT and MRI 
Technical guidelines for cross-sectional imaging are provided in Section 10.2. Additional CT and MRI 
guidelines are available on the COG Member site at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
16.4.2 FDG-PET 
FDG-PET scans may be performed according to local institutional standards. Guidelines are included 
institutions requiring them (Appendix I) 
 
16.5 
Submitting Imaging for Central Review 
PET studies as well as MRI or CT scan images of the area involved with tumor obtained prior to study entry 
and those obtained prior to local control with the corresponding radiology reports will be submitted to 
QARC for central review.  
 
Submission of diagnostic imaging data in digital format is required. Digital files must be in DiCOM format. 
These files can be burned to a CD and mailed to QARC. Multiple studies for the same patient may be 
submitted on one CD; however, please submit only one patient per CD. Electronic submission of the scans 
is acceptable via Dicommunicator. Contact QARC at Dicommunicator@QARC.org for further information. 
Alternative electronic methods, e.g., sFTP are possible. Contact QARC for more information. 
 
Please submit to: 
Quality Assurance Review Center (QARC) 
Building A, Suite 201 
640 George Washington Highway,  
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
  
 
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17.0 
RADIATION THERAPY GUIDELINES  
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT facilities (per 
COG Administrative Policy 3.9) or at approved RTOG RT facilities.  
 
 
 
 
 
 
 
 
 
17.1 
General Guidelines 
The radiation therapy guidelines for this study were developed specifically for patients with newly 
diagnosed Ewing sarcoma. 
 
17.1.1 Special Note for Very Young Children 
The long-term morbidity of RT or aggressive surgery for very young children makes appropriate local 
control challenging. Many clinicians are unwilling to follow standardized local control guidelines for very 
young children. This study encourages adherence to standardized local control guidelines for all children 
regardless of age.  
 
17.1.1.2 
Required Benchmark and Questionnaires 
All therapy units used on this protocol must have their calibrations verified by the Radiological Physics 
Center (RPC). RT using photons (either 3-D conformal [3-D CRT] or intensity modulated [IMRT]), 
electrons and protons, will be allowed in this study. Centers participating in this protocol using 3-D CRT 
are required to complete the 3-D benchmark; those using IMRT must complete the IMRT questionnaire 
and benchmark or phantom (QARC or RPC) and those using protons must complete the proton benchmark 
and questionnaire. 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. 
For information regarding the IMRT phantoms, please contact the RPC (http://rpc.mdanderson.org/rpc). 
 
17.1.1.3 
Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of IMRT in 
National Cancer Institute sponsored cooperative group trials. These guidelines are available through 
www.qarc.org. These guidelines require that the protocol explicitly state their requirements and methods 
for localization and immobilization; the use of volumetric imaging; target and organ motion management; 
nomenclature, definitions and rationale for targets and organs at risk; target volume coverage and normal 
tissue dose constraints; effects of heterogeneity in tissues; and quality assurance. 
 
 
17.1.1.4 
Guidelines and Requirements for the Use of Proton Beam Therapy 
Investigators using proton beam therapy will be required to comply with the guidelines for the use of 
protons in National Cancer Institute sponsored cooperative group trials developed in 2007. These guidelines 
shall be available through www.qarc.org. These guidelines specify the following for the participating 
institution: only passively or actively scattered proton beams will be used; the IAEA TRS 398 protocol 
shall 
be 
used 
for 
beam 
calibration; 
dose 
reporting 
will 
be 
in 
Cobalt Gy 
Equivalent 
(1 CGE = 1 proton Gy * 1.1). Radiation doses shall be prescribed protocol specified definitions for gross 
(GTV) and clinical (CTV) target volumes. For set-up uncertainties and target motion, additional margin, 
smearing, range of modulation will be added on a per beam basis. The proton institution is required to 
participate in on-site and remote review according to COG guidelines. 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed 
therapy and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and 
family logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per 
COG administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
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17.1.1.5 
Guidelines and Requirements for the Use of Brachytherapy or Intraoperative Radiation 
Therapy  
Brachytherapy, using either high dose rate or low dose rate radioactive sources may be used on this protocol. 
Typically, brachytherapy or intraoperative radiation therapy will be used for conformal RT of residual 
disease in the operative bed of the primary tumor for select patients.  
 
17.2 
Indications for Radiation Therapy 
See Section 4.3 for a general discussion of local control. 
 
Definitive radiation therapy 
Unresected tumor 
Pre-operative radiation therapy 
Resectable tumor* 
Post-operative radiation therapy 
(1) Post-operative gross or microscopic residual tumor 
(2) Intra-operative spill 
Special presentations 
(1) Chest wall tumor with ipsilateral pleural-based secondary tumor 
nodules or positive pleural fluid cytology 
(2) Pathologically involved lymph nodes 
*Patients considered for pre-operative radiation (see Section 4.3.1.3) 
 
Patients having microscopic or gross residual disease after planned pre-operative radiation therapy will 
receive additional radiation therapy (see table Section 17.7.2.1).  
 
Patients who have had a complete surgical excision of the involved area of bone and/or soft tissue mass 
with adequate surgical margins (see Sections 4.3.1, 14.3.1 and 17.7.2.1) will not receive postoperative 
radiation. 
 
17.3 
Timing of Radiotherapy 
 
17.3.1  
All patients should be seen in consultation by a radiation oncologist as early as possible if RT may be 
indicated according to the protocol. The purpose of the consultation is to participate in staging and to review 
the adequacy of the initial diagnostic imaging studies that will be used for subsequent RT planning. 
 
17.3.2  
Patients treated with radiation as the primary local control measure, preoperatively or postoperatively will 
have radiotherapy delivered beginning concurrently with the beginning of Consolidation chemotherapy. If 
wound healing is incomplete the possibility of a delay in initiation of radiation should be discussed with 
the protocol radiation oncologist. Ifosfamide and etoposide chemotherapy may be given concurrently with 
radiotherapy (See Section 4.0).  
 
The objective of preoperative radiotherapy should not be an attempt to make an inoperable tumor operable. 
Patients who are to be treated with planned lower dose (36 Gy) radiation followed by planned excision 
should be treated with radiation during Weeks 1 through 4 of Consolidation, and then proceed onto surgical 
resection of the tumor as soon as possible (ideally within 2 weeks). If post-operative radiotherapy boost is 
required, radiation therapy should be scheduled to start as soon as recovery from surgery permits, usually 
within 2 weeks. Following surgery, the next cycle of chemotherapy should be given as soon as possible 
post-operatively; this can be given concurrently with boost radiotherapy if necessary.  
  
 
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17.3.3  
Patients who require emergency radiotherapy such as patients with spinal cord compression may receive 
radiotherapy to their emergency site on Day 1 if deemed necessary by the treating physician. This is 
expected to be a rare event, since most patients will respond quickly and dramatically to chemotherapy. 
The entire course of the emergency radiotherapy should be administered starting Day 1, rather than splitting 
the treatment and concluding the course at the beginning of Consolidation (Week 14). In cases requiring 
urgent or emergency radiotherapy, notify the study radiation oncologist. Note that doxorubicin courses must 
not be given during radiation with the exception of consolidation cycle 1 where concurrent start of 
chemotherapy and radiation is allowed. If emergency radiotherapy is required during induction the order of 
the six planned chemotherapy cycles may be altered in order to avoid concurrent administration of 
doxorubicin with radiation. Ifosfamide/etoposide courses and vincristine-topotecan-cyclophosphamide 
courses may be given concurrently. 
 
 
17.3.4 Mesna 
In the past, mesna was held during radiation therapy. There is no data to suggest that mesna is a 
radioprotector. Mesna will therefore not be held during radiation. 
 
17.4 
Emergency Radiation Therapy 
Radiation therapy may be delivered on an emergent basis to patients with spinal cord compression, loss of 
vision or other function-threatening conditions. The decision to irradiate emergently should be made by the 
treating physicians. If emergent radiation is initiated, the entire course of the radiotherapy for that site should 
be delivered using the protocol specified doses, rather than waiting until the protocol specified times for 
irradiation. Doxorubicin should be withheld if patients receive emergency radiation therapy.  
 
17.5 
Equipment and Methods of Delivery and Verification  
 
Equipment 
Photons 
(any energy) 
Electrons 
(any energy) 
IMRT 
(4-10MV) 
Protons 
Brachytherapy* 
Linear Accelerator** 
X 
X 
X 
 
 
Proton Beam  
 
 
 
X 
 
Intraoperative Radiation Therapy 
X 
X 
 
 
X 
Brachytherapy - 
high or low dose rate  
 
 
 
 
X 
* 
Permanent radioactive implants are not allowed on this protocol. 
** For tumors adjacent or included in lung tissue, photon beam energy should be < 10 MV. 
 
17.5.1 Treatment planning 
CT-treatment planning: All patients will undergo CT treatment planning for this protocol. Slices no more 
than 0.5cm thick (0.2-0.3cm is recommended) shall be taken throughout the extent of the irradiated volume. 
 
CT (volumetric) based planning is required to optimize dose to the PTV while protecting normal tissues. 
Organs within the irradiated volume should be contoured including those required by treatment site (Section 
17.10). A DVH is necessary to determine target coverage and evaluate dose to normal tissues. In the event 
that a patient must start emergently with a non-volumetric treatment plan, a volumetric plan will be 
accomplished as soon as is reasonably possible and the previously utilized beams must be incorporated into 
the composite plan. 
 
 
 
 
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17.5.2 In-room verification of spatial positioning  
Two-dimensional or volumetric imaging may be used to verify correct patient positioning. Portal imaging 
using EPIDs is the most common two-dimensional method, particularly when the target volume possesses 
a fixed spatial relationship with visualized bony anatomy. Film is discouraged but is acceptable. For IMRT 
and 3-D CRT treatments, a pair of images (usually orthogonal AP and lateral) is required to verify that the 
isocenter is in correct alignment relative to the treatment plan; these may be MV or kV images. 
 
Volumetric imaging for position verification may be in-room kV or MV cone beam or conventional CT 
imaging.  
 
Imaging submission requirements: 
• 
For 2D imaging, the portal and isocenter setup verification images should be submitted along with 
the DRRs from the treatment plan. Images should be sent in the form of screen captures or in 
hardcopy format.  
 
• 
For volumetric imaging, submit representative axial slices showing the treatment scan registered to 
the planning scan and indicating correct positioning either by isocenter location or overlay of the 
isodoses. 
 
17.6 
Target Volumes 
 
17.6.1 Standard tumor and target volume definitions 
International Commission on Radiation Units and Measurements (ICRU) Reports 50, 62 and 78 
(www.icru.org) define prescription methods and nomenclature that will be utilized for this study. Treatment 
planning will be based on the following definitions and applies only to the primary tumor site: 
 
Photons 
• 
Gross tumor volume (GTV) is the volume occupied at diagnosis by visible or palpable disease.  
 
• 
Clinical target volume (CTV) includes the GTV and sites with potential occult tumor involvement 
including lymph nodes adjacent to the GTV that may be clinically involved.  
 
• 
Planning target volume (PTV) is the CTV surrounded by a geometric margin to account for 
variability in set-up, breathing or motion during treatment. 
 
Protons 
• 
GTV is the same for protons and photons. 
 
• 
CTV is the same for protons and photons. 
 
• 
PTV is not the same as photons due to differences in beam penetration with movement and set up 
uncertainty. PTV varies with each individual field and coverage and will require additional 
adjustment to (1) the lateral margins, (2) smearing of compensator, (3) range of beam (depth of 
penetration) and, (4) modulation (number of required Bragg peaks). Adjustments to any of the 
aforementioned parameters (usually 2-7 mm) will be based on the set up error determined for the 
particular body site at the individual proton institution. Motion of the target volume in three 
dimensions (cranial, caudal, anterior to posterior, and lateral) may be determined by 4-dimensional 
CT, respiratory gated CT, or other accepted techniques. 
 
 
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Brachytherapy 
• 
GTV is the same as for photons. 
 
• 
CTV is the same as for photons. 
 
• 
PTV is equal to CTV. 
 
17.6.2 Initial tumor and target volume definitions 
The definitions for GTV1, CTV1 and PTV1 apply to all definitive, preoperative and postoperative treatment 
scenarios for which radiation therapy is indicated. Treatment will be prescribed to the PTV, which will be 
derived from the GTV and CTV 
 
17.6.2.1 GTV1 
GTV1 is defined as the visible and/or palpable disease defined by physical examination, computed 
tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET scan) prior 
to any surgical debulking or chemotherapy. It also includes enlarged but unresected, regional lymph nodes. 
For patients who undergo initial surgery, operative notes and pathology reports may be helpful. GTV1 may 
require modification for initial tumors that exhibit a “pushing margin” into body cavities (ie, thorax, 
abdomen). If the tumor has responded to chemotherapy and normal tissues have returned to their natural 
position, GTV1 excludes the pre-chemotherapy volume where that volume extends into the cavity. 
Examples include tumors that indent the lung, intestine or bladder that clearly return to a more normal 
anatomic position following chemotherapy. The modified GTV1 includes initially infiltrative disease which 
has responded to chemotherapy. 
 
17.6.2.2 CTV1 
If there are no sites that warrant irradiation for potential occult tumor, then the CTV1 is defined as the 
GTV1 plus 1 cm (but not extending outside of the patient). It also includes regional lymph node chains for 
clinically or pathologically involved nodes. For tumors with no evidence of nodal involvement (N0), the 
draining regional lymph nodes are not irradiated. For some sites, the definition of CTV is modified to 
account for specific anatomic barriers to tumor spread. When lymph nodes are clinically or pathologically 
involved with tumor, the entire lymph node drainage chain should be included in the CTV. 
 
17.6.2.3  PTV1 
For external beam photon techniques, the PTV1 is defined as the CTV1 plus an institutional specified 
margin to account for day-to-day setup variation related to the ability to immobilize the patient and 
physiologic motion of the CTV1. The minimum margin is 0.5 cm but does not have to be uniform in all 
dimensions. Institutions with daily image-guidance may be able to reduce PTV based on institution-specific 
guidelines. For proton planning, beam specific PTV expansions will be required as described in Section 
17.5. 
 
17.6.3 Volume reduction tumor and target volume definitions 
The definitions for GTV2, CTV2, and PTV2 apply to all definitive, preoperative, and postoperative 
treatment scenarios for which radiation therapy is indicated.  
 
17.6.3.1  GTV2 
GTV2 is defined as residual visible or palpable tumor as assessed by CT, MRI, PET scan or physical exam 
following induction chemotherapy with or without surgery. For unresected tumors, GTV2 includes the pre-
treatment abnormalities in bone and the gross residual tumor in soft tissue after induction chemotherapy. 
For partially resected tumors, GTV2 includes residual abnormalities in bone and the gross residual tumor 
in soft tissue and the tumor bed harboring microscopic residual tumor. For tumors with microscopic residual 
and >90% necrosis, this is the post-induction chemotherapy target volumes determined on pre-operative 
imaging. 
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Special Considerations: In the case of extraosseous primaries with a complete response to chemotherapy 
or with intra-operative spill, there is only a single GTV (GTV1=GTV2). 
 
17.6.3.2  CTV2 
CTV2 is defined as the GTV2 + 1 cm (but not extending outside the patient) and areas at risk for 
microscopic disease and modified to account for specific anatomic barriers to tumor spread. CTV2 includes 
lymph nodes adjacent to the GTV when appropriate. CTV2 should not extend outside of the patient. 
 
17.6.3.3  PTV2 
PTV2 is defined as the CTV2 with an institution and modality specific margin (minimum: 0.5 cm) to 
account for day to day setup variation and physiologic motion of the CTV2. For proton planning, beam 
specific PTV expansions will be required as described in Section 17.5. 
 
Special Presentations:  
 
1) Chest Wall Tumors with Ipsilateral Pleural Nodules and/or Isolated Pleural Fluid Involvement (CTV3, 
PTV3) 
These patients will require irradiation of the ipsilateral hemithorax followed by irradiation to the primary 
site, and if applicable, pleural based nodules. Target volumes for ipsilateral hemithorax irradiation are 
designated CTV3, PTV3 and will be irradiated first. Irradiation of the primary site or pleural based disease 
will follow. The GTV1, CTV1, PTV1 and GTV2, CTV2, and PTV2 for the primary are defined and treated 
as outlined in previous sections after completion of hemithorax irradiation. If the primary has been resected 
with adequate margins, and irradiation of the primary site is not indicated, the primary will not be treated 
and radiation will be administered only to PTV3. For ipsilateral or bilateral lung irradiation, the lung and 
pleural cavity is defined as the CTV3. PTV3 is an expansion of CTV3 to account for organ motion during 
respiration as well as a 0.5-1 cm geometric expansion to account for day to day set-up uncertainty. Organ 
motion can be determined with a 4D simulation, fluoroscopy, or lateral chest radiograph at full inspiration 
to document diaphragmatic excursion. The GTV1 and GTV2 for the primary and for the pleural based 
metastases are defined and treated as outlined in previous sections, however, there will be no GTV2 
assigned to pleural based metastases having complete response to chemotherapy. The CTV1 and CTV2 of 
the primary and the CTV1 and CTV2 for the pleural based metastases respectively, may be combined if 
they can be treated in a single field based on the judgment of the radiation oncologist. Similarly a composite 
for the CTV3 including the pleural surfaces of the entire hemithorax and including the primary site and the 
pleural based metastases may be created to simplify treatment planning as long as dose requirements to 
these regions are met. 
 
2) Pathologically Involved Lymph Nodes 
Nodal target volumes are included in the definitions of GTV1, CTV1, PTV1. Nodal target volumes are 
included in the definitions of GTV2, CTV2, and PTV2 with some modifications: 
 
In the case of a primary tumor which is resected with adequate margins, the nodal PTV should be drawn 
without the primary site and will be the only volume treated. The GTV for the primary site and GTV for 
the lymph nodes should initially be determined independently. If the volumes are contiguous the treating 
radiation oncologist should consider combining the volumes (especially after CTV and PTV expansions). 
The doses for the primary site and lymph nodes should be determined independently. 
 
GTV2 is only defined for unresected lymph nodes and includes the nodal volume after 
chemotherapy. GTV2 cannot be defined for resected lymph nodes or when there has been a 
complete response to chemotherapy. 
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CTV2 is only defined for unresected lymph nodes and its definition depends on the response to 
chemotherapy. CTV2 is defined as the original involved nodal region for unresected lymph nodes 
that have had a complete response to chemotherapy. CTV2 is defined as the original involved nodal 
region with an additional margin of 1.0 cm surrounding GTV2 for unresected lymph nodes after a 
partial response to chemotherapy.  
 
PTV2 is only defined for unresected lymph nodes and includes an additional margin of 0.5-1.0 cm 
surrounding CTV2. 
 
Vertebral Body Tumors 
The GTV1 and GTV2 are defined as outlined in previous sections. At a minimum, CTV1 is defined as the 
entire vertebral body. PTV1 is the CTV1 volume with an institution specific margin of approximately 0.5 
cm to account for day to day variation in set-up and physiologic motion. For the field-reduction boost, 
CTV2 is defined as GTV2 plus an additional 0.5-1.0 cm margin to account for sub-clinical areas of residual 
disease but confined by anatomic boundaries (e.g. does not enter the spinal canal if initial disease did not 
enter the canal). PTV2 is the CTV2 volume with an additional margin of approximately 0.5 cm to account 
for day to day variation in set-up and physiologic motion. Institutions with daily image-guidance may be 
able to reduce PTV based on institution-specific guidelines. 
 
Extremity Tumors 
The CTV should be modified at the discretion of the radiation oncologist to avoid circumferential irradiation 
of extremity lymphatics and treatment across a joint unless absolutely necessary for tumor coverage. A strip 
of tissue must be provided for extremity tumors, so that lymphatic obstruction and unacceptable morbidity 
can be avoided. If any of the treatment margins necessitates irradiating the epiphysis of an adjacent bone 
and there is no extension across the joint space, a smaller margin may be considered so that the adjacent 
epiphysis can be excluded. If the patient has a diaphyseal lesion, every attempt should be made to exclude 
at least one epiphysis (or both) of the affected bone. The most active growing epiphyses are those about the 
knee in the lower extremity and those in the shoulder and wrist area of the upper extremity. The gross tumor 
volume (GTV) should be treated to the prescribed dose whenever possible. 
 
Head and Neck Tumors 
Many of these tumors may be considered unresectable due to close proximity to critical structures and 
surgical risks contributing to functional or cosmetic deficits. Every attempt should be made to minimize 
dose to the brain, cochlea, optic chiasm and orbit including eye, lacrimal gland, and optic nerve. 
 
Orbital Tumors 
For orbit primaries, the CTV will not extend outside of the bony orbit, providing there is no bone erosion 
of the orbit. 
 
Chest Wall/Intrathoracic Tumors 
Tumors which have displaced a significant amount of lung parenchyma then returned to normal anatomic 
position following surgery or chemotherapy will have the GTV defined as the preoperative 
(prechemotherapy) tumor volume excluding the component of intrathoracic tumor which was removed by 
surgery or decreased in size by chemotherapy. All areas of pleural involvement will be included in the GTV 
regardless of whether the radiation is delivered pre or postoperatively. 
 
Intra-abdominal/Retroperitoneal/Pelvic Tumors 
Tumors which have displaced a significant amount of bowel then returned to normal anatomic position 
following surgery or chemotherapy will have the GTV defined as the preoperative (prechemotherapy) 
tumor volume excluding the component of intra-abdominal or intra-pelvic tumor which was removed by 
surgery or decreased in size by chemotherapy. All areas of peritoneal or mesenteric involvement will be 
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included in the GTV regardless of whether the radiation is delivered pre- or post-operatively. Whole 
abdomen RT is indicated for malignant ascites or diffuse peritoneal involvement. In such cases the entire 
peritoneal cavity is considered the CTV. 
 
17.7 
Target Dose 
Integrated boost radiotherapy plans are not permitted. 
 
17.7.1 Dose Definition  
Photon dose is to be specified in centigray (cGy)-to-muscle. For proton beam, the absorbed dose is specified 
in CGE, which is the same as ICRU 78 DRBE using a standard RBE of 1.10 with respect to water.  
 
17.7.2 Prescribed dose and fractionation 
Dose should be prescribed to an isodose surface that encompasses the PTV and allows the dose uniformity 
requirements to be satisfied. The protocol-specified dose per fraction is 180cGy. The treatment should be 
limited to one fraction per day. The dose per fractionation may be reduced from 180cGy to 150cGy when 
large volumes are treated (i.e., whole abdomen and pelvis) or when tolerance is poor (i.e., mucositis or 
diarrhea). Changes to the fractionation regimen should be noted in the treatment record and submitted 
information. 
 
17.7.2.1 Radiation dose guidelines for all targeted volumes, excluding lymph nodes, and chest wall tumors 
with malignant pleural effusion or pleural nodules 
Tumor Site and Presentation 
PTV1 
PTV2 
Definitive RT 
45 Gy 
10.8 Gy 
Definitive RT – vertebral bony lesion 
45 Gy 
5.4 Gy 
Definitive RT – extraosseous ESFT without bony involvement 
 
 
with CR to Chemotherapy 
50.4 Gy 
N/A 
Preop RT 
36 Gy 
N/A 
Postop RT after pre-op RT: microscopic residual, >90% necrosis  
N/A 
14.4 Gy  
Postop RT after pre-op RT: microscopic residual, <90% necrosis 
14.4 Gy 
N/A 
Postop RT after pre-op RT: gross residual 
19.8 Gy 
 
Postop RT –microscopic residual, >90% necrosis 
N/A 
50.4 Gy 
Postop RT – microscopic residual, <90% necrosis 
50.4 Gy 
N/A 
Postop RT – gross residual 
45 Gy 
10.8 Gy 
 
17.7.2.2 
Radiation dose guidelines for pathologically involved lymph nodes 
Involved Lymph Nodes Doses 
PTV1 
PTV2 
LN resected – separate from primary site 
50.4 Gy 
 
LN resected – contiguous with primary site 
50.4 Gy 
 
LN unresected - primary adequately resected 
45 Gy 
10.8 Gy 
LN unresected - primary inadequately resected 
(microscopic residual) 
45 Gy 
10.8 Gy 
Whole abdomen RT for malignant ascites or diffuse 
peritoneal involvement 
24 Gy* 
 
* Whole abdomen RT will be administered at 1.5 Gy per fraction 
 
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17.7.2.3 
Radiation dose guidelines for pathologically involved pleural fluid 
 
Chest wall tumors with positive fluid cytology 
Age 
PTV1* 
PTV2* 
PTV3^ 
< 6  
32.4 Gy 
10.8 Gy 
12 Gy 
> 6  
30.6 Gy 
9 Gy 
15 Gy 
*PTV1 and PTV2 - 1.8 Gy per fraction 
^PTV3 - 1.5 Gy per fraction  
Note: Heterogeneity correction must be used for lung irradiation 
 
17.7.2.4 
Radiation dose guidelines for pleural nodules 
 
Chest wall tumor with secondary soft tissue only pleural nodules, radiographic PR 
Age 
PTV1* 
PTV2* 
PTV3^ 
< 6  
23.4 Gy 
19.8 Gy 
12 Gy 
> 6  
21.6 Gy 
19.8 Gy 
15 Gy 
Chest wall tumor with secondary soft tissue only pleural nodules, radiographic CR 
Age 
PTV1* 
PTV2* 
PTV3^ 
< 6  
37.8 Gy 
 
12 Gy 
> 6  
36 Gy 
 
15 Gy 
 
*PTV1 and PTV2 - 1.8 Gy per fraction 
^PTV3 - 1.5 Gy per fraction  
Note: Heterogeneity correction must be used for lung irradiation 
 
17.7.3 Dose uniformity 
At least 95% of the protocol-specified dose should encompass 100% of the PTV1/PTV2 and no more than 
10% of PTV1 (PTV2 for patients with a volume reduction) should receive greater than 110% of the protocol 
dose as evaluated by DVH. The 100% isodose should be equal to the prescribed dose. Wedges, 
compensators and other methods of generating more uniform dose distributions are encouraged. 
 
17.7.4 Tissue heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed with CT-based treatment 
planning to generate dose distributions and treatment calculations from CT densities. 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). 
 
 
17.7.5 Environment of care - Interruptions, delays and dose modifications 
There will be no planned rests or breaks from treatment. Once radiation therapy has been initiated, treatment 
will not be interrupted except for severe myelosuppression associated with complications which in the 
opinion of the treating physicians preclude administration of RT. Blood product support should be instituted 
according to institutional/protocol guidelines. Side effects that require treatment interruption include 
significant stomatitis or mucositis (> Grade 3). The reason for any interruptions greater than three treatment 
days should be recorded in the patient’s treatment chart and submitted with the QA documentation. When 
interruptions or delays occur, the total number of fractions or cumulative dose should not be modified. 
 
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17.8 
Treatment Technique 
 
17.8.1 Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without compromising coverage of the 
target volume. Three-dimensional conformal therapy (coplanar or non-coplanar) or IMRT are required to 
minimize dose to normal tissues.  
 
17.8.2 Selection of proton beam arrangements 
There are uncertainties (1-3 mm) in the distal range of the proton beam in which the RBE may be greater 
than 1.1; therefore, single proton beam plans which stop in a critical organ will not be allowed. Individual 
proton beams which are a component of a multi-field proton beam, which stop within such an organ, will 
be allowed. 
 
17.8.3 Field Shaping  
Field shaping for photons will be done with either customized cerrobend blocking or multileaf collimation. 
The field shaping for protons will be done with either brass apertures or proton-specific multileaf 
collimation. 
 
17.8.4 Simulation including patient positioning and immobilization 
 
17.8.4.1 
Patient positioning  
Reproducible setups are critical and the use of immobilization devices is strongly encouraged. 
The patient may be treated in any appropriate, stable position. Consideration should be given to implications 
for inter and intrafraction motion when using non-standard position approaches. 
 
17.8.4.2 
Immobilization devices 
Standard immobilization devices for the torso, extremities or head and neck are to be used. 
For IMRT delivery approaches, the methods used for localization and immobilization of both patient and 
tumor are critical. The imaging studies should provide a clear assessment of the target volume with the 
patient in the treatment position.  
 
17.8.5 Special considerations  
Anesthesia or sedation may be required in certain patients, such as very young patients, to prevent 
movement during simulation and daily treatments.  
 
17.8.6 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 internal motion (IM) component of the PTV and is meant to account 
for potential motion of the CTV. If adequate clinical data do not exist to define the IM component of the 
PTV margin, the following suggestions are provided: 
• 
For a CTV susceptible to physiologic motion, a margin of at least 0.5cm should be added to the 
CTV prior to PTV margin expansion or a PTV margin of 1.0cm 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 0.5cm 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 4-D CT) of the remaining tumor motion 
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should be submitted on the Motion Management Reporting Form with the Quality Assurance 
Documentation materials as noted in Section 17.11. 
 
17.8.7 Brachytherapy 
Single Plane Implant 
It is expected that most patients will be treated by a single plane implant to the tumor bed after gross 
resection with microscopic residual disease or in the case of less than minimal margins. The target volume 
should include all sites of potential microscopic disease with at least 1.0 cm margin on all sides. A template, 
mesh or applicator can be used to keep the catheters parallel. If the area to be implanted is larger than 50cm2, 
external beam radiation therapy should be considered. Catheters should be parallel and positioned 1cm 
apart. To ensure sufficient coverage the catheters should be placed with the distal end of the catheter 
projecting 1-2cm beyond the target volume.  
 
Double or Multiple Plane Implant 
A double plane implant will be performed for unresectable tumors less than 2 cm thick. A larger tumor may 
require a volume (multiplane) implant. These techniques should not be used for patients with unresected 
boney disease. The target volume should include the entire palpable or post chemotherapy tumor volume 
with at least a 0.5cm margin on all sides. If the thickness of tissue to be implanted is larger than 3 cm, 
external beam radiation therapy should be considered, but is not required. Catheters are to be implanted 1 
cm apart throughout the tumor volume for these cases. The target volume is the entire palpable or post 
chemotherapy tumor with at least a 0.5 cm margin on all sides. 
 
Brachytherapy Dosimetry 
CT planning shall be used for post-implant dosimetry. The GTV, CTV, and PTV shall be outlined on the 
CT. DVHs for the GTV, CTV, and PTV shall be calculated and submitted for review. 
 
Sources used shall have assay directly traceable to NIST. 
 
CT or MRI planning shall be used for postimplant dosimetry. The GTV and CTV shall be outlined on the 
CT or MRI. The PTV is identical to the CTV for purposes of brachytherapy planning. DVHs for the GTV, 
CTV, and PTV shall be calculated and submitted for review. 
 
Implants should be designed to meet the following dose uniformity criteria: 
 
CTVD100 ≥ 95% of the prescribed dose 
 
Dose homogeneity index 
80
.0
100
150
100
≥
−
=
V
V
V
HI
CTV
CTV
CTV
 
 
Where CTVD100 is the dose received by 100% of the CTV, CTVV100 is the fraction of the CTV receiving the 
prescribed dose, and CTVV150 is the fraction of the CTV receiving 150% of the prescribed dose. 
 
It is recognized that the dose distribution from brachytherapy implants is inherently non-uniform and that 
for some implant geometries the above criteria for dose homogeneity index may be difficult to meet. 
 
When a brachytherapy implant is used, the isodose distribution shall be calculated in descriptive planes (3 
perpendicular planes passing through the target center and in two transverse planes 2cm from the ends of 
the implant). CT-based planning shall be used. 
 
Total dose/fractionation and dose rate 
In the rare circumstance that postoperative brachytherapy is used instead of external beam radiation, then 
the following recommendations apply: 
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LDR brachytherapy 
Total dose: 2600cGy  
Dose rate range: 40-100cGy/hour.  
 
HDR brachytherapy 
 
Total dose: 2100cGy  
 
Dose per fraction: 300cGy BID (separate fractions by ≥ 6 hours) 
 
Number of fractions: 7  
Brachytherapy should not begin until postoperative Day 5 to allow for wound healing.  
 
In the rare circumstance that brachytherapy is used instead of external beam radiation for an unresectable 
tumor, the following recommendations apply: 
 
LDR brachytherapy 
Total dose: 5000 cGy  
Dose rate range: 40-100cGy/hour.  
 
 
17.9 
Organs at Risk 
The organs at risk guidelines in this section are recommendations. If the recommended doses to the organs 
at risk are exceeded because of target volume coverage requirements or other conditions, an explanation 
should be included in the quality assurance documentation. Normal tissue dose recommendations are the 
same for photons and protons (proton dose measured in CGE). 
 
 
 
Table 17.9: Organs at risk dose recommendations 
 
Organ 
Volume (%) 
Dose (cGy) 
Single organs 
 
 
Bladder 
100% 
4500  
Esophagus 
50% 
4000 
Heart  
100% 
3000 
Liver  
100% 
2340 
 
50% 
3000 
Rectum  
100% 
4500 
Optic chiasm 
100% 
5400 
Small Bowel 
75% 
4500 
Spinal Cord 
Any volume 
5040 
Paired organs  
 
 
Kidney (bilateral) 
50% 
2400 
Kidney (bilateral) 
100% 
1440 
Lung (bilateral)^ 
20% 
2000 
Lung (bilateral) ‡ 
35% 
2000 
Lung (bilateral)  
100% 
1500 
Optic nerve 
100% 
5400 
Eye 
100% 
4500 
Lens 
100% 
600 
Cochlea 
100% 
4000 
Paired organs - % refers to one of the paired organs unless specified as bilateral (kidney, lung) in 
which both of the paired organs are included in the %. 
 
^ V20 of 20% applies to patients not requiring hemithorax RT 
 
‡ V20 of 35% applies to patients who require hemithorax RT and boost treatment of the chestwall 
or pleura 
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17.10 Dose Calculations and Reporting 
 
17.10.1 Prescribed Dose 
The prescribed dose for each target volume and/or phase of treatment shall be calculated and 
submitted using the RT-1/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.  
 
17.10.2 Normal Tissue Dosimetry 
The total dose to the critical organs indicated should be calculated whenever they are directly included in a 
radiation field. The dose shall be reported on the RT-2 Radiotherapy Total Dose Record form and the 
appropriate dose-volume histograms shall be submitted. If IMRT is used for the primary tumor, a DVH 
must be submitted for a category of tissue called “unspecified tissue,” which is defined as tissue contained 
within the skin, but which is not otherwise identified by containment within any other structure. 
 
Table 17.10.2: Required normal tissue DVH data according to primary treatment site(s)  
 
Treatment Area 
Required DVH 
Head 
Brain  
 
Chiasm 
 
Cochlea  
 
Eyes (contour each separately) 
 
Lenses  
 
Optic nerves (contour each separately) 
Neck 
Esophagus 
 
Thyroid  
Chest 
Esophagus  
 
Heart  
 
Left Lung  
 
Right Lung  
Abdomen/Pelvis 
Bladder  
 
Left Kidney  
 
Liver 
 
Rectum  
 
Right Kidney  
 
Small Bowel (contour peritoneal cavity) 
 
Stomach 
All axial tumors 
Spinal Cord 
 
17.11 Quality Assurance Documentation 
Key Points 
• 
Data for the primary site only must be submitted for quality assurance review within 3 days of the 
start of treatment (see checklist). 
 
Institutions are required to submit the treatment plan in digital format. An institution’s treatment 
planning system must have the capability of exporting data in 1 of 2 formats: 
• 
RTOG 
Data 
Exchange 
Format, 
Version 
3.20 
or 
later 
(specifications 
at 
http://itc.wustl.edu/exchange_files/tapeexch400.htm); or 
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• 
DICOM 3.0 in compliance with the Advanced Technology Consortium's (ATC) DICOM 3.0 
Conformance Statement. A list of commercial systems that are known to have this capability are 
listed on the ATC Website (http://atc.wustl.edu/credentialing/atc_compliant_tps.html). 
• 
The data may be submitted on a CD or sent electronically via ftp to QARC. Instructions for digital 
submissions may be found on the QARC Website - www.qarc.org, under Digital Data, RT 
Treatment Planning. 
 
Please submit the following for the Primary Site Target Volume: 
External Beam Treatment Planning System  
• 
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. 
• 
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. A DVH shall be submitted for the organs at risk specified in 
Section 17.9. 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. 
 
 
Digital Data 
• 
Submission of the treatment plan for the primary site in digital format is required. Please 
refer to www.QARC.org and click on "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. If there are any problems with digital data submission, 
please contact QARC. 
 
Supportive Data 
• 
All diagnostic imaging used to plan the target volume. This includes CT or MRI PRIOR to 
attempted surgical resection of the primary tumor. Digital format is preferred. 
• 
Documentation of an independent check of the calculated dose when IMRT is used. 
• 
For protons, a description of the rationale for the PTV margins.  
• 
If the recommended doses to the organs at risk are exceeded, an explanation should be 
included for review by the QARC and the radiation oncology reviewers. 
• 
If modifications are made for patients with age < 24 months, documentation should be 
provided. 
 
Forms 
• 
RT-1/IMRT Dosimetry Summary Form. 
• 
Proton Reporting Form (if applicable). 
• 
Motion Management Reporting Form (if applicable, see Section 17.8.6). 
 
Please submit the following additional primary site information for brachytherapy: 
• 
Treatment planning CT used for post-implant dosimetry 
• 
Computer printouts of the isodose distribution and associated CT-based calculations. 
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• 
Dose volume histograms for each GTV, CTV, and PTV. 
• 
A completed Brachytherapy Physics Reporting Form. 
• 
A copy of the written directive. 
 
Please submit the following information for intra-operative radiation therapy: 
o Radiotherapy record (treatment chart) including prescription and daily and cumulative 
doses to all required areas and organs at risk 
o Physician’s note describing the procedure, dose calculation and description of the 
applicator along with any relevant dosimetric characteristics (i.e., percent depth dose 
for the prescribed energy) 
 
Within 1 week of the completion of radiotherapy submit the following items: 
• 
Radiotherapy record (treatment chart) including prescription and daily and cumulative doses 
to all required areas and organs at risk. 
• 
RT-2 Radiotherapy Total Dose Record Form. 
• 
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). 
• 
Completed AEWS1031 Local Control Checklist 
 
These data should be forwarded to: 
Quality Assurance Review Center 
Building A, Suite 201 
640 George Washington Highway 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753 7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
Building A, Suite 201 
Quality Assurance Review Center 
640 George Washington Highway 
Lincoln, Rhode Island 02865-4207 
 
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17.12 Definition of Minor and Major Deviations  
 
Definitions of deviation in protocol performance will be applied to the treatment of the primary lesion only. 
 
 
 
 
 
 
DEVIATION 
 
Minor 
Major 
Prescription Dose 
 
 External beam 
Prescription dose is >5% but < 10% greater or less 
than protocol-specified dose 
Prescription dose is > 10% greater or 
less than protocol-specified dose 
Brachytherapy 
Prescription dose is > 5% but < 10%greater or less 
than protocol-specified dose 
Prescription dose is > 10% greater or 
less than protocol-specified dose 
Dose Uniformity 
     External beam 
> 10% PTV receives > 110% of prescription dose 
or 
95% isodose covers < 90% of the PTV or < 100% 
but > 90% of the CTV 
95% isodose covers < 90% of CTV. 
     Brachytherapy 
95% isodose covers <100% of CTV 
90% isodose covers < 100% of CTV. 
Volume 
CTV or PTV margins are smaller than specified in 
the protocol. 
The contoured GTV does not include 
imaging-visible residual tumor 
Organs at Risk 
Will be assessed at time of data review. 
Will be assessed at time of data review. 
  
 
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APPENDIX I: GUIDELINES FOR OPTIONAL FDG-PET IMAGING 65 
 
1 
Pregnancy 
All female patients ≥ 10 years of age should be asked about their pregnancy potential prior to FDG 
injection. Patients who are sexually active and unsure of their pregnancy status should undergo a urine 
pregnancy test prior to FDG injection. Pregnant guardians should not be allowed in the FDG uptake room. 
The estimated maximum absorbed radiation dose for each patient based on weight is given in the table 
below. The lifetime risk of second malignancy from radiation exposure is estimated to be 8 X 10-4/Rem.  
 
Radiation dose estimates for 18F-FDG by intravenous injection 
 
Newborn 
1-year old 
5-year old 
10-year old 
15-year old 
Adult 
Estimated weight (kg) 
3.2 
10.2 
18.5 
32.4 
55.5 
70 
Administered activity 
(mCi), based on 
recommended dose of 
140 to 150 µCi/kg 
(minimum dose 1.0 mCi 
and maximum dose 
12 mCi) 
1.0 
1.4 
2.6 
4.5 
7.8 
9.8 
Effective 
Dose 
(ED) 
(rem) 
0.86 
0.49 
0.56 
0.63 
0.86 
0.88 
 
2 
Technique 
Patients will be fasted for at least 4 hours before imaging. Total parenteral nutrition and intravenous fluids 
containing glucose should also be discontinued for at least 4 hours before the study. The patient should be 
well hydrated (oral or intravenous fluid administration) before administration of FDG. Fluids administered 
for hydration should not contain glucose. 
 
If intravenous access is not already in place, this should be obtained, typically in the ante-cubital fossa, for 
patient hydration (if needed), determination of serum glucose and FDG administration. 
 
It is recommended that blood glucose be measured and recorded just prior to injection of the FDG and must 
be ≤ 200 mg/dL. If the blood glucose concentration exceeds 200 mg/dL, the patient should not be injected 
and rescheduling of the study recommended. 
 
In patients with tumors in the pelvis, placement of a Foley catheter is recommended. Patients in whom a 
Foley catheter is not placed should be asked to void prior to imaging in order to minimize bladder activity 
and to reduce their radiation exposure. Patients with bladder tumors should not undergo PET imaging for 
purposes of evaluating the primary tumor. PET-CT, however, may be useful in these patients if the tumor 
can be accurately localized on the co-registered CT images. The nuclear medicine physician should be 
consulted prior to planned imaging of bladder tumors to advise on modifying standard protocols. 
 
3 
FDG Dosing and Injection 
0.15 mCi/kg (minimum: 2 mCi, maximum: 12 mCi) FDG will be administered intravenously followed by 
administration of 5-10 mL saline solution with the patient resting comfortably. The dose of FDG within the 
syringe used for injection must be measured immediately before administration. The injected dose must be 
+/- 10% of the prescribed dose for the patient. Should the dose not meet this requirement a decision will be 
made, by the physician who will interpret the PET scan, as to whether or not to proceed with the injection 
and imaging study. The postinjection syringe dose must be determined after the radioisotope is injected in 
order to calculate the actual injected dose as follows:  
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Injected dose = Pre-injection syringe dose - Post-injection syringe dose 
 
The time of FDG injection must be recorded by the nuclear medicine technologist so that accurate standard 
uptake values (SUVmax) can be determined (described in detail below). The clock in the FDG uptake room 
must be synchronized with the clock in the PET scanner in order to accurately determine the time after 
injection that the imaging is performed for purposes of SUV determination. The patient should remain 
supine, resting comfortably, until the time of imaging.  
 
4 
PET Scanning Protocol 
A whole-body PET scan covering the area from the vertex of the skull to the toes should be performed. The 
patient will be positioned supine, with arms either comfortably positioned above the head or at the side of 
the patient.  
 
Patients can be imaged head-first or feet-first. However, individual patients must be imaged in the same 
manner each time (eg, if feet-first for the first scan, feet-first for all subsequent scans). 
 
Transmission scanning matching the areas covered by the emission scan will need to be performed for 
attenuation correction of the emission scan. This will be done after injection of FDG. With a combined 
PET/CT scanner, attenuation correction should be done with CT data per manufacturer recommendations. 
 
Emission scans are to be initiated 60 ± 10 minutes after injection of FDG. The time that the emission scan 
is started must be recorded for accurate SUVmax calculation. In addition, the timing at which the scanning 
is initiated must be consistent for all scans of the same patient (eg, if the first scan is performed at 50 minutes 
after injection, all subsequent scans are to be performed on the same or similar machine and at 50 minutes 
post tracer administration). 
 
Emission data must be collected for at least 5 minutes per bed position for BGO, LSO, and GSO systems 
operated in the 2-D mode; at least 3 minutes per bed position for BGO, LSO, and GSO systems operated 
in the 3-D mode. Images will be corrected for scatter, random events, and dead-time losses using 
manufacturer's software. Bed positions should be overlapped to avoid large changes in sensitivity at the 
joints between the bed positions. 
 
5 
After Completion of the PET Scan 
The patient must empty his or her urinary bladder as soon as possible after imaging. Image reconstruction 
will depend on the scanner manufacturer. We recommend an iterative reconstruction method with 
parameters chosen to yield 6-8 mm resolution in the reconstructed images. 
 
6 
FDG Handling and Dose Documentation 
FDG is to be synthesized by standard methods and tested for pyrogenicity and radiochemical purity on each 
production run, or purchased from nuclear pharmacies licensed to sell FDG. The radiochemical purity of 
the FDG should be > 90%. The PET scans will be submitted electronically to QARC and stored in an 
electronic database. The scans will be used for visual interpretation. 
 
 
 
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7 
PET Imaging Quality Control Standards 
FDG-PET imaging will be performed using "state-of-the-art" equipment – a PET CT. 
 
Daily and monthly steps will be taken to assure quantitative accuracy of PET imaging studies and reliable 
imaging results at all performance sites. Daily quality assurance includes a simplified chi-square test to 
assure consistent performance of the PET scanner. The calculation provides a quantitative means of 
monitoring drift of the scanner electronics with time. A blank scan is also performed daily for later 
attenuation correction. Either of these measurements may be viewed routinely as an additional measure of 
performance. A liquid-filled or standardized sealed-source cylinder phantom is used monthly to validate 
the quantitative accuracy of the images against a dose calibrator. The dose calibrator is itself calibrated 
daily against standards for constancy and annually for accuracy using NIST-traceable standards. Each 
month, fine gain calibration of all detectors in the PET system will be performed, followed by recalculation 
of the sensitivity normalization factors for the scanner. 
 
Transmission scans will be obtained with CT data from a combined PET/CT scanner, in accordance with 
manufacturer’s recommendations). An algorithm to correct for activity in the field of view should be used 
for processing of these postinjection transmission images, if provided by the vendor. Then the 
corresponding emission images, each at least 5 minutes per bed position for BGO, LSO and GSO systems 
operated in the 2-D mode; at least 3 minutes per bed position for BGO, LSO, and GSO systems operated 
in the 3-D mode. Alternatively, the individual emission and transmission scans may be acquired in 
alternating fashion. The PET images will be reconstructed by standard vendor-provided reconstruction 
algorithms, using either filtered back projection with a Hanning filter (frequency cutoff 0.6 x Nyquist [Nq] 
= 0.3 cycle/pixel) or the manufacturer’s recommended iterative reconstruction algorithm with an 
appropriate filter. Segmentation of transmission images should be used for attenuation correction. Emission 
data will be corrected for randoms, dead-time and scatter using vendor-provided algorithms. Multiple-bed 
position studies must be corrected for radioactive decay. The emission images will be reconstructed both 
with and without attenuation correction. 
 
8 
Standard Uptake Value 
The local radiologist or internist assigned to this protocol will determine the FDG-PET standard uptake 
value (SUV) for each primary tumor. The SUV will be determined by manually drawing a region of interest 
over the area of FDG activity corresponding to the tumor in question. The SUV is a measure of the amount 
of tracer taken up in a particular tissue normalized by the dosage of tracer administered and the weight of 
the patient. The equation for calculation of the SUVmax is: 
 
SUV =                  radioactivity concentration [Bq cm-3] in the region of interest 
Injected dose Bq/weight of patient 
 
Factors that influence the magnitude of the SUV include patient size, imaging time, plasma glucose levels, 
partial volume effects, region-of-interest depth, and recovery coefficient effects. Factors that we can control 
are the region of interest size, injected dose and time to imaging. The region of interest size will vary 
depending on the size of the tumor because it will be manually drawn to include the entire area that 
demonstrates FDG activity. Therefore, in order to address differences in tumor size, we will record both 
the maximum SUV value for the entire area as well as the average intensity for all pixels within the area. 
The injected dose, as previously described, will be based on body weight as per local institutional protocol. 
The time to imaging will be kept to no longer than 2 hours after the injection of FDG. When a tumor 
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demonstrates no obvious FDG activity, the SUV measurement will not be attempted. To enable accurate 
and meaningful SUVs to be calculated, the following information must be recorded for each scan: 
 
 injection time  
 injected tracer dosage (pre-injection syringe dose minus post-injection syringe dose) 
 start-of-emission scan time 
 emission scan duration 
 patient height (to be measured on the day of scan) 
 patient weight (to be measured on the day of scan) 
 
 
 
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APPENDIX II: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY – AEWS1031 
(for children from 8 - 12 years of age) 
 
(Intensive Multi-Drug Therapy for Patients with Localized Ewing Sarcoma) 
 
1. We have been talking with you about Ewing sarcoma. Ewing sarcoma is a type of cancer that grows 
in the bones or in the soft tissues around the bones. After doing tests, we have found that you have 
this type of cancer. 
 
2. Now we want to ask you to take part in a research study because you have Ewing sarcoma. A 
research study is when doctors work together to try out new ways to treat people who are sick. In 
this study, we are trying to learn more about how to treat Ewing sarcoma. We will do this by adding 
another drug to the treatment often used for Ewing sarcoma. We do not know how well the new 
way will work in children. That is why we are doing this study.  
 
3. Children who are part of this study will be randomly assigned to receive standard chemotherapy 
(anti-cancer drugs) or standard treatment plus another drug. This is called randomization. This is a 
lot like flipping a coin. A computer decides which treatment plan you will get and not your doctor. 
You will also have surgery and/or receive radiation therapy. Radiation therapy is the use of high 
energy X-rays to kill cancer cells.  
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits”. We hope that a benefit to you of being part of this study is that you are able 
to get rid of the cancer but we don’t know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” Being in this study may involve special risks, which your doctor will discuss 
with you. Other things may happen to you that we don’t know about yet.  
 
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. Please talk this over with your parents. Together you can 
decide if you want to take part in the study or not. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
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INFORMATION SHEET REGARDING RESEARCH STUDY – AEWS1031 
(for teens from 13 - 18 years of age) 
 
 (Intensive Multi-Drug Therapy for Patients with Localized Ewing Sarcoma) 
 
1. We have been talking with you about Ewing sarcoma. Ewing sarcoma is a type of cancer that grows 
in the bones or in the soft tissues around the bones. After doing tests, we have found that you have 
this type of cancer. 
 
2. We are asking you to take part in a research study because you have Ewing sarcoma. A research 
study is when doctors work together to try out new ways to treat people who are sick. In this study, 
we are trying to learn more about how to treat Ewing sarcoma. We will do this by seeing how well 
adding another chemotherapy (anti-cancer) drug called topotecan to the standard chemotherapy 
works in children and teens with Ewing sarcoma. 
 
3. Children and teens who are part of this study will be randomly assigned to either Regimen A- 
standard treatment plan or Regimen B - standard treatment + topotecan. This is called 
randomization. This is a lot like flipping a coin. A computer will decide which treatment plan you 
will get and not your doctor. The reason for this is to make sure there are same numbers of people 
on both treatments. Studies like this are done to learn which type of treatment works best. We do 
not know if one treatment is better than another treatment plan. Your treatment will also include 
surgery and/or radiation therapy. Radiation therapy is the use of high-energy X-rays to kill cancer 
cells. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits”. We hope that a benefit to you of being part of this study is that the treatment 
you get will help make your health better. If you get topotecan, we hope it will be better at getting 
rid of the cancer, but, we don’t know this for sure. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” Chemotherapy can cause side effects. For example, some types of chemotherapy 
cause changes in the blood cells. These changes can make a person feel tired or get an infection 
easier. Side effects can be increased when chemotherapy drugs are combined. If you receive 
topotecan, there is a chance that you will have more side effects. Being in this study may involve 
other special risks, which your doctor will discuss with you. Other things might happen to you that 
we don’t know about yet. 
 
6. People who decide they don’t want to take part in the study can still get treatment for their cancer. 
This treatment would be chemotherapy (with the 5 standard drugs) and possibly surgery and/or 
radiation therapy.  
 
7. Please talk this over with your parents. You and your parents have a choice about taking part in the 
study. If you choose to be part of this study now but later decide you don’t want to be anymore, 
you can talk to your parents about withdrawing from this study. If you and your parents agree to 
withdraw from this study, you can do so and it will not affect your right to get other treatments and 
services. No one will be mad or upset with you. 
 
 
 
 
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APPENDIX III CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES 
 
 
CTSU ADDRESS AND CONTACT INFORMATION 
To submit site 
registration documents, 
contact: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
For patient enrollments, contact: 
 
CTSU Patient Registration 
Voice Mail – 1-888-462-3009 
Fax – 1-888-691-8039  
Hours: 9:00 AM – 5:30 PM Eastern 
Time, Monday – Friday (excluding 
holidays) 
 
[Registrations received after 5:00 
PM ET will be handled the next 
business day. For CTSU patient 
enrollments that must be completed 
within approximately one hour, or 
other extenuating circumstances, 
call 301-704-2376 between 9:00 am 
and 5:30 pm.] 
Submit study data 
directly to COG, unless 
otherwise specified in 
the protocol. 
 
All data submission will 
be via eRDES; access is 
available on the COG 
website. After patient 
enrollment, COG will 
provide the site with a 
username and password 
and assign two roles at 
the site, treating 
physician and CRA for 
data submission. 
 
Do not submit study data 
or forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions.    
For patient eligibility or treatment-related questions contact the Study PI of the 
Coordinating Group. 
 
 
For questions unrelated to patient eligibility, treatment, or data submission contact the 
CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
For detailed information on the regulatory and monitoring procedures for CTSU sites 
please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU 
members’ website   https://www.ctsu.org 
 
 
 
Registration/Randomization 
Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. 
Each investigator must have an NCI investigator number and must maintain an “active” investigator 
registration status through the annual submission of a complete investigator registration packet (FDA Form 
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1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, 
DCTD, NCI. These forms are available on the CTSU Web site (enter credentials at https://www.ctsu.org; 
then click on the Register tab) or by calling the PMB at 301-496-5725 Monday through Friday between 
8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before 
they can enroll patients. Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU members’ area at 
https://www.ctsu.org  
 
All forms and documents associated with this study can be downloaded from the AEWS1031 Web page on 
the CTSU members’ area of the website (https://www.ctsu.org). Patients can be registered only after pre-
treatment evaluation is complete, all eligibility criteria have been met, and the study site is listed as 
‘approved’ in the CTSU RSS.   
 
Requirements for AEWS1031 Site Registration: 
• 
All therapy units used on this protocol must have their calibrations verified by the Radiological Physics 
Center (RPC). RT using photons (either 3-D conformal [3-D CRT] or intensity modulated [IMRT]), 
electrons and protons, will be allowed in this study. Centers participating in this protocol using 3-D 
CRT are required to complete the 3-D benchmark; those using IMRT must complete the IMRT 
questionnaire and benchmark or phantom (QARC or RPC) and those using protons must complete the 
proton benchmark and questionnaire. 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. For information regarding the IMRT phantoms, please contact the RPC 
(http://rpc.mdanderson.org/rpc). 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
• 
IRB-approved consent form  
• 
CTSU RT Facilities Inventory Form 
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy component 
must participate in the Radiological Physics Center (RPC) monitoring program. For sites enrolling 
through the CTSU an RT Facilities Inventory From must be on file with CTSU. If this form has been 
previously submitted to CTSU it does not need to be resubmitted unless updates have occurred at the 
RT facility. 
 
Pre-Study Requirements For Patient Enrollment On AEWS1031 
• 
Patient must meet all inclusion criteria, and no exclusion criteria should apply 
• 
Patient and/or their parents or legal guardian has signed and dated all applicable consents and 
authorization forms 
• 
All baseline laboratory tests and pre study evaluations performed within the time period specified in 
the protocol.  
 
CTSU Procedures for Patient Enrollment 
1. 
Contact the CTSU Patient Registration Office by calling 1-888-462-3009 between 9:00 a.m. and 
5:30 p.m. Eastern Time, Mon-Fri. Leave a voicemail to alert the CTSU Patient Registrar that an 
enrollment is forthcoming. For immediate registration needs, e.g. within one hour, call the registrar 
cell phone at 1-301-704-2376. 
 
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2.  
Complete the following forms (all these below forms must be submitted with each enrollment): 
 
• 
CTSU Patient Enrollment Transmittal Form 
• 
AEWS1031 Eligibility Checklist  
• 
COG Patient Transfer Form  
• 
COG Roster Form 
 
3.  
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 9:00 a.m. 
and 5:30 p.m., Mon-Fri, Eastern Time (excluding holidays); however, please be aware that 
registrations received after 5:00 p.m. will be processed the next day. The CTSU registrar will check 
the investigator and site information to ensure that all regulatory requirements have been met. The 
registrar will also check that forms are complete and will follow-up with the site to resolve any 
discrepancies. 
4.  
Once investigator eligibility is confirmed and enrollment documents are reviewed for compliance, 
the CTSU registrar will contact the COG, to obtain a unique patient ID (to be used on all future 
forms and correspondence) and randomize the patient to one of two treatment arms. A 
Biopathology Center (BPC) number will also be assigned as part of the registration process 
The CTSU registrar will confirm registration/enrollment/random assignment by fax.  
5. 
COG will provide CTSU sites with a unique username and password to access the COG website. 
An email from COG with this information will be sent to the site within 24 hours of enrollment, 
excluding weekends. COG will include the username and password and assign two roles at the site, 
treating physician and CRA for data submission. 
The date protocol therapy is projected to start must be no later than five (5) calendar days after enrollment.  
 
Data Submission And Reconciliation 
1. 
All case report forms (CRFs) associated with this study must be downloaded from the AEWS1031 
Web page located on the CTSU members’ area of the website (https://www.ctsu.org). Sites must 
use the current form versions and adhere to the instructions and submission schedule outlined in 
the protocol.  
 
 
2. 
Submit all completed CRFs (with the exception of patient enrollment forms) directly to the COG 
via eRDES [see contacts table].  
 
3. 
The COG Statistics and Data Center (SDC) will have query notices and delinquency reports 
accessible via SADD for reconciliation (see contacts table). Please send query responses and 
delinquent data to the COG Statistics and Data Center (SDC) via SADD and do not copy the CTSU 
Data Operations. Each site should have a designated CTSU Administrator and Data Administrator 
and must keep their CTEP IAM account contact information current. This will ensure timely 
communication between the clinical site and the COG Statistics and Data Center. 
 
 
 
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Special Materials or Sub-studies 
Required Pathology Review (Section 14.0) and Imaging Studies (Section 16.0) 
• 
Collect, prepare, and submit specimens and/or imaging data as outlined in the protocol. 
• 
Do not send specimens, supporting clinical reports, or transmittals to the CTSU 
• 
For specific details, please read Sections 14.0 and 16.0. 
 
SERIOUS Adverse Event (AE) Reporting (Section 11.0) 
1. 
CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) 
regarding documentation and submission of adverse events. Local IRBs must be informed of all 
reportable serious adverse reactions.  
 
2.  
CTSU sites will assess and report adverse events according to the guidelines and timelines specified 
in the protocol. You may navigate to the CTEP Adverse Event Expedited Report System (AdEERS) 
from either the Adverse Events tab of the CTSU members’ side of the website 
(https://www.ctsu.org) or by drilling down to the Adverse Event Reporting Forms link under the 
documents folder of the AEWS1031 Web page.  
 
3. 
Do not send adverse event reports to the CTSU. 
 
Drug Procurement (Section 6.0) 
Commercial agents: Cyclophosphamide, Vincristine, Doxorubicin, Topotecan, Ifosfamide, Etoposide 
 
1. 
Information regarding the agents used in this trial can be found at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/CommercialAgentsMonograp
hs.pdf 
 
2. 
You may navigate to the drug forms by selecting Pharmacy Forms from the document center tree 
on the AEWS1031 Web page.  
  
 
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REFERENCES 
 
1. 
Grier HE, Krailo MD, Tarbell NJ, et al: Addition of ifosfamide and etoposide to standard 
chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. NEJM 348(8):694-
701, 2003 
2. 
Granowetter L, Womer R, Devidas M, et al: Dose-intensified compared with standard chemotherapy 
for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 
27(15):2536-41, 2009 
3. 
Womer RB, West DC, Krailo M, et al: Randomized comparison of every-two-week v. every-three 
week chemotherapy in Ewing sarcoma family tumors (ESFT). J Clin Oncol 26, 2008 
4. 
Saylors RL, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children with recurrent 
or refractory solid tumors: A Pediatric Oncology Group phase II study. JCO 19(15):3463-9, 2001 
5. 
Hunold A, Ahrens S, Boldering N, et al: Topotecan and Cyclophosphamide for Ewing tumour relapse. 
SIOP abstracts O.025:333, 2004 
6. 
Thompson J, George EO, Poquette CA, et al: Synergy of topotecan in combination with vincristine 
for treatment of pediatric solid tumor xenografts. Clin Cancer Res 5(11):3617-31, 1999 
7. 
Walterhouse DO, Lyden ER, Breitfeld PP, et al: Efficacy of topotecan and cyclophosphamide in a 
phase 2 window trial in children with newly diagnosed metastatic rhabdomyosarcoma: A Children's 
Onncology Group Study. J Clin Oncol 22:1398-1403, 2004 
8. 
Gidding CE, Kellie SJ, Kamps WA, et al: Vincristine Revisited Crit Rev Onc Hemat :. 29(3):267-87, 
1999 
9. 
Houghton JA, Meyer WH, Houghton PJ: Scheduling of vincristine: drug   accumulation and response 
of xenografts of childhood rhabdomyosarcoma determined by frequency of administration. Cancer 
Treatment Reports 71(7-8):717-2, 1987 
10. Kricher JP, Epstein S, Cuthbertson DD: Clinical cardiotoxicity following anthracycline treatment of 
childhood cancer:. The Pediatric Oncology Group Experience JCO 15:1544-52, 1997 
11. Lipshultz SE, Rifai N, Dalton VM, et al: The effect of dexrazoxane on myocardial injury in 
doxorubicin treated children with acute lymphoblastic leukemia. NEJM 35(2):145-53, 2004 
12. Wexler LH, Andrich MP, Venzon D, et al: Randomized trial of the cardioprotective agent ICRF-187 
in pediatric sarcoma patients treated with doxorubicin. JCO 14(2):362-72, 1996 
13. Mulrooney DA, Yeazel MW, Kawashima T, et al: Cardiac outcomes in a cohort of adult survivors of 
childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study 
cohort. BMJ 339:b4606, 2009 
14. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-
containing therapy in advanced breast cancer. JCO 15:1318-1332, 1997 
15. Anderson B: Dexrazoxane for the prevention of cardiomyopathy in anthracycline treated pediatric 
cancer patients. Pediatr Blood Cancer 44, 2005 
16. Swain SM, Whaley FS, Gerber MC, et al: Delayed administration of dexrazoxane provides protection 
for patients with advance breast cancer treated with doxorubicin-containing therapy. JCO 15(4):1333-
40, 1997 
17. Schuchter LM, Hensley ML: Meropol, Winer EP for the American Society of Clinical Oncology 
Chemotherapy and Radiation Expert Panel. 2002 Update of recommendations for the use of 
chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of 
Clinical Oncology. JCO 20(12):2895-2903, 2002 
18. Berrak SG, Ewer MS, Jaffe N, et al: Doxorubicin cardiotoxicity in children: reduced incidence of 
cardiac dysfunction associated with continuous infusion schedule. Onc. Rep 8(3):611-4, 2001 
19. Hortobagyi GN, Frye D, Buzdar AU, et al: Decreased cardiac toxicity of doxorubicin administered by 
continuous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer Treatment 
Reports 63(1):37-45, 1989 
Version date: 03/04/16 
 
Page 115 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AEWS1031 
20. Lipshultz SE, Giantris AL, Lipsitz SR, et al: Doxorubicin administration by continuous infusion is not 
cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. JCO 20(6):1677-
82, 2002 
21. Levitt GA, Dorup I, Sorensen K, et al: Does anthracycline administration by infusion in children affect 
late cardiotoxicity. Br.J. Haem 124(4):463-8, 2004 
22. Gupta M, Steinherz PG, Cheung NK, et al: Late cardiotoxicity after bolus versus infusion 
anthracycline therapy for childhood cancers. MPO 40(6):343-7, 2003 
23. Stöger H, Samonigg H, Krainer M, et al: Dose intensification of epidoxorubicin and 
cyclophosphamide in metastatic breast cancer: a randomised study with two schedules of granulocyte-
macrophage colony stimulating factor. Eur J Cancer 34(4):482-8, 1998 
24. Hudis C, Fornier M, Riccio L, et al: 5-year results of dose-intensive sequential adjuvant chemotherapy 
for women with high-risk node-positive breast cancer: A phase II study. J Clin Oncol 17(4):1118, 
1999 
25. Lorigan P, Woll PJ, O'Brien ME, et al: Randomized phase III trial of dose-dense chemotherapy 
supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl 
Cancer Inst. 97(9):666-74, 2005 
26. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally 
scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant 
treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and 
Leukemia Group B Trial 9741. J Clin Oncol. 21(8):1431-9, 2003 
27. Del Mastro L, Venturini M, Lionetto R, et al: Accelerated-intensified cyclophosphamide, epirubicin, 
and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a 
multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella 
Inter Gruppo Group. J Clin Oncol 19(8):2213-21, 2001 
28. Sculier JP, Paesmans M, Lecomte J, et al: A three-arm phase III randomised trial assessing, in patients 
with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of 
haematological growth factor or oral antibiotics. Br J Cancer 85(10):1444-51, 2001 
29. Mascarenhas L, Krailo M personal communication.  
30. Paulussen M, Ahrens S, Dunst J, et al: Localized Ewing tumor of bone: Final results of the Cooperative 
Ewing’s Sarcoma Study CESS 86. JCO 19:1818-29, 2001 
31. Personal Communication Dr. Mark Krailo.  
32. Yock TI, Krailo M, Fryer CJ, et al: Local control in pelvic Ewing sarcoma: analysis from INT-0091-
-a report from the Children's Oncology Group. J Clin Oncol 24:3838-43, 2006 
33. Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al: Efficacy of combined surgery and irradiation 
for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer 43(3):229-36, 2004 
34. Arai Y, Kun LE, Brooks MT, et al: Ewing's sarcoma: local tumor control and patterns of failure 
following limited-volume radiation therapy. Int J Radiat Oncol Biol Phys 21:1501-8, 1991 
35. Rube CE, van Valen F, Wilfert F, et al: Ewing's sarcoma and peripheral primitive neuroectodermal 
tumor cells produce large quantities of bioactive tumor necrosis factor-alpha (TNF-alpha) after 
radiation exposure. Int J Radiat Oncol Biol Phys 56:1414-25, 2003 
36. Dunst J, Schuck A: Role of Radiotherapy in Ewing tumors. Pediatr Blood Cancer 42:465-70, 2004 
37. O'Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-
tissue sarcoma of the limbs: a randomised trial. Lancet 359:2235-41, 2002 
38. Sawamura S, Hornicek FJ: Gebhardt Complications and Risk Factors for Failure of Rotationplasty: 
Review of 25 patients Clin Orthop Relat Res. 2008 
39. Indelicao DJ, Keole SR, Shahlaee AH, et al: Long-term clinical and functional outcomes after 
treatment for localized Ewing’s tumor of the lower extremity . Int. J. Radiation Oncology Biol. Phys 
70(2):501-9, 2008 
40. Myers GJ, Abudu AT, Carter SR, et al: Endoprosthetic replacement of the distal femur for bone 
tumors: long-term results. J Bone Joint Surg Br 89(5):706, 2007 
Version date: 03/04/16 
 
Page 116 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AEWS1031 
41. Gyorke T, Zajic T, Lange A, et al: Impact of FDG PET for staging of Ewing sarcomas and primitive 
neuroectodermal tumours. Nucl Med Commun 27:17-24, 2006 
42. Kneisl JS, Patt JC, Johnson JC, et al: Is PET useful in detecting occult nonpulmonary metastases in 
pediatric bone sarcomas? Clin Orthop Relat Res 450:101-4, 2006 
43. Brisse H, Ollivier L, Edeline V, et al: Imaging of malignant tumors of long bones in children 
monitoring response to neoadjuvant chemotherapy and preoperative assessment. Pediat. Radiology 
34(8):595-605, 2004 
44. Schuetze SM, Rubin BP, Vernon C, et al: Use of positron emission tomography in localized extremity 
soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer Treatment Reports 103(2):339-
48, 2005 
45. Barker LM, Pendergrass TW, Sanders JE, et al: Survival after recurrence of Ewing's sarcoma family 
of tumors. J Clin Oncol 23:4354-62, 2005 
46. Borinstein SC, Pollard J WL, DS H: Pegfilgrastim for prevention of chemotherapy-associated 
neutropenia in pediatric patients with solid tumors. Pediatr Blood Cancer 53:375-8, 2009 
47. Burstein HJ, Parker LM, Keshaviah A, et al: Burstein HJ, Parker LM, Keshaviah A, et al: Efficacy of 
pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant 
breast cancer chemotherapy. J Clin Oncol 23:8340-7, 2005 
48. Dang C, D'Andrea G, Lake D, et al: Prolonged dose-dense epirubicin and cyclophosphamide followed 
by paclitaxel in breast cancer is feasible. Clin Breast Cancer 8:418-24, 2008 
49. Fox E, Widemann BC, Hawkins DS, et al: Randomized trial and pharmacokinetic study of 
pegfilgrastim versus filgrastim after dose-intensive chemotherapy in young adults and children with 
sarcomas. Clin Cancer Res 15:7361-7, 2009 
50. Hecht JR, Pillai M, Gollard R, et al: A randomized, placebo-controlled phase ii study evaluating the 
reduction of neutropenia and febrile neutropenia in patients with colorectal cancer receiving 
pegfilgrastim with every-2-week chemotherapy. Clin Colorectal Cancer 9:95-101, 2010 
51. Spunt SL, Irving H, Frost J, et al: Phase II, randomized, open-label study of pegfilgrastim-supported 
VDC/IE chemotherapy in pediatric sarcoma patients. J Clin Oncol 28:1329-36, 2010 
52. Miller AA, Wang XF, Gu L, et al: Phase II randomized study of dose-dense docetaxel and cisplatin 
every 2 weeks with pegfilgrastim and darbepoetin alfa with and without the chemoprotector BNP7787 
in patients with advanced non-small cell lung cancer (CALGB 30303). J Thorac Oncol 3:1159-65, 
2008 
53. Barthel F MS, Babiker A, Royston P, et al: Evaluation of sample size and power for multi-arm survival 
trials allowing for non-uniform accrual, non-proportional hazards, loss to follow-up and cross over. 
Stat Med 25:2521-2542, 2006 
54. Fine JP, Gray RJ: A proportional hazards for the subdistribution of a competing risk. J Amer Statistic 
Assoc 94:496-509, 1999 
55. Eggli KD, Close P, Dillon PW, et al: Three-dimensional quantitation of pediatric tumor bulk. Pediatr 
Radiol 25:1-6, 1995 
56. Sohaib SA, Turner B, Hanson JA, et al: CT assessment of tumour response to treatment: comparison 
of linear, cross-sectional and volumetric measures of tumour size. Br.J.Radiol 73:1178-1184, 2000 
57. Prasad SR, Jhaveri KS, Saini S, et al: CT tumor measurement for therapeutic response assessment: 
comparison of unidimensional, bidimensional, and volumetric techniques initial observations. 
Radiology 225:416-419, 2002 
58. Srinivasa RP, Kartik SJ, Sanjay S, et al: CT tumor measurementfor therapeutic response assessment: 
Comparison of unidirectional, bidirectional and volumetric techniques-initial observations. Radiology 
225:416-419, 2002 
59. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response 
criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17(4):1244-1253, 1999 
60. Bowden L, Booher RJ: The principles and techniques of resection of soft parts for sarcoma. Surgery 
44:963, 1958 
Version date: 03/04/16 
 
Page 117 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AEWS1031 
61. Simon MA, Enneking WF: The management of soft tissue tumors of the extremities. J Bone Joint Surg 
58A:317, 1976 
62. Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal 
sarcoma. Clin Orthop 153:106, 1980 
63. Enneking WF, Spanier SS, Malawer MA: The effect of the anatomic setting on the results of surgical 
procedures for soft parts sarcoma of the thigh. Cancer 1005:47-50, 1981 
64. Picci P RB, Bacci G, Neff JR, Sangiorgi L, Cazzola A, Baldini N, Ferrari S, Mercuri M, Ruggieri P, 
Caldora P, Benassi MS, Fabbri N, Monti C, Campanacci M: Prognostic significance of histopathologic 
response to chemotherapy in nonmetastatic Ewing’s sarcoma of the extremities. Journal of Clinical 
Oncology 11:1763-1769, 1993 
65. Shankar LK, Hoffman JM, Bacharach S, et al: Consensus recommendations for the use of 18F-FDG 
PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med 
47:1059-66, 2006 
 
Version date: 03/04/16 
 
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