Conditions: Localized Osteosarcoma Metastatic Osteosarcoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1334
Healthy volunteers: no

Brief summary:
This randomized phase III trial is studying combination chemotherapy followed by surgery and two different combination chemotherapy regimens with or without PEG-interferon alfa-2b to compare how well they work in treating patients with osteosarcoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Biological therapies, such as PEG-interferon alfa-2b, may interfere with the growth of tumor cells. Giving combination chemotherapy before surgery may shrink the tumor so it can be removed. Giving combination chemotherapy together with PEG-interferon alfa-2b after surgery may kill any remaining tumor cells. It is not yet known whether giving combination therapy together with PEG-interferon alfa-2b is more effective than two different combination chemotherapy regimens alone after surgery in treating osteosarcoma.

Detailed description:
PRIMARY OBJECTIVES:

I. Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor histological response (HR) to neoadjuvant induction therapy comprising MAP.

II. Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP.

SECONDARY OBJECTIVES:

I. Compare overall survival of patients treated with these regimens. II. Compare short- and long-term toxicity of these regimens in these patients. III. Compare quality of life of patients treated with these regimens. IV. Compare event-free survival and overall survival of patients with localized osteosarcoma treated with these regimens.

V. Correlate biological or clinical changes with histological response and outcomes in patients treated with these regimens.

VI. Determine outcomes of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study.

INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients also receive high-dose methotrexate (MTX)\* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10. Patients then proceed to surgery.

NOTE: \*Patients must receive \>= 2 but =\< 6 doses of high-dose MTX.

SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is evaluated for histological response to induction therapy. Patients whose tumor is not amenable to macroscopically complete surgical resection undergo radiotherapy and/or other investigational therapy off study. Patients who undergo macroscopically complete surgical resection of the primary tumor or metastases AND who have no disease progression or unacceptable toxicity proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological response (good \[\< 10% viable tumor\] vs poor \[≥ 10% viable tumor\]). Patients in each group are stratified according to site of primary tumor and presence of metastases.

GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within 35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29.

ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104.

GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms within 35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.

ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32.

In both groups, treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 1½-3 months for 2 years, every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Arms:
arm 1: Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29. arm 2: Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104. arm 3: Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I. arm 4: Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32.

Interventions: intervention 1: Cisplatin intervention 2: Doxorubicin Hydrochloride intervention 3: Etoposide intervention 4: Ifosfamide intervention 5: Methotrexate intervention 6: Peginterferon Alfa-2b intervention 7: Quality-of-Life Assessment intervention 8: Questionnaire Administration intervention 9: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given subcutaneously intervention 7: Ancillary studies intervention 8: Ancillary studies intervention 9: Undergo amputation or limb salvage surgery

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
AOST0331 
 
 
Page 1 
Activated: 
November 14, 2005 
Version Date: 09/06/11 
Closed: 
06/30/2011 
Amendment #6 
 
  
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
APPENDIX FOR 
 
 
AOST0331 
A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize 
Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to 
Pre-Operative Chemotherapy (
 
 
A Phase III Intergroup Study 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC 
INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR 
CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN‟S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND 
SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED 
MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN THIS PROTOCOL 
ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT 
PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO 
CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR 
HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistics and Data Center Contact:  https://members.childrensoncologygroup.org 


 
 
AOST0331 
 
 
Page 2 
TABLE OF CONTENTS 
SECTION 
PAGE 
COG STUDY COMMITTEE 
5 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
10 
2.0 
BACKGROUND 
10 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
10 
3.1 
Study Enrollment 
10 
3.2 
Patient Criteria 
12 
4.0 
TREATMENT PLAN 
14 
4.1 
General Treatment Information 
16 
4.2 
Administration schedule for MAP Cycles 1-2, All Patients 
17 
4.3 
Administration Schedule for Good Responders and Poor Responders Randomized to 
MAP Therapy (Cycles 3-4) 
20 
4.4 
Administration Schedule for Good Responders and Poor Responders Randomized to 
MAP Therapy (Cycles 5 – 6) 
22 
4.5 
Administration Schedule for Good Responders Randomized to MAPifn Therapy  
(Cycles 3-4) 
24 
4.6 
Administration Schedule for Good Responders Randomized to MAPifn 
 
Therapy (Cycles 5-6) 
26 
4.7 
Administration Schedule for Pegylated Interferon alfa-2b Therapy for Good Responders 
Randomized to MAPifn, (Weeks 30-104) 
28 
4.8 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy 
 
(Cycles 3 and 7) 
31 
4.9 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy 
 
(Cycles 4, 6 and 8) 
33 
4.10 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy  
(Cycle 5) 
35 
4.11 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy  
(Cycle 9) 
37 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
39 
5.1 
Dose Modifications for Doxorubicin/Cisplatin 
39 
5.2 
Dose Modifications for Methotrexate 
40 
5.3 
Dose Modifications for Ifosfamide/Etoposide 
41 
5.4 
Dose Modifications for Doxorubicin/Ifosfamide 
43 
5.5 
Dose Modifications for Pegylated interferon alfa-2b 
45 
6.0 
DRUG INFORMATION 
47 
6.1 
DOXORUBICIN (Adriamycin®) NSC #123127  
47 
6.2 
CISPLATIN (Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC 
#119875 
48 
6.3 
METHOTREXATE (MTX, amethopterin, Trexall®) NSC #000740  
50 
6.4 
IFOSFAMIDE 
51 
6.5 
ETOPOSIDE 
53 
6.6 
PEGINTERFERON ALFA-2B (Pegylated interferon alfa-2b, PEG-Intron®) NSC # 
720033 
55 


 
 
AOST0331 
 
 
Page 3 
6.7 
MESNA   (sodium 2-mercaptoethane sulfonate,UCB 3983, Mesnex ) NSC #113891    57 
6.8 
LEUCOVORIN CALCIUM (LCV, Wellcovorin®, citrovorum factor, folinic acid) 
58 
6.9 
DEXRAZOXANE (ICRF-187, ADR-529, ZINECARD ) NSC #169780  
59 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
60 
7.1 
Required and Suggested Observations 
61 
7. 2 
Disease-related follow-up after completion of chemotherapy 
62 
8.0 
SUPPORTIVE CARE GUIDELINES 
62 
8.1 
Venous Access 
62 
8.2 
Antiemetics 
62 
8.3 
Neutropenia 
62 
8.4 
Anemia and thrombocytopenia 
63 
8.5 
Pneumocystis carinii 
63 
8.6 
Magnesium supplementation 
63 
8.7 
Neurotoxicity associated with ifosfamide 
63 
8.8 
Hydration Routines 
63 
8.9 
Bisphosphonates 
64 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
64 
9.1 
Criteria for Removal from Protocol Therapy 
64 
9.2 
Off Study Criteria 
64 
10.0 
STATISTICAL CONSIDERATIONS 
65 
10.1 
Endpoints 
65 
10.2 
Sample Size 
65 
10.3 
Sample size for patients with localized disease 
65 
10.4 
Intended Analysis 
66 
10.5 
Interim Analyses 
66 
10.6 
Gender and Minority Accrual Estimates 
67 
11.0 
EVALUATION CRITERIA 
67 
11.1 
Common Terminology Criteria for AdEERS v4.0 (CTCAE) 
67 
11.2 
Response Criteria for Patients with Solid Tumors 
68 
11.3 
Best Response 
68 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
69 
12.1 
Purpose 
69 
12.2 
Determination of reporting requirements 
69 
12.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
69 
12.4 
Reporting methods 
70 
12.5 
When to report an event in an expedited manner 
71 
12.6 
Other recipients of adverse event reports 
71 
12.7 
Reporting of Adverse Events for investigational agents 
71 
12.8 
Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 72 
12.9 
Routine Adverse Event Reporting 
73 
13.0 
RECORDS AND REPORTING 
73 
13.1 
Categories of Research Records 
73 
13.2 
CDUS 
73 
14.0 
SURGICAL GUIDELINES 
74 
14.1 
Biopsy 
74 
14.2 
Definitive Surgery 
74 


 
 
AOST0331 
 
 
Page 4 
14.3 
Treatment of Relapsed Disease 
76 
15.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
76 
15.1 
Biopsy 
76 
15.2 
Resection/amputation 
77 
15.3 
Procedure for Quantitation 
78 
16.0 
SPECIAL STUDIES 
78 
16.1 
Quality of Life 
78 
16.2 
QL Instruments 
79 
16.3 
Timing of QL Assessments 
79 
17.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
79 
17.1 
Osteosarcoma Imaging Recommendations 
80 
18.0 
RADIATION THERAPY GUIDELINES 
81 
18.1 
Radiation Therapy Guidelines 
81 
19.0 
RECOMMENDED GUIDELINES FOR TREATMENT ADMINISTRATION 
87 
19.1 
Doxorubicin/Cisplatin  
87 
19.2 
Doxorubicin/Ifosfamide 
87 
19.3 
High Dose Methotrexate 
87 
19.4 
Ifosfamide/Etoposide 
89 
APPENDIX I:  TABLE OF CLINICALLY RELEVANT DRUG SUBSTRATES FOR CYP 2C9 
AND CYP2D6 
90 
APPENDIX II 
YOUTH INFORMATION SHEETS 
91 
SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
96 
SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
112 
SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
125 
 
 


 
 
AOST0331 
 
 
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AOST0331 
 
 
Page 6 
 
 
 
 
 
 
   
 
 
 
   
 
   
 
 
 
 
     
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
AOST0331 
 
 
Page 7 
 
For Group Operations (GOC) and  
 
Statistics and  Data Center (SDC) contacts see: 
 
http://members.childrensoncologygroup.org 
 
Telephone: 
(626) 447-0064 
 
 
 
AGENT NSC# 
 
 
Doxorubicin #123127 
 
Cisplatin # 119875 
 
Methotrexate #000740 
 
Ifosfamide #109724 
 
Etoposide #141540 
 
Pegylated interferon alfa-2b # 720033 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 15.0 FOR SPECIMEN SHIPPING ADDRESSES 
 
 
 


 
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AOST0331 
 
 
Page 8 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate protects 
against the involuntary release of information about subjects collected during the course of our covered 
studies. The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings. However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances.  For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm 
to self or others 
 
 
ABSTRACT 
EURAMOS 1 is a joint protocol of four of the world‟s leading multi-institutional osteosarcoma groups 
(COG, COSS, EORTC/MRC, SSG). The collaboration‟s main aim is to optimize the treatment of patients 
suffering from osteosarcoma. The EURAMOS 1 trial is open for all patients with resectable high-grade 
osteosarcoma of the limbs or axial skeleton, whether the tumor is localized or primarily metastatic, who 
are considered suitable for neo-adjuvant chemotherapy. The trial takes into account the strong prognostic 
value of tumor response to preoperative chemotherapy and divides patients accordingly. All patients 
registered will receive a standard three-drug induction regimen consisting of 2 cycles of cisplatin and 
doxorubicin along with four cycles of methotrexate (MAP). After recovery from chemotherapy, patients 
then proceed to surgical resection. Post-operative therapy is determined by the histological response of 
the tumor. Good responders (< 10% viable tumor) will be randomized to continue with MAP, or receive 
pegylated interferon alfa-2b as maintenance therapy after MAP (MAPifn). Poor responders (  10% viable 
tumor) will be randomized to continue with MAP or to receive the same regimen with the addition of 
ifosfamide and etoposide (MAPIE). Event-free survival is the primary endpoint. 
 
 
 
 
 
 
 


 
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Page 9 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 
Study Enrollment 
↓ 
Induction Therapy 
MAP 
↓ 
Surgery 
Assessment of Histologic Response 
↓ 
↓ 
Good Histologic Response – 
Randomization 
Poor Histologic Response – 
Randomization 
↓ 
↓ 
↓ 
↓ 
MAP 
MAPifn 
MAP 
MAPIE 
 
 
 
 
MAP = doxorubicin, cisplatin, methotrexate 
MAPIE = doxorubicin, cisplatin, methotrexate, ifosfamide, etoposide 
MAPifn = doxorubicin, cisplatin, methotrexate, pegylated interferon alfa-2b 
 


 
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Page 10 
 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
Primary: 
 
1.1 
In a randomized setting, to examine whether the addition of ifosfamide and etoposide (IE) to post-
operative chemotherapy with cisplatin, doxorubicin and methotrexate improves the event-free survival for 
patients with resectable osteosarcoma and a poor histological response to 10 weeks of pre-operative 
chemotherapy. 
 
1.2 
In a randomized setting, to examine whether the addition of pegylated interferon alfa-2b as maintenance 
therapy after post-operative chemotherapy with cisplatin, doxorubicin and methotrexate improves the 
event-free survival for patients with resectable osteosarcoma and a good histological response to 10 
weeks of pre-operative chemotherapy. 
 
Secondary: 
 
1.3  
To investigate whether the addition of IE to post-operative therapy for poor responders, and the addition of 
Peg-Intron as maintenance therapy for good responders, leads to an improvement in the following outcomes: 
a. 
Overall survival 
b. 
Short-term toxicity 
c. 
Long-term toxicity 
d. 
Quality of life 
 
1.4 
To investigate whether the addition of IE to post-operative therapy for poor responders, and the addition of 
Peg-Intron as maintenance therapy for good responders, leads to an improvement in event-free and overall 
survival in patients with localized osteosarcoma at entry. 
 
1.5 
To investigate whether biological or clinical correlates to histological response and outcome can be identified 
by encouraging enrollment on a COG osteosarcoma specimen collection study. 
 
1.6 
To examine the outcome of the entire cohort of patients. 
 
 
2.0 
BACKGROUND  
Please see EURAMOS 1 protocol document for complete background and references. 
 
 
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 


 
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AOST0331 
 
 
Page 11 
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 
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. 
 
3.1.4 
Timing 
Study enrollment must take place within five calendar days of beginning protocol therapy. If enrollment 
takes place before starting therapy, the date protocol therapy is projected to start must be no later than five 
(5) calendar days after enrollment.  
 
3.1.5 
Bilingual Services 
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
 
3.1.6 
Post-Surgical Randomization 
Patients will be randomized based on local institutional assessment of histologic response in primary 
tumor following definitive surgery. Institutions are also required to submit surgical specimens for central 
review within 21 days of surgical procedure. Randomization to one of the treatment arms after induction 
therapy and evaluation must be performed within 35 days from date of definitive surgery. Treatment will 
be allocated using permuted tables, stratified by group, site of primary tumor and presence of metastases. 
Patients with a good histologic response to pre-operative therapy will be randomized to either continuing 
MAP (cisplatin, doxorubicin and methotrexate) or MAP plus Pegylated interferon alfa-2b. Patients with a 
poor histologic response will be randomized to continuing MAP or MAP plus ifosfamide and etoposide. 


 
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Page 12 
 
Patients must fulfill the following criteria for post-surgical randomization to occur: 
 
3.1.6.1 
Local institutional assessment of histologic response in the primary tumor following definitive surgery. 
 
3.1.6.2 
The combination of cisplatin and doxorubicin must have been administered exactly twice before surgery. 
 
3.1.6.3 
Methotrexate must have been administered at least twice but no more than six times before surgery.  
 
3.1.6.4 
Recovery from prior therapy allowing administration of chemotherapy as detailed in the protocol. 
 
 
3.1.6.5  
No evidence of disease progression as defined in section 11.2.5 
 
3.1.6.5.1 
No definite progression of metastatic disease and no evidence of new metastatic disease. 
 
3.1.6.5.2 
If local disease progression has resulted in surgery being performed prior to the administration of 
chemotherapy as required in Sections 3.1.6.2 and 3.1.6.3, the patient is off protocol therapy and will not 
be randomized (see Section 9.1).  
 
3.1.6.6 
Macroscopically complete surgical resection of the primary tumor 
 
3.1.6.7 
In patients with metastatic disease, complete removal of all metastases or complete removal planned and 
deemed feasible. 
 
3.2 
Patient Criteria 
Important note:  The eligibility criteria listed below are interpreted literally and cannot be waived (per 
COG policy 7.2).  All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient's medical/research record which will serve as the 
source document for verification at the time of audit. 
 
3.2.1 
Age 
Patients must be ≥ 5 years and   40 years on date of diagnostic biopsy. 
 
3.2.2 
Diagnosis  
 
3.2.2.1  
Patients must have high grade osteosarcoma. This includes second malignancies. 
 
3.2.2.2  
Submission of diagnostic biopsy for rapid central review of diagnostic biopsy materials is required on this 
study. 


 
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Page 13 
 
3.2.2.3 
The site of the primary tumor must be in: 
Long bone of upper limb, scapula (C40.0) 
Short bone of upper limb (C40.1) 
Long bone of lower limb (C40.2) 
Short bone of lower limb (C40.3) 
Vertebral column (C41.2) 
Ribs, sternum, clavicle (C41.3) 
Pelvic bones, sacrum, coccyx (C41.4) 
Craniofacial osteosarcoma is NOT included. 
 
3.2.2.4 
All tumor (primary, metastatic, or both) is resectable or is expected to become resectable after the initial 
chemotherapy.  
 
 
3.2.3 
Performance Level  
Patients must have a Karnofsky score  50 or WHO/ECOG ≥ 2 for patients age ≥ 16, Lansky score  50 
for 
patients 
age 
< 
16 
(for 
Performance 
Status 
Scales 
Scoring 
see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for 
Protocols). Patients whose performance status is adversely affected by a pathologic fracture but who are 
able to undergo treatment are eligible. 
 
3.2.4 
Prior Therapy:  
No previous treatment for osteosarcoma or previous chemotherapy for any disease.  Previous radiotherapy 
for a prior cancer (other than osteosarcoma) is permitted. 
 
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.  
 
See Also Appendix A.3 of the Intergroup document (AOST0331_euramos.pdf). 
 
3.2.5.2 Adequate cardiac function defined as: 
- 
Shortening fraction of   28% by echocardiogram, or 
- 
Ejection fraction of   50% by radionuclide angiogram. 


 
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Page 14 
 
3.2.5.3 Adequate hematologic function defined as: 
- 
Neutrophils  1.5  109/L (or WBC  3  109/L if neutrophils are not available) and platelet 
count   100  109/L 
 
3.2.5.4 Adequate liver function defined as: 
- 
Total bilirubin  1.5 x upper limit of normal (ULN) for age 
 
3.2.6 
Other criteria 
 
3.2.6.1 
Female patients must have a negative pregnancy test.  
 
3.2.6.2 
Female patients who are lactating must agree to stop breast-feeding. 
 
3.2.6.3 
Patients must not be known to be HIV positive. Testing for HIV is not mandatory. 
 
3.2.6.4 
Sexually active patients of childbearing potential must agree to use effective contraception. 
 
3.2.6.5 
Patients must be able to cooperate fully with all planned protocol therapy.  
 
3.2.7 
Regulatory 
 
3.2.7.1  
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.7.2  
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
4.0 
TREATMENT PLAN  
 
 
 
 
 
 
 
 
 
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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Page 15 
TREATMENT SCHEMA 
 
A=   Doxorubicin 37.5mg/m2/day.  Days 1-2 
P=    Cisplatin 60mg/m2/day           Day 1, 2 
M=   Methotrexate 12g/m2/day 
E=    Etoposide 100mg/m2/day x 5 days 
I=     Ifosfamide 2.8gm/m2/dose x 5days 
i=     Ifosfamide 3g/m2/dose x 3days 
Ifn= Pegylated Interferon-α 2b 0.5mcg/kg -
 
1mcg/kg weekly 


 
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Page 16 
4.1 
General Treatment Information 
 
4.1.1 
Induction – MAP Therapy- All Patients 
Induction therapy lasts 10 weeks and consists of two cycles of MAP (doxorubicin-cisplatin and high dose 
methotrexate therapy). If administrative issues preclude surgical resection at Week 10, patients may 
receive up to two additional cycles of high dose methotrexate (maximum of 6 cycles of methotrexate) 
before surgical resection/amputation. In addition, if a patient develops mucositis or transaminase 
elevations precluding administration of back-to-back methotrexate cycles, the patient may receive only 2 
cycles of high dose methotrexate (instead of four) before the surgical procedure. 
 
Drug administration instructions should be followed except when they vary from institutional 
chemotherapy standards developed for purposes of promoting medication safety, and approved by 
the institutional Therapeutic Standards Committee or equivalent body. 
 
4.1.2 
Local Control 
At Week 11 surgery will be done (see Section 14.0 for complete surgical directions).  An evaluation of 
histologic response is essential (see Section 15.0 for information about this evaluation). 
 
Please note: All chemotherapy doses should be calculated using pre-surgery body surface area with 
no adjustment for limb loss. 
 
Radiation therapy is not recommended for patients on this study. However, if treating physicians must use 
radiation therapy for compelling clinical reasons, COG radiation therapy guidelines have been provided in 
Section 18. 
 
At randomization, the institutional assessment of histologic response will be used in determining 
whether the criteria for randomization have been met. Institutions are also required to submit the 
surgical specimen for central review. See Section 15.0 for further details.  
 
4.1.3 
Treatment assignment after induction 
Patients must fulfill the following criteria for randomization after surgery: 
 
Local institutional assessment of histological response in primary tumor following definitive 
surgery  
 
Exactly  two courses of cisplatin and doxorubicin must have been administered before surgery 
 
At least two courses and no more than six courses of methotrexate must have been administered 
before surgery 
 
No severe toxicity precluding post-operative treatment 
 
No progression of metastatic disease or new metastatic disease 
 
No progression of localized tumor (see Section 9.1) 
 
Macroscopically complete surgical resection of the primary tumor 
 
In patients with metastatic disease, complete removal of all metastases or complete removal 
planned and deemed feasible 
 
Essential data for eligibility, chemotherapy, surgery, and pathology provided to SDC 
 
Written consent to undergo randomization obtained 
 
4.1.3.1  
Patients with good histologic response after induction therapy will be randomized to receive either 
therapy with MAP (29 total weeks of therapy) or with MAP plus pegylated interferon alfa-2b (104 total 
weeks of therapy). Week 12 and Week 15 MAP therapy may be started before randomization assignment 
is made, if the patient meets criteria to begin treatment but the pathology on the definitive surgical 
specimen has not yet been obtained. 


 
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Page 17 
4.1.3.2 
Patients with poor histologic response after induction therapy will be randomized to receive either therapy 
with MAP (29 total weeks of therapy) or with MAP plus ifosfamide and etoposide (40 total weeks of 
therapy). Week 12 and Week 15 MAP therapy may be started before randomization assignment is made, 
if the patient meets criteria to begin treatment but the pathology on the definitive surgical specimen has 
not yet been obtained. 
 
4.1.3.3 
Patients who did not receive sufficient chemotherapy to allow randomization are recommended to receive 
post-operative chemotherapy with MAP.  Patients who experience tumor progression during pre-operative 
treatment are recommended to receive post-operative treatment with MAPIE.  Patients who are not 
eligible for randomization because macroscopically complete surgical resection could not be done should 
receive radiotherapy and/or other experimental treatments as determined at the treating institution.    
 
All patients enrolled on AOST0331 will remain on-study for follow-up information until the conditions in 
Section 9.2 are met.  
 
For imaging guidelines while on study and at end of therapy and during follow-up see Section 17.0. For 
general 
Supportive 
Care 
Guidelines 
see 
https://members.childrensoncologygroup.org/prot/ 
reference_materials.asp, under standard sections for protocols. 
 
 
4.2 
Administration schedule for MAP Cycles 1-2, All Patients  
 
See also Appendix B.6 of the Intergroup document  
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf). 
 
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy.  
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Weeks 1 and 6.  
Dose: 37.5 mg/m²/Daily dose (Total dose is 75 mg/m²/48 hour infusion). 
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1and 2 of Weeks 1 and 6, immediately following dexrazoxane (Start DOXOrubicin infusion after 
completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane infusion). 
 
CISplatin: IV over 4 hours 
Days: 1 and 2 of Weeks 1 and 6. 
Dose: 60 mg/ m²/dose 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 4, 5, 9, and 10. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH:  A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 


 
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Page 18 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
Growth factor:  
Myeloid growth factor support is recommended when a previous doxorubicin/cisplatin cycle has been 
complicated by fever and neutropenia with non-catheter related sepsis or prolonged hospitalization (> 7 
days). Begin myeloid growth factor support at least 24 hours after completion of chemotherapy. If given 
daily then continue until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of 
chemotherapy.  
 
If administrative issues preclude surgical resection at Week 11, patients may receive up to two additional 
cycles of high dose methotrexate (maximum of 6 cycles of methotrexate) before surgical 
resection/amputation. When additional cycles of high dose methotrexate are planned, give one week off 
after the last scheduled methotrexate and then give one or two extra doses weekly depending on when 
resection can be scheduled. In addition, if a patient develops mucositis or transaminase elevations 
precluding administration of back-to-back methotrexate cycles, the patient may receive only 2 cycles of 
high dose methotrexate (instead of four) before the surgical procedure. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map for MAP Cycles 1 and 2 is on the next page. 
Following completion of Cycle 2 MAP, surgery and assessment of histologic response in primary tumor 
will occur. Upon evaluation of histological response, patients will be randomized to receive MAP, 
MAPIE, or MAPifn therapy beginning at Week 12. See Section 4.1.3 for randomization information.  
 
For Good and Poor responders randomized to receive MAP – see Section 4.3 
For Good responders randomized to receive MAPifn –see Section 4.5 
For Poor responders randomized to receive MAPIE –see Section 4.8 
 


 
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Page 19 
 
4.2.1 MAP Cycles 1-2, All patients 
 
Each cycle lasts 5 weeks. This therapy delivery map relates to Weeks 1-5 and Weeks 6-10 of 
MAP therapy. 
______________________            
Patient name or initials 
____________________________ 
DOB   
 
This therapy delivery Map is on one (1) page. Treatment details are provided in Section 4.2. ANC must be ≥ 750/µL 
and platelets ≥ 75,000/µL to start a cycle of therapy. Methotrexate at Weeks 4, 5, 9 and 10 can be administered as 
long as ANC is at least 250/µL and platelets at least 50 000/µL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS (See 
Section 7.1 for baseline 
observations) 
DOXOrubicin* 
(DOXO) 
IV over 
48 hours 
37.5 mg/m²/Daily dose* 
1-2  
of 
Weeks 1 and 6 
*Total dose: 75 mg/m²/48 hours. 
Avoid extravasation. 
 
See Section 4.2 for 
administration with dexrazoxane. 
a) 
CBC/Diff/Platelets 
b) H & P, PS 
c) 
Urinalysis 
d) Electrolytes including 
Ca++, PO4, Mg++, 
bicarbonate; 
creatinine, BUN, 
SGOT, SGPT, 
bilirubin, alk phos 
e) 
GFR 
f) 
QOL assessment 
 
See Section 17.0 for imaging 
requirements 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
CISplatin 
(CDDP) 
IV over 
4 hours  
60 mg/ m²/dose  
 
1 and 2 
of 
Weeks 1 and  6 
 
Methotrexate 
(MTX) 
IV over  
4 hours 
12 g/m²/dose 
 
1  
of 
Weeks 4, 5, 9 
and  10 
Maximum dose 20 g 
 
See Section 4.2. 
Leucovorin+ 
(LCV) 
PO or 
IV 
Varies according to MTX 
excretion levels. 
 
2  
of 
Weeks 4, 5, 9 
and  10 
+Leucovorin rescue must begin 
24 hours after start of MTX 
infusion. 
 
See Sections 4.2 and 19.3 for 
details. 
 
Cycle (circle one):  1    2   (use this map twice) 
 Ht_____cm 
        Wt____kg          BSA____m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
DOXO 
______ mg 
CDDP 
______ mg 
MTX 
______g 
LCV 
______ mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
 
1 or 6 
1 
______ mg 
______ mg 
 
 
a, b, c, d, e@ 
 
 
 
 
2 
______ mg 
______ mg 
 
 
a$ 
 
 
 
4 or 9  
1 
 
 
______ g 
 
a$ 
 
 
 
 
2 
 
 
 
______ mg 
 
_______(date of last LCV dose)% 
 
 
5 or 10  
1 
 
 
______ g 
 
a$  
 
 
 
 
2 
 
 
 
______ mg 
 
_______(date of last LCV dose)% 
 
 
 
7 
 
 
 
 
f ^ 
 
 
 
 
 
See Sections 4.1.2 and 4.1.3 for details on local control and 
randomization following Cycle 2.  
For patients randomized to receive MAP -  see Section 4.3 
For patients randomized to receive MAPifn –see Section 4.5 
For patients randomized to receive MAPIE –see Section 4.8 
 
 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ - Weekly after methotrexate and twice weekly after doxorubicin/cisplatin. 
^ -  End of Cycle 1 (after second MTX) and prior to start of Cycle 2. (see Section 16.3 for details). 
% - Continue until serum methotrexate level is < 0.1 µmol/L ( 1x10-7M) (see Section 19.3 for details) 
 
See Section 5.0 for Dose Modifications for Toxicities.  See Section 8.0 for Supportive Care. 


 
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Page 20 
 
4.3 
Administration Schedule for Good Responders and Poor Responders Randomized to MAP 
Therapy (Cycles 3-4) 
 
See also Appendix B.6 of the Intergroup document  
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf). 
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Weeks 12 and 17.  
Dose: 37.5 mg/m²/dose/ Daily dose. (Total dose is 75 mg/m²/48 hour infusion).  
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1and 2 of Weeks 12 and 17, immediately following dexrazoxane (Start DOXOrubicin infusion 
after completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane 
infusion). 
 
CISplatin: IV over 4 hours 
Days: 1 and 2 of Weeks 12 and 17. 
Dose: 60 mg/ m²/dose. 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 15, 16, 20 and 21. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH: A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
Growth factor:  
Myeloid growth factor support is recommended when a previous doxorubicin/cisplatin cycle has been 
complicated by fever and neutropenia with non-catheter related sepsis or prolonged hospitalization 
(> 7 days). Begin myeloid growth factor support at least 24 hours after completion of chemotherapy. If 
given daily then continue until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next 
cycle of chemotherapy. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map for MAP Cycles 3- 4 is on the next page. Following completion of MAP Cycle 
4, begin MAP Cycles 5 (see Section 4.4).  
 


 
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Page 21 
 
4.3.1 Good Responders and Poor Responders Randomized to MAP  
(Cycles 3-4) 
 
Each cycle lasts 5 weeks. This therapy delivery map relates to Weeks 12-16 and Weeks 17-21 of 
MAP therapy. 
_________________________ 
 
Patient name or initials 
____________________________ 
DOB 
 
This therapy delivery Map is on one (1) page. Treatment details are provided in Section 4.3. ANC must be ≥ 750/µL 
and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 15, 16, 20 and 21 can be administered as long 
as ANC is at least 250/µL and platelets at least 50,000/µL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
DOXOrubicin 
(DOXO) 
IV over 
48 hours 
37.5mg/m²/Daily dose* 
 
1 - 2 
of Weeks 
12 and 17 
*Total dose: 75 mg/m²/48 
hours 
Avoid extravasation. 
See Section 4.3 for 
administration with 
dexrazoxane. 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urine Analysis 
d) Electrolytes including Ca++, 
PO4, Mg++, bicarbonate; 
creatinine, BUN, SGOT, 
SGPT, bilirubin, alk phos 
e) ECHO or MUGA 
f) Audiogram 
g)  GFR 
 
See Section 17.0 for imaging 
requirements. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
  
CISplatin 
(CDDP) 
IV over 
4 hours  
60 mg/ m²/dose  
 
1 and 2 
of Weeks 
12 and 17 
 
Methotrexate+ 
(MTX) 
IV over  
4 hours 
 
12 g/m²/dose 
 
1  
of Weeks 
15, 16, 20 
and 21 
Maximum dose 20 g. 
See Section 4.3. 
Leucovorin+ 
(LCV) 
PO or 
IV 
Varies according to 
MTX excretion levels. 
 
2 of 
Weeks 
15, 16, 20 
and 21 
+Leucovorin rescue must 
begin 24 hours after start of 
MTX infusion. 
See Sections 4.3 and 19.3 for 
details. 
 
Cycle (circle one):  3    4   (use this map twice) 
 Ht_____cm 
        Wt____kg          BSA____m2 
Do not attempt to correct BSA for amputation  
 
Date 
Due 
Date 
Given 
Week 
Da
y 
DOXO 
____mg 
CDDP 
____mg 
MTX 
____g 
LCV 
___mg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
 
 
 
12  or 17 
1 
____mg 
____mg 
 
 
a, b, c, d, e+, f^ , g@ 
 
 
 
 
2 
____mg 
____mg 
 
 
a$ 
 
 
 
15 or 20 
1 
 
 
____g 
 
a$ 
 
 
 
 
2 
 
 
 
___mg 
 
________ (date of last LCV 
dose)% 
 
 
16 or 21 
1 
 
 
____g 
 
a$ 
 
 
 
 
2 
 
 
 
___mg 
 
________ (date of last LCV 
dose)% 
 
 
 
 
For Cycle 5 MAP (see Section 4.4). Begin next cycle ANC ≥ 750/µL and 
platelets ≥ 75 000/µL post nadir. 
 
 
+ -   Prior to Cycle 3. 
^ -   Prior to Cycles 3 and 4. 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin/cisplatin. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L (1x10-7 M) (see Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 


 
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Page 22 
 
4.4 
Administration Schedule for Good Responders and Poor Responders Randomized to MAP 
Therapy (Cycles 5 – 6) 
 
See also Appendix B.6 of the Intergroup document  
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf). 
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Weeks 22 and 26.  
Dose: 37.5 mg/m²/ Daily dose. (Total dose is 75 mg/m²/48 hour infusion).  
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1 and 2 of Weeks 22 and 26, immediately following dexrazoxane (Start DOXOrubicin infusion 
after completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane 
infusion). 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 24, 25, 28 and 29. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH: A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
Growth factor: 
Myeloid growth factor support is recommended when a previous doxorubicin/cisplatin cycle has been 
complicated by fever and neutropenia with non-catheter related sepsis or prolonged hospitalization (> 7 
days).  Begin myeloid growth factor support at least 24 hours after completion of chemotherapy. If given 
daily then continue until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of 
chemotherapy. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map for MAP Cycles 5-6 is on the next page. Therapy ends after MAP Cycle 6 for 
patients randomized to receive MAP therapy.  
 
See Section 7.1 for required observations at the end of therapy and Section 17.0 for imaging studies 
required at the end of therapy. 


 
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Page 23 
 
4.4.1 Good Responders and Poor Responders Randomized to MAP  
(Cycles 5 - 6) 
 
Each cycle lasts 4 weeks. This therapy delivery map relates to Weeks 22-25 and Weeks 26-29 of 
MAP therapy.     
____________________________ 
   Patient name or initials 
____________________________ 
DOB   
 
This therapy delivery Map is on one (1) page. Treatment details are provided in Section 4.4. ANC must be ≥ 750/µL 
and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 24, 25, 28 and 29 can be administered as long 
as the ANC is at least 250/µL and platelets at least 50,000/µL 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
 
DOXOrubicin 
(DOXO) 
IV, over 
48 hours 
37.5 mg/m²/Daily dose* 
1 - 2  
of Weeks 
22 and 26 
*Total dose: 75 mg/m²/48 hours  
Avoid extravasation. 
See Section 4.4 for 
administration with 
dexrazoxane. 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
CA++, PO4, MG++, 
bicarbonate; creatinine, 
BUN, SGOT, SGPT, 
bilirubin, alk phos 
e) ECHO or MUGA 
f) QOL assessment 
g) GFR 
 
See Section 17.0 for imaging 
requirements 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Methotrexate 
(MTX) 
IV over  
4 hours 
 
12 g/m²/dose 
 
1  
of Weeks 
24, 25, 28, 
and 29 
Maximum dose: 20 g. 
 
See Section 4.4. 
Leucovorin+ 
(LCV) 
PO or IV 
Varies according to 
MTX excretion levels. 
 
2  
of Weeks 
24, 25, 28, 
and 29 
+Leucovorin rescue must begin 
24 hours after start of MTX 
infusion. 
 
See Sections 4.4 and 19.3 for 
details. 
 
Cycle (circle one):  5    6   (use this map twice) 
 Ht_____cm 
        Wt____kg          BSA____m2 
Do not attempt to correct BSA for amputation. 
 
 
 
+ -   Prior to Cycle 5 and Cycle 6. 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin. 
^-   After recovery from doxorubicin of Week 22/Cycle 5 and prior to methotrexate of Week 24/Cycle 5. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L (1x10-7 M) (see Section 19.3 for details). 
 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 
Date 
Due 
Date 
Given 
Week 
Day 
DOXO 
______mg 
MTX 
______g 
LCV 
______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and 
actual dose administered below 
 
 
 
 
22 or 26 
1 
______mg 
 
 
a, b, c, d, e+, g@  
 
 
 
 
2 
______mg 
 
 
a$ 
 
 
 
24 or 28 
1 
 
______g 
 
a$ , f ^ 
 
 
 
 
2 
 
 
______mg 
 
______ (date of last LCV 
dose)% 
 
 
25 or 29 
1 
 
______g 
 
a$ 
 
 
 
 
2 
 
 
______mg 
 
______ (date of last LCV 
dose)% 
 
 
 
 
Therapy ends after completion of Cycle 6 for patients on 
MAP. See Section 7.1 for required observations at end of 
therapy. 
 


 
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Page 24 
 
4.5 
Administration Schedule for Good Responders Randomized to MAPifn Therapy (Cycles 3-4) 
 
See also Appendix B.6 of the Intergroup document  
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf) 
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Weeks 12 and 17.  
Dose: 37.5 mg/m²/Daily dose. (Total dose is 75 mg/m²/48 hour infusion).  
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1 and 2 of Weeks 12 and 17, immediately following dexrazoxane (Start DOXOrubicin infusion 
after completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane 
infusion). 
 
CISplatin: IV over 4 hours 
Days: 1 and 2 of Weeks 12 and 17. 
Dose: 60 mg/ m²/dose 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 15, 16, 20 and 21. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH: A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
Growth factor:   
Myeloid growth factor support is recommended when a previous doxorubicin/cisplatin cycle has been 
complicated by fever and neutropenia with non-catheter related sepsis or prolonged hospitalization (> 7 
days).  Begin myeloid growth factor support at least 24 hours after completion of chemotherapy. If given 
daily then continue until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of 
chemotherapy. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map for MAPifn Cycles 3-4 is on the next page. Following completion of MAPifn 
Cycle 4, begin MAPifn Cycle 5 (see Section 4.6). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AOST0331 
 
 
Page 25 
 
4.5.1 Good Responders Randomized to MAPifn  (Cycles 3-4) 
  
Each cycle lasts 5 weeks. This therapy delivery map relates to Weeks 12-16 and Weeks 17-21 
of MAPifn therapy.     
 
_________________________ 
   Patient name or initials 
____________________________ 
DOB   
 
This therapy delivery map is on one (1) page. Treatment details are provided in Section 4.5. ANC must be ≥ 750/µL 
and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 15, 16, 20 and 21 can be administered as long 
as the ANC is at least 250/µL and platelets at least 50,000/µL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
DOXOrubicin 
(DOXO) 
IV, over 
48 hours 
37.5mg/m²/Daily dose* 
1 - 2 
of Weeks 
12 and 17 
*Total dose: 75 mg/m²/48 hours 
Avoid extravasation. 
See Section 4.5 for 
administration with 
dexrazoxane. 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
CA++, PO4, MG++, 
bicarbonate; creatinine, 
BUN, SGOT, SGPT, 
bilirubin, alk phos 
e) ECHO or MUGA 
f) Audiogram 
g) GFR 
 
See Section 17.0 for imaging 
requirements 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
CISplatin 
(CDDP) 
IV over 
4 hours  
60 mg/ m²/dose 
 
1 and 2 
of 
Weeks 
12 and 17 
See Section 4.5 
Methotrexate 
(MTX) 
IV over  
4 hours 
12 g/m²/dose 
 
1 
of 
Weeks 15, 
16, 20 and 21 
Maximum dose 20 g. 
 
See Section 4.5 
 
 
Leucovorin+ 
(LCV) 
PO or IV 
Varies according to 
MTX excretion levels. 
 
2 
of Weeks 
15, 16, 20 
and 21 
+Leucovorin rescue must begin 
24 hours after start of MTX 
infusion. 
 
See Sections 4.5 and 19.3 for 
details.  
 
Cycle (circle one):  3    4   (use this map twice) 
 Ht_____cm 
        Wt____kg          BSA____m2 
Do not attempt to correct BSA for amputation 
 
Date 
Due 
Date 
Given 
Week 
Day 
DOXO 
______mg 
CDDP 
______mg 
MTX 
______g 
LEUC 
_____mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
12 or 17  
1 
______mg 
______mg 
 
 
a, b, c, d,  e+ , f ^, g@   
 
 
 
2 
______mg 
______mg 
 
 
a$ 
 
 
 
15 or 20  
1 
 
 
_______g 
 
a$ 
 
 
 
 
2 
 
 
 
______mg 
 
_______(date of last LCV 
dose)% 
 
 
16 or 21 
1 
 
 
 
_______g 
 
a$ 
 
 
 
 
2 
 
 
 
______mg 
 
_______(date of last LCV 
dose)% 
 
 
 
 
For Cycle 5 MAPifn (see Section 4.6). Begin next cycle when 
ANC ≥ 750/µL and platelets ≥ 75000/µL post nadir. 
 
 
+ -   Prior to Cycle 3. 
^ -   Prior to Cycles 3 and 4. 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin/cisplatin. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L (1x10-7 M)  (see Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AOST0331 
 
 
Page 26 
 
4.6 
Administration Schedule for Good Responders Randomized to MAPifn Therapy (Cycles 5-6) 
 
See also Appendix B.6 of the Intergroup document 
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf)  
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Weeks 22 and 26.  
Dose: 37.5 mg/m²/ Daily dose. (Total dose is 75 mg/m²/48 hour infusion).  
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1 and 2 of Weeks 22 and 26, immediately following dexrazoxane (Start DOXOrubicin infusion 
after completion of dexrazoxane infusion and within 30 minutes after the beginning of dexrazoxane 
infusion). 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 24, 25, 28 and 29. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH:  A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
Growth factor:   
Myeloid growth factor support is recommended when a previous doxorubicin/cisplatin cycle has been 
complicated by fever and neutropenia with non-catheter related sepsis or prolonged hospitalization (> 7 
days).  Begin myeloid growth factor support at least 24 hours after completion of chemotherapy. If given 
daily then continue until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of 
chemotherapy. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map for MAPifn Cycles 5- 6 is on the next page. Patients on MAPifn therapy 
will start pegylated interferon alfa-2b after completion of Cycle 6 MAPifn (see Section 4.7). 
 
 


 
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AOST0331 
 
 
Page 27 
 
4.6.1    Good Responders Randomized to MAPifn (Cycles 5- 6) 
  
Each cycle lasts 4 weeks. This therapy delivery map relates to Weeks 22-25 and Weeks 26-29 
of MAPifn therapy.    
 
____________________________ 
   Patient name or initials 
____________________________ 
DOB   
 
This therapy delivery map is on one (1) page. Treatment details are provided in Section 4.6.ANC must be ≥ 750/µL 
and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 24, 25, 28 and 29 can be administered as long 
as the ANC is at least 250/µL and platelets at least 50,000/µL. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
 
DOXOrubicin 
(DOXO) 
IV, over 
48 
hours 
37.5mg/m²/Daily dose* 
1 - 2 
of Weeks 
22 and 26 
*Total dose: 75 mg/m²/48 hours. 
Avoid extravasation. 
See Section 4.6 for administration 
with dexrazoxane. 
 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
CA++, PO4, MG++, 
bicarbonate; creatinine, 
BUN, SGOT, SGPT, 
bilirubin, alk phos 
e) ECHO or MUGA 
f) QOL assessment 
g) GFR 
See Section 17.0 for imaging 
requirements 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Methotrexate 
(MTX) 
IV over  
4 hours 
 
12 g/m²/dose 
 
1 
of Weeks 
24, 25, 28 
and 29 
Maximum dose 20 g. 
 
See Section 4.6. 
 
Leucovorin+ 
(LCV) 
PO or 
IV 
Varies according to 
MTX excretion levels. 
 
2 
of Weeks 
24, 25, 28 
and 29 
+Leucovorin rescue must begin 24 
hours after start of MTX infusion. 
  
See Sections 4.6 and 19.3 for 
details. 
 
 
Cycle (circle one):  5    6   (use this map twice) 
 Ht_____cm 
        Wt____kg          BSA____m2 
Do not attempt to correct BSA for amputation 
 
 
Date 
Due 
Date  
Given 
Week 
Day 
DOXO 
______mg 
MTX 
______g 
LCV 
_____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
 
 
22 or 26 
1 
______mg 
 
 
a, b, c, d, e+, g@  
 
 
 
 
2 
______mg 
 
 
a$ 
 
 
 
24 or 28 
1 
 
______g 
 
a$, f ^ 
 
 
 
 
2 
 
 
______mg 
 
________(date of last LCV dose)% 
 
 
25 or 29 
1 
 
______g 
 
a$ 
 
 
 
 
2 
 
 
______mg 
 
________(date of last LCV dose)% 
 
 
 
 
Patients on MAPifn will start pegylated interferon alfa-
2b after completion of Cycle 6 MAPifn. (See Section 4.7). 
 
 
+ -   Prior to Cycle 5 and Cycle 6. 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin. 
^ - After recovery from doxorubicin of Week 22/Cycle 5 and prior to methotrexate of Week 24/Cycle 5. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L (1x10-7 M) (see Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AOST0331 
 
 
Page 28 
 
 
4.7 
Administration Schedule for Pegylated Interferon alfa-2b Therapy for Good Responders 
Randomized to MAPifn, (Weeks 30-104) 
 
See also Section 9.1.8.6 of the Intergroup document 
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf)  
 
Criteria for beginning pegylated interferon alfa-2b therapy:  
 
- 
Bilirubin ≤ 1.5 x ULN and SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for 
age. 
- 
Baseline ophthalmologic evaluation WNL. 
- 
Triglycerides WNL ,  Amylase WNL and Pancreatic fraction amylase or lipase WNL. 
- 
Hemoglobin ≥ 8 g/dL; ANC ≥ 750/µL or WBC ≥ 2000/ µL and platelets ≥ 75,000/µL. 
- 
Creatinine ≤ 1.5 x ULN. 
- 
Karnofsky ≥ 60 (age ≥ 16) or Lansky ≥ 60 (age < 16). 
 
Pegylated interferon alfa-2b: SubQ 
 
Starting Dose 
Days: 1 of Week 30, 31, 32, and 33.  
Dose:  0.5 microgram/kg/dose (Maximum dose 50 microgram). 
If well tolerated (no more than Grade 2 flu-like symptoms with no other toxicity more than Grade 1) 
during first 4 weeks of therapy, escalate dose. 
 
Escalated Dose 
Days: 1 of Weeks 34-104. 
Dose: 1 microgram/kg/dose (Maximum dose 100 microgram). 
 
NOTE: Pretreatment with acetaminophen/paracetamol (10-15mg/kg/dose, maximum dose 1000 mg) 
given 30-60 minutes before each dose of pegylated interferon alfa-2b is recommended. 
 
Autoimmune hepatitis is a contraindication for drug administration. Any AST/ALT elevation > Grade 3 
would preclude administration of interferon. Decompensated liver disease is a contraindication for use of 
interferon. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for MAPifn Weeks 30-104 is on the next 2 pages. 
 
Patients randomized to receive MAPifn therapy will complete their therapy at the end of Week 104. 
 
See Section 17.0 for imaging requirements and Section 7.1 for required observations at the end of 
therapy. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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Page 29 
 
Criteria for beginning pegylated interferon alfa-2b therapy:  
- 
Bilirubin ≤ 1.5 x ULN and SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. 
- 
Baseline ophthalmologic evaluation WNL. 
- 
Triglycerides WNL, Amylase WNL and Pancreatic fraction amylase or lipase WNL. 
- 
Hemoglobin ≥ 8 g/dL; ANC ≥ 750/µL or WBC ≥ 2000/ µL and platelets ≥ 75,000/µL. 
- 
Creatinine ≤ 1.5 x ULN 
- 
Karnofsky ≥ 60 (age ≥ 16) or Lansky ≥ 60 (age < 16). 
       
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Pegylated interferon 
alpha-2b 
 
 
SubQ 
Starting dose: 
0.5 microgram/kg*  
 
 
 
 
Dose escalation: to 
1 microgram/kg **  
1 of 
Weeks 
30--104  
*Maximum starting dose: 
50 microgram. 
 
If starting dose is well-
tolerated, escalate dose at 
Week 34 %  
 
**Maximum escalated 
dose: 100 microgram. 
 
Pretreat with 
acetaminophen/paracetamol. 
See Section 4.7. 
 
a) CBC/Diff/Platelets& 
b) H & P, PS& 
c) (Electrolytes/CA++, PO4, MG++, bicarbonate; 
creatinine, BUN, SGOT, SGPT, bilirubin, alk 
phos)& 
d) Evaluation of liver function & 
e) Triglyceride level& 
f) Thyroid function& 
g) Ophthalmologic evaluation 
h) QOL assessment 
 
&- Obtain weekly for first 8 weeks, and if stable, 
monthly during subsequent therapy. 
 
See Section 17.0 for imaging requirements. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
 
 Use this record of doses for the entire 75 weeks or until Pegylated interferon alfa-2b is stopped, whichever occurs first. 
 
Note Patient’s starting weight:  _____kg       Starting Dose: ______ microgram         Escalated Dose: ______ microgram  
 
Note Patient’s weight at start of increased dose:  ______kg (Weight may change over these 75 weeks). 
Comments 
(Include any held 
doses, or dose 
modifications) 
Week 
30$ 
31 
32 
33 
34% 
35 
36 
37 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
38 
39 
40 
41 
42 
43 
44 
45 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
46 
47 
48 
49 
50 
51 
52 
53 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
54 
55 
56 
57 
58 
59 
60 
61 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
62 
63 
64 
65 
66 
67 
68 
69 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
$-  Obtain observations a- g prior to the first dose of pegylated interferon alfa-2b 
% -  Dose escalates at Week 34 if no more than Grade 2 flu-like symptoms with no other toxicity more than Grade 1 during the 
first  4 weeks.  
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 
The therapy delivery map for Pegylated interferon alpha-2b therapy (Weeks 70-104) is continued on next page. 
4.7.1     Pegylated interferon alfa-2b Therapy for Good Responders Randomized to 
MAPifn (Weeks 30-104) 
 
This therapy delivery map relates to 75 weeks of pegylated interferon alpha- 2b therapy and is 
on two (2) pages. 
_____________________________   
   Patient name or initials 
____________________________ 
DOB   
Page 1 of 2 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AOST0331 
 
 
Page 30 
 
Criteria for beginning pegylated interferon alfa-2b therapy:  
- 
Bilirubin ≤ 1.5 x ULN and SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. 
- 
Baseline ophthalmologic evaluation WNL 
- 
Triglycerides WNL ,  Amylase WNL and Pancreatic fraction amylase or lipase WNL 
- 
Hemoglobin ≥ 8 g/dL; ANC ≥ 750/µL or WBC ≥ 2000/ µL and platelets ≥ 75,000/µL. 
- 
Creatinine ≤ 1.5 x ULN 
- 
Karnofsky ≥ 60 (age ≥ 16) or Lansky ≥ 60 (age < 16). 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Pegylated interferon 
alpha-2b 
 
 
SubQ 
Starting dose:   
0.5 microgram/kg * 
 
Dose escalation: to  
1 microgram/kg** 
1 of 
Weeks 
30--104 
*Maximum starting dose:  
50 microgram. 
 
If starting dose is well-
tolerated, escalate dose at 
Week 34  
 
**Maximum escalated dose: 
100 microgram. 
 
Pretreat with 
acetaminophen/paracetamol. 
See Section 4.7. 
 
a) 
CBC/Diff/Platelets& 
b) H & P, PS 
c) 
(Electrolytes/CA++, PO4, MG++, bicarbonate; 
creatinine, BUN, SGOT, SGPT, bilirubin, alk    
phos)& 
d) Evaluation of liver function& 
e) 
Triglyceride level& 
f) 
Thyroid function & 
g) Ophthalmologic evaluation 
h) QOL assessment 
 
&- Obtain weekly for first 8 weeks, and if stable, 
monthly during subsequent therapy. 
 
See Section 17.0 for imaging requirements. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
 
 
Use this record of doses for the entire 75 weeks or until Pegylated interferon alfa-2b is stopped, whichever occurs first. 
 
 
Note Patient’s starting weight:  _____kg       Starting Dose: ______ microgram         Escalated Dose: ______ microgram 
 
Note Patient’s weight at start of increased dose:  ______kg (Weight may change over these 75 weeks).  
Comments 
(Include any held 
doses, or dose 
modifications) 
Week 
70 
71 
72# 
73 
74 
75 
76 
77 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
78 
79 
80 
81 
82 
83 
84 
85 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
86 
87 
88 
89 
90 
91 
92 
93 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
94 
95 
96 
97 
98 
99 
100 
101 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
Week 
102 
103 
104 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Dose 
 
 
 
 
 
 
 
 
 
 
Therapy ends after completion of Week 104 for patients on MAPifn. See Section 7.1 for 
required observations at end of therapy.  
 
#- QOL assessment at Week 72 from start of therapy (+/–  4 weeks). (See Section 16.3 for details.) 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 
 
 
4.7.1    Pegylated interferon alfa-2b Therapy for Good Responders Randomized to 
MAPifn (Weeks 30-104) 
 
This therapy delivery map relates to 75 weeks of pegylated interferon alpha- 2b therapy and is 
on 2 pages. 
_____________________________   
   Patient name or initials 
____________________________ 
DOB   
 Page 2 of 2 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AOST0331 
 
 
Page 31 
4.8 Administration Schedule for Poor Responders Randomized to MAPIE Therapy (Cycles 3 and 7) 
 
See also Appendix B.6 of the Intergroup document  
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf).      
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Weeks 12 and 28.  
Dose: 37.5 mg/m²/Daily dose (Total dose is 75 mg/m²/48 hour infusion).  
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1 & 2 of Weeks 12 & 28, immediately following dexrazoxane (Start DOXOrubicin infusion after 
completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane infusion). 
 
CISplatin: IV over 4 hours 
Days: 1 and 2 of Weeks 12 and 28. 
Dose: 60 mg/ m²/dose. 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 15 and 31. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH:  A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
Growth factor:  
Myeloid growth factor support is recommended when a previous doxorubicin/cisplatin cycle has been 
complicated by fever and neutropenia with non-catheter related sepsis or prolonged hospitalization (> 7 
days).  Begin myeloid growth factor support at least 24 hours after completion of chemotherapy. If given 
daily then continue until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of 
chemotherapy. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map for MAPIE Cycles 3 and 7 is on the next page. 
Following completion of Cycle 3 MAPIE, begin Cycle 4 MAPIE (see section 4.9). 
Following completion of Cycle 7 MAPIE, begin Cycle 8 MAPIE (see section 4.9). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
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Page 32 
 
4.8.1    Administration Schedule for Poor Responders Randomized to MAPIE Therapy 
(Cycles 3 and 7) 
 
Each cycle lasts 4 weeks. This therapy delivery map relates to Weeks 12-15 and Weeks 28-31of 
MAPIE therapy.     
 
 
____________________________ 
   Patient name or initials 
____________________________ 
DOB   
This Therapy delivery Map is on one (1) page. Treatment details are provided in Section 4.8. ANC must 
be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 15 and 31 can be administered as 
long as the ANC is at least 250/µL and platelets at least 50,000/µL. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
DOXOrubicin 
(DOXO) 
IV, over 
48 hours 
37.5 mg/m²/Daily dose* 
1 - 2 
of Weeks 
12 and 28 
*Total dose: 75 mg/m²/48 hours. 
Avoid extravasation. See Section 
4.8 for dosing with dexrazoxane. 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
CA++, PO4, MG++, 
bicarbonate; 
creatinine, BUN, 
SGOT, SGPT, 
bilirubin, alk phos 
e) ECHO or MUGA 
f) 
Audiogram 
g) GFR 
 
 
See Section 17.0 for 
imaging requirements 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
CISplatin 
(CDDP) 
IV over 
4 hours  
60 mg/ m²/dose 
 
1 and 2 
of Weeks 
12 and 28 
 
Methotrexate 
(MTX) 
IV over  
4 hours 
 
12 g/m²/dose 
 
1 
of Weeks 
15 and 31 
Maximum dose 20 g. 
 
See Section 4.8. 
Leucovorin+ 
(LCV) 
PO or IV 
Varies according to 
MTX excretion levels. 
 
2 
of Weeks 
15 and 31 
+Leucovorin rescue must begin 
24 hours after start of MTX 
infusion. 
See Sections 4.8 and 19.3 for 
details. 
 
 
Cycle (circle one):  3    7   (use this map twice) 
 Ht_____cm 
        Wt____kg          BSA____m2 
Do not attempt to correct BSA for amputation 
Date 
Due 
Date 
Given 
Week 
Day 
DOXO 
______mg 
CDDP 
_______mg 
MTX 
________g 
LCV 
_____mg   
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
12  or 28 
1 
____mg 
____mg 
 
 
a, b, c, d, e+, f +, g@ 
 
 
 
 
2 
____mg 
____mg 
 
 
a$ 
 
 
 
15 or 31 
1 
 
 
____g 
 
a$ 
 
 
 
 
2 
 
 
 
____mg 
 
____(date of last LCV 
dose)% 
 
 
 
 
For Cycle 4 and Cycle 8 MAPIE (see Section 4.9) 
Begin next cycle when ANC ≥ 750/µL and platelets ≥ 75,000/µL post 
nadir. 
 
 
+ - Prior to Cycle 3 and Cycle 7. 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin/cisplatin. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L (1x10-7 M) (See Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 


 
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AOST0331 
 
 
Page 33 
 
4.9 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy (Cycles 4, 6 
and 8) 
 
See also Appendix B.6 of the Intergroup document 
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf).      
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
Ifosfamide: IV over 4 hours 
Days: 1-5 of Weeks 16, 24 and 32. 
Dose: 2.8 g/m²/dose. 
 
Etoposide: IV over 1 hour 
Days: 1-5 of Weeks 16, 24 and 32. 
Dose: 100 mg/m²/dose. 
 
Growth factor:  
Myeloid growth factor support is recommended after all ifosfamide/etoposide cycles. Begin myeloid 
growth factor support at least 24 hours after completion of chemotherapy. If given daily then continue 
until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of chemotherapy. 
 
Mesna: IV over 24 hours 
Days: 1-5 of Weeks 16, 24 and 32. 
Dose: 2.8 g/m²/24 hours. 
Alternatively, mesna may be administered in 3-4 divided doses; administer until at least 12 hours 
following completion of ifosfamide dose. 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 19, 27 and 35  
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH: A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for MAPIE Cycles 4, 6 and 8 is on the next page. 
 
Following completion of Cycle 4 MAPIE, begin Cycle 5 MAPIE (see Section 4.10). 
Following completion of Cycle 6 MAPIE, begin Cycle 7 MAPIE (see Section 4.8). 
Following completion of Cycle 8 MAPIE, begin Cycle 9 MAPIE (see Section 4.11). 
 


 
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Page 34 
 
This Therapy delivery Map is on one (1) page. Treatment details are provided in Section 4.9. ANC must 
be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 19, 27 and 35 can be administered 
as long as the ANC is at least 250/µL and the platelets at least 50,000/µL. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 4 
hours 
2.8 g/m²/dose 
1-5 of Weeks 
16, 24 and 32 
See Section 4.9 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
CA++, PO4, MG++; 
bicarbonate, creatinine, 
BUN, SGOT, SGPT, 
bilirubin, alk phos 
e)  GFR 
 
See Section 17.0 for 
imaging requirements. 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Etoposide 
(ETOP) 
IV over 1 
hour 
100 mg/m²/dose 
1-5 of Weeks 
16, 24 and 32 
Slow rate of administration if 
hypotension occurs. See Section 4.9. 
MESNA* 
IV over 
24 hours* 
2.8 g/m²/dose 
1-5 of Weeks 
16, 24 and 32 
*Dose may be divided into 3 or 4 
doses and administered until at least 
12 hours after start of ifosfamide 
dose. 
See Section 4.9 
Methotrexate 
(MTX) 
IV over 4 
hours 
12 g/m²/dose 
 
1 of Weeks 
19, 27 and 35  
Maximum dose: 20 g. 
See Section 4.9 
 
Leucovorin+ 
(LCV) 
PO or IV 
Varies 
according to 
MTX excretion 
levels. 
2 of Weeks 
19, 27 and 35 
+Leucovorin rescue must begin 24 
hours after start of MTX infusion. 
See Sections 4.9 and 19.3 for details. 
 
Cycle (circle one): 4     
6        8   (use this map three times)  Ht_____cm 
        Wt____kg         BSA____m2 
Do not attempt to correct BSA for amputation 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
______g 
ETOP 
_____mg 
MESNA 
______g 
MTX 
_____g 
LCV 
____mg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
 
16 or 24 or 32 
1 
______g 
_____mg 
______g 
 
 
a, b, c, d ,e@ 
 
 
 
 
2 
______g 
_____mg 
______g 
 
 
a$ 
 
 
 
 
3 
______g 
_____mg 
______g 
 
 
 
 
 
 
 
4 
______g 
_____mg 
______g 
 
 
 
 
 
 
 
5 
______g 
_____mg 
______g 
 
 
 
 
 
 
19 or 27 or 35 
1 
 
 
 
_____g 
 
a$ 
 
 
 
 
2 
 
 
 
 
____mg 
 
______(date of last 
LCV dose)% 
 
For Cycle 5 MAPIE (see Section 4.10).  
For Cycle 7 MAPIE (see to Section 4.8).  
For Cycle 9 MAPIE (see Section 4.11).  
Begin next cycle when ANC ≥ 750/µL and platelets ≥ 75,000/µL post nadir. 
 
 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after ifosfamide/etoposide. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L (1x10-7 M) (See Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 
4.9.1    Administration Schedule for Poor Responders Randomized to MAPIE Therapy 
(Cycles 4, 6 and 8) 
 
Each cycle lasts 4 weeks. This therapy delivery map relates to Weeks 16-19, Weeks 24-27 and 
Weeks 32-35 of MAPIE therapy.     
____________________________ 
Patient name or initials 
____________________________
DOB    


 
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Page 35 
 
 
4.10 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy (Cycle 5) 
 
See also Appendix B.6 of the Intergroup document 
 (https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf).   
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Week 20.  
Dose: 37.5 mg/m²/ Daily dose. (Total dose is 75 mg/m²/48 hour infusion).   
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1 & 2 of Week 20, immediately following dexrazoxane (Start DOXOrubicin infusion after 
completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane infusion). 
 
Ifosfamide: IV over 4 hours 
Days: 1, 2 and 3 of Week 20. 
Dose: 3 g/m²/dose. 
 
Growth factor:  
Myeloid growth factor support after all doxorubicin/ifosfamide cycles is recommended. Begin myeloid 
growth factor support at least 24 hours after completion of chemotherapy. If given daily then continue 
until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of chemotherapy. 
 
Mesna: IV over 24 hours 
Days: 1, 2 and 3 of Week 20  
Dose: 3 g/m²/24 hours. 
Alternatively, may be administered in 3-4 divided doses. Administer until at least 12 hours following 
completion of ifosfamide dose. 
 
Methotrexate: IV over 4 hours 
Days: 1 of Week 23.  
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Urine pH:  A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7 M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7 M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for MAPIE Cycle 5 is on the next page. Following completion of 
MAPIE Cycle 5, patients will begin MAPIE Cycle 6 (see Section 4.9). 


 
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Page 36 
 
4.10.1 Administration Schedule for Poor Responders Randomized to MAPIE (Cycle 5) 
 
This cycle lasts 4 weeks. This therapy delivery map relates to Weeks 20-23. 
________________________ 
   Patient name or initials 
____________________________ 
DOB   
 
This Therapy Delivery Map is on one (1) page. Treatment details are provided in Section 4.10.ANC must 
be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Week 23 can be administered as long as 
the ANC is at least 250/µL and the platelets at least 50,000/µL.  
 
DRUG 
ROUTE 
      DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
DOXOrubicin 
(DOXO) 
IV over 
48 hours 
37.5mg/m²/Daily 
dose* 
 
1-2 of 
Week 20 
*Total dose: 75 mg/m²/48 hours. 
Avoid extravasation. See Section 
4.10 for administration with 
dexrazoxane. 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
Ca++, PO4, Mg++, 
bicarbonate; creatinine, 
BUN, SGOT, SGPT, 
bilirubin, alk phos 
e) GFR 
f) QOL assessment 
 
 
See Section 17.0 for 
imaging requirements  
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Ifosfamide 
(IFOS) 
IV over 4 
hours 
3 g/m²/dose 
1, 2, 3 of  
Week 20 
See Section 4.10. 
MESNA* 
IV over 
24 hours 
3 g/m²/dose 
1, 2, 3 of  
Week 20 
*Dose may be divided into 3 or 
4 doses and administered until at 
least 12 hours after start of 
ifosfamide dose. 
 
See Section 4.10. 
Methotrexate 
(MTX) 
IV over 4 
hours 
12 g/m²/dose 
 
1 of 
Week 23 
Maximum dose 20 g 
See Section 4.10  
Leucovorin+ 
(LCV) 
PO or IV 
Varies according to 
MTX excretion 
levels. 
 
2 of Week 
23 
+Leucovorin rescue must begin 
24 hours after start of MTX 
infusion. 
See Section 4.10 and Section 
19.3 for details 
 
 
  
Ht_____cm 
         
Wt____kg 
         
 
 
BSA____m2 
 
Do not attempt to correct BSA for amputation 
Date 
Due 
Date 
Given 
Week 
Day 
DOXO 
______mg 
IFOS 
______g 
MESNA 
______g 
MTX 
______g 
LCV 
______mg 
Studies 
Comments (Include 
any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
20 
1 
______mg 
______g 
______g 
 
 
a, b, c, d, e@ 
 
 
 
 
2 
______mg 
______g 
______g 
 
 
a$ 
 
 
 
 
3 
 
______g 
______g 
 
 
a$ 
 
 
 
23 
1 
 
 
 
______g 
 
a$, f ^ 
 
 
 
 
2 
 
 
 
 
______mg 
 
______ (date of last 
LCVdose)% 
 
 
 
For Cycle 6 MAPIE (See Section 4.9). Begin next cycle when ANC ≥ 750/µL and 
platelets ≥ 75,000/µL post nadir.  
 
 
@-  Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin/ifosfamide. 
^  -   After recovery from Week 20 doxorubicin/ifosfamide and prior to methotrexate at Week 23. 
% -  Continue until serum methotrexate level  is < 0.1 µmol/L ( 1x10-7 M) (See Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 


 
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Page 37 
 
4.11 
Administration Schedule for Poor Responders Randomized to MAPIE Therapy (Cycle 9) 
 
See also Appendix B.6 of the Intergroup document 
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf).   
 
ANC must be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. 
 
DOXOrubicin: IV over 48 hours 
Days: 1-2 of Week 36.  
Dose: 37.5 mg/m²/Daily dose. (Total dose is 75 mg/m²/48 hour infusion).  
Avoid extravasation. 
Hydration: 3000 mL/m2/day. 
Cardioprotection: Dexrazoxane may be used if a 10% fall in LVEF or similar fall within the normal range 
of SF occurs. If cardioprotection is used, 37.5 mg/m2 of doxorubicin will be given as a 15 minute infusion 
on days 1 and 2 of Week 36, immediately following dexrazoxane (Start DOXOrubicin infusion after 
completion of dexrazoxane infusion but within 30 minutes of beginning of the dexrazoxane infusion). 
 
Ifosfamide: IV over 4 hours 
Days: 1, 2 and 3 of Week 36. 
Dose: 3 g/m²/dose. 
 
Growth factor:  
Myeloid growth factor support after all doxorubicin/ifosfamide cycles is recommended. Begin myeloid 
growth factor support at least 24 hours after completion of chemotherapy. If given daily then continue 
until WBC ≥ 5000/µL after nadir and discontinue at least 2 days prior to next cycle of chemotherapy. 
 
Mesna: IV over 24 hours 
Days: 1, 2 and 3 of Week 36. 
Dose: 3 g/m²/24 hours. 
Alternatively, may be administered in 3-4 divided doses, until at least 12 hours following completion of 
ifosfamide dose. 
 
Methotrexate: IV over 4 hours 
Days: 1 of Weeks 39 and 40. 
Dose: 12 g/m²/dose (Maximum dose 20 g). 
Hydration: Adequate fluid with electrolytes and bicarbonate must be given to maintain a urine 
output > 80 % of the fluid intake, measured every four hours and alkalinization. This should be 
maintained until serum methotrexate level is < 0.1 µmol/L (1x10-7M). 
Urine pH: A urinary pH > 7 must be achieved before starting methotrexate infusion and maintained until 
serum methotrexate level is < 0.1 µmol/L (1x10-7M). 
Leucovorin rescue must begin 24 hours after start of methotrexate infusion and be continued until serum 
methotrexate level is < 0.1 µmol/L (1x10-7M) or delayed excretion criteria is reached. See Section 19.3 
for details. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
The Therapy Delivery Map for MAPIE Cycle 9 is on the next page. Therapy ends after Cycle 9 for 
patients randomized to receive MAPIE. 
 
See Section 7.1 for required observations at end of therapy and Section 17.0 for imaging studies to 
be performed at end of therapy. 


 
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Page 38 
 
4.11.1    Administration Schedule for Poor Responders Randomized to MAPIE (Cycle 9) 
 
This cycle lasts 5 weeks. This therapy delivery map relates to Weeks 36-40. 
____________________________ 
   Patient name or initials 
____________________________ 
DOB   
 
This Therapy Delivery Map is on one (1) page. Treatment details are provided in Section 4.11. ANC must 
be ≥ 750/µL and platelets ≥ 75,000/µL to start a cycle of therapy. MTX at Weeks 39 and 40 can be administered as 
long as the ANC is at least 250/µL and the platelets at least 50,000/µL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
DOXOrubicin 
(DOXO) 
IV over 
48 hours 
37.5 mg/m²/Daily dose* 
1-2 
of 
Week 36 
*Total dose: 75 mg/m²/48 hours. 
Avoid extravasation. See Section 
4.11 for administration with 
dexrazoxane. 
a) CBC/Diff/Platelets 
b) H & P, PS 
c) Urinalysis 
d) Electrolytes including 
Ca++, PO4, Mg++, 
bicarbonate; 
creatinine, BUN, 
SGOT, SGPT, 
bilirubin, alk phos 
e) ECHO or MUGA 
f) GFR 
 
See Section 17.0 for 
imaging requirements  
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Ifosfamide 
(IFOS) 
IV over 4 
hours 
3 g/m²/dose 
1, 2, 3 of 
Week 36 
 
See Section 4.11. 
MESNA* 
IV over 
24 hours 
3 g/m²/dose 
1, 2, 3 
of Week 36 
*Dose may be divided into 3 or 4 
doses and administered until at 
least 12 hours after start of IFOS 
dose. 
See section 4.11. 
Methotrexate 
(MTX) 
IV over 4 
hours 
12 g/m²/dose 
 
1 of Weeks 
39 and 40 
Maximum dose: 20 g. 
See Section 4.11. 
Leucovorin+ 
(LCV) 
PO or IV 
Varies according to 
MTX excretion levels. 
 
2 of Weeks 
39 and 40 
+Leucovorin rescue must begin 24 
hours after start of MTX infusion. 
 
See Sections 4.11 and 19.3 for 
details.  
 
 
  
Ht_____cm 
 
Wt____kg 
 
 
BSA____m2 
Do not attempt to correct BSA for amputation 
Date 
Due 
Date 
Given 
Week 
Day 
DOXO 
______mg   
IFOS 
______g  
MESNA 
______g 
MTX 
______g 
LCV 
______mg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
36 
1 
______mg 
______g  
______g 
 
 
a, b, c, d, e, f@ 
 
 
 
 
2 
______mg 
______g 
______g 
 
 
a$ 
 
 
 
 
3 
 
______g 
______g 
 
 
 
 
 
 
39 
1 
 
 
 
______g 
 
a$ 
 
 
 
 
2 
 
 
 
 
______mg 
 
______ (date of last 
LCV dose)% 
 
 
40 
1 
 
 
 
______g 
 
a$ 
 
 
 
 
2 
 
 
 
 
______mg 
 
______ (date of last 
LCV dose)% 
 
 
 
 
Therapy ends after completion of Cycle 9 for patients on MAPIE.  
See Section 7.1 for required observations at end of therapy. 
 
 
@ - Calculated or measured GFR (see Appendix A.3 of the Intergroup document). 
$ -   Weekly after methotrexate and twice weekly after doxorubicin/ifosfamide. 
% - Continue until serum methotrexate level  is < 0.1 µmol/L ( 1x10-7M) (see Section 19.3 for details). 
 
See Section 5.0 for Dose Modifications for Toxicities. See Section 8.0 for Supportive Care. 


 
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Page 39 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Dose Modifications for Doxorubicin/Cisplatin 
Toxicity 
Grade 
Action 
Myelosuppression 
On Day 1 of cycle 
ANC < 0.75 x 109/L   
Plts  < 75 x 109/L        
 
Delay and repeat within 3-4 days until criteria are met 
Retreat at full dose unless previous dose reduction 
For repeated delay (>7 days) use growth factor support starting at least 
24 hours post chemotherapy and continuing until  
WBC >5,000/uL post nadir. If delayed >7 days in spite of growth factor 
support reduce cisplatin by 25%. 
Febrile 
Neutropenia  
 
 
Febrile neutropenia accompanied by either sepsis or a microbiologically 
documented infection should prompt administration of growth factor 
support starting at least  24 hours after chemotherapy and continuing 
until WBC >5,000/µL post-nadir. 
Further episodes of febrile neutropenia accompanied by either sepsis or 
a microbiologically documented infection requiring prolonged 
hospitalizations should result in cisplatin dosage reduction by 25%.  
Investigators can consider the same dose reduction if there are persistent 
delays >7 days in therapy administration despite GCSF 
Mucositis , Severe 
abdominal pain,  
Diarrhea,  
Typhlitis 
Grade 4 mucositis or 
typhlitis  
        or 
repeated Grade 3 
mucositis 
Delay until resolved & decrease subsequent doxorubicin to 60 
mg/m2/cycle 
 
 
  
Audiology 
> 30 dB at  2kHz 
Discontinue cisplatin 
 
Cardiotoxicity 
 
 LVEF < 50%  
   or  
SF ≤ 28%  
 
Repeat echo or MUGA in one week. If echo or MUGA within normal 
range proceed with chemotherapy.  If LVEF does not normalize, omit 
all further doxorubicin 
 
Renal Toxicity 
Serum 
creatinine > 2 x 
baseline 
or 
GFR < 70 
mL/min/1.73 m2  
 
 
Delay for one week 
  
If renal function does not improve, omit cisplatin and give  doxorubicin 
alone 
 
Resume cisplatin at future courses if GFR ≥ 70 mL/min/1.73 m2 
Hepatic Toxicity 
 
 
 
 
 
 
 
Raised Total 
Bilirubin 
 
 
 
 
Reduce doxorubicin as follows: 
      Concentration                                         % Dose 
          0 – 21 mol/L     (0     -1.24 mg/dL)      100% 
        22 – 35 mol/L     (1.25-2.09 mg/dL)        75% 
        36 – 52 mol/L     (2.1  -3.05 mg/dL)        50% 
        53 – 86 mol/L     (3.06-5.0   mg/dL)        25% 
             > 87 mol/L     (     > 5.0   mg/dL)          0% 
Peripheral 
neurotoxicity 
Grade 2 
 
≥ Grade 3 
Reduce cisplatin by 25% for all future courses 
 
Omit cisplatin for all future courses 
An attempt to give any omitted doxorubicin/cisplatin cycles should be made after the end of scheduled protocol 
chemotherapy, if the patient fulfills the necessary organ function requirements.  Patients scheduled to receive 
pegylated interferon alfa-2b should complete all standard cytotoxic chemotherapy and have a 7-day interval prior to 
beginning pegylated alfa interferon.  


 
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Page 40 
 
5.2 
Dose Modifications for Methotrexate 
Note that no dose reductions will apply. See Section 19.0 for MTX/leucovorin management. 
Toxicity 
Grade 
Action 
Myelosuppression 
On Day 1 of cycle ANC  < 0.25 
x 109/L  
Or WBC < 1.0 x 109/L                 
Plt    < 50 x 109/L  
 
Delay until recovery according to group practice (see 
appendix B.6) 
Mucositis,  Severe 
abdominal pain,  
Diarrhea 
Grade 3-4 mucositis or diarrhea 
after MTX 
 
If persists for >1 Week  & is 
present in Week 4 of  MAP 
cycle 
Consider Leucovorin Rescue Adjustment. Reminder: 
exclude drugs interfering with excretion 
 
Omit Day 29 methotrexate (of this cycle only) & proceed 
to next cycle (or surgery) 
Renal Toxicity 
GFR  
< 70 mL/min/1.73m2 
 
 
 
Delay until recovery.  
If renal function does not improve within 1 week, omit 
MTX & proceed to next possible cycle.  If renal function 
subsequently improves, MTX can be resumed  
 
(Patients receiving DOXO alone may continue to receive 
the drug) 
Abnormal LFTs 
Not MTX induced 
LFTs elevated  
 
Probably MTX induced i.e. up 
to 3 weeks after MTX 
 
 
 
 
 
Bilirubin > 1.5 x N 
 
Delay one week. Give if ALT < x10 N 
 
It is expected that patients receiving high dose 
Methotrexate will develop hypertransaminasemia and 
occasionally hyperbilirubinemia. These elevations can last 
up to two weeks following the methotrexate infusion and 
will not be considered toxicity requiring discontinuation of 
the drug. 
 
Persistent hyperbilirubinemia for longer than three weeks 
will result in discontinuation of MTX 
 
 
An attempt to give any omitted MTX doses should be made after the end of scheduled protocol 
chemotherapy, if the patient fulfills the necessary organ function requirements. 


 
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Page 41 
 
5.3 
Dose Modifications for Ifosfamide/Etoposide 
 
Toxicity 
Grade 
Action 
Myelosuppression 
On Day 1 of cycle  
ANC    < 0.75 x 109/L 
Or WBC < 2.0 x 109/L 
Plt        < 75 x 109/L 
Delay and repeat within 3-4 days; retreat at full dose unless 
previous dose reduction.  Consider reduction if cycle is delayed 
>7 days in spite of growth factor support (20% dose reduction 
by omitting the last day of the cycle). 
 
Febrile neutropenia after 
previous IFOS/ETOP 
Consider for grade 3 All Grade 4 
Doses should be reduced in patients who experience febrile 
neutropenia with clinically significant or microbiologically 
documented infection.  Reduce both drugs by 20% i.e. omit last 
day of cycle.  If a second episode occurs, omit ETOP. 
 
Mucositis, severe 
abdominal pain, diarrhea, 
typhlitis 
Grade 4 mucositis after previous 
IFOS/ETOP 
Repeated Grade 3 mucositis 
 
 
Reduce ETOP by 50%  
Renal Toxicity – 
glomerular 
Serum Creatinine  1.5 x baseline  
or 
GFR < 70 mL/min/1.73 m2 
 
 
GFR 10-50 mL/min 
 
GFR < 10 mL/min 
Delay for one week. If renal function does not improve, 
discontinue IFOS, confirm GFR and consider substituting 
cyclophosphamide and MESNA, both 500mg/m2 x 5 days  
 
Decrease dose ETOP  by 25% 
 
Decrease dose ETOP  by 50% 
 
Renal Toxicity – tubular 
(based on GFR, serum 
bicarbonate, need for 
electrolyte replacement, 
or TmP/GFR) 
Grade 1 
No change 
Grade 2 
 
Consider reduction of IFOS by 20%  i.e. omit last day 
 
Grade 3 or 4 
No further IFOS. Consider substituting cyclophosphamide and 
MESNA, both 500 mg/m2 x 5 days 
Hematuria 
(exclude vaginal bleeding 
and if microscopic, 
confirm where possible 
by microscopy) 
Dipstick positive prior to IFOS 
Give additional MESNA bolus of 600 mg/m2 then continuous 
infusion at double dose 
Microscopic during IFOS ≥ 2 
occasions (>50 RBC/HPF) 
 
No further IFOS. If hematuria resolves completely, ifosfamide 
with double dose MESNA could be considered for the next 
ifosfamide containing cycle.  Investigators could also consider 
substituting cyclophosphamide and MESNA, both 500 mg/m2 x 
5 days  
≥ Grade 2 
Exclude other causes; double 
MESNA dose +/- increase 
hydration.  
 
Discontinue IFOS, continue double dose MESNA and hydration 
for 24 hours after IFOS;  consider cystoscopy;  In subsequent 
IFOS containing cycles, consider substituting cyclophosphamide 
and MESNA, both 500 mg/m2 x 5 days  
Neurological toxicity – 
confusion or depressed 
level of consciousness  
Grade2 
No change unless persistent and distressing.  Then decrease 
IFOS by 20% (omit last day‟s dose).  If persists, reduce by a 
further 20% 
Grade 3 
Stop IFOS for this cycle.  Decrease IFOS by 20% (omit last 
day‟s dose) during the next cycle.  If persists, reduce by a further 
20% 
Grade 4 
If Grade 4 neurotoxicity occurs during ifosfamide 
administration, investigators may consider administration of 
methylene blue at 2 mg/kg (maximum dose 50 mg) on the day 
this occurs.  The dose may be repeated at 4 hours and 8 hours 
after, following which ifosfamide should be discontinued and no 
further ifosfamide will be administered.  Investigators should 
consider substituting cyclophosphamide and MESNA, both 500 
mg/m² x 5 days. Hypersensitivity, renal impairment and G-6PD 
deficiency are contraindications to administer methylene blue. 
Table continued on next 
page 
 
 


 
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Page 42 
Toxicity 
Grade 
Action 
Neurological toxicity - 
seizures 
Grade 2 
 
 
Consider anticonvulsants (benzodiazepines preferred) and/or 
stopping IFOS for this cycle.  Continue future cycles at same 
dose. 
Grade 3 
 
Stop IFOS for this cycle.  Consider future cycles at same dose 
with anticonvulsant coverage 
Grade 4 
 
If Grade 4 neurotoxicity occurs during ifosfamide 
administration, investigators may consider administration of 
methylene blue at 2 mg/kg (maximum dose 50 mg) on the day 
this occurs.  The dose may be repeated at 4 hours and 8 hours 
after, following which ifosfamide should be discontinued and no 
further ifosfamide will be administered.  Investigators should 
consider substituting cyclophosphamide and MESNA, both 500 
mg/m² x 5 days. Hypersensitivity, renal impairment and G-6PD 
deficiency are contraindications to administer methylene blue. 
Neurological toxicity – 
peripheral neuropathy 
(exclude other causes) 
 ≥ Grade 2 
Omit further IFOS. Consider substituting cyclophosphamide and 
MESNA, both 500 mg/m2 x 5 days 
 
An attempt to give any omitted ifosfamide/etoposide cycles should be made after the end of scheduled protocol 
chemotherapy, if the patient fulfills the necessary organ function requirements.  Patients scheduled to receive 
pegylated interferon alfa-2b should complete all standard cytotoxic chemotherapy and have a 7-day interval prior to 
beginning pegylated interferon alfa-2b.  


 
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Page 43 
 
5.4 
Dose Modifications for Doxorubicin/Ifosfamide 
Toxicity 
Grade 
Action 
Myelosuppression 
On Day 1 of cycle, ANC 
<750/µL and platelets < 
75,000/µL 
Delay and repeat within 3-4 days.  Retreat at full dose unless previous dose 
reduction.  For repeated delay Investigators can consider reducing IFOS dose to 
6 g/m² by eliminating the last day of the Cycle. 
Febrile Neutropenia 
after previous 
DOXO/IFOS 
All Grade 4, consider for 
Grade 3 
If despite GCSF, reduce ifosfamide to total 6 g/m2 by eliminating the last day of 
the cycle 
 
Mucositis, Severe 
abdominal  pain, 
Diarrhea, Typhlitis 
Grade 4 mucositis after 
DOXO/ CDDP  or 
repeated Grade 3 
mucositis 
Delay until resolved & decrease subsequent doxorubicin to 60 mg/m2/cycle; 
Note: if previous DOXO dose reductions other than for cardiotoxicity or Grade 4 
mucositis, decrease doxorubicin to 50 mg/m2/cycle  and ifosfamide to 6 g/m2 by 
eliminating the last day of the cycle 
 
Cardiotoxicity 
 
 
LVEF < 50%    or  SF ≤ 
28%  
Repeat echo or MUGA in one week; If echo or MUGA within normal range 
proceed with chemotherapy.  If LVEF does not normalize, omit all further 
DOXO 
 
Hepatic Toxicity 
 
 
 
 
 
 
 
Elevated  Total Bilirubin 
 
 
 
 
Reduce doxorubicin as follows: 
      Concentration                                        % Dose 
          0 – 21 mol/L     (0     -1.24 mg/dL)      100% 
        22 – 35 mol/L     (1.25-2.09 mg/dL)        75% 
        36 – 52 mol/L     (2.1  -3.05 mg/dL)        50% 
        53 – 86 mol/L     (3.06-5.0   mg/dL)        25% 
          > 87 mol/L        (     > 5.0   mg/dL)          0% 
Renal Toxicity – 
glomerular 
Serum Creatinine    1.5 x 
baseline or 
GFR < 70 mL/min/1.73 
m2 
Delay for one week.  If renal function does not improve, omit IFOS, confirm 
GFR and consider substituting cyclophosphamide and MESNA, both 500 mg/m2 
x 3 days for future cycles  
Renal Toxicity – 
tubular 
(based on GFR, 
serum Bi, electrolyte 
replacement, 
TmP/GFR) 
Grade 1 
No change 
Grade 2 
Reduce IFOS to 6 g/m2  (by eliminating last day) 
Grade 3/4 
No further IFOS 
Hematuria 
(exclude vaginal 
bleeding and if 
microscopic, confirm 
where possible by 
microscopy) 
Dipstick positive prior to 
IFOS  
Exclude other causes; double MESNA dose +/- increase hydration.  
Microscopic during IFOS  
≥ 2 occasions  (>50 
RBC/HPF) 
Give additional 600 mg/m² MESNA bolus then continuous infusion at double 
dose. If persists, discontinue IFOS .  If hematuria resolves completely, 
ifosfamide with double dose MESNA could be considered for the next 
ifosfamide containing cycle.  Investigators could also consider substituting 
cyclophosphamide and MESNA, both 500 mg/m2 x 5 days  
 
≥ Grade 2 
 
Discontinue ifosfamide, continue double dose MESNA and hydration for 24 
hours after ifosfamide; consider cystoscopy;  For the next ifosfamide containing 
cycle, consider substituting cyclophosphamide and MESNA, both 500 mg/m2 x 5 
days 
Neurological toxicity 
– confusion or 
depressed level of 
consciousness  
Grade2 
No change unless persistent and distressing.  For further cycles decrease 
ifosfamide to 6 g/m2. (eliminating last day of cycle)  If persists further, omit 
ifosfamide. Consider substituting cyclophosphamide and MESNA, both 500 
mg/m2 x 3 days 
Grade 3 
Decrease ifosfamide to 6 g/m2 (eliminating last day of cycle).  If persists further, 
omit ifosfamide. Consider substituting cyclophosphamide and MESNA, both 500 
mg/m2 x 3 days 
Grade 4 
If Grade 4 neurotoxicity occurs during ifosfamide administration, investigators 
may consider administration of methylene blue at 2 mg/kg (maximum dose 50 
mg) on the day this occurs.  The dose may be repeated at 4 hours and 8 hours 
after, following which ifosfamide should be discontinued and no further 
ifosfamide will be administered.  Investigators should consider substituting 
cyclophosphamide and MESNA, both 500 mg/m² x 5 days. Hypersensitivity, 
renal impairment and G-6PD deficiency are contraindications to administer 
methylene blue. 
Table continued-next 
page 
 
 


 
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Page 44 
Toxicity 
Grade 
Action 
Neurological toxicity 
- seizures 
Grade 2 
 
 
Consider anticonvulsants (benzodiazepines preferred) and/or stopping IFOS for 
this cycle.  Continue future cycles at same dose. 
Grade 3 
 
Stop IFOS for this cycle.  Consider future cycles at same dose with 
anticonvulsant coverage 
Grade 4 
 
If Grade 4 neurotoxicity occurs during ifosfamide administration, investigators 
may consider administration of methylene blue at 2 mg/kg (maximum dose 50 
mg) on the day this occurs.  The dose may be repeated at 4 hours and 8 hours 
after, following which ifosfamide should be discontinued and no further 
ifosfamide will be administered.  Investigators should consider substituting 
cyclophosphamide and MESNA, both 500 mg/m² x 5 days. Hypersensitivity, 
renal impairment and G-6PD deficiency are contraindications to administer 
methylene blue. 
Neurological toxicity 
– peripheral 
neuropathy 
(exclude other 
causes) 
 ≥ Grade 2 
Omit further IFOS. Consider substituting cyclophosphamide and MESNA, both 
500 mg/m2 x 3 days 
 
An attempt to give any omitted doxorubicin/ifosfamide cycles should be made after the end of scheduled protocol 
chemotherapy, if the patient fulfills the necessary organ function requirements.  Patients scheduled to receive 
pegylated interferon alfa-2b should complete all standard cytotoxic chemotherapy and have a 7-day interval prior to 
beginning pegylated interferon alfa-2b.  


 
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Page 45 
 
5.5 
Dose Modifications for Pegylated interferon alfa-2b 
Toxicity 
Grade 
Action 
Fever, chills, 
fatigue, 
headache etc 
Any 
 
May improve with continued treatment. 
May be decreased with bedtime administration. 
Treat with paracetamol/acetaminophen and if severe, NSAID providing platelet count is 
maintained. 
Dose reduction appropriate only if sustained and not relieved by above. 
Hyperglycemia not controlled by drugs – discontinue ifn. 
Triglycerides persistently > 1000 associated with symptoms of potential pancreatitis or 
pancreatitis, hold ifn until resolution. Restart at lower dose level. If recurs, discontinue 
ifn. 
Hemoglobin 
Grade 3-4 
Persistent and symptomatic 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.  If no resolution within 4 weeks, stop ifn. 
Leucopenia 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%. If resolves to < grade 2, resume the previous dose level and, if at the starting dose 
level (0.5 mcg/kg/week), the planned dose escalation 4 weeks later. 
If no resolution within 4 weeks, stop ifn until resolved to ≤ Grade 2, then resume at 
reduced dose level (starting dose level 0.5 mcg/kg/week, or, at 25% below the starting 
dose level if toxicity was encountered at starting dose level). If toxicity recurs, stop ifn. 
 
Stop ifn until toxicity has resolved to  ≤ Grade 2, then resume ifn at starting dose level  
( 0.5 mcg/kg/week), or, if at starting dose level, decrease by 25%. If grade 3 or greater 
toxicity recurs, stop ifn. 
Neutrophils 
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
Reduce dose by 25% (if patient receiving 0.5 mcg/kg/week) or to starting dose (if 
patient receiving 1 mcg/kg/week).  If toxicity resolves to < grade 2 and patient reduced 
to starting dose attempt escalation to 1 mcg/kg/week after 4 weeks.  If toxicity resolves 
to < grade 2 and patient at 25% dose reduction, then attempt escalation to starting dose.  
If toxicity recurs after dose escalation, drop dose by 25% (if patient at 0.5 
mcg/kg/week) or to starting dose (if patient at 1 mcg/kg/week) and wait for resolution to 
< grade 2. Do not attempt further escalation and continue ifn at reduced dose (starting 
dose or 25% dose reduction).   
 If no resolution of grade 3 neutropenia within 4 weeks of dropping dose (starting dose 
or 25% dose reduction) hold ifn until resolved to ≤ Grade 2,  then resume ifn at starting 
dose level (if patient receiving 1 mcg/kg/week) or at 25% dose reduction (if patient 
receiving 0.5 mcg/kg/week).  If patient tolerates dose reduction x 4 weeks without 
toxicity attempt escalation to starting dose level (0.5 mcg/kg/week) or if at starting dose 
level to 1 mcg/kg/week.  If toxicity recurs after dose escalation, decrease dose to 
starting dose (if patient receiving 1 mcg/kg/week) or to 25% dose reduction (if patient 
receiving 0.5 mcg/kg/week).  Do not attempt further dose escalation. 
Grade 4 neutropenia: Hold ifn until toxicity has resolved to ≤ Grade 2, then resume 
ifn at starting dose level (if patient receiving 1 mcg/kg/week) or at 25% dose reduction 
(if patient receiving 0.5 mcg/kg/week).  If patient tolerates dose reduction x 4 weeks 
without toxicity attempt escalation to starting dose level (0.5 mcg/kg/week) or if at 
starting dose level to 1 mcg/kg/week.  If toxicity recurs after dose escalation, decrease 
dose to starting dose (if patient receiving 1 mcg/kg/week) or to 25% dose reduction (if 
patient receiving 0.5 mcg/kg/week).  Do not attempt further dose escalation. 
 
If grade 3 or greater toxicity recurs after resuming ifn at reduced dose, then hold ifn 
until toxicity has resolved to ≤ Grade 2, then resume ifn at starting dose level (0.5 
mcg/kg/week), or, if at starting dose level, decrease by 25%.  If grade 3 or greater 
toxicity recurs, permanently discontinue ifn. 
 


 
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Page 46 
Platelets 
Grade 2 
 
 
 
 
 
 
 
Grade 3-4 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.. If resolves to < grade 1, resume the previous dose level and, if at the starting dose 
level (0.5 mcg/kg/week), the planned dose escalation 4 weeks later. 
If no resolution within 4 weeks, stop ifn until resolved to ≤ Grade 1, then resume at 
reduced dose level (starting dose level 0.5 mcg/kg/week, or, at 25% below the starting 
dose level if toxicity was encountered at starting dose level). If toxicity recurs, stop ifn. 
 
Stop ifn until toxicity has resolved to  ≤ Grade 1, then resume ifn at starting dose level  
( 0.5 mcg/kg/week), or, if at starting dose level, decrease by 25%. If grade 2 or greater 
toxicity recurs, stop ifn. 
Renal toxicity – 
raised creatinine 
Grade 2 
 
Grade 3-4 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.  If no resolution within 4 weeks, stop ifn. 
Discontinue. 
Neurotoxicity 
incl. Mood 
disturbance 
Grade 2 or 
greater 
 
Any mood 
disturbance 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.  If no resolution within 4 weeks, stop ifn. 
 
Undertake psychiatric assessment.  Consider discontinuation. 
Cardiotoxicity 
e.g. arrhythmia 
 
Grade 2   
 
Grade 3-4 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.  If no resolution within 4 weeks, stop ifn. 
Discontinue. 
Pancreatitis 
 
Elevated triglycerides can result in pancreatitis.  PEG-intron should be discontinued in 
patients who develop pancreatitis. 
Hepatic Toxicity 
-raised bilirubin 
 Grade 3 
 
Grade 4 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.  If no resolution within 4 weeks, stop ifn. 
Discontinue. 
Table continued 
on next page 
 
 
Toxicity 
Grade 
Action 
Gastro-intestinal 
e.g. vomiting or 
diarrhea 
Grade 2 for > 2 
weeks or ≥ grade 
3 
Reduce to starting dose (0.5 mcg/kg/week), or, if at starting dose level, decrease by 
25%.  If no resolution within 4 weeks, stop ifn. 
Thyroid 
dysfunction 
Any 
Assess and treat thyroid as appropriate.  Continue ifn unless not controlled. 
Triglycerides 
>8.5 ULN 
Stop ifn until triglycerides <8.5 ULN. 


 
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Page 47 
 
6.0 
DRUG INFORMATION 
 
6.1 
DOXORUBICIN (Adriamycin®) NSC #123127  
 
 
 
(03/25/08) 
 
Source and Pharmacology: An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. 
The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought 
to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. 
Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of 
doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important 
mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane binding may affect a 
variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, 
reductases and dehydrogenases generate highly reactive species including the hydroxyl free radical 
(OH•). Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and 
Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been shown to manifest the 
characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-
induced apoptosis may be an integral component of the cellular mechanism of action relating to 
therapeutic effects, toxicities, or both. 
 
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 5 minutes 
suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours reflects a slow 
elimination from tissues. Steady-state distribution volumes exceed 20 to 30 L/kg and are indicative of 
extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 20 mL/min/kg and is 
predominately by metabolism and biliary excretion.  The P450 cytochromes which appear to be involved 
with doxorubicin metabolism are CYP2D6 and CYP3A4.  Approximately 40% of the dose appears in the 
bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same 
time period. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 
74 to 76% and is independent of plasma concentration of doxorubicin. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out of 
every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink or red 
color to urine, sweat, tears and 
saliva 
Hyperuricemia, facial flushing, 
sclerosis of the vein 
Diarrhea, anorexia, erythematous 
streaking of the vein (flare reaction), 
extravasation (rare) but if occurs = 
local ulceration, anaphylaxis, fever, 
chills, urticaria, acute arrhythmias 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression (leukopenia, 
thrombocytopenia, anemia), 
alopecia  
Mucositis (stomatitis and 
esophagitis), hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
Any time later during 
therapy 
 
 Cardiomyopathy1 (CHF occurs 
in 5-20% at  cumulative doses 
≥ 450 mg/m²) (L) 
 
Cardiomyopathy1 (CHF occurs in  
< 5% at  cumulative doses 
≤ 400 mg/m²) (L), ulceration and 
necrosis of colon, 
hyper-pigmentation of nail bed and 
dermal crease, onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac dysfunction 
CHF (on long term follow up in 
pediatric patients) 
Secondary malignancy (in 
combination regimens) 
Unknown Frequency 
and Timing:   
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin have been noted 
in animal models. Doxorubicin is excreted into breast milk in humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
 (L) Toxicity may also occur later. 


 
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Page 48 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 50 mg¹, 150 mg² 
vials and a preservative free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 75 mg¹, 200 mg² vials. 
¹:  Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF  (rapid dissolution   formula) 
also contains methylparaben 1 mg per each 10 mg of doxorubicin to enhance dissolution. 
²   Multiple dose vial contains lactose, 0.9%NS, HCl to adjust pH to 3. 
 
Aqueous Solution: Store refrigerated 2° - 8°C, (36° - 46°F). Protect from light. Retain in carton until 
contents are used. 
 
Powder for Injection:  Store unreconstituted vial at room temperature 15° - 30°C (59° - 86°F). Retain in 
carton until contents are used. Reconstitute with preservative-free normal saline to a final concentration of 
2 mg/mL. After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The 
reconstituted solution is stable for 7 days at room temperature under normal room light (100 footcandles) 
and 15 days under refrigeration 2°- 8°C (36° -46°F). Protect from exposure to sunlight. Doxorubicin may 
be further diluted in 0.9%NaCl or dextrose containing solutions and administered by infusion. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol.  
 
Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl preferably into a large 
vein .Protect the diluted solution from sunlight. To avoid extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for further information. 
 
6.2 
CISPLATIN (Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC #119875  
(04/12/10) 
 
Source and Pharmacology: 
Cisplatin is an inorganic, water-soluble complex containing a central platinum atom, 2 chlorine atoms and 
2 ammonia molecules. In aqueous solution, the chloride ions are slowly displaced by water generating a 
positively charged aquated complex. This activated complex is then available to react with nucleophilic 
sites on DNA, RNA, or protein resulting in the formation of bi-functional covalent links, very similar to 
alkylating reactions. The intra-strand cross-links, in particular with guanine and cytosine, change DNA 
conformation and inhibit DNA synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. 
Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents.  Cisplatin has a 
rapid distribution phase of 25-80 minutes with a slower secondary elimination half-life of 60-70 hours. The 
platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including 
albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end 
of a three hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin 
and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a 
minimum half-life of five days or more. Platinum is present in tissues for as long as 180 days after the last 
administration. Both cisplatin and platinum are excreted through the kidneys ranging from 10-50%. Fecal 
elimination is minimal. Cisplatin‟s penetration into the CNS is poor. 


 
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Page 49 
Toxicities: 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  Available as an aqueous solution containing 1mg/ml of cisplatin and 9mg 
(1.54mEq)/ml of sodium chloride in 50ml, 100ml and 200 ml multi-dose non-preserved vials. Store at  
15°- 25°C (68º-77ºF). Do not refrigerate. Protect unopened container from light. The cisplatin remaining 
in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under 
fluorescent room light. Cisplatin removed from its amber container should be protected from light if not 
used within 6 hours. 
 
Guidelines for Administration: See the Treatment and Dose Modifications sections of this protocol.  
 
Cisplatin may be further diluted in dextrose and saline solutions provided the solution contains ≥ 0.2% 
sodium chloride. Dextrose/saline/mannitol containing solutions, protected from light, are stable 
refrigerated or at room temperature for 24 to 72 hours, however, cisplatin solutions should not be stored 
in the refrigerator to avoid precipitation. Cisplatin is incompatible with sodium bicarbonate and alkaline 
solutions. 
 
Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not 
be used for preparation or administration. Aluminum reacts with cisplatin causing precipitate formation 
and a loss of potency. 
 
Accidental extravasation with solutions that are > 0.5mg/mL may result in significant tissue toxicity.   
 
Supplier:  Commercially available from various manufacturers. See package insert for more detailed 
information.  
 
Common 
Happens to 21-100 children out of every 
100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to <5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea (L), vomiting (L) 
 
Metallic taste (L) 
Anaphylactic reaction ( facial 
edema, wheezing, tachycardia, and 
hypotension), phlebitis,  
extravasation (rare) but if occurs = 
local ulceration (only in concentration  
> 0.5mg/ml) 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Anorexia (L), myelosuppression, 
hypomagnesemia (L), high 
frequency hearing loss (L), 
nephrotoxicity (↑ Cr, BUN, Uric 
Acid) (L) 
Electrolyte disturbances (L) 
(hypocalcemia, natremia, 
kalemia, & phosphatemia),  
peripheral neuropathy, 
(paresthesias in a stocking-
glove distribution) (L) 
 Vestibular dysfunction, tinnitus 
(L), rash, seizure (L), elevated liver 
function tests(L),  
Delayed: 
Any time later during 
therapy 
 
Hearing loss in the normal 
hearing range 
Areflexia, loss of proprioception 
and vibratory sensation, (very rarely 
loss of motor function)  (L), optic 
neuritis, papilledema, cerebral 
blindness, blurred vision and altered 
color perception (improvement or 
total recovery usually occurs after 
discontinuing), chronic renal 
failure, deafness 
Late: 
Any time after 
completion of treatment 
 
 
Secondary malignancy 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cisplatin have been noted in animals and cisplatin can cause 
fetal harm in humans. Cisplatin is excreted into breast milk. 


 
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Page 50 
 
6.3 
METHOTREXATE (MTX, amethopterin, Trexall®) NSC #000740 
 
(10/15/08) 
 
Source and Pharmacology: 
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that reduces folic acid to 
tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one carbon fragments 
necessary for the synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis 
of DNA and cell reproduction. The polyglutamated metabolites of MTX also contribute to the cytotoxic 
effect of MTX on DNA repair and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute 
drug concentration and the duration of drug exposure. MTX is actively transported across cell membranes. 
At serum methotrexate concentrations exceeding 0.1µmol/mL, passive diffusion becomes a major means of 
intracellular transport of MTX. The drug is widely distributed throughout the body with the highest 
concentration in the kidney, liver, spleen, gallbladder and skin. Plasma concentrations following high dose 
IV MTX decline in a biphasic manner with an initial half-life of 1.5-3.5 hours, and a terminal half life of 8-
15 hours. About 50% is bound to protein. MTX is excreted primarily by the kidneys via glomerular 
filtration and active secretion into the proximal tubules. Renal clearance usually equals or exceeds creatinine 
clearance. Small amounts are excreted in the feces. There is significant entero-hepatic circulation of MTX.  
The distribution of MTX into third-space fluid collections, such as pleural effusions and ascitic fluid, can 
substantially alter MTX pharmacokinetics. The slow release of accumulated MTX from these third spaces 
over time prolongs the terminal half-life of the drug, leading to potentially increased clinical toxicity. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to <5 children out of every 100 
Immediate: 
Within 1-2 days of receiving 
drug 
Transaminase elevations Nausea, vomiting, anorexia,  
Anaphylaxis, chills, fever, dizziness, 
malaise,  drowsiness, blurred vision, 
acral erythema, urticaria, pruritis, toxic 
epidermal necrolysis, Stevens-Johnson 
Syndrome, tumor lysis syndrome, 
seizures1, photosensitivity 
Prompt: 
Within 2-3 weeks, prior to 
the next course 
 
Myelosuppression, stomatitis, 
gingivitis, photosensitivity, 
fatigue 
Alopecia, folliculitis, acne, renal toxicity 
(ATN, increased creatinine/BUN, 
hematuria), enteritis, GI ulceration and 
bleeding, acute neurotoxicity1 
(headache, drowsiness, aphasia, paresis, 
blurred vision, transient blindness, 
dysarthria, hemiparesis, decreased 
reflexes) diarrhea, conjunctivitis 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
Learning disability1 (L) 
Pneumonitis, pulmonary fibrosis(L), 
hepatic fibrosis (L), osteonecrosis (L), 
leukoencephalopathy1 (L), pericarditis, 
pericardial effusions, hyperpigmentation 
of the nails, 
Late: 
Any time after the 
completion of therapy 
 
 
Progressive CNS deterioration1 
Unknown Frequency and 
Timing:   
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of methotrexate have been 
noted in humans.  The toxicities include: congenital defects, chromosomal abnormalities, severe 
newborn myelosuppression, low birth weight, abortion, and fetal death.  Methotrexate is excreted into 
breast milk in low concentrations. 
1 May be enhanced by HDMTX and/or cranial irradiation. 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  Methotrexate for Injection is available as a lyophilized powder for injection 
in 20 mg and 1 g vials. The powder for injection contains approximately 0.14 mEq sodium in the 20 mg 
vial; 7 mEq sodium in the 1 g vial. Methotrexate for Injection is also available as a 25mg/mL solution in 
2,4,8,10,20 and 40ml preservative free vials and 2 and 10mL vials with preservative. The 2, 4, 8, 10, 20, 


 
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Page 51 
and 40 mL solutions contain approximately 0.43, 0.86, 1.72, 2.15, 4.3, and 8.6 mEq sodium per vial, 
respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative and must not be used for 
intrathecal or high dose therapy. 
 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF ); excursions permitted to 
15º-30ºC (59º- 86 Fº ). Protect from light  
 
Guidelines for Administration: See Treatment and Dose Modification sections of protocol. 
 
For IM/IV use:  Powder for injection: Dilute 1 gm vial with 19.4 ml of non-preserved SWFI, Dextrose 
5% in Water or 0.9% Sodium Chloride Injection for a 50mg/mL concentration. Dilute the 20mg vial to a 
concentration ≤ 25 mg/mL with above diluents. The powder for injection may be further diluted in 0.9% 
sodium chloride or dextrose containing solutions to a concentration of <25mg/mL for IV use. 
 
The 25mg/mL solution may be given directly for IM administration or further diluted in Saline or 
Dextrose containing solutions for IV use. Do not use the preserved solution due to risk of benzyl 
alcohol toxicity. Methotrexate dilutions are chemically stable for at least 7 days at room temperature but 
contain no preservative and should be used within 24 hours. Diluted solutions especially those containing 
bicarbonate exposed to direct sunlight for periods exceeding 4 hours should be protected from light. 
 
High dose Methotrexate requires alkalinization of the urine, adequate hydration and leucovorin rescue.  
Avoid probenecid, penicillins, cephalosporins, aspirin, and NSAIDS as renal excretion of MTX is inhibited 
by these agents. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.4 
IFOSFAMIDE 
(Isophosphamide, Iphosphamide, Z4942, Ifex®) NSC #109724 (03/30/09) 
 
Source and Pharmacology: 
Ifosfamide is a structural analogue of cyclophosphamide.  Ifosfamide requires hepatic microsomal activation 
(P450 3A isoenzymes) for the production of the reactive 4-hydroxyoxazaphorine intermediate which serves 
as a carrier molecule for the ultimate intracellular liberation of acrolein and phosphoramide mustard which 
is an active bifunctional alkylating species.  Acrolein is thought to be the cause of the hemorrhagic cystitis 
as seen with cyclophosphamide.  Ifosfamide demonstrates dose-dependent pharmacokinetics whereby the 
terminal half-life ranges from 7 to 16 hours at doses of 1.6-2.4 g/m² to 3.8-5 g/m², respectively. At 1.6 -
 2.4 g/m²/d, 12 to 18% of the dose was excreted as unchanged drug in the urine, whereas at a 5 g/m² single-
dose, 61% was excreted in the urine as the parent drug.  Evidence also exists to suggest that ifosfamide 
metabolism is inducible, with more rapid clearance occurring in the second and later doses when a course of 
therapy is given as fractionated doses over 3 to 5 days.  There is more chloroethyl side chain oxidation of 
ifosfamide (up to 50%) than of cyclophosphamide (< 10%), and the degree of such metabolism is more 
variable than with cyclophosphamide. Oxidation of the chloroethyl groups produces chloroacetaldehyde, 
which is thought to be responsible for the neurotoxicity and renal toxicity that have been seen with 
ifosfamide therapy. 


 
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Page 52 
 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea & vomiting 
(acute and delayed) 
CNS toxicity (somnolence, 
depressive psychosis and 
confusion) 
Anorexia, diarrhea, constipation, 
encephalopathy which may progress to coma 
(L), seizure,  SIADH, phlebitis, hypokalemia 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, anemia, 
cardiac toxicities 
(arrhythmia, asymptomatic 
ECG changes),  
microscopic hematuria, 
metabolic acidosis 
↑ liver enzymes,  ↑ bilirubin,  hemorrhagic 
cystitis with macroscopic hematuria, dysuria, 
cystitis,  and urinary frequency (<5% with 
mesna and vigorous hydration) (L), bladder 
fibrosis 
Delayed: 
Any time later during 
therapy 
Gonadal dysfunction : 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
 
Renal failure acute or chronic, renal tubular 
acidosis, Fanconi-like  syndrome gonadal 
dysfunction, ovarian failure1 (L), CHF 
 
Late: 
Any time after 
completion of 
treatment 
Moderate nephrotoxicity 
(↓ in glomerular filtration 
rate, renal tubular 
threshold for phosphate,  
and serum bicarbonate) 
 
Secondary malignancy, hypophosphatemic 
rickets  
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of ifosfamide have been noted in animals.  Ifosfamide is 
excreted into breast milk.   
1 Dependent on dose, age, gender and degree of pubertal development at time of treatment 
 (L) Toxicity may also occur later. 
 
Formulation and Stability: Available in 1 g and 3 g single dose vials of lyophilized white powder without 
preservatives. Reconstitute with sterile water for injection or bacteriostatic water for injection, 20ml for the 
1gm vial or with 60mL for the 3gm vial to produce a final concentration of 50mg/ml ifosfamide. Use sterile 
water for injection without benzyl alcohol for neonates and infants < 2 years of age or patients with 
hypersensitivity to benzyl alcohol Although the reconstituted product is stable for 7 days at room 
temperature and up to 6 weeks under refrigeration, the manufacturer recommends refrigeration and use 
within 24 hours to reduce the possibility of microbial contamination. Store unreconstituted vials at room 
temperature 20°-25°C (68°-77° F). Protect from temperatures above 30°C (86° F).  Ifosfamide may 
liquefy at temperatures > 35°C 
 
Guidelines for Administration:  
See Treatment and Dose Modification sections of the protocol. 
 
Solutions of ifosfamide may be diluted further to concentrations of 0.6 to 20 mg/mL in dextrose or saline 
containing solutions. Such admixtures, when stored in large volume parenteral glass bottles, Viaflex bags 
or PAB bags, are physically and chemically stable for 1 week at 30°C (86°F) or 6 weeks at 5°C (41°F). 
The manufacturer recommends refrigeration and use within 24 hours to reduce the possibility of microbial 
contamination. 
 
Mesna must always be administered in conjunction with ifosfamide. Adequate hydration is required. 
Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. 
 
Supplier:  Commercially available from various manufacturers. See package insert for further information.  


 
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6.5 
ETOPOSIDE 
(VePesid®, Etopophos®,VP-16)  NSC #141540  
 
 
(03/30/09) 
 
Source and Pharmacology:  A semisynthetic derivative of podophyllotoxin that forms a complex with 
topoisomerase II and DNA which results in single and double strand DNA breaks. Its main effect appears 
to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 
to 11 hours. It is primarily excreted in the urine. In children, approximately 55% of the dose is excreted in 
the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 
35% of the total body clearance over a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by 
both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on 
plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide 
elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism 
accounts for most of the non renal clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high 
degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum 
albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. 
Preliminary data suggests that systemic exposure for unbound etoposide correlates better than total 
(bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely converted to 
etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide phosphate is 
bioequivalent to etoposide when it is administered in molar equivalent doses. 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension during infusion; 
anaphylaxis (chills, fever, tachycardia, dyspnea, 
bronchospasm, hypotension) 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression (anemia, 
leukopenia), alopecia  
Thrombocytopenia,  diarrhea, 
abdominal pain, asthenia, 
malaise, rashes and urticaria 
Peripheral neuropathy, mucositis, 
hepatotoxicity, chest pain, thrombophlebitis, 
congestive heart failure, Stevens-Johnson 
Syndrome, exfoliative dermatitis  
Delayed: 
Any time later during 
therapy 
 
 
Dystonia, ovarian failure, amenorrhea, 
anovulatory cycles,  hypomenorrhea, 
onycholysis of  nails  
Late: Any time after 
completion of 
treatment 
 
 
Secondary malignancy (preleukemic or 
leukemic syndromes) 
 
UnknownFrequency 
and Timing: 
Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 1/20th of the human dose.  It 
is unknown whether the drug is excreted in breast milk. 
 
 
Formulation and Stability: 
Etoposide for Injection is available in sterile multiple dose vials. The pH of the clear, nearly colorless to 
yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial 
headspace contains nitrogen. 
 
Unopened vials of etoposide are stable until expiration date on package at controlled room temperature 
(20°-25°C or 68°-77°F).  
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized powder in 
single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate 
USP, and 300 mg dextran 40.  


 
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Page 54 
Etoposide phosphate must be stored under refrigeration 2°-8°C or 36°- 46°F). Unopened vials of 
etoposide phosphate are stable until the expiration date on the package. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Etoposide: 
Dilute etoposide to a final concentration < 0.4 mg/mL in 5% Dextrose Injection, USP or 0.9% Sodium 
Chloride Injection, USP.  Etoposide infusions are stable at room temperature for 96 hours when diluted to 
concentrations of 0.2mg/ml; stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. 
The time to precipitation is highly unpredictable at concentrations > 0.4mg/mL. Use in-line filter during 
infusion secondary to precipitate formation risk. However, the use of an in-line filter is not mandatory 
since etoposide precipitation is unlikely at concentrations of 0.1-0.4 mg/mL. Do not administer 
etoposide by rapid intravenous injection. Slow rate of administration if hypotension occurs. 
 
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred with etoposide 
0.4mg/mL in 0.9% sodium chloride solution. To avoid leaching, prepare the etoposide solution as close as 
possible, preferably within 4 hours, to the time of administration or alternatively as per institutional 
policy, glass or polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be used. 
 
Etoposide Phosphate: 
Dilute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, USP; 5% Dextrose Injection, USP; 
0.9% Sodium Chloride Injection, USP; Bacteriostatic Water for Injection with Benzyl Alcohol; or 
Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol for a concentration equivalent to 20 
mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), respectively. Use 
diluents without benzyl alcohol for neonates and infants < 2 years of age or patients with 
hypersensitivity to benzyl alcohol. 
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or plastic containers 
under refrigeration for 7 days. When reconstituted with a diluent containing a bacteriostat, store at 
controlled room temperature for up to 48 hours. Following reconstitution with Sterile Water for Injection,  
5% Dextrose Injection, or 0.9% Sodium Chloride Injection, store at controlled room temperature for up to 
24 hours.  
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as low as 0.1 
mg/mL of etoposide with 5% Dextrose Injection or 0.9% Sodium Chloride Injection. The diluted solution 
can be stored under refrigeration or at controlled room temperature for 24 hours. 
 
Supplier:  Commercially available from various manufacturers.  See package insert for more detailed 
information. 
 
CANADIAN SITES 
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites may purchase and 
import the USA commercial supply from Bristol Laboratories via an International Distributor (Pharma 
Exports LLC, phone: 1-412-885-3700, fax: 1-412-885-8022, email: pharexp@aol.com) under the 
authority of the protocol‟s No Objection Letter (NOL). A “Fax Notification” of the lot number and expiry 
date of each lot received in a Canadian pharmacy must be faxed to Health Canada, Clinical Trials Quality 
Division, Bureau of Pharmaceutical Sciences at 613-954-8867, Attention: Michael Bourdon or designee 
by the site pharmacist. A lot must not be used until Health Canada has been notified by fax. Note: 
Etopophos® may have orders placed and Drug Accountability Logs maintained on a multiple protocol 
basis (Multiple Protocol - Imported Therapeutic) as long as each protocol has a NOL.   


 
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6.7 
MESNA   (sodium 2-mercaptoethane sulfonate,UCB 3983, Mesnex ) NSC #113891      
(03/30/09) 
 
Source and Pharmacology:  Mesna was developed as a prophylactic agent to reduce the risk of 
hemorrhagic cystitis induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna 
disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly eliminated 
by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol compound, mesna, which 
reacts chemically with the urotoxic ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) resulting 
in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy-
ifosfamide forming a nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of 
acrolein and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model studies, 
mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed 
to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half lives for mesna and diMesna are 0.36 hours and 1.17 hours, respectively. 
Approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna 
and dimesna, respectively. The majority of the dose recovered was eliminated within 4 hours. Mesna 
tablets have an oral bioavailability of 45-79% and a urinary bioavailability which ranged from 45-79% of 
intravenously administered mesna.  The oral bioavailability is unaffected by food. When compared to 
intravenously administered mesna, the intravenous plus oral dosing regimen increases systemic exposures 
(150%) and provides more sustained excretion of mesna in the urine over a 24-hour period. 
 
Toxicity1: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of every 
100 
Immediate: 
Within 1-2 days of receiving 
drug 
Bad taste with oral use 
Nausea, vomiting, stomach 
pain, fatigue, headache, 
Facial flushing, fever, pain in arms, 
legs, and joints, rash, transient 
hypotension, tachycardia, dizziness, 
anxiety, confusion, periorbital 
swelling, anaphylaxis, coughing 
Prompt: Within 2-3 weeks, 
prior to the next course 
 
Diarrhea 
 
Unknown Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 10 times 
the recommended human doses. There are, however, no adequate and well-controlled studies in 
pregnant women. It is not known if mesna or dimesna is excreted into human milk 
1All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has been associated 
with death in pre-term infants weighing less than 2500 g and receiving 99-405 mg/kg/day. Benzyl alcohol is 
normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. In 
pre-term infants, however, this metabolic pathway may not be well developed. Onset of toxic illness in these infants 
occurred between several days and a few weeks of age with a characteristic clinical picture that included metabolic 
acidosis progressing to respiratory distress and gasping respirations. Many infants also had central-nervous-system 
dysfunction, including convulsions and intracranial hemorrhage; hypotension leading to cardiovascular collapse 
was a late finding usually preceding death. [For comparison in the ICE regimen of 3000 mg/m²/day of ifosfamide 
and a daily mesna dose of 60% of the ifosfamide dose = to 1800 mg/m²/day; a child would be expected to receive 
18 mL/m²/day of mesna (concentration of 100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2  mg/m²/day of benzyl 
alcohol or 6.24 mg/kg/day.]   
 
Formulation and Stability:    
Mesna for injection is available as 100 mg/mL 10 ml multidose vials which contain 0.25 mg/mL edetate 
disodium and sodium hydroxide for pH adjustment. Mesna Injection multidose vials also contain 


 
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Page 58 
10.4 mg/mL of benzyl alcohol as a preservative. Store product at controlled room temperature 15 -25 C 
(68 -77ºF). Mesna is not light-sensitive, but is oxidized to dimesna when exposed to oxygen. Mesna as 
benzyl alcohol-preserved vials may be stored and used for 8 days. 
Mesna non-preserved ampoules are no longer provided by Bristol-Myer Squibb Company. 
 
Guidelines for Administration: See Treatment, Dose Modifications and Supportive Care sections of the 
protocol. 
 
For IV administration, dilute to 20 mg/mL with dextrose or saline containing solutions. Mesna may be 
mixed with ifosfamide or cyclophosphamide. After dilution for administration, mesna is physically and 
chemically stable for 24 hours at 25ºC (77ºF).  Carefully expel air in syringes prepacked for use to avoid 
oxidation to dimesna. 
 
Mesna may cause false positive test for urinary ketones.  
 
Supplier:  Commercially available from various manufacturers. See package insert for further 
information. 
 
CANADIAN SITES 
Preservative-free Mesna is commercially available in Canada from Baxter Corporation (Urometixan®); 
supplied as 100mg/mL solution which contains edentate disodium and sodium hydroxide for pH 
adjustment, 4mL and 10mL single-use ampoules. 
 
 
6.8 
LEUCOVORIN CALCIUM (LCV, Wellcovorin®, citrovorum factor, folinic acid)  
NSC #003590  
 
 
 
 
 
 
 
(03/25/09) 
 
Source and Pharmacology:   
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). 
The biologically active compound of the mixture is the (-)- l-isomer, known as Citrovorum factor or (-)-
folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to 
participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of 
leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, 
which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and 
toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Leucovorin is readily 
converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of 
fluorodeoxyuridylic acid  (an active metabolite of 5-FU) to thymidylate synthase and thereby enhances 
the inhibition of this enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at 
approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form.  The terminal half-life of total reduced 
folates was approximately 6.2 hours.  Following oral administration, leucovorin is rapidly absorbed and 
expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer (the 
biologically active form) but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin is 
saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 
50 mg, and 37% for 100 mg doses. Both oral and parenteral leucovorin raise the CSF folate levels. 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to <5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Anaphylaxis, urticaria, seizure 
Unknown Frequency and timing: Fetal toxicities and teratogenic effects of leucovorin in humans are unknown.  It is unknown 
whether the drug is excreted in breast milk. 
 


 
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Page 59 
Formulation and Stability:  Leucovorin calcium for injection is supplied as a sterile ready to use liquid 
and a sterile powder for injection. The 10 mg/mL preservative free liquid is available in 50 mL vials 
containing sodium chloride 400 mg/vial. Store preservative free liquid in the refrigerator at 2°-8°C (36°-
46°F) protected from light. The powder for injection is available in 50 mg, 100 mg, 200 mg, 350 mg and 
500 mg vials. Store at room temperature 15°-25°C (59°-77°F) protected from light. Reconstitute the sterile 
powder with sterile water for injection or bacteriostatic water for injection to a concentration of 10mg/mL 
leucovorin calcium. Do not use diluents containing benzyl alcohol for doses >10 mg/m² or in infants 
< 2 years of age or patients with allergy to benzyl alcohol. When Bacteriostatic Water is used, the 
reconstituted solution is good for 7 days.  If reconstituted with sterile water, use solution immediately as it 
contains no preservative. One milligram of leucovorin calcium contains 0.004 mEq of leucovorin and 
0.004 mEq of calcium. 
 
The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive ingredients 
vary depending on manufacturer but tablet formulations may include: corn starch, dibasic calcium 
phosphate, magnesium stearate, pregelatinized starch, lactose, microcrystalline cellulose, and sodium 
starch glycolate. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol.  
 
 Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be 
injected intravenously per minute (16 mL of a 10 mg/mL solution per minute). IV leucovorin and sodium 
bicarbonate are incompatible. 
 
Oral leucovorin should be spaced evenly (e.g.: every six hours) throughout the day and may be taken 
without regard to meals. Doses > 25 mg should be given IV due to the saturation of absorption. 
 
Leucovorin should not be administered < 24 hours after intrathecal injections which contain methotrexate 
unless there are special circumstances. 
 
Supplier:  Commercially available from various manufacturers. See package insert for further 
information. 
 
6.9 
DEXRAZOXANE (ICRF-187, ADR-529, ZINECARD ) NSC #169780  
(03/25/09) 
Source and Pharmacology:  Dexrazoxane is a synthetic chemical, a cyclic derivative of EDTA that 
readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted 
intracellularly to a ring opened chelating agent that interferes with iron mediated free radical generation 
thought to be responsible, in part, for anthracycline-induced cardiomyopathy. The disposition kinetics of 
dexrazoxane are dose-dependent with administered doses from 60 to 900 mg/m2. The plasma half-life is 2 
to 2.5 hours. Qualitative metabolism studies have confirmed the presence of unchanged drug, a diacid-
diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. 
Metabolite levels were not measured in the pharmacokinetics studies. Urinary excretion plays an 
important role in the elimination of dexrazoxane: 42% of the drug (500 mg/m2) was excreted in the urine. 
In vitro studies have shown that dexrazoxane is not bound to plasma proteins. The pharmacokinetics of 
dexrazoxane have not been evaluated in patients with hepatic or renal insufficiency. There was no 
significant effect of dexrazoxane on the pharmacokinetics of doxorubicin (50 mg/m2) or its predominant 
metabolite, doxorubicinol in a crossover study in cancer patients. 
 
 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
 
Pain on injection, phlebitis transient increases 
in triglycerides and amylase, increase in SGPT 
Anorexia, malaise, 
extravasation (rare) but if 


 
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Page 60 
receiving drug 
(ALT)/SGOT (AST) and bilirubin, mild  
nausea, vomiting, diarrhea, increase in serum 
iron, decrease in serum zinc and calcium  
occurs may = ulceration 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression  
 
Prolongation of PT/PTT  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancies 
(have been reported with oral 
razoxane; the racemic mixture, 
of which dexrazoxane is the 
S(+)-enantiomer) 
Unknown 
Frequency and 
Timing:   
Fetal toxicities and teratogenic effects have been noted in animals. Dexrazoxane was maternotoxic, 
embryotoxic and teratogenic when given to pregnant rats and rabbits during the period of organogenesis. It 
is not known whether dexrazoxane is excreted in human milk. 
 
 
Formulation and Stability:  
Dexrazoxane for Injection is available as a sterile, pyrogen-free lyophilized powder in the following 
strengths: 250 mg single dose vial packaged with a 25 mL vial of 0.167 Molar (M/6) Sodium Lactate 
Injection, USP and 500 mg single dose vial  packaged with a 50 mL vial of 0.167 Molar (M/6) Sodium 
Lactate Injection, USP. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). 
 
Dexrazoxane must be reconstituted with 0.167 Molar (M/6) Sodium Lactate Injection, USP, to give a 
concentration of 10 mg dexrazoxane for each mL of sodium lactate. Reconstituted dexrazoxane, when 
transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at 
controlled room  temperature, 15°-30°C (59°-86°F) or under refrigeration, 2°-8°C (36°-46°F).  
 
The reconstituted dexrazoxane solution may be further diluted with either 0.9% Sodium Chloride 
Injection, USP or 5.0% Dextrose Injection, USP to a concentration range of 1.3 to 5.0 mg/mL in 
intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room 
temperature, 15°-30°C (59°-86°F) or under refrigeration, 2°-8°C (36°-46°F).  
 
Guidelines for Administration:  See Treatment and Dose Modifications sections of the protocol. 
 
For the prevention of anthracycline-induced cardiomyopathy, administer IV push immediately prior to 
anthracycline dose. Administer the anthracycline after completing the infusion of dexrazoxane but within 
30 minutes of beginning of the dexrazoxane infusion. 
 
Supplier:  Commercially available. See package insert for further information. 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
 
 
 
 
 
 
 
 
 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on 
established standards of care.  Minor unavoidable departures (up to 72 hours) from 
protocol directed therapy and/or disease evaluations (and up to 1 week for surgery) for 
valid clinical, patient and family logistical, or facility, procedure and/or anesthesia 
scheduling issues are acceptable per COG Administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  


 
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7.1 
Required and Suggested Observations 
All entry/eligibility hematologic and biochemical studies must be performed within 1 week prior to entry onto the trial (unless otherwise 
specified).  Imaging studies are required within 1 month prior to study entry. Rapid central review of biopsy and surgical specimens is required. 
Enrollment on an osteosarcoma specimen collection study is strongly encouraged. 
 
STUDIES TO BE OBTAINED 
Study Entry 
Twice weekly 
Before each 
Cycle 
Post-op  
Prior to  
PEG-Intron 
End of 
Therapy 
During 
Follow-up 
History 
X 
 
X 
 
 
X 
Suggested 
Physical Exam (Ht, Wt, BSA, VS) 
X 
 
X 
 
 
X 
Suggested 
Performance Status 
X 
 
X 
 
 
X 
Suggested 
CBC, differential, platelets 
X 
X1 
X 
 
 
X 
Suggested 
Urinalysis 
X 
 
X 
 
 
X 
Suggested 
Urine phosphate and creatinine 
X 
 
--- 
 
 
X 
Suggested 
Electrolytes including Ca++, PO4, Mg++, 
bicarbonate 
X 
 
X 
 
 
X 
Suggested 
Creatinine, BUN, SGOT, SGPT, 
bilirubin, alk phos 
X 
 
X 
 
 
X 
Suggested 
Evaluation for liver function 
 
 
 
 
X 
 
 
Total protein/albumin 
X 
 
 
 
 
X 
Suggested 
Coagulation profile 
X 
 
 
 
 
 
Suggested 
Glomerular Filtration Rate 2 
X 
 
X 
 
 
X 
Suggested 
Left ventricular function (Echo or 
MUGA) 
X 
 
 X3 
 
 
 
Suggested 
Audiogram 
X 
 
 X4 
 
 
X 
Suggested 
Ophthalmologic evaluation 
 
 
 
 
X 
 
 
Triglyceride level 
 
 
 
 
X 
 
 
Thyroid function 
 
 
 
 
X 
 
 
Quality of Life assessment (*see Section 
16.3 for specific time points; also see 
administration guidelines) 
 
 
 
 X* 
 
X* 
 
 
 
X*  
Specimen submission (see Section 15.0) 
X 
 
 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
Sperm banking recommended 
X 
 
 
 
 
 
 
Imaging Requirements (#see Section 17.0 
for specific time points) 
X 
 
X# 
X# 
 
X 
Suggested 
1 Weekly during methotrexate cycles 
2 There must be some measure of renal function via calculated or measured GFR (see Appendix A.3)  
3 Every other doxorubicin containing cycle until 4 administered doxorubicin doses, then before every doxorubicin containing cycle. 
4 Before 3rd and 4th Doxorubicin/Cisplatin cycle 
5 At least once a year; more frequently if clinically indicated 


 
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7. 2 
Disease-related follow-up after completion of chemotherapy 
General follow-up after completion of chemotherapy 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.childrensoncologygroup.org/disc/LE/default.htm 
 
7. 2.1. Schedule 
Participating institutions will follow all patients for 10 years after the patient is enrolled on the study, for 
relapse and survival, regardless of protocol violation. The date of relapse will be defined as the date on 
which evidence of relapse is confirmed, whether radiologically or clinically. If relapse is detected at any 
site, a complete diagnostic investigation (chest CT scan, bone scan, imaging of primary tumor site) is 
suggested. Refer to Section 17.0 for an overview of suggested imaging studies during follow-up.  
 
7. 2.2. Clinic visits after end of chemotherapy 
The following are minimum guidelines for timing of follow-up visits to ensure consistency in the 
detection of relapse or progression. 
            Years 1-2 
every 6 weeks-3 months 
Years 3-4 
every 2-4 months 
Years 5-10 
every 6 months 
Thereafter 
every 6-12 months according to local practice 
 
7. 2.3 Toxicity/Late – Effects Related Follow-Up 
Multimodal therapy of osteosarcoma may be associated with permanent alterations of cardiac, renal, 
auditory, and reproductive function, orthopedic problems and other late effects including secondary 
malignancies. Appropriate additional investigations are suggested in order to ensure optimal patient care. 
Cardiac toxicity, renal toxicity and ototoxicity are of particular interest in this study. Refer to the COG 
form packet for follow-up requirements. . 
 
 
8.0 
SUPPORTIVE CARE GUIDELINES 
 
8.1 
Venous Access  
The presence of a double lumen central venous access device (VAD) is recommended but not required. 
 
8.2 
Antiemetics  
All patients must be treated with appropriate antiemetics according to institutional practice.  
 
8.3 
Neutropenia 
 
8.3.1 
Neutropenic fever  
Antibiotic coverage is at the discretion of the investigator. Broad spectrum antibiotics should be chosen in 
consideration of local microbials. Since nephrotoxic agents are used in this therapy, aminoglycosides 
should be used with caution. 
 
8.3.2 
Growth factor support: Since treatment intensity is important, myeloid growth factor support is preferable 
to dose reduction and should begin at least 24 hours after completion of chemotherapy. If given daily then 
continue until WBC ≥ 5000/µL after nadir. The recommended dose indicated in the package insert should 
be used. Chemotherapy should not be given until a patient has been off myeloid growth factor support for 
2 days. 


 
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8.4 
Anemia and thrombocytopenia 
 
8.4.1 
Transfuse to maintain hemoglobin levels according to institutional practice. Erythropoietin is not 
recommended as standard therapy but may be used at the discretion of the investigator e.g. for patients 
who refuse transfusion on religious grounds.  
 
8.4.2 
Suggested platelet transfusions for bleeding associated with thrombocytopenia. Give platelet transfusions 
prophylactically when counts drop below 10,000/ l. Some institutions may use higher thresholds for 
platelet transfusion, e.g. 20,000/ L. Higher thresholds should also be used during septic episodes. 
 
8.4.3 
Appropriate national and institutional guidelines should be followed regarding filtering and irradiation of 
blood products.  
 
8.5 
Pneumocystis carinii  
Pneumocystis carinii prophylaxis is recommended even though the risk of pneumocystis infection in this 
population is relatively low.  
Trimethoprim/Sulfamethoxazole (TMP/SMX) should not be administered with or close to the 
administration of high dose methotrexate. Sulfonamides can displace methotrexate from plasma 
binding sites and increase free methotrexate. Trimethoprim can interfere with the microbiological DHFR 
assay for methotrexate; no interference occurs with the RIA. In addition, both agents have similar 
toxicities, and the administration of TMP/SMX increases the risk of high dose methotrexate toxicity.  
 
8.6 
Magnesium supplementation  
It may be helpful to supplement magnesium beginning with the first cisplatin-containing course and up to 
approximately three months after completion of chemotherapy.  Intravenous magnesium supplementation 
in the hydration fluids should be considered during administration of cisplatin or ifosfamide. This would 
involve: 
 
Post-cisplatin - hydration with D5W ½ NS + 10 mEq KCl/L + 20mEq MgSO4/L at 125 mL/m2/hr 
 
After therapy - supplement Mg with preparations such as:  
Magnesium oxide (2 caps/m2 - 7 mEq /140 mg capsule) or  
Magnesium gluconate (6 tablets/m2 - 2.2 mEq/500mg tab) or 
Maalox #1 (2 tabs/m2 - 7 mEq/tab) 
 
8.7 
Neurotoxicity associated with ifosfamide  
Guidance for dose adjustment is found in section 5.3 & 5.4. If Grade 4 neurotoxicity occurs during 
ifosfamide administration, investigators may consider administration of methylene blue at 2 mg/kg 
(maximum dose 50 mg) on the day this occurs.  The dose may be repeated at 4 hours and 8 hours after, 
following which ifosfamide should be discontinued and no further ifosfamide will be administered.  
Investigators should consider substituting cyclophosphamide and mesna, both 500 mg/m² x 5 days. 
Hypersensitivity, renal impairment and G-6PD deficiency are contraindications to administering 
methylene blue. 
 
8.8 
Hydration Routines  
Hydration routines for chemotherapy administration are detailed above.  


 
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8.9 
Bisphosphonates  
Some investigators may choose to use bisphosphonates after surgery.  The benefits of this have as yet not 
been prospectively evaluated in this group of patients.  Administration of bisphosphonates should be 
recorded on Form (end of treatment) 
 
 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
9.1 
Criteria for Removal from Protocol Therapy 
The duration of the MAP regimen is 29 weeks and the duration of the MAPIE regimen is 40 weeks.  In 
the MAPifn arm, duration of therapy will be two years in total.  Surgery is intended to be performed at 
Week 11 in all arms. 
 
Patients may be withdrawn from protocol treatment for the reasons listed below. 
 
 
Relapse, or tumor progression 
 
Serious adverse events (including second malignancies) or other major toxicity 
prohibiting continuation of protocol therapy 
 
Pregnancy 
 
Personal wish of the patient 
 
Any other situation where continued protocol treatment may not be in the best interest 
of the patient 
 
The reason for terminating treatment should be recorded on the appropriate data entry screen along with 
all other post-treatment investigations (see Section 7.1). 
 
Patients who do not meet the criteria for randomization are off protocol therapy, however, these patients 
will be followed up for 10 years after the last patient starts the study, for the purpose of follow-up. 
Treatment recommendations for patients who are not randomized are: 
 
 
If the required amount of pre-operative chemotherapy to qualify a patient for randomization has 
not been given, then give post-operative chemotherapy according to the MAP schedule.  
 
 
If patients experience tumor progression during pre-operative treatment, give post-operative 
chemotherapy according to the MAPIE schedule. 
 
 
If the surgery is not macroscopically complete, the patient should receive radiotherapy and/or 
other experimental treatment as appropriate. 
 
 
9.2 
Off Study Criteria 
 
 
Death. 
 
Lost to follow-up. 
 
Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at recurrence). 
 
Withdrawal of consent for any further data submission. 
 
Tenth anniversary of study entry  


 
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10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Endpoints 
The primary endpoint for EURAMOS-1 is event-free survival (EFS), secondary endpoints are overall 
survival (OS), toxicity and quality of life.  For the statistical comparison of the randomized arms, EFS 
and OS will be measured from date of randomization to date of the event or death as appropriate; 
surviving patients will be censored at the date last known to be alive.  For reporting EFS and OS 
estimates at specific timepoints, these measures will be calculated from date of diagnostic biopsy.  
Treatment comparisons of EFS and OS will also be conducted in the subgroup of localized patients.  Trial 
conclusions will be based on all endpoints.  Events are defined as death, detection of local recurrence or 
metastasis, progression of metastatic disease, or detection of a secondary malignancy. Toxicity will be 
assessed using the CTCAE v3.0. Good histological response is defined as < 10% viable tumor. 
 
10.2 
Sample Size 
Sample size calculations for this trial have been calculated using the method of George and Desu (George 
and Desu, 1974).  The good histological response rate for the MAP induction regimen, estimated from 
INT 0133, is 45%. Analysis of EFS is planned to take place around two years after the closure to 
recruitment to the trial, analysis of OS is planned for around four years after closure. 
 
Based on the previous experience of the participating groups, 3-year EFS for the MAP regimen is 
expected to be 70% for good responders and 45% for poor responders; 5-year OS is also expected to be 
70% for good responders and 45% for poor responders. 
 
Setting a two-sided significance level of 5% and 80% power, around 525 events are required. Assuming 
400 patients registered per year, it is proposed that 1260 patients be randomized into EURAMOS-1.  The 
original planning parameters indicated that, of these, 567 were anticipated to be good responders and 693 
poor responders. Data that became available in September 2010 confirming the proportion of good:poor 
responders was, instead, around 53:47, rather than the expected 45:55. Previous data from COSS 
suggested that 10% of patients registered at the start of treatment are not randomized following surgery 
because of disease progression. In EURAMOS-1, the non randomization rate has been higher at around 
30-35% for many reasons, including disease progression, insufficient pre-operative chemotherapy and 
withdrawal of consent.  Thus enrollment will be extended to 30 June 2011 to obtain the maximum 
enrollment of 2300. 
 
To detect an absolute improvement of 10% in good responders from 70% to 80% (hazard ratio 0.63), in 
3-year EFS and 5-year OS requires around 147 events to be reported. To detect an absolute improvement 
of 10% in poor responders, from 45% to 55% (hazard ratio 0.75), in 3-year EFS and 5-year OS requires 
around 378 events. The analysis for the randomized question amongst good responders and for the poor 
responders should be undertaken in the third quarter of 2013. 
 
10.3 
Sample size for patients with localized disease 
At least 85% of patients randomized into EURAMOS 1 are expected to have localized disease at 
registration. A minimum of 650 good responders with localized disease and 565 poor responders with 
localized disease may thus be available for analysis.  Due to the better prognosis for localized disease, 
EFS and OS are expected to be slightly higher for this cohort compared to the whole trial population. 
 
In good responders with localized disease, assuming a two-sided significance level of 5% and 80% 
power, 98 events are required to detect an improvement of 10%, from 75% to 85% (hazard ratio 0.56) in 
3-year EFS and 5-year OS. In poor responders with localized disease, 270 events are required to detect an 
improvement of 11%, from 50% to 61% (hazard ratio 0.71), in 3-year EFS and 5-year OS (2-sided 


 
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Page 66 
significance level of 5%, 80% power). With the assumed proportion of patients having localized disease, 
it is expected to have reasonable power in the localized disease setting when the main analyses are 
performed. 
 
10.4 
Intended Analysis 
The two arms will be compared on an intention-to-treat basis.  Differences in event-free survival and 
overall survival will be assessed using the logrank test and expressed using hazard ratios with appropriate 
confidence intervals. Proportions of patients experiencing grade 3 and 4 toxicities will be compared using 
chi-square tests or Fisher‟s exact tests where appropriate.  Differences in EFS and OS will be assessed for 
the subgroup of patients with localized disease.  No other subgroup analyses are planned but the 
consistency of treatment effect within specified groups, e.g. site of disease, will be examined. A full 
statistical analysis plan will be developed separately. 
 
10.5 
Interim Analyses 
The data will be reviewed and formal interim analyses performed at regular intervals (approximately 6 
monthly) by an IDMC who will be asked to give advice on whether the accumulated data from the trial, 
together with results from other relevant trials, justifies continuing recruitment of further patients. 
 
A decision to discontinue recruitment, in all patients or in selected subgroups will be made only if the 
result is likely to convince a broad range of clinicians including participants in the trial and the general 
clinical community.  If a decision is made to continue, the IDMC will advise on the frequency of future 
reviews of the data on the basis of accrual and event rates. 
 
The Haybittle-Peto stopping rule will be adopted for this trial (Haybittle, 1971; Peto et al, 1976).  The 
trial will be stopped for good or poor responders if the p-value for the analysis of EFS is below 0.001.  
This approach has the advantage of not requiring the number of interim analyses to be specified, and not 
increasing the Type I error of the final analysis by more than a nominal amount.  The IDMC will make 
recommendations to the TSC as to the continuation of the trial. 
 
It is important that interim analyses of EURAMOS-1 examine the safety of the patients who have been 
entered into it.  If, at interim analysis, the lower bound of the 95% confidence interval for the proportion 
of patients in each arm who died due to toxicity exceeds 3%, the future of the trial will be discussed with 
the TSC.  The minimum number of toxic deaths for which the lower bound of the 95% CI exceeds 3% is  
shown in the table below. 
 
Number of patients 
Number of toxic deaths 
50 
5 
100 
8 
150 
10 
200 
12 
250 
14 
300 
16 
 
At each interim analysis, all reported grade 4 CTCAE toxicities will be presented by arm.  Any perceived 
excess in grade 4 toxicity, in any arm, will lead to further investigation to determine the safety of that 
arm.  As the toxicity profiles of MAP and MAPIE are known from the results of INT 0133 and P9754, 
further stopping rules for chemotherapy toxicity are not warranted.  
 
The role of the TSC is to provide overall supervision for the trial and provide advice through its 
independent Chairman. The ultimate decision for the continuation of the trial lies with the TSC.  See 
Appendix A.1 for details on trial committees. 


 
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10.5.1 Stopping rules for pegylated interferon alfa-2b 
Experience from the Karolinska Hospital in Sweden suggests that interferon-  is not associated with 
major acute or long-term toxicity in osteosarcoma (Strander et al, 1995).  Interferon-  has an excellent 
safety record in other diseases, and we would not expect to see major toxicities arising from it in this trial.  
However, it would be prudent to monitor the safety of patients who receive pegylated interferon -2b 
carefully. 
 
If any toxic death occurs that is attributable to pegylated interferon α-2b, the IDMC and TSC will be 
consulted within 7 days with a view to discontinuing this arm.  If, at interim analysis, > 25% of patients 
who started pegylated interferon α-2b have subsequently ceased treatment for any reason other than 
disease progression, relapse or death, the TMG will discuss whether to discontinue this arm with the 
IDMC and TSC.  Permanent, early discontinuation of pegylated interferon α-2b should be discussed with 
the regional PI whenever possible.  At interim analysis, all grade 4 toxicities observed during treatment 
with pegylated interferon α-2b will be reported.  If any individual non-hematological toxicity criterion is 
associated with grade 4 toxicity in more than 5% of patients, the continuation of this arm will be reviewed 
with the IDMC and TSC. 
 
10.6 
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 
143 
171 
Not Hispanic or Latino 
943 
1186 
2129 
Ethnic Category: Total of all subjects 
971 
1329 
2300 
Racial Category 
 
American Indian or Alaskan Native 
0 
20 
20 
Asian 
47 
47 
94 
Black or African American 
201 
171 
372 
Native Hawaiian or other Pacific Islander 
10 
0 
10 
White 
713 
1091 
1804 
Racial Category: Total of all subjects 
971 
1329 
2300 
 
 
 
 
This information was derived from the last POG/CCG intergroup localized osteosarcoma study P9754 
 
 
11.0 
EVALUATION CRITERIA  
 
11.1 
Common Terminology Criteria for AdEERS v4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting via AdEERS beginning 
October 1, 2011.  All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0 and a copy can be downloaded from the CTEP web site (http://ctep.cancer.gov). 


 
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11.2 
Response Criteria for Patients with Solid Tumors 
 
11.2.1 Measurable Disease  
The presence of at least one lesion that can be accurately measured in at least one dimension with the 
longest diameter at least 20 mm.  With spiral CT scan, lesions must be at least 10 mm. The investigator 
will identify up to 10 measurable lesions to be followed for response. 
 
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 lesion at baseline and during follow-up. 
 
11.2.2 Quantification of Disease Burden 
Product of the maximal transverse dimensions (X, Y, and Z) as described: 
a. 
In the axial plane, find the imagine showing the largest area of tumor and measure the tumor 
in the longest dimension (X). 
b. 
On the same axial image, measure the tumor in longest dimension (Y) perpendicular to (X). 
c. 
Then, determine the length of the tumor (Z) in the longitudinal axis. 
The disease burden measurement is the product of X Y x Z. 
 
11.2.3 Complete Response (CR)  
Disappearance of all target lesions.  
 
11.2.4 Partial Response (PR) 
At least a 30% decrease in the disease measurement, taking as reference the disease measurement done to 
confirm measurable disease at study entry. 
 
11.2.5 Progressive Disease (PD)  
 
At least a 20% increase in the disease measurement, taking as reference the smallest disease 
measurement recorded since the start of treatment IN ASSOCIATION WITH clinical features of 
progression such as increased pain, inflammatory signs, rising alkaline phosphatase. Clinical 
assessment must be repeated in no less than 3 weeks to be regarded as progressive disease. (OR) 
 
 
The appearance of one or more new lesions. 
 
Also 
refer 
to 
Appendix 
A.6 
of 
the 
Intergroup 
document 
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf). 
 
11.2.6 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. 
 
11.2.7 Response Assessment 
Each patient will be classified according to their “best response” for the purposes of analysis of treatment 
effect. Best response is determined from the sequence of the objective statuses described above. 
 
11.3 
Best Response 
Two objective status determinations of CR before progression are required for best response of CR.  Two 
determinations of PR or better before progression, but not qualifying for a CR, are required for a best 
response of PR.  Two determinations of stable/no response or better before progression, but not qualifying as 
CR or PR, are required for a best response of stable/no response; if the first objective status is unknown, only 
one such determination is required.  Patients with an objective status of progression on or before the second 


 
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evaluations (the first evaluation is the first radiographic evaluation after treatment has been administered) will 
have a best response of increasing disease.  Best response is unknown if the patient does not qualify for a best 
response of increasing disease and if all objective statuses after the first determination and before progression 
are unknown. 
 
 
 
 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
12.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Certain adverse events must be reported in an expedited manner to allow for timelier 
monitoring of patient safety and care. The following sections provide information about expedited 
reporting. 
 
12.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient has received an 
investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New Drug Application 
(IND).  In some instances, the investigational agent may be available commercially, but is actually being 
tested for indications not included in the approved package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source. The NCI, rather than a commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply. 
 
Concurrent administration: When an investigational agent is used in combination with a 
commercial agent, the combination is considered to be investigational and expedited 
reporting of adverse events would follow the guidelines for investigational agents. 
 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a period of 
time prior to starting the investigational agent, expedited reporting of adverse events which 
occur prior to starting the investigational agent would follow the guidelines for commercial 
agents.  Once therapy with the investigational agent is initiated, all expedited reporting of 
adverse events follow the investigational agent reporting guidelines. 
 
12.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria v. 4.0 (CTCAE).  The 
CTCAE provides descriptive terminology and a grading scale for each adverse event listed.  A copy of the 
CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment 
locations should have access to a copy of the CTCAE. 
 
Step 2: Grade the event using the NCI CTCAE. 
 


 
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Step 3: Determine the attribution of adverse event in relation to the protocol therapy.   Attribution 
categories are: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Step 4: Determine the prior experience of the adverse event.   
For investigational agents that are not commercially available and are being studied under a company‟s 
IND or an investigator held IND, expected AEs are usually based on the Investigator‟s Brochure.   
Guidance on expectedness of the agent is provided in the Drug Information Section of this protocol. 
 
Step 5: Review Tables A and/or B in this section to determine if: 
 
there are any protocol-specific requirements for expedited reporting of specific adverse 
events that require special monitoring; and/or 
 
there are any protocol-specific exceptions to the reporting requirements. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included an investigational 
agent, a commercial agent, or a combination of investigational and commercial agents.  
 
Note: If the patient received at least one dose of investigational agent, follow the guidelines in Table A.  
If no investigational agent was administered, follow the guidelines in Table B. 
 
12.4 
Reporting methods 
 
 
The reporting methods described below are specific for clinical trials evaluating agents for 
which the IND is held by COG, an investigator, or a pharmaceutical company.  It is 
important to note that these procedures differ slightly from those used for reporting AEs for 
clinical trials for which CTEP holds the IND.   
 
 
Use the NCI‟s Adverse Event Expedited Reporting System (AdEERS). The NCI‟s 
guidelines for AdEERS can be found at http://ctep.cancer.gov. 
 
 
An AdEERS report must be submitted by one of the following methods: 
 
- 
Electronically submit the report via the AdEERS Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm,  
or 
- 
If the AdEERS web-based application is unavailable, Fax to COG (626-241-1795;  
attention COG AE Coordinator) the completed NCI Adverse Event Expedited Report on the 
paper template.  
 
Fax supporting documentation for AEs related to investigational agents to: 
 COG (fax # 626-241-1795; attention: COG AE Coordinator).  
 
DO NOT send the supporting documentation for AEs related to commercial agents to 
the NCI. Fax this material to COG (fax # 626-241-1795; attention: COG AE Coordinator).  
 
ALWAYS include the ticket number on all faxed documents. 
 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 


 
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12.5 
When to report an event in an expedited manner 
 
 
Some adverse events require notification within 24 hours (refer to Table A) via e-mail to the 
COG AE Coordinator.  
 
 
Submit the report within 5 calendar days of learning of the event. 
 
12.6 
Other recipients of adverse event reports 
 
COG will forward reports and supporting documentation to the Study Chair, to the drug company (for 
industry sponsored trials) and to the FDA (when COG holds the IND). 
 
Adverse events determined to be reportable must also be reported according to the local policy and 
procedures to the Institutional Review Board responsible for oversight of the patient. 
 
12.7 
Reporting of Adverse Events for investigational agents  
 
Reporting requirements are provided in Table A.  The investigational agent used in this study is PEG-
Intron (pegylated interferon alfa-2b) 
.  COG is the IND holder. 
 
Table A 
 
Phase 2 and 3 Trials and COG Group-wide Pilot Studies utilizing an Agent under a CTEP IND or a 
Non-CTEP IND:  AdEERS Expedited Reporting Requirements for Adverse Events That Occur 
Within 30 Days1 of the Last Dose of the Investigational Agent 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
43 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
5 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as 
follows: 
AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in Non-CTEP IND studies) followed by complete report within 5 calendar days for: 
 Grade 4 and Grade 5 unexpected events  
 
AdEERS 5 calendar day report: 
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization (see exceptions 
below 
 Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a 
full report is required as outlined in the table. 
3 Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 
 
 
Note: All deaths on study require timely reporting to COG via RDE regardless of causality.  Attribution 
to treatment or other cause must be provided.   


 
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Expedited AE reporting timelines defined: 
 
“24 hours; 5 calendar days” – The investigator must initially report the AE via e-
mail to COG AE Coordinator within 24 hours of learning of the event followed by 
a complete AdEERS report within 5 calendar days of the initial 24-hour report. 
 
“5 calendar days” - A complete AdEERS report on the AE must be submitted 
within 5 calendar days of the investigator learning of the event.  
 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
 
Protocol specific reporting of AEs, in addition to the AdEERS requirements, are to be entered in 
the COG remote data entry system.   
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Phase 2 
and 3 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND: 
 Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence/progression must be reported via AdEERS per the timelines outlined in the 
table above. 
 
 Grades 1- 4 myelosuppression do not require expedited reporting unless unexpected. 
 
12.8 
Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 
The following are expedited reporting requirements for adverse events experienced by patients on study 
who have not received any doses of an investigational agent on this study. 
 
Commercial reporting requirements are provided in Table B.  
 
COG requires the AdEERS report to be submitted within 5 calendar days of learning of the event. 
 
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. 
 


 
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12.9 
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.  For this study, routine reporting 
will include all Grade 3 and higher Adverse Events.  
 
As of August 25, 2010, all secondary malignancies should be reported via AdEERS. 
 
 
13.0 
RECORDS AND REPORTING 
 
13.1 
Categories of Research Records 
Research records for this study can be divided into three categories: 
1. 
Non-computerized Information:  Pathology Narrative Reports, Surgical Reports.  These forms are 
submitted through the Document Imaging System in the eRDES. 
 
2. 
Reference Labs‟ required reports, and QARC data:  These data accompany submissions to these 
centers, which forward their review data electronically to the COG Statistics and Data Center. 
3. 
Computerized Information Electronically Submitted:  All other computerized data will be entered 
in the COG Remote Data Entry System with the aid of schedules and worksheets (essentially paper 
copies of the RDE screens) provided in the data form packet. 
 
See separate Data Form Packet posted on the COG web site, which includes submission schedule. 
 
13.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.1.  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. 


 
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14.0 
SURGICAL GUIDELINES 
 
 
 
14.1 
Biopsy 
The diagnosis of high-grade osteosarcoma must be verified histologically within 14 days of study 
enrollment. In order to ensure appropriate biopsy techniques and an appropriate evaluation of the obtained 
material, it is strongly recommended that biopsies should only be performed in specialized centers. Open 
biopsy may be performed in order to obtain sufficient material for rapid central review and ancillary 
studies. The biopsy specimen should be forwarded to the institutional pathologist without prior fixation.  
Enrollment on a COG osteosarcoma specimen collection study is strongly encouraged. 
 
14.2 
Definitive Surgery  
For osteosarcoma, surgery is the local treatment of choice. Complete surgical removal of all affected sites 
is mandatory whenever feasible. Rapid central review will be done on the surgical specimen. 
 
14.2.1 Definitive Surgery of the Primary Tumor 
Surgery of the primary tumor is scheduled for 11 weeks after the commencement of chemotherapy. 
Surgery should be performed in a manner which guarantees wide or radical margins according to 
Enneking‟s classification. While it is most often possible to reach such margins without sacrificing the 
affected limb, mutilating surgery may become necessary if this is not the case. The indication for limb-
salvage must be made with particular caution if a poor tumor response to preoperative chemotherapy is 
anticipated by clinical investigations or appropriate imaging studies. Marginal or intralesional surgery 
should be avoided whenever possible and must be restricted to situations where wide or radical margins 
are not achievable by any means. As inappropriate surgery may easily lead to local recurrence and death 
in otherwise curable patients, it is strongly recommended that osteosarcoma surgery should only be 
performed in specialized centers.  
 
14.2.2 Definitive Surgery Guidelines 
 
14.2.2.1. Prior to definitive surgery the following parameters are recommended: 
Neutrophils 
>1.0 x 109/L 
Platelets 
> 80 x 109/L 
 
14.2.2.2 Indications for limb salvage surgery: 
 
Tumor resectable with wide margins 
 
Reconstruction possible and likely to be successful 
 
Patient aware of risks/benefits of limb salvage 
 
14.2.2.3 Indications for amputation: 
 
Inability to completely resect the tumor without leaving residual disease 
 
Extensive involvement of neurovascular bundle 
 
Patient preference 
 
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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There will be many situations where the decision is not easy, in particular when there has  been 
a 
poor 
response to chemotherapy, there is extensive soft tissue involvement and the tumor is adjacent to the main 
neurovascular bundle. In these situations seek a second opinion from one of the main surgical centers.  
 
14.2.3 Reconstruction after limb salvage surgery 
There are many types of limb salvage reconstruction available. Remember that the principle aim of the 
surgeon is to completely resect the tumor with wide margins. This principle should never be sacrificed in 
order to make limb salvage reconstruction easier. The patient will want a reconstruction that will function 
well and have few complications. In some situations an amputation may give a better and more 
predictable result than attempts at reconstruction (e.g. distal tibia).  
 
The following reconstruction options represent standard treatment but are NOT meant to exclude other 
options: 
 
14.2.3.1 
Distal Femur – in most cases use of an endoprosthesis will give a good result.  If the tumor involves the 
knee joint an extra-articular resection should be carried out.  
 
14.2.3.2 
Proximal Tibia - use of an endoprosthesis will work well if the extensor mechanism is reconstructed. A 
gastrocnemius muscle flap should be part of the soft tissue reconstruction. 
 
14.2.3.3 
Proximal Femur – modular endoprostheses work well. Because of the significant risk of dislocation a 
large unipolar or bipolar head is recommended. 
 
14.2.3.4 
Proximal Humerus – reconstructive options include the use of a prosthesis, a fibula graft (vascularized) or 
a turn down of the clavicle (claviculo pro humero). 
 
14.2.3.5 
Pelvis – all surgical reconstructions are high risk and should be carried out at a center with appropriate 
expertise. 
 
 
14.2.3.6 
Diaphyseal tumor – When the joints can be spared above and below a tumor in a long bone then a 
biological reconstruction is preferred – either using an allograft or an autograft (or a combination) 
 
14.2.3.7 
Young children with long bone tumors – extendable endoprostheses have proved useful but have a 
significant risk of complications. Families must be fully informed about risks/benefits and the 
inevitability of the need for further surgery. Rotation plasty should be considered in these cases. 
IF 
THERE 
IS 
INSUFFICIENT 
LOCAL 
EXPERTISE, 
REFER 
TO 
A 
SURGICAL 
REPRESENTATIVE ON THE COG AOST0331 COMMITTEE 
 
14.2.4 Surgery of pelvic and other axial tumors 
Osteosarcomas arising in the axial skeleton (excluding craniofacial bones) which are deemed resectable 
with curative intent are eligible for inclusion in this protocol.  Subsequent surgical management of such 
tumors may include amputation (fore or hind quarter for shoulder girdle and pelvic tumors) or complex 
reconstruction.  The chosen approach should be anticipated to achieve the safest oncological margin and 
at least  macroscopic resection. 
 


 
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14.2.5 Surgery of primary metastases 
If primary metastases are present, all of these must also be resected completely, regardless of their 
number and site, if the affected patient is treated with curative intent.  Resection is strongly recommended 
for patients felt to have definite or possible pulmonary metastases at initial diagnosis.  The preferred time-
point for surgery of primary metastases may be between protocol weeks 11 and 20, but other dates may 
be chosen at the discretion of the treating physicians. For pulmonary metastases, thoracotomy with 
manual exploration of both lungs is strongly recommended, even when imaging studies suggest unilateral 
disease. The use of thoracoscopic techniques is strongly discouraged, as they lack sensitivity and may be 
associated with an increased risk of intraoperative tumor dissemination. In order to avoid complications 
associated with delayed methotrexate excretion due to third-spacing into pleural effusions, thoracotomy 
should not be followed by high-dose methotrexate, but rather by other chemotherapeutic agents. 
 
14.3 
Treatment of Relapsed Disease 
EFS is the primary endpoint of EURAMOS 1 and therapy of relapsed disease is not prescribed in this 
trial.  In order to achieve a homogeneous standard of patient care, the EURAMOS investigators have 
summarized their joint opinion about how patients who experience a relapse following therapy on the 
EURAMOS 1 trial might be treated in Appendix A.7. COG institutions are reminded to check the COG 
website for open COG studies for osteosarcoma. 
 
 
15.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
Before entering patients in this trial clinicians should discuss this protocol with their pathologist and 
provide them with appropriate documents. 
 
15.1 
Biopsy 
All COG patients enrolled on AOST0331 require rapid central review of their diagnostic biopsy material. 
Biopsy materials must be submitted in a timely manner so that the review results can be reported back to 
the treating institution within 14 days of study enrollment, and within 21 days of the diagnostic 
procedure. Lisa Teot, M.D. is the COG reviewer for AOST0331 specimens.  Do NOT send specimens 
directly to Dr. Teot. Send all specimens to the Biopathology Center as specified below. 
Please label all materials with the patient‟s COG Patient Identification Number and the surgical pathology 
identification (SPID) from the corresponding institutional pathology report(s). 
 
Required materials at the time of the initial biopsy for rapid central review are: 
 
Representative paraffin blocks with tumor, or if blocks are unavailable, send 1 unstained slide 
from a representative block with tumor 
 
One H & E stained slide from each block 
 
A copy of the institutional pathology report(s) 
 
A copy of the institutional surgical report 
 
The AOST0331 Pathology Checklist  
 
Radiological Imaging (copy of plain radiograph, CT, MRI) or electronic image submission and 
institutional Radiology Report(s)  
 
Specimen Transmittal Form 
 
 
Materials should be sent by Federal Express Overnight carrier for next day delivery using account number 
2504-6481-9.  Mark the parcel “Osteosarcoma AOST0331 Rapid Review.”  Ship the specimens to: 
 
Biopathology Center 
Nationwide Children‟s Hospital 
700 Children‟s DR Room WA1340 
Columbus OH 43205 
Phone:  614-722-2894 


 
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It is the responsibility of the Principal Investigator at the institution to ensure that the pathologist is 
informed of each patient enrolled on AOST0331 and request that the materials be forwarded to the 
Biopathology Center. The Biopathology Center and the review pathologist will not request materials. 
 
Enrollment on a COG osteosarcoma specimen collection study is strongly encouraged for all patients 
enrolled on AOST0331. Please see the specimen collection study for specific instructions on specimen 
preparation and shipment.  Fresh tissue is requested whenever possible. 
 
15.2 
Resection/amputation 
Given the goals of the present trial, timely resection specimen analysis is of paramount importance. This 
means that at all times the handling of the resected specimens are of peak priority including the initial 
handling, decalcification, administration, and dispatching the material for central review.  
 
The examination has three objectives: 
1) Assessment of resection margins 
2) Assessment of the response to chemotherapy (See Section 15.3) 
3) Estimation of the amount of cartilaginous differentiation being more or less than 30% of the tumor 
volume. 
 
To provide documentation of the soft tissue margins, the initial gross examination should be performed 
on the fresh specimen. Measurement of the narrowest resection margin (mm) is of most value.  
Histological sections should be taken in any area where excision margins appear dubious. Ideally, the 
specimen should be prepared by dividing it longitudinally in the plane of maximum tumor diameter, and 
the whole of this slab should be divided into blocks for preparation of histological sections. Radiological 
imaging of the specimen is of value in determining the maximum tumor diameter. A photograph and a 
diagrammatic map of the specimen should be prepared indicating the site of individual blocks. For 
quantitating the effects of chemotherapy only the sections where tumor was present or was thought to 
have been present should be assessed. Normal adjacent bone and soft tissue areas should not be included 
in the area quantitated. If there is difficulty in handling specimens at any stage the review pathologists are 
anxious to help. 
 
Sections from each block encompassing the largest diameter of the resected tumor (not the complete 
specimen) will be required by a review pathologist.  
 
With Amendment #3, institutional assessment of histologic response will be used to determine whether 
the patient meets the criteria for randomization within 35 days of the surgical procedure. However, every 
effort should be made to obtain Rapid central review of the surgical material to assess histologic response 
and provide the required materials to the BPC within 21 days of the resection/amputation in order to 
complete the review within 35 days of the surgical procedure.  
 
Please label all materials with the patient‟s COG Patient Identification Number and the surgical pathology 
identification (SPID) from the corresponding institutional pathology report(s). 
 
Materials required at the time of resection/amputation: 
 Representative paraffin blocks with tumor or if blocks are unavailable send 1 unstained slide from 
each block encompassing the largest diameter of the resected tumor. 
 One H&E stained slide from each tumor block of the resected specimens 
 Map indicating from which point sections are taken  
 A copy of the institutional pathology report(s) which includes measurement of the tumor in two 
dimensions and margins of excision (mm) 
 A copy of the institutional surgical report 


 
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 Radiological Imaging  (copy of plain radiograph, CT, MRI) or electronic image submission and 
institutional Radiology Report(s)  
 The AOST0331 Pathology Checklist 
 Specimen Transmittal Form 
 
It is the responsibility of the Principal Investigator enrolling a patient on this trial to request the 
submitting pathologist to send the appropriate set of forms, local pathology report including the schematic 
block map, and specimens to the Biopathology Center. 
Materials should be sent by Federal Express Overnight carrier for next day delivery using account number 
2504-6481-9. Mark the parcel “Osteosarcoma AOST0331 Rapid Review.” Ship the specimens to: 
 
Biopathology Center 
Nationwide Children‟s Hospital 
700 Children‟s Drive, WA 1340 
Columbus, OH 43205 
Phone:  (614) 722-2894 
 
15.3 
Procedure for Quantitation 
The amount of viable tumor is reported as less than 10% of the tumor area in cases showing a good 
response and greater than or equal to 10% in cases showing a poor response.  
 
In most cases, the amount of viable remnant tumor is obvious (<10% vital or nearly all vital).  In these 
instances, one can assign response to one of the above-mentioned categories. For problematic (non-
obvious) cases, graph paper with 2mm squares can be photocopied (actual size) on to acetate sheets for 
overhead projection. This may be cut into rectangles and fixed over the cover slip using double-sided 
Sellotape. The entire tumor-bearing areas can thus be measured and totaled.  
 
The same method may be used for quantifying the amount of cartilaginous differentiation.  When more 
than 30% of an osteosarcoma is composed of chondroblastic areas, intimately associated and mixed with 
non-chondroid-elements it is considered as chondroblastic osteosarcoma.  Viable chondroblastic areas are 
characteristically composed of nodular, bluish hyaline cartilage, with moderately to severely pleomorphic 
malignant cells. The microscopic appearance is of chondrosarcoma grade 2-3. Necrotic cartilaginous 
areas are recognized as a confluent, very pale to light eosinophilic homogeneous matrix with vesicular-
appearing lacunae in which shadows of necrotic cells can be seen. Grossly, an overt chondroid 
appearance is rare so the diagnosis is made on histology.  
 
 
16.0 
SPECIAL STUDIES  
 
16.1 
Quality of Life 
Treatment for osteosarcoma is associated with both short and long-term toxicities from chemotherapy as 
well as functional disability as a result of the need for skeletal reconstruction after resection of the 
primary tumor.  The toxicity profile of the standard chemotherapy in this protocol is well recognized but 
additional toxicities may be anticipated with the addition of ifosfamide and etoposide for poor responders 
(MAPIE) and with pegylated interferon alfa-2b for good responders. 
 
The main objective of QL assessment within AOST0331 is to determine the impact on QL (both short- 
and long-term) for two interventions in two groups of patients: (1) poor responders: the impact of the 
addition of ifosfamide and etoposide to the standard chemotherapy; and (2) good responders: the impact 
of maintenance therapy with interferon.  Describing and comparing the impact of these regimens on QL 
will lead to a better understanding, from the patients‟ perspective, of the nature of treatment related side-


 
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Page 79 
effects, both short- and long-term.  These data will help define future treatment options for these patients.  
Additionally, the assessment of QL within EURAMOS 1 will allow more global concerns to be 
addressed, for example whether QL is affected by surgical factors, patient maturity (emotional and 
physical) and other characteristics such as gender, and site of primary tumor.  
 
16.2 
QL Instruments 
For patients aged 16 and over, QOL will be assessed using the EORTC QLQ-C30 questionnaire. Those 
completing the EORTC questionnaire will not have a parent questionnaire. For patients aged 15 and under 
the Peds QL questionnaire will be used, which has been validated in North America, but not in all 
European languages.2 Peds QL has questionnaires for three age groups: 5-7 years, 8-12 years and 13-15 
years. For those 5 to 7 years old there is an interviewer administered questionnaire. For patients 8 to 15 
there are self-report questionnaires.  A parent questionnaire must be completed for all patients aged 5 to 
15. Patients who become 16 years old during the course of the trial should continue to use the pediatric 
instrument for further assessments. Peds QL has been validated up to the age of 18.  Please see the 
administration guidelines for details. 
 
16.3 
Timing of QL Assessments 
o 1st QOL Time Point:  1st QOL assessment for child (and parent if applicable) is to be 
completed at the end of Cycle 1(after 2nd methotrexate) and prior to start of Cycle 2. 
o 2nd QOL Time Point: 
 
MAP arm and MAPifn Arms: 2nd QOL assessment for the child (and parent if 
applicable) is to be completed after recovery from the doxorubicin of Week 
22/Cycle 5 and prior to the methotrexate of Week 24/Cycle 5. 
 
MAPIE Arm: 2nd QOL assessment for the child (and parent if applicable) is to be 
completed after recovery from the doxorubicin and ifosfamide of Week 20/Cycle 
5 and prior to the start of methotrexate of Week 23/Cycle 5 
o 3rd QOL Time Point: 3rd QOL assessment at week 72+/- 4. (18 months after the start of 
treatment) 
o 4th QOL Time Point: 4th QOL assessment at week 144+/- 4 weeks (3 years after the start 
of treatment) 
 
Once completed, QL forms should be returned to the COG Statistics and Data Center. The COG Patient 
Identification number and date of completion should be recorded on each form. 
 
 
17.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care.  Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations 
(and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure 
and/or anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  


 
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17.1 
Osteosarcoma Imaging Recommendations 
 
17.1.1 Imaging at Presentation and Immediately Prior to Surgery 
Site 
Anatomic Imaging 
Functional Imaging 
Primary and bone metastases 
AP and lateral radiographs 
 
Primary and bone metastases 
MRI with gadolinium 
 
 
Whole body* 
 
MDP bone scintigraphy  (add SPECT of 
lungs if pulmonary metastases 
suspected) 
Whole body* 
 
Thallium scintigraphy 
Whole body* 
 
FDG-PET (if available) 
Chest 
CT 
 
Chest 
AP and lateral radiographs 
 
*Not all three studies are required for study entry.  Please use same method at subsequent evaluations. 
 
Definition of lung metastases: minimum criteria determined by spiral CT scanning are 3 or more lesions, 
which are ≥ 5 mm in maximum diameter or a single lesion ≥ 1 cm.  These patients will be classified as 
having “certain” pulmonary metastases.  Scans of patients registered as having metastatic disease with 
fewer or smaller lesions will be classified as “possible” metastatic disease.   
 
Definition of bone metastases: must include confirmation of bone scintigraphy or plain radiograph 
abnormalities either by MRI scan or biopsy or both. 
 
17.1.2 Baseline imaging after surgery 
Site 
Anatomic Imaging 
Functional Imaging 
Timing 
Primary and 
bone metastases 
AP and lateral radiographs 
 
Within 2 weeks of surgery 
Primary and 
bone metastases 
MRI with gadolinium; MRI 
may not be useful if a massive 
internal prosthesis is in place 
 
6 weeks post-surgery   
 
17.1.3 Surveillance imaging while on Chemotherapy 
Site 
Anatomic Imaging 
Functional Imaging 
Timing 
Primary and 
bone 
metastases 
AP and lateral 
radiographs 
 
q 16 weeks 
Primary and 
bone 
metastases 
MRI with gadolinium 
 
If required for symptoms or 
abnormal imaging 
Whole body 
 
MDP bone scintigraphy  
(add SPECT of lungs – if 
available -  if pulmonary 
metastases suspected) 
q 16 weeks 
Whole body 
 
Thallium scintigraphy 
(optional) 
If required for abnormal imaging 
Whole body 
 
FDG-PET (if available) 
If required for abnormal imaging 
Chest 
CT 
 
q 16 weeks if previously 
abnormal, sooner if indicated 
Chest 
AP and lateral 
radiographs 
 
q 2 months 


 
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17.1.4 Surveillance imaging Post-Chemotherapy 
 
This table is provided as a guideline and surveillance imaging post-chemotherapy should occur as per 
local institutional standards and as appropriate for individual patient care.  
Site 
Anatomic Imaging 
Functional Imaging 
Timing 
Primary and 
bone 
metastases 
AP and lateral 
radiographs 
 
q 3 months x  4 
q 6 months x 4 
q 12 months x  2 
Primary and 
bone 
metastases 
MRI with gadolinium 
 
If required for symptoms or 
abnormal imaging 
Whole body 
 
MDP bone scintigraphy  
(add SPECT of lungs if 
pulmonary metastases 
suspected) 
q 3 months x 4 
q 6 months x 4 
q 12 months x 2 
Whole body 
 
Thallium scintigraphy 
If required for abnormal imaging 
Whole body 
 
FDG-PET (if available) 
If required for abnormal imaging 
Chest 
CT 
 
q 3 months x 4 
q 6 months x 2 
then if abnormal radiographs 
Chest 
AP and lateral 
radiographs 
 
q 6 months x 6 (starting after last 
scheduled chest CT 
 
 
 
18.0 
RADIATION THERAPY GUIDELINES  
Radiation therapy for patients on COG protocols can only be delivered at approved COG RT 
facilities (see Administrative Policy 3.9,) 
 
18.1 
Radiation Therapy Guidelines 
As stated above, complete surgery is the local treatment of choice in osteosarcoma. Radiotherapy is 
reserved for situations where complete surgery cannot be achieved. Radiotherapy is, however, 
recommended for inoperable sites or those that could only be operated with inadequate margins. It is 
strongly suggested that participating institutions use the information and consulting systems set up by 
their respective groups before assuming inoperability, because some lesions which at first seem 
inoperable may turn out to be operable for specialized tumor surgeons. Further recommendations about 
how to proceed in specific situations may vary between groups. When radiotherapy is indicated, 
chemotherapy should not be interrupted for radiotherapy which is generally best deferred until the end of 
chemotherapy. Radiotherapy may be administered during treatment with interferon but it is not 
anticipated that the need will arise except in most uncommon circumstances. 
 
Chemotherapy can be continued during radiotherapy, but enhancement of radiation toxicity is likely to 
occur with several agents and at the radiation doses recommended may result in severe acute and late side 
effects.  This is of particular concern where spinal cord is in the field. High-dose methotrexate should be 
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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avoided during radiotherapy.  Doxorubicin should be avoided in radiation treatment of axial tumors as 
intestinal toxicity will be enhanced and this agent will also increase skin toxicity. Concurrent ifosfamide 
should be avoided where significant volume of bladder is in the radiation field 
 
The patients treated with post-operative irradiation should receive a total dose of 60 Gy in 2 Gy fractions 
where margins are microscopically involved and 66 Gy where macroscopic tumor tissue is left behind. 
For definitive radiotherapy of an inoperable osteosarcoma a radiation dose of 70 Gy should always be 
attempted. 
 
The use of intraoperative electron boost irradiation or brachytherapy by high-dose rate afterloading 
techniques is permitted in cases where macroscopic tumor tissues are left behind or where the surgical 
margins obviously are inadequate. 
 
Three-dimensional planning is required for this study. The use of IMRT is allowed. If 3D conformal 
planning is used, institutions must have an approved 3D benchmark on file at QARC.  If IMRT is used, 
the IMRT Questionnaire and Benchmark must be completed and submitted to QARC. The benchmark 
material is available from the QARC website (www.qarc.org).   
 
18.1.1 Equipment 
 
18.1.1.1 Modality 
X-rays with nominal energy of 4 MV or greater. Co-60 is not allowed on this study. Proton Radiation is 
not allowed on this study. 
 
18.1.1.2 Calibration 
The calibration of therapy machines used in this protocol shall be verified by the Radiological Physics 
Center (RPC). 
 
18.1.2 Target Volume Definitions 
ICRU-50 and 62 prescription methods and nomenclature shall be utilized for this study.   
 
Gross Tumor Volume (GTV): The GTV is the gross tumor, either palpable or visible/demonstrable by 
imaging techniques. Its delineation should preferentially be done in collaboration with a radiologist. 
Clinical Target Volume (CTV): The CTV contains the demonstrable GTV and/or sub-clinical 
microscopic malignant disease. Original tumor extension should guide the delineation of CTV. Ideally 
this should be done in collaboration with the treating surgeon. In axial tumors a safety margin of 2 cm 
added to GTV should be attempted.  For an extremity osteosarcoma a margin of 4-5 cm may be advisable.  
Planning Target Volume (PTV): For the purpose of this study, a margin for set up error or patient 
movement is to be added to the Clinical Target Volume. The PTV for this study will be 0.5 to 1.0 cm. 
 
18.1.3 Target Dose 
 
18.1.3.1 Prescription Point 
The prescription point is at or near the isocenter. If IMRT is used, dose may be prescribed to an isodose 
surface that encompasses the PTV provided that the dose uniformity requirements in Section 18.1.3.5 are 
satisfied. 
 
18.1.3.2 Dose Definition 
Dose is specified in Gy to muscle. 


 
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18.1.3.3 Tissue Heterogeneity 
Density corrections are not required, however, inhomogeneity correction for air or bone attenuation may be 
applied. This typically applies in the setting of CT-based treatment planning where radiation dose 
distributions and treatment calculations are automatically generated based upon the CT densities of the 
treatment-planning scan. 
 
18.1.3.4 Prescription Dose and Fractionation 
The patients treated with post-operative irradiation should receive a total dose of 60 Gy in 2 Gy fractions 
where margins are microscopically involved and 66 Gy where macroscopic tumor tissue is left behind. 
For definitive radiotherapy of an inoperable osteosarcoma a radiation dose of 70 Gy should always be 
attempted. 
 
18.1.3.5 Dose Uniformity 
A maximum dose variation within the PTV between 95-105% according to the dose plan should be 
attempted. Hot spots outside the PTV with a maximum of 110% are acceptable only if total volume is less 
than 10 cm3. Moreover, single hot spots should not exceed 5 cm3. Wedges, compensators, beam 
segmentation, and other methods of generating a uniform dose distribution are encouraged. 
 
18.1.3.6 Rests/interruptions 
There are no planned rests on this study. In case of holidays or machine breakdowns, the overall treatment 
time might be extended where the indication is adjuvant, whereas in case of macroscopic tumor tissue 
compensation by adding an extra fraction (separated by a minimum of 6 hours on a treatment day) should 
be considered. This may not be appropriate where spinal cord, brachial or lumbar plexus is in the high 
dose volume.  Please justify in the comments any interruptions for greater than three treatment days.   
 
18.1.4 Treatment Technique 
 
18.1.4.1 
Volume-based (CT scan) treatment planning is required in this protocol.  Techniques which shield/protect 
normal tissue are essential providing that they do not compromise treatment of the PTV.  The use of 
IMRT is allowed.  Fields should be chosen to minimize dose to organs at risk as defined in section 18.1.5.  
Multiple beam techniques, both coplanar and non-coplanar may be used to achieve the objective.  If the 
target volume extends to the surface of the patient, adequate dose coverage should be obtained using 
bolus material rather than a mixed beam technique. Intraoperative radiation therapy (IORT) and 
brachytherapy are also allowed on this study. 
 
18.1.4.2 IORT 
If IORT is delivered, the electron energy chosen must insure appropriate target dose at both the surface 
and at depth. The electron energy will be calculated to the 90% line. Bolus may be permitted to insure 
appropriate surface dose. The IORT Physics Reporting Form and RT-2 form must be filled out with IORT 
as a separate target if this mode of therapy is used. CT scan is required for submission with the target area 
and dosimetry identified on the CT study. IORT may be delivered at the time of primary surgical 
excision. 
 
18.1.4.3 Brachytherapy 
Both high dose rate (multiple fractions acceptable) and low dose rate techniques are permitted for this 
study. If multiple fractions are chosen for high dose rate, the total dose should remain as stated in Section 
18.1.3.4. The dose should be calculated to a 1 cm depth or appropriate depth as defined on computer 
tomography. CT study with the catheters in place is strongly encouraged with dosimetry placed on the CT 


 
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Page 84 
study for review. If CT is not available, then orthogonal images and dosimetry in at least two planes is 
required for submission and review. 
 
18.1.4.2 Patient Position 
Reproducible setups are critical and the use of immobilization devices is strongly encouraged. 
 
18.1.4.3 Field Shaping 
Field shaping can be done with blocks or multi-leaf collimation. 
 
18.1.5 Organs at Risk: 
All structures that may be associated with serious late toxicity should be delineated and dose-volume-
histograms generated. The following maximum radiation doses should be respected:  
Cervical cord (more that 5 cm length): 45 Gy 
Cervical cord (less 5 cm): 50 Gy 
Brain tissue: 60 Gy 
Optic nerve/chiasm: 50 Gy 
Intestine: 50 Gy, depending on volume  
Liver: 
Whole liver 20Gy: If less than ¼ volume is irradiated, 50 Gy 
Kidney: 20 Gy (> 1/3) 
Heart: 30 Gy 
Lung: 20 – 60 Gy depending on volume  
Urinary bladder: 60 Gy 
 
18.1.6 Dose Calculation and Reporting 
If conformal techniques are used to treat patients on this study, a 3D treatment planning benchmark needs 
to be completed and submitted to QARC. If IMRT is used, the IMRT Questionnaire and Benchmark must 
be submitted.  The benchmark material can be obtained from QARC (www.QARC.org). 
 
18.1.6.1 Prescribed Dose 
For 3D conformal techniques:  The monitor units required to deliver the prescribed dose must be 
submitted using the RT-1 Dosimetry Summary Form for each field.  
 
For IMRT techniques: The monitor units required to deliver the prescribed dose shall be calculated and 
submitted using the IMRT Dosimetry Summary Form. 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 plan‟s fluence distributions can be recomputed for a 
phantom geometry. 
 
 
For IORT: The IORT Physics Reporting Form shall be submitted. 
 
For brachytherapy: The Brachytherapy Physics Reporting Form shall be submitted. 
 
18.1.6.2 Dose Uniformity 
The maximum and minimum doses in the PTV shall be calculated and reported. These may be extracted 
from isodose distributions, calculated separately or derived from DVH‟s. 
 
18.1.6.4 Critical Organs 
Dose volume histograms for the critical organs indicated in section 18.1.5 shall be calculated whenever 
the critical organs are included in the radiation therapy treatment fields. The appropriate dose volume 
histograms shall be submitted with the QA documentation.   


 
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18.1.6.5 Isodose Distribution 
A hard copy isodose distribution for the total dose plan in the axial, sagittal and coronal planes at the 
center of the planning target volume must be submitted.  These dose distributions must include the 
following: 
A sufficient number of isodose contours should be shown to determine that the dose distribution 
conforms to the protocol guidelines.  These isodoses should be superimposed over treatment 
planning CT images.  However, if such hard copy presents difficulty, similar plots without gray 
scale image are acceptable if enough critical contours are identifiable to verify the dose 
distribution to target volumes and critical normal structures.  Specifically, include those volumes 
for which there are dose volume histograms. 
 
18.1.7 Quality Assurance Documentation 
 
18.1.7.1  
Within three days of the start of radiotherapy, the following data for 3D or IMRT plans shall be submitted 
for on treatment review: 
a. Copies of all diagnostic materials used in defining the target volume.  The initial (pre-
study) imaging is required. 
b. Photographs of the patient in the treatment position with the fields marked. 
c. Prescription sheet for the entire treatment course. 
d. Copies of the worksheets and printouts used for calculations of monitor settings to give 
the prescribed dose. 
e. Color copies of isodose distributions to demonstrate that the dose variation is within 
protocol guidelines.  The target volume must be clearly shown. 
f. Documentation of an independent check of the calculated dose if IMRT is used. 
g. Simulator films (if used as part of the treatment planning process) and digitally 
reconstructed radiographs of each treatment portal (if possible). If these are used as the 
basis for defining coverage it is imperative that the GTV and PTV be outlined on the 
simulator films or DRR‟s of all fields. 
h. First day portal films (or hard copy of real time portal images) if achievable. 
i. 
A completed appropriate (RT-1 or IMRT) Dosimetry Summary Form. 
j. 
One set of orthogonal anterior/posterior and lateral films for isocenter localization for 
each group of concurrently treated beams. If portals being submitted contain an 
orthogonal set, this is sufficient. 
k. Beam‟s eye views if 3D conformal planning is used. 
l. 
A “room view” display of all fields and their angles, if available, should be submitted. 
m. Dose volume histograms for the total treatment for the GTV and PTV and the normal 
tissues specified in section 18.1.6.  If IMRT is used, a DVH shall also be submitted for a 
category of tissue called “unspecified tissue,” which is defined as tissue contained within 
the skin, but which is not otherwise identified by containment within any other structure. 
 
18.1.7.2  
For brachytherapy the following data shall be submitted: 
a. The Brachytherapy Physics Reporting Form. 
b. The strength of the isotope. 
c. Appropriate films used for localization of sources. 
d. Computer printouts of the isodose distribution and the algorithm used for the 
calculations. 
e. Copies of all diagnostic materials used in defining the target volume. 


 
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18.1.7.3 
For IORT the following data shall be submitted: 
a. The IORT Physics Reporting Form. 
 
18.1.7.3  
Within one week of the completion of radiotherapy, the following data shall be submitted. 
a. Copies of additional simulation films and verification (portal) films for any major field 
modifications made subsequent to the initial reporting data. 
b. The RT-1 or IMRT Dosimetry Summary Form if any changes have been made 
subsequent to submission of previous. 
c. The RT-2 Radiotherapy Total Dose Record form. 
d. A copy of the patient‟s radiotherapy record including the prescription, and daily and 
cumulative doses to all required areas, including target volumes and normal tissues. 
e. Copies of calculations performed subsequent to the submission of the previous data. 
 
These data should be forwarded to: 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, Rhode Island 02903-1025 
Telephone 401-454-4301 
FAX 401-454-4683 
 
Questions regarding the dose calculations or documentation should be directed to: 
QARC Protocol Dosimetrist 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, Rhode Island 02903-1025 
Telephone 401-454-4301 
 
Questions regarding the radiotherapy section of this protocol should be directed to: 
 
18.1.8 Definitions of Deviations in Protocol Performance 
18.1.8.1 Prescription Dose: 
Minor Deviation: The dose to the prescription point differs from that in the protocol by between 6% and 
10%. 
 
Major Deviation: The dose to the prescription point differs from that in the protocol by more than 10% 
 
18.1.8.2 Dose Uniformity: 
Minor Deviation: Dose variations greater than that specified in Section 18.1.3.5. 
 
18.1.8.3 Volume: 
Minor Deviation: Margins less than specified or fields excessively large as deemed by the study. 
 
Major Deviation: Transection of tumor (GTV) or potentially tumor bearing area (CTV) (i.e. geographic 
miss of any part of the GTV). 


 
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19.0 
RECOMMENDED GUIDELINES FOR TREATMENT ADMINISTRATION 
 
Please see Appendix B6 of the Intergroup Study document on the protocol page for detailed information  
(https://members.childrensoncologygroup.org/Prot/AOST0331/AOST0331_Euramos.pdf).  
 
19.1 
Doxorubicin/Cisplatin (including recommendations for hydration).  Cisplatin and doxorubicin 
may be given simultaneously through 2 separate lines connected via a side port (Y-site). 
 
19.1.1 
Prehydration: Achieve SG  1.010.  Administer oral or IV hydration of 1.5-2 L/m2 over 12 hours (or 
employ similar regimen). 
 
19.1.2   
Day 1-2 
Hour 0: Start doxorubicin 75 mg/m2 by intravenous infusion over 48 hours.  Dilute doxorubicin in 
480 mL D5W and administer at 10 mL/hr x 48 hours 
Hour 0-2: Mannitol 10 g/m2 in 500 mL/m2 D5W ½ NS  
Hour 2-6: Cisplatin 60 mg/m2 in 1000 mL/m2 D5W NS + 10g/m2 mannitol.  Repeat x 2 days  
Hour 6-24: Post-cisplatin hydration with D5W ½ NS + 10 mEq KCl/L + 20mEq MgSO4/L at 125 
mL/m2/hr.  Repeat on day 2 
 
19.2 
Doxorubicin/Ifosfamide  
 
19.2.1  
Day 1,2 Doxorubicin 75 mg/m2 IV over 48 hours.  Dilute in 480 mL D5W and administer at 10 
mL/hr x 48 hours 
 
19.2.2  
Day 1,2,3  Ifosfamide/Mesna:   
Hours -4 to 0: 1 liter/m2 of oral or IV fluids to achieve urine specific gravity ≤1.010 
Hours 0-4: Ifosfamide 3 g/m2 IV over 4 hr in 800 mL/m2 D5W ½ NS with Mesna 600 mg/m2  
Hours 4-7:  Mesna 600 mg/m2 IV in 600 cc D5W ¼ NS 
Hours 7,10,13: Mesna 600 mg/m2 IV over 15 minutes 
Hours 7-24: IV or PO hydration with D5W ¼ NS+ 10 mEq KCL/L @ 100 mL/m2/hr. 
Alternatively the identical dose of Mesna can begin by continuous infusion. 
 
19.3 
High Dose Methotrexate  
(including recommendations for hydration and monitoring of fluid status) High-dose methotrexate 
should be given at pre-surgery dose with no adjustment for limb loss. 
 
19.3.1 
Hours -6 to 0: D5W +40-60mEq NaHCO3/L +10 mEq KCl/L at 200 mL/m2/hr to achieve urine pH ≥ 7.0. 
 
19.3.2 
Hours 0-4:  Methotrexate 12g/m2 in 500 mL/m2 D5W +40 mEq NaHCO3/L at 125 mL/m2/hr (maximum  
dose: 20 grams) IV over 4 hours. All doses should be rounded up to next highest full gram value. 
 
19.3.3 
Hours 4-54: Post-hydration with D5W +40mEq NaHCO3/L +10 mEq KCl/L at 125 mL/m2/hr.  
 
19.3.4 
Hour 24: Begin Leucovorin 15 mg/m2 PO/IV, q6 hrs. Beginning at T= 24h (from beginning of 


 
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Page 88 
methotrexate infusion) and continuing until serum methotrexate is < 0.1 M or until delayed excretion 
criteria is reached (see section below).  
 
19.3.5 
MTX levels - Ideally these should be obtained at T=4, 24, 48, 72, (96) hrs with immediately available 
results.  IF only AM values can be immediately available, draw MTX levels at T=4, 24, and q AM. 
 
19.3.5.1  
Methotrexate toxicity—recommendations for management*  
 
Excretion/Toxicity 
24 Hour MTX Level 
48 Hour MTX Level 
72 Hour MTX Level 
Leucovorin 
Dosing/Intervention 
Expected Excretion 
< 10 µM 
(1 x 10-5 M) 
< 1 µM 
(1 x 10-6 M) 
 
< 0.1 µM 
(1 x 10-7 M) 
 
Maintain hydration 
125 ml/m2/hr 
15 mg/m2 q6h PO/IV 
Until MTX level 
< 0.1µM (1 x 10-7 M) 
Grade I  
 
(Mild toxicity-delayed 
excretion) 
 
 
≥ 0.1 µM and <0.5 µM 
(1-5 x 10-7 M) 
 
Maintain hydration 
125 ml/m2/hr 
15 mg/m2 q6h PO/IV 
Recheck level @ 96hrs 
if < 0.08µM (8 x 10-8 M)  
discontinue leucovorin 
If parameters not met @ 
96 
hours 
discontinue 
leucovorin when level < 
0.05µM (5 x 10-8 M) 
 
Grade I 
 
(Mild toxicity) 
>10 and < 50 µM 
(1-5 x 10-5 M) 
AND/OR 
25- 50 % increase 
in serum creatinine, 
Grade I-II stomatitis 
≥ 1 µM and < 5 µM 
(1-5 x 10-6 M) 
AND/OR 
25- 50 % increase 
In serum creatinine, 
Grade I-II stomatitis 
0.5-5 µM 
(0.5 -5 x 10-6 M) 
AND/OR 
25- 50 % increase in 
serum creatinine, 
Grade I-II stomatitis 
Increase hydration 
200 ml/m2/hr 
15 mg/m2 q6h PO/IV 
Until MTX level 
< 0.1µM (1 x 10-7 M) 
or 
Until criteria for delayed 
excretion met 
 
 
Excretion/Toxicity 
24 Hour MTX Level 
48 Hour MTX Level 
72 Hour MTX Level 
Leucovorin 
Dosing/Intervention 
Grade II 
 
(Moderate toxicity) 
>10 and < 50 µM 
(1-5 x 10-5 M) 
AND/OR 
 50- 100 % increase in 
serum creatinine,  
 On previous or current 
course of HDMTX: 
Grade III-IV 
stomatitis, 
myelosuppression 
≥ 1 µM and < 5 µM 
(1-5 x 10-6 M) 
AND/OR 
50- 100 % increase 
in serum creatinine, 
On previous or 
current course of 
HDMTX: Grade III-
IV stomatitis, 
myelosuppression 
0.5-5 µM 
(0.5 -5 x 10-6 M) 
AND/OR 
 50- 100 % increase in 
serum creatinine,  
 On previous or current 
course of HDMTX: 
Grade III-IV 
stomatitis, 
myelosuppression  
Increase hydration 
200 ml/m2/hr 
15 mg/m2 q3h IV** 
Until MTX level 
< 0.1µM (1 x 10-7 M)  
         or 
Until criteria for  
Delayed excretion met 
Grade III 
 
(Severe toxicity) 
 
Consider 
Glucarpidase*** 
(Carboxypeptidase G2) 
≥ 50 µM and  
< 500 µM  
(5-50 x 10-5 M) 
OR 
> 100 % increase 
In serum creatinine 
 
≥ 5 µM and <100 µM 
(5x 10-6 M) – 
(1 x 10-4 M) 
OR 
> 100 % increase 
In serum creatinine 
≥ 5-50 µM 
(0.5-5 x 10-5 M) 
OR 
> 100 % increase 
In serum creatinine 
 
Increase hydration 
200 ml/m2/hr 
150 mg/m2 q3h IV** 
Until MTX level 
< 0.1µM (1 x 10-7 M) or 
Until criteria for  
Delayed excretion met 


 
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Page 89 
Grade IV 
 
(Life threatening) 
 
Consider 
Glucarpidase***  
(Carboxypeptidase G2) 
 
≥ 500 µM 
(5 x 10-4 M) 
 
≥ 100 µM 
(1 x 10-4 M) 
 
≥ 50 µM 
(5 x 10-5 M) 
 
Increase hydration 
200 ml/m2/hr 
1500 mg/m2 q6h IV** 
(maximum dose 1500mg) 
Until MTX level< 0.1µM 
 (1 x 10-7 M) or 
Until criteria for  
Delayed excretion met 
* For elevated methotrexate levels or delayed excretion monitor serum creatinine q12-24 hours and methotrexate 
levels q 24 hours. Doses of leucovorin > 25 mg PO should be given IV due to the saturation of absorption. During 
methotrexate administration maintain urine pH > 7.0 at all times. 
 
** It is possible to reduce the dose of leucovorin on the following days in relation to the reduction in the 
methotrexate level.  When the methotrexate level is in the range of 0.2 – 0.9 µM, give doses of 15mg/m2 every 6 
hours until one dose after the serum level is <0.1 µM or until criteria for delayed excretion met. Please note that 
leucovorin contains calcium and should not be given at rate faster than 160mg per minute. 
 
***Glucarpidase (Carboxypeptidase G2, Voraxaze
) is as an investigational agent and is available in the 
US under a Treatment Protocol for patients receiving high dose methotrexate. To obtain supplies of 
glucarpidase in the US contact AAIPharma 24-hour Access Call Center at 866-918-1731. Additional 
information can be found at http://www.btgplc.com/BTGPipeline/273/Voraxaze.html.  
 
SEVERE TOXICITY REQUIRES PROMPT INTERVENTION - In cases of severe MTX toxicity, 
contact AAIPharma 24-hour Access Call Center at 866-918-1731 to obtain supplies of carboxypeptidase 
(glucarpidase, 
Voraxase). 
Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/BTGPipeline/273/Voraxaze.html 
 
Patients with severe Methotrexate (MTX) toxicity may experience renal failure, hepatic dysfunction and 
myelosuppression.  Monitor I & O, weight, CBC, differential, platelets, BP, SGPT, bilirubin, serum 
creatinine, and MTX levels daily.  Patients may have severely delayed MTX excretion with MTX 
levels > 10-7 M (0.1 M) and serum creatinine > 50% of baseline levels for more than 2l days.  
 
It is expected that patients receiving high dose Methotrexate will develop hypertransaminasemia and 
occasionally hyperbilirubinemia.  These elevations can last up to two weeks following the infusion and 
will not be considered toxicity requiring discontinuation of the drug.  Persistent hyperbilirubinemia and/or 
Grade 3 or 4 hypertransaminasemia for longer than 3 weeks will result in discontinuation of MTX if no 
other etiology is apparent.  Notify study coordinator. 
 
In the event of severe toxicity or recurrent moderate toxicity that does not have an obvious 
correctable cause, consider decreasing MTX cycles to individual rather than two paired weekly 
MTX cycles.  If moderate or severe toxicity recurs, consider eliminating MTX cycles.   
 
19.4 
Ifosfamide/Etoposide (including recommendations for hydration, supportive care) 
 
19.4.1 
Day 1-5:  Ifosfamide/Mesna/Etoposide 
Hours -4 to 0: D5W ½ NS at 250 mL/m2/hr to achieve SG ≤ 1.010 
Hours 0-1: Etoposide 100 mg/m2 in 250 mL/m2 D5W ½ NS 
Hours 1-5: Ifosfamide 2.8 gm/m2 over 4 hr in 800 mL/m2 D5W ½ NS with Mesna 560 mg/m2 
Hours 5-8:  Mesna 560 mg/m2 IV in 600 cc D5W ¼ NS 
Hours 8,11,14: Mesna 560 mg/m2 IV over 15 minutes 
Hours 8-24: IV or PO hydration with D5W ½ NS + 10 mEq KCl/L @ 100mL/m2/hr. 
Alternatively the identical dose of Mesna can begin by continuous infusion. 


 
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APPENDIX I:  TABLE OF CLINICALLY RELEVANT DRUG SUBSTRATES FOR CYP 2C9 
AND CYP2D6  
 
CYP 2C9 
SUBSTRATES 
CYP 2D6 
 
NSAIDs: 
diclofenac 
ibuprofen 
piroxicam  
Oral Hypoglycemic Agents: 
tolbutamide 
glipizide  
Angiotensin II Blockers: 
NOT candesartan 
irbesartan 
losartan 
NOT valsartan 
Other: 
celecoxib 
fluvastatin naproxen 
phenytoin 
sulfamethoxazole 
tamoxifen 
tolbutamide 
torsemide 
warfarin 
Beta Blockers: 
S-metoprolol 
propafenone 
timolol 
 
Antidepressants: 
amitriptyline 
clomipramine 
desipramine 
imipramine 
paroxetine  
 
Antipsychotics: 
haloperidol 
risperidone 
thioridazine 
 
Other: 
aripiprazole 
codeine 
dextromethorphan 
duloxetine 
flecainide 
mexiletine 
ondansetron 
tamoxifen 
tramadol 
venlafaxine 
 
 
Adapted from table prepared by Division of Pharmacology School of medicine Indiana University located 
at http://medicine.iupui.edu/flockhart/ 


 
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APPENDIX II YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AOST0331 (EURAMOS 1) 
(for children 7 through 12 years of age) 
 
 A Treatment Study for Children with Osteosarcoma Based on Tumor Response to 
Chemotherapy Given Before Surgery 
 
 
1. We have been talking with you about your bone tumor(s), called osteosarcoma. After doing 
tests we have found you have this kind of tumor. 
 
2. We are asking you to take part in a research study to try a new way of treating your 
osteosarcoma. A research study is when doctors work together to try out new ways to help 
people who are sick. In this study, we are trying a new way to treat osteosarcoma. 
 
3. Children who are part of this study will have two parts to their treatment. One part will be to 
get chemotherapy (a medicine that kills cancer cells), and then have an operation (surgery) 
to remove the tumor(s). The second part will be to start a new chemotherapy plan. Which 
new plan you get will depend on how well the earlier chemotherapy worked for you.  
 
4. In the second part of the study you will be randomly assigned to get either the same 
chemotherapy you received in the first part or you will receive the same therapy plus new 
drug. This is called Randomization. This is a lot like flipping a coin. A computer decides 
which chemotherapy plan you will be on, not you or your doctor. The reason for this is to 
make sure there are the same number 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.  
 
5. Something called a central line is often used for children getting chemotherapy into a vein, 
so they can receive chemotherapy through it instead of getting poked by a needle. A central 
line is a special type of tubing that is put into a large vein in your chest. If you have a central 
line you should not have to get poked too many times to get chemotherapy or have blood 
samples taken. 
 
6. 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 one of the 
experimental treatments, we hope the experimental treatment will be better at getting rid of 
the cancer than the normal treatment. But, we don’t know for sure if there is any benefit of 
being part of this study. 
 
7. Sometimes bad things can happen to people when they are in a research study.  These bad 
things are called “risks.” If you get one of the experimental treatments, a risk to you from this 
study is that you may have more side effects from the experimental treatment. Other risks 
are that your treatment will take longer to complete and may not be any better than the 
normal treatment in getting rid of the cancer. Other things may happen to you that we don’t 
yet know about. 
 


 
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Page 92 
8. Your family can choose to be part of this study or not. Your family can also decide to stop 
being in this study at any time once you start. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you 
have. 
 
9. We are asking your permission to save some of the tumor tissue that was taken during your 
operation to use for future research. You do not have to agree to let us save this tissue to be 
a part of this study. 
 
10. We are also asking you to answer some questions about what your life is like and how you 
feel about your diagnosis and treatment. We would ask these questions 4 different times 
during or after your treatment. You do not have to agree to answer these questions to be a 
part of this study. After you get your chemotherapy, you will be checked regularly in the clinic 
to see how well the drugs are working and to answer the questions about how you feel. 
 
 
 


 
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INFORMATION SHEET REGARDING RESEARCH STUDY AOST0331 (EURAMOS 1) 
(for teens 13 through 17 years of age) 
 
 A Treatment Study for Children and Teens with Osteosarcoma Based on Tumor Response to 
Chemotherapy Given Before Surgery 
 
 
1. We have been talking with you about your bone tumor(s), called osteosarcoma. After 
doing tests we have found you have this kind of tumor. 
 
2. We are asking you to take part in a research study because you have osteosarcoma.  A 
research study is when doctors work together to try out new ways to help people who 
are sick. In this study, we are trying to a new way to treat osteosarcoma. 
 
3. Children and teens who are part of this study will receive treatment in two parts. One 
part will be to get chemotherapy (a medicine that kills cancer cells), and then have an 
operation (surgery) to remove the tumor(s).  
 
The second part will be to start a new chemotherapy plan, which will be determined by 
how well the earlier chemotherapy worked for you: 
 
If the chemotherapy worked really well (90% or more of the cancer cells were 
destroyed), you will either continue with the same chemotherapy OR get the 
same chemotherapy PLUS one new drug.  
 
If the chemotherapy worked not so well (fewer than 90% of the cancer cells were 
destroyed), you will either continue with the same chemotherapy OR get the 
same chemotherapy PLUS two new chemotherapy drugs.  
 
If the chemotherapy did not affect the cancer cells at all, your doctor will take you 
off this study and develop a new treatment plan for you.  
 
4. The second part of the study is called a randomized study, because you will be randomly 
assigned to get one treatment plan or the other. This is like flipping a coin and saying, 
“Heads means I get the same chemotherapy, but tails means I get the same 
chemotherapy AND something new,” except that a computer will determine which 
chemotherapy plan you would be on.  The decision about which treatment you receive is 
not made by you or your doctor directly. The reason for this is to make sure there are the 
same number 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.  
 
5. Something called a central line is often used for people getting chemotherapy into a 
vein, so they can receive chemotherapy through it instead of getting poked by a needle. 
A central line is a special type of tubing that is put into a large vein in your chest. If you 
have a central line you should not have to get poked to get chemotherapy or have blood 
samples taken. 
 
6. 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 one of the 
experimental treatments, we hope the experimental treatment will be better at getting rid 
of the cancer than the standard treatment. But, we don’t know for sure if there is any 
benefit of being part of this study. 


 
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Page 94 
 
 
7. Sometimes bad things can happen to people when they are in a research study.  These 
bad things are called “risks.” If you get one of the experimental treatments, a risk to you 
from this study is that you may have more side effects from the experimental treatment.  
Other risks are that the experimental treatment will take longer to complete and may not 
be any better than the standard treatment in getting rid of the cancer. Other things may 
happen to you that we don’t yet know about. 
 
8. Your family can choose to be part of this study or not. Your family can also decide to 
stop being in this study at any time once you start. There may be other treatments for 
your illness that your doctor can tell you about. Make sure to ask your doctors any 
questions that you have. 
 
9. We are also asking your permission to save some of the tumor tissue that was taken 
during your operation to use for future research about cancer and other diseases. You 
do not have to agree to let us save this tissue to be a part of this study. 
 
10. We are also asking you to answer some questions about what your life is like and how 
you feel about your diagnosis and treatment. We would ask these questions 4 different 
times during or after your treatment. You do not have to agree to answer these 
questions to be a part of this study. After you get your chemotherapy, you will be 
checked regularly in the clinic to see how well the drugs are working and to answer the 
questions about how you feel. 


 
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REFERENCES 
 
1. 
Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 85:365-76, 1993 
2. 
Varni JW, Burwinkle TM, Katz ER, et al: The PedsQL in pediatric cancer: reliability and validity 
of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, 
and Cancer Module. Cancer 94:2090-106, 2002 
 
 


 
 
 
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This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Institutions should use the sections of this document which are 
in bold type in their entirety. Editorial changes to these sections may be made as long as they 
do not change information or intent. If the local IRB insists on making deletions or more 
substantive modifications to any of the sections in bold type, they must be justified in writing by 
the investigator at the time of the institutional audit.  
 
SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
 
AOST0331, A Randomized Trial of the European and American Osteosarcoma Study 
Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on 
Histologic Response to Pre-Operative Chemotherapy (EURAMOS 1) 
 
If you are a parent or legal guardian of a child who may take part in this study, 
permission from you is required and the assent (agreement) of your child may be 
required.  When we say “you” in this consent form, we mean you or your child; “we” means the 
doctors and other staff. 
 
PART 1- INDUCTION THERAPY 
This study is a clinical trial (a research study involving human subjects). Clinical trials only 
include individuals who choose to take part in them. Please take your time to make your 
decision.  Discuss your decision with your friends and family. 
 
You are being asked to take part in this study because you have osteosarcoma, a form of 
cancer that develops in bone. Osteosarcoma is the most common cancerous bone tumor in 
children and young adults. Study doctors would like to find out how best to treat subjects with 
osteosarcoma by comparing how subjects do when treated with different anti-cancer drugs.  
The EURAMOS 1 trial is open to all osteosarcoma subjects who have high grade tumor that can 
be removed by surgery; high grade tumor means that the osteosarcoma tumor cells grow very 
fast. The tumors must be in the legs, arms, or backbone, and can still be in the place(s) where 
they first started (this is called localized disease) or can have spread to other places in the body 
(this is called metastatic disease) as long as all the tumors can be taken out with surgery. 
 
Why is this study being done? 
This study is being done to try to find out the best way to treat osteosarcoma subjects who have 
tumors that can be removed by surgery. The standard anti-cancer drugs used to treat subjects 
with osteosarcoma are doxorubicin, cisplatin, and methotrexate (together called MAP). In 
previous research studies using MAP study doctors found that by looking at pieces of the tumor 
under a microscope after some MAP has been given, they can estimate how many tumor cells 
have been killed; if the tumor cells are almost all destroyed (about 90% or more, called a good 
response), there is a good chance that the tumor will go away if we continue to use these 
standard drugs. If the tumor cells are not as easily killed by MAP (less than 90% of the cells 
killed, called a poor response), the chance that the disease will go away is not as good, 
meaning the tumor is more likely to return later. 
 
For subjects who have a poor tumor response to MAP, study doctors would like to find out if 
adding two other common anti-cancer drugs (ifosfamide and etoposide) to MAP will help get rid 
of the tumor in more subjects. We do not know if adding ifosfamide and etoposide to the MAP 
regimen will increase the chance of getting rid of the tumor. Ifosfamide and etoposide have 
been chosen for use in this study because in some previous studies of children with metastatic 


 
 
 
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osteosarcoma, the addition of ifosfamide and etoposide to MAP brought about a better 
outcome. Adding ifosfamide and etoposide to the MAP chemotherapy treatment is experimental. 
For subjects who have a good tumor response to MAP therapy, study doctors would like to 
know if adding a “biologic” drug, interferon, after MAP, will help make sure the tumor cells do not 
return later. Interferon is produced naturally in the body. The exact way interferon works is not 
known; it may directly kill cancer cells, or it may interfere with the blood supply to the tumor, or it 
may make the body’s immune system work better (the immune system recognizes and destroys 
“foreign” cells). This study will use pegylated interferon alfa-2b, interferon that has been 
modified to last longer in the body so it can be given less often. The use of interferon was 
shown in some previous studies of subjects with other diseases to increase the time before the 
disease came back: we do not know if giving interferon will increase the chance of getting rid of 
the tumor for subjects with osteosarcoma. Adding pegylated interferon alfa-2b after the MAP 
chemotherapy treatment is experimental. 
 
Because this study will have a large number of subjects treated in the same ways, study doctors 
will be able to tell if these drugs do improve the outcome for subjects with osteosarcoma. It is 
important to study the addition of these chemotherapy drugs and the biologic drugs because the 
addition of these drugs will also add side effects and lengthen the total amount of treatment 
time. 
 
The aims of this study are, then: 
 
To see if the addition of ifosfamide and etoposide to MAP chemotherapy will help 
get rid of the disease in subjects who have a poor tumor response to MAP alone. 
 
To see if the addition of interferon after MAP chemotherapy can help get rid of the 
disease in subjects who have a good tumor response to standard chemotherapy. 
 
Study doctors would also like to look at the tumor tissue to see if there are things about the 
genetic make-up of these tumors that can be used to predict how subjects will respond to 
therapy. Study doctors would also like to know how the disease and the therapy affect the lives 
of subjects and their families. 
 
How many people will take part in the study? 
There will be about 2300 subjects taking part in this study. 
 
What will happen if I take part in this research study?   
Before you begin the study …  
If you take part in this study, you will have the following tests and procedures. These are part of 
regular cancer care and may be done even if you do not join in this study:  
 
History and physical examination 
 
Blood tests 
 
Urine tests 
 
Pregnancy Test* 
 
Echocardiogram (picture of the heart in motion) 
 
MRI (magnetic resonance imaging) of disease sites 
 
X-ray of disease sites and the chest 
 
CT scan (an X-ray procedure) of disease sites and the chest 
 
Bone Scan (picture of the bones) 
 
Audiogram (hearing test) 
 
Nuclear Medicine Scans  
* Given to females of childbearing age prior to treatment 


 
 
 
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Because you are in this study we will want to know your view of how your life has been affected 
by cancer and its treatment. You will be asked to fill out some questionnaires; these are called 
Quality of Life Assessments; they will be done after you have had about 6 weeks of 
chemotherapy, about three months after surgery, at 18 months after the start of all the study 
therapy, and at 3 years after the start of all the study therapy. It will take about 10 minutes to 
complete the questionnaires; if your child is on this study, you and your child will be given 
different questionnaires. You do not have to take part in these Quality of Life assessments to be 
part of this research study. 
 
All subjects who are enrolled on this study will begin treatment with the standard drugs for 
osteosarcoma therapy: doxorubicin, cisplatin and methotrexate (MAP). Following 10 weeks of 
chemotherapy subjects will have surgery to take out the tumor(s). The tumor tissue will be 
looked at under a microscope to find out how many of the tumor cells have been killed; briefly, if 
90% or more of the tumor cells have been killed, this will be called a good tumor response.  If 
less than 90% of the tumor cells have been killed, this will be called a poor tumor response.  If 
there is no change in the tumor, you will be taken off therapy and other treatment options will be 
discussed. 
 
The therapy you will get on the second part of the study will depend on whether you have a 
good or a poor tumor response, and then will depend on randomization to one of two different 
treatment regimens. Randomization means that you are being put into a group by chance. It is 
like flipping a coin. Which group you are put in is done by a computer. Neither you nor the 
researcher will choose which group you will be put in. You will have an equal chance of being 
placed in any group. Your study doctor will discuss the treatments with you and you will be 
asked to sign another consent for the second part of the study. Your study doctor may think that 
you need to start chemotherapy after your surgery and before all the information is known for 
the randomization. In this case, you will start on a cycle of MAP chemotherapy before signing 
the consent for the randomized part of the study. 


 
 
 
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Here is the treatment plan for the entire study: 
Phase 
Treatment 
Treatment Details 
Part 1 
Induction Therapy 
Same for all subjects 
 
MAP Chemotherapy: (Methotrexate, Doxorubicin, 
and Cisplatin) 
Approximately 10 weeks of therapy 
Surgery 
Local Control 
Occurs at week 11 
 
% of tumor cells killed will be determined 
Discussion about Part II treatment 
Signing another consent for Part 2 
treatment 
Part 2 
Maintenance therapy 
Begins after recovery from surgery 
 
Good response to MAP - Randomization to 
either: 
i. 
MAP (Methotrexate, Adriamycin, 
Cisplatin) 
                      or 
ii. 
MAPifn (Methotrexate, Adriamycin, 
Cisplatin + Pegylated interferon alfa-
2b) 
 
 
 
Poor response to MAP – Randomization to 
either: 
i. 
MAP(Methotrexate, Adriamycin, 
Cisplatin) 
                      or 
ii. 
MAPIE (Methotrexate, Adriamycin, 
Cisplatin + Ifosfamide, Etoposide) 
 
 
Treatment duration approximately 7 
months 
 
Treatment duration approximately 7 
months for chemotherapy, and  up to 2 
years of Pegylated interferon alfa-2b (as 
long as the treatment does not cause 
significant side effects and there is no 
evidence of disease progression) 
 
 
Treatment duration approximately 7 
months 
 
Treatment duration approximately 10 
months 
 
Methods for Giving Drugs 
Various methods will be used to give the drugs to you. Some drugs may be given by tablet or 
liquid through the mouth (oral). Some drugs may be given using a needle inserted just under the 
skin (subcutaneous). Other drugs may be given using a needle inserted into a vein (IV, or 
intravenous). 
The drugs for the induction therapy on this study are given in this way: 
 
MAP (Induction) 
Week 
Day Drug  
Method 
1,6 
1,2 
1,2 
Doxorubicin* 
Cisplatin 
Given as a continuous infusion through a vein over 48 hours 
Given by vein over 4 hours 
4,5,9,10 1 
2 
Methotrexate 
Leucovorin# 
Given by vein over 4 hours 
Given by vein 24 hours after the start of Methotrexate, every 6 
hours, until Methotrexate level has sufficiently cleared from the 
blood (determined by a blood test) 
If surgery is delayed, you (your child) may get more 
methotrexate prior to surgery. If you have (your child has) 
difficulty recovering from the effects of the methotrexate 
therapy you (your child) may only have methotrexate twice 
before surgery instead of four times. 
11 
 
 
Surgical removal of tumor 
*Dexrazoxane may be given with doxorubicin. 
# Small doses may be given by mouth. 
 


 
 
 
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Central Line 
For drugs to be given by vein, your study doctor will likely recommend that you have a central 
venous line placed. A central line is a type of tubing inserted into a large vein in the chest by a 
surgeon during a short operation. The central line is used to administer chemotherapy drugs 
and to withdraw small amounts of blood for testing during treatment. How the tubing is inserted 
and all the risks associated with central lines will be explained to you, and all of your questions 
about the central line will be answered, when you sign a separate consent for the central line. 
 
Surgery 
Subjects on this study will undergo surgery after Induction chemotherapy. You will be asked to 
sign a separate consent form for the surgical procedure. The planned surgery will be explained 
to you and your questions about it answered by your surgeon when you sign the consent for the 
surgical procedure. 
 
Some of the tissue already taken to make your diagnosis will be sent to a central review center 
as part of COG quality control; there will also be central review of the slides used to find out how 
many cancer cells have been killed after the induction therapy with MAP. 
 
Radiation therapy 
A small number of subjects on this study may need to have radiation therapy to help control the 
tumor; this would only be done if the tumor cannot be completely taken out with surgery. You 
will be asked to sign a separate consent for the radiation therapy. All your questions about the 
radiation therapy will be answered and the procedure explained when you sign the consent for 
radiation therapy. 
 
 
How long will I be in the study? 
 
We think if you complete therapy with MAP alone on this study, the treatment will last for about 
7 months. Treatment on the MAPIE therapy will last about 10 months. Treatment with MAP plus 
pegylated interferon alfa-2b will take about 7 months for the completion of MAP, but you will get 
pegylated interferon alfa-2b for up to two years, as long as the treatment does not cause bad 
side effects and there is no evidence the disease has come back. After treatment, subjects will 
have follow-up examinations and medical tests. We will continue to collect some medical 
information about how you are doing for 10 years after you start the study.  
 
The study doctors may decide to take you off the study if your cancer gets worse or you have 
side effects from the treatment that are too bad. 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
therapy can be evaluated by your doctor. Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 


 
 
 
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What side effects or risks can I expect from being in the study?  
 
While on Part 1 of this study you are at risk for the side effects known about MAP therapy 
listed in the attached Appendix. You should discuss these with the study doctor and/or 
your regular doctor. There are other drugs that may be given to make the side effects of 
the drugs less serious and uncomfortable. There are no additional risks to you from the 
MAP therapy on Part 1 of the study as compared to getting this standard therapy without 
being on the study. 
 
In Part 2 of the study, the addition of ifosfamide and etoposide for subjects with a poor 
tumor response to pre-surgery MAP will cause additional side effects and prolong the 
length of treatment and may not improve the chance that the disease will go away.  The 
addition of Pegylated interferon alfa-2b for subjects with a good tumor response will 
cause additional side effects and prolong the length of treatment and may not improve 
the chance that the disease will go away. There may also be other side effects that we 
cannot predict when these drug combinations are used. 
 
Many side effects go away shortly after the study drugs are stopped, but in some cases 
side effects can be serious, long lasting, permanent, or even fatal.  You will be watched 
closely and the drugs will be stopped if bad side effects develop. Finally, a few subjects 
who survive cancer develop a second form of cancer.  
 
Surgical risks:  
The surgeon will talk to you about the risks of the surgery when you sign the consent for surgery 
after induction chemotherapy. In general, surgery may result in one or more of the following side 
effects: bleeding, infection, problems with wound healing, pain, scar, adhesions, loss of nerve or 
organ function, or blood vessel damage. Depending on the type of anesthesia required, there 
may be one or more of the following side effects: nausea, vomiting, air passage obstruction, 
breathing problems, or heart irregularity. In rare instances death may occur during or after 
surgery. 
 
 
Reproductive Risks 
For Women: 
The treatment on this study can affect an unborn child. You should not become pregnant or 
breast feed your baby while being treated on this study.  If you are sexually active and are at 
risk of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex.  The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study.  You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctors about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation.  If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor.  If you 
become pregnant during the research study, please tell the study doctor and your regular doctor 
immediately. 
 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctors about the length of time you need to avoid nursing. 


 
 
 
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For Men: 
The treatment on this study can damage sperm.  You should not father a child while on this 
study as the treatment may indirectly affect an unborn child.  If you are sexually active and are 
at risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex.  The study doctor will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study.  You will 
have to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctors about the length of time you need to 
avoid pregnancy or abstain. Natural family planning and the rhythm method will not be 
permissible means of avoiding pregnancy during study participation. If you have questions 
about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor.  If your partner becomes pregnant during the research study, please tell the study doctor 
and your regular doctor immediately. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better. While doctors hope the drug 
therapy in this study will be more useful against cancer compared to the usual treatment, there 
is no proof of this yet. We do know that the information from this study will help doctors learn 
more about treating osteosarcoma. This information could help future cancer patients. 
 
 
What other choices do I have if I do not take part in this study? 
Instead of being on this study, you have these options: 
 
The standard treatment for osteosarcoma, which is chemotherapy with doxorubicin, cisplatin 
and methotrexate (MAP) without being on this study 
 
Another experimental treatment (if available) 
 
 
Please discuss these options with your regular doctor as well as other trusted personal and 
family advisors.  
 
 
Will my medical information be kept private?  
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is attached at end of this consent. 
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance and data analysis include: 
 
 The Children's Oncology Group, 
 Representatives of the National Cancer Institute (NCI), Food and Drug Administration 
(FDA), and other U.S. and international governmental regulatory agencies involved in 
keeping research safe for people, 
 The Institutional Review Board (IRB) of this hospital, 
 The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute, 


 
 
 
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 Representatives of Schering-Plough, the company that will be supplying pegylated 
interferon alfa-2b for this study 
 Representatives of the cooperating pediatric research groups. 
 
It is very unlikely that the research testing might uncover important information about you or 
your current or future health. If this unlikely event occurs, the researchers may contact your 
doctor through Children’s Oncology Group about what the test results might mean. Only your 
doctor will be notified and the information will remain confidential. Your doctor may discuss this 
unexpected finding with you, and may recommend consultation with a genetic counselor and/or 
repeat testing in a clinical (not research) laboratory if necessary. It is possible that your doctor 
may recommend that no additional action is necessary. 
 
What are the costs of taking part in this study? 
 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study. Some health plans will not pay these costs for people taking 
part in studies. Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost 
of getting regular cancer treatment. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
This study includes providing specimens to the researcher, there are no plans for you to profit 
from any new products developed from research done on your specimens.   
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study. You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment. The study has no plans to pay for 
medical treatment.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time. No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. Leaving the study will not affect your medical care. You can still get your 
medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 


 
 
 
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In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For 
questions 
about 
your 
rights 
while 
taking 
part 
in 
this 
study, 
call 
the 
________________________ [name of center] Institutional Review Board (a group of people who 
review the research to protect your rights) at __________________ (telephone number).  (Note to 
Local Investigator: Contact information for patient representatives or other individuals in a local 
institution who are not on the IRB or research team but take calls regarding clinical trial questions 
can be listed here)    
 
Please note:  This section of the informed consent form is about additional research studies that 
are being done with subjects who are taking part in the main study. You may take part in these 
additional studies if you want to.  You can still be a part of the main study even if you say ‘no’ to 
taking part in any of these additional studies. 
 
Consent to take part in Quality of Life Assessment research: 
We want to know your view of how your life has been affected by cancer and its treatment. This 
“Quality of Life” study looks at how you feel, physically and emotionally, during the cancer 
treatment. It also looks at how your family adapts to the cancer treatment. This information will 
help doctors and nurses better understand how subjects and families feel during treatments and 
what effects the medicines are having. 
You will be asked to complete surveys at 4 time points: after you have had about 6 weeks of 
chemotherapy, about three months after surgery, 18 months after the start of study therapy, and 
3 years after the start of study therapy. If your child is on this study, you and your child will be 
given different questionnaires. It takes about 10 minutes to fill out the questionnaires and this 
usually can be done during a clinic visit.   
 
If any questions make you (or your child) feel uncomfortable, you (or your child) may skip those 
questions and not give an answer. 
 
If you agree to take part in the Health Related Quality of Life Assessment, we will do our best to 
make sure that your answers to the questionnaires are kept private.   
 
You may change your mind about completing the questionnaires at any time. If you change your 
mind, please let the study doctor know and you will not be given any more questionnaires. 
 
Please circle your answer. After circling “yes “or “no” please write your initials in the space 
provided.  
 
I choose to take part in the Quality of Life Assessment.  I agree to fill out (and allow my child 
to fill out) the four Quality of Life Questionnaires. 
 
YES 
 
 
NO 
 
INITIALS________ 
 
DATE_______ 


 
 
 
AOST0331 
 
 
Page 105 
Consent to Use Tissue for Research [do not use this section if the patient has already enrolled 
on a specimen collection study] 
 
You had a biopsy to see if you had cancer. You had or will have surgery to remove your 
tumor(s). Information about the tumor will be given to you by your doctor and will be used to 
plan your care.  
 
We would like to keep some of the tissue that is leftover from your biopsy and any surgery for 
future research. If you agree, this tissue will be kept, labeled only with a code number, and may 
be used in research to learn more about cancer and other diseases. Please read the information 
sheet called " Providing Your Tissue For Research: What You Need To Know?" to learn more 
about tissue research.  
 
[Note to Local Investigator: This information sheet is available on the COG web site at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp  under CONSENTS 
AND IRB FORMS]  
 
Your tissue may be helpful for research whether you do or do not have cancer. The research 
that may be done with your tissue is not designed specifically to help you. It might help people 
who have cancer and other diseases in the future.  
 
Reports about research done with your tissue will not be given to you or your doctor. These 
reports will not be put in your health record. The research will not have an effect on your care.  
 
 
Things to Think About  
The choice to let us keep the leftover tissue for future research is up to you. No matter what you 
decide to do, it will not affect your care.  
 
If you decide now that your tissue can be kept for research, you can change your mind at any 
time. Just contact us and let us know that you do not want us to use your tissue. Then any 
tissue that remains will no longer be used for research.  
 
In the future, people who do research may need to know more about your health. While this 
institution may give them reports about your health, it will not give them your name, address, 
phone number, or any other information that will let the researchers know who you are.  
 
Sometimes tissue is used for genetic research (about diseases that are passed on in families). 
Even if your tissue is used for this kind of research, the results will not be put in your health 
records.  
 
Your tissue will be used only for research and will not be sold. The research done with your 
tissue may help to develop new products in the future.  


 
 
 
AOST0331 
 
 
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Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, 
circle "Yes" or "No" and write your initials in the space provided.  
If you have any questions, please talk to the study doctor or nurse, or call our research review 
board at IRB's phone number.  
No matter how you answer the following two questions, it will not affect your care. 
 
1. My tissue may be kept for use in research to learn about, prevent, or treat cancer.     
YES 
 
 
 
NO 
 
 
 
 
Initials ___________ 
 
 
2. My tissue may be kept for use in research to learn about, prevent or treat other health 
problems (for example: diabetes, Alzheimer's disease, or heart disease).  
YES 
 
 
 
NO 
 
 
 
 
Initials ___________ 
    
 
Where can I get more information? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor can get you this Handbook, or you can get it at www.curesearch.org/ 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/ 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615  
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/ 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.   
I have read it or it has been read to me.  
 
I have reviewed the information and have had my questions answered.  I agree to take part in 
the first part (Induction) of this study. 
 
Participant _______________________________  
Date_____________ 
 
Parent (or Guardian) _______________________  
Date_____________ 


 
 
 
AOST0331 
 
 
Page 107 
APPENDIX I: Risks and side effects related to MAP chemotherapy 
 
Risks and side effects related to doxorubicin include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Nausea 
 
Vomiting 
 
Temporary hair loss 
 
Pink or red color to 
urine, sweat, tears, 
saliva 
 
Fewer white blood 
cells, red blood cells 
and platelets in the 
blood. 
○ A low number of 
red blood cells 
can make you feel 
tired and weak 
○ A low number of 
white blood cells 
can make it easier 
to get infections 
○ A low number of 
platelets causes 
you to bruise and 
bleed more easily 
 
Slight damage to the 
heart muscle that is 
unlikely to have any 
noticeable effects on 
your heart function 
 
 Inflammation and/or sores 
in the mouth (and/or throat 
and /or esophagus, the tube 
that leads from the mouth to 
the stomach) that may make 
swallowing difficult and are 
painful (painful mouth 
sores) 
 Damage to the heart muscle 
which may make you tired, 
weak, feel short of breath, 
and retain fluid 
 Facial Flushing 
 Fever/chills 
 Hives 
 High levels of uric acid in 
the blood which could 
damage the kidneys 
 Dark discoloration of the 
hands, feet and under the 
fingernails with possible 
separation of the nail from 
the nail bed. 
 Damage to the skin if the 
medication leaks from a 
vein 
 Thickening and hardening 
of the veins through which 
the medication is given 
 Reddening reaction of the 
vein through which the 
drug is given 
 Elevation in the blood of 
certain enzymes found in 
the liver which may indicate 
liver irritation or damage 
 Tearing and inflammation of 
the eyes 
 Loss of appetite 
 Redness and burning at 
sites which have received 
radiation in the past  
 Diarrhea 
 
Severe allergic reaction 
which can be life 
threatening with 
shortness of breath, low 
blood pressure and a 
rapid heart rate 
 
Ulceration of the lower 
intestinal tract  
 
An irregular heart beat 
which can be life-
threatening 
 
Severe damage to the 
heart muscle which may 
lead to severe heart 
failure 
 
A new cancer or 
leukemia resulting from 
this treatment. 
 
 
The risk of heart damage may be greater in very young children than in older ones.  


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


 
 
 
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Risks and side effects related to methotrexate include those which are: 
Likely 
Less Likely 
Rare but Serious 
 
High levels 
of liver 
enzymes in 
the blood 
which may 
mean liver 
irritation or 
damage 
 
Nausea 
 
Vomiting 
 
Loss of appetite 
 
Diarrhea 
 
Chills and/or fever 
 
Inflammation and/or sores 
in the mouth, gums, throat 
and/or esophagus 
 
Inflammation of the 
intestines which may 
cause bleeding 
 
Sensitivity to sunlight and 
increased risk of sunburn 
 
Fewer white blood cells, 
red blood cells and 
platelets in the blood. 
○ A low number of red 
blood cells can make 
you feel tired and 
weak. 
○ A low number of white 
blood cells can make it 
easier to get 
infections. 
○ A low number of 
platelets causes you to 
bruise and bleed 
 Learning disability 
 Dizziness 
 Sense of not feeling well 
or tiredness 
 Drowsiness 
 Blurred vision 
 Rashes with itching and 
hives 
 Hair loss, inflammation of 
the hair follicles 
 Acne 
 Tearing and inflammation 
of the eyes 
 Darkening of the 
fingernails  
 
Severe allergic reaction which can be 
life threatening with shortness of 
breath, low blood pressure and a rapid 
heart rate 
 
The rapid death of large numbers of 
tumor cells which can cause the 
potassium and phosphate salts and 
the uric acid in the blood to rise 
quickly and this could lead to a life-
threatening irregular heart beat or 
damage to the kidneys.  
 
Severe rashes which can cause loss 
of skin or damage to mucous 
membranes or which can cause 
peeling, redness and pain on the 
palms of the hands and soles of the 
feet  
 
Damage, inflammation and/or scarring 
of lung tissue which may make you 
short of breath and cough 
 
Seizures 
 
Temporary damage to the brain such 
that you may experience headaches, 
drowsiness, difficulty speaking or 
forming words, blurred vision or 
temporary blindness, and decreased 
reflexes 
 
Temporary loss of function or feeling 
in the lower part of the body (partial 
paralysis) 
 
Severe damage to brain tissue which 
over time could lead to difficulty 
carrying out normal daily tasks or 
could lead to a coma. 
 
Inflammation and scarring of the liver  
 
Damage to the bone which could lead 
to arthritis pain and weakness of the 
bone 
 
Inflammation of the heart 
 
Fluid buildup around the heart 
 
Damage to the kidney  
 
 
 
 
 
 


 
 
 
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Leucovorin is given with methotrexate:  
 
Risks and side effects related to leucovorin include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
 Rash with itching 
and/or hives 
 
 Severe allergic reaction which 
can be life-threatening with 
shortness of breath, low blood 
pressure, rapid heart rate, chills 
and fever 
 Convulsions 
 
 
Sometimes dexrazoxane is given along with doxorubicin to help prevent heart damage.  
 
Side effects of dexrazoxane include those which are: 
Likely 
Less Likely 
Rare but serious 
 Fewer white blood 
cells, red blood cells 
and platelets in the 
blood. 
○ A low number of 
red blood cells 
can make you feel 
tired and weak 
○ A low number of 
white blood cells 
can make it easier 
to get infections 
○ A low number of 
platelets causes 
you to bruise and 
bleed more easily 
 
Mild nausea and/or 
vomiting 
 
Loss of appetite 
 
A feeling of extreme 
tiredness or not feeling 
well 
 
Diarrhea 
 
Increases in the blood of 
fats (triglycerides) and 
an enzyme made by the 
pancreas (amylase) 
 
Temporary increases in 
the blood of iron and 
decreases in the blood 
of calcium and zinc 
 
Damage to the skin if the 
medication leaks from a 
vein 
 
Thickening and 
hardening of the veins 
or pain in the vein 
through which the 
medication is given 
 
Temporary elevation in 
the blood of certain 
enzymes and bilirubin 
found in the liver 
 
It may take longer for the 
blood to clot 
 A new cancer or 
leukemia 
resulting from 
this treatment 
 
 


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


 
 
 
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This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Institutions should use the sections of this document which are 
in bold type in their entirety. Editorial changes to these sections may be made as long as they 
do not change information or intent. If the local IRB insists on making deletions or more 
substantive modifications to any of the sections in bold type, they must be justified in writing by 
the investigator at the time of the institutional audit.  
 
SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH  
 
AOST0331, A Randomized Trial of the European and American Osteosarcoma Study 
Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on 
Histologic Response to Pre-Operative Chemotherapy (EURAMOS 1) 
 
PART 2- For subjects with a good tumor response to Induction Therapy 
 
Why is this part of the study being done? 
Now that you have finished Part 1 of therapy you are being asked to continue on Part 2 of the 
study. Because your tumor has shown a good response to the MAP therapy in Part 1 (more 
than 90% of the tumor cells have been killed) you are eligible to be randomized to get either 
more MAP chemotherapy or MAP chemotherapy plus pegylated interferon alfa-2b. 
 
Continuing with MAP therapy alone should result in a very good outcome, but study doctors 
would like to know if adding the “biologic” drug interferon, after all MAP therapy is complete, will 
help make sure the tumor cells do not return later.  Adding pegylated interferon alfa-2b after 
MAP chemotherapy treatment is experimental.  
 
This study will use pegylated interferon alfa-2b, interferon that has been modified to last longer 
in the body so it can be given less often.   
 
How many people will take part in the study? 
There will be about 706 subjects with a good tumor response continuing on to Part 2 of the 
study. 
 
What will happen if I take part in this part of the research study?   
You will be assigned to one of the two treatments by randomization.  Randomization means that 
you are being put into a group by chance.  It is like flipping a coin. Which group you are put in is 
done by a computer. Neither you nor the study doctor will choose which group you will be put in.  
You will have an equal chance of being placed in any group.  You will be randomized to get 
continued standard treatment with MAP or treatment with MAP and then pegylated interferon 
alfa-2b (MAPifn); this is called maintenance therapy. 
 
If you join in Part 2, you will also continue to have common medical tests to help your doctor find 
out about your health and how the treatment is going.  These tests are part of regular cancer 
care and may be done even if you do not join in this study: 
 
History and physical examination 
 
Blood tests 
 
Urine tests 
 
Echocardiogram (picture of the heart in motion) 
 
MRI (magnetic resonance imaging) of disease sites 


 
 
 
AOST0331 
 
 
Page 113 
 
X-ray of disease sites and the chest 
 
CT scan (an X-ray procedure) of disease sites and the chest 
 
Bone Scan (picture of the bones) 
 
Audiogram (hearing test) 
 
Nuclear Medicine Scans  
 
Methods for Giving Drugs 
Various methods will be used to give the drugs to you (your child). Some drugs may be given by 
tablet or liquid through the mouth (oral).  Some drugs may be given using a needle inserted just 
under the skin (subcutaneous). Other drugs may be given using a needle inserted into a vein (IV 
or intravenous). 
 
The drugs for the study are given in this way: 
MAP 
Week 
Day Drug  
Method 
12, 17  
1,2 
1,2 
Doxorubicin* 
Cisplatin 
Given as a continuous infusion through a vein 
over 48 hours 
Given by vein over 4 hours 
22, 26 
1,2 
Doxorubicin 
Given as a continuous infusion through a vein 
over 48 hours 
15,16,20,21,24,25,28,29 1 
2 
Methotrexate 
Leucovorin# 
Given by vein over 4 hours 
Given by vein 24 hours after the start of 
Methotrexate, every 6 hours, until 
Methotrexate level has sufficiently cleared 
from the blood (determined by a blood test) 
 
* Dexrazoxane may be given with doxorubicin. 
# Small doses may be given by mouth. 
 
 
MAPifn 
Week 
Day Drug  
Method 
12, 17  
1,2 
1,2 
Doxorubicin* 
Cisplatin 
Given as a continuous infusion through a 
vein over 48 hours 
Given by vein over 4 hours 
22, 26 
1,2 
Doxorubicin 
Given as a continuous infusion through a 
vein over 48 hours 
15,16,20,21,24,25,28,29 
 
 
 
1 
2 
Methotrexate 
Leucovorin# 
Given by vein over 4 hours 
Given by vein 24 hours after the start of 
Methotrexate, every 6 hours, until 
Methotrexate level has sufficiently cleared 
from the blood (determined by a blood test) 
Weekly from week  
30-104 * 
1 
Pegylated 
Interferon Alfa-
2b 
Given as an injection into the tissue under 
the skin 
*Therapy could last until week 104 as long as 
the treatment does not cause significant side 
effects and there is no evidence that the 
disease has come back. 
 
*Dexrazoxane may be given with doxorubicin. 
# Small doses may be given by mouth. 


 
 
 
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Central Line 
For drugs to be given by vein, your study doctor will likely recommend that you (your child) have 
a central venous line placed. A central line is a type of tubing inserted into a large vein in the 
chest by a surgeon during a short operation. The central line is used to administer 
chemotherapy drugs and to withdraw small amounts of blood for testing during treatment. How 
the tubing is inserted and all the risks associated with central lines will be explained to you, and 
all of your questions about the central line will be answered, when you sign a separate consent 
for the central line. 
 
How long will I be in the study? 
 
If you join in the second part of the study, we think you will be treated for about 7 months if 
randomized to MAP therapy alone, and about 7 months for the basic chemotherapy plus up to 
two years of therapy with weekly pegylated interferon alfa-2b (as long as there is benefit) if 
randomized to the pegylated interferon alfa-2b therapy.. After treatment, subjects will have 
follow-up examinations and medical tests. We will continue to collect some medical information 
about how you are doing for 10 years after you start the study.  
 
The study doctors may decide to take you off the study if your cancer gets worse or you have 
side effects from the treatment that are too bad 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
therapy can be evaluated by your doctor. Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
 
While on this part of the study you are at risk for the side effects listed in Appendix I for MAP 
therapy as you were in Part 1. You should discuss these with the study doctor and/or your 
regular doctor.  
 
If you are randomized to get pegylated interferon alfa-2b, you will be at risk for additional side 
effects. The length of treatment will be longer and the drug may not improve the chance that the 
disease will go away. You will be watched closely and the pegylated interferon alfa-2b will be 
stopped if bad side effects develop. 
 


 
 
 
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Page 115 
 Risks and side effects related to Peginterferon alpha-2b include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Nausea  
 
Fever and chills 
including shaking chills   
 
Flu like symptoms with 
headache, tiredness, 
aches and pains 
 
Aches and pains in the 
joints and/or muscles 
 
Pain, irritation and 
bruising or redness at 
the site of the injection 
 
Mood changes including 
depression, inability to 
sleep, irritability and 
agitation, anxiety, and 
mood swings 
 
Loss or thinning of hair 
 
 
 
Vomiting 
 
Constipation or Diarrhea 
 
Loss of Appetite 
 
Weight Loss 
 
Pain in the abdomen 
 
An upset stomach 
 
A dry mouth 
 
High blood sugar which may 
require treatment 
 
High levels of fats 
(triglycerides) in your blood 
 
Elevation in the blood of 
certain enzymes found in the 
liver which may indicate liver 
irritation or damage 
 
Dizziness 
 
Throat or sinus irritation, 
runny nose and cough 
 
A decrease in blood pressure 
 
Rash, hives or itchiness  
 
Heart problems including an 
irregular or rapid heart beat, 
chest pain 
 
Low blood pressure 
 
Facial flushing with redness 
and a feeling of warmth   
 
Fewer white cells, red cells 
and platelets in the blood  
o 
a low number of white 
blood cells may make it 
easier to get infections  
o 
a low number of red blood 
cells can make you feel 
tired and weak 
o 
a low number of platelets 
causes you to bruise and 
bleed more easily 
 
Increased sweating  
 
Confusion and difficulty with 
concentration when doing 
various tasks 
 
Decrease or increase in your 
thyroid hormones 
 
Shortness of breath 
 
Feeling of weakness  
 
Sleepiness 
 
An irregular menstrual cycle 
(period) 
 A severe allergic reaction 
that can be life-threatening 
and may lead to difficulty in 
breathing, a drop in blood 
pressure, and an irregular 
heart beat. 
 Heart attack or fluid 
collecting around the heart 
that can be life-threatening 
or fatal. 
 Life threatening or fatal 
changes in moods have 
occurred including severe 
depression or feelings of 
suicide; feelings of 
aggressiveness that may 
even lead to the desire to 
commit murder.   
 Inflammation of your colon 
(large bowel) which could 
lead to bloody diarrhea and 
may be life threatening 
 Inflammation of your 
pancreas which could 
cause pain in your 
abdomen and may be life-
threatening 
 If you have ever been told 
that you have a disease 
such as lupus, rheumatoid 
arthritis or other disease 
that is caused by a 
disturbance in your 
immune system 
“autoimmune disease”. 
Peginterferon may cause 
these to be worse. 
 Bleeding into the eye 
leading to loss of sight or 
blurred vision 
 Damage to your lungs 
which could lead to 
shortness of breath and 
may be life threatening 
 Severe blood infections 
which will need to be 
treated and may be life 
threatening  
 Severe sudden onset of 
kidney damage 
 
 
 


 
 
 
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Reproductive Risks 
For Women: 
The treatment on this study can affect an unborn child.  You should not become pregnant 
or breast feed your baby while being treated on this study.  If you are sexually active and are at 
risk of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex.  The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study.  You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctors about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation.  If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor.  If you 
become pregnant during the research study, please tell the study doctor and your regular doctor 
immediately. 
 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctors about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage sperm.  You should not father a child while on this 
study as the treatment may indirectly affect an unborn child.  If you are sexually active and are 
at risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex.  The study doctor will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study.  You will 
have to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctors about the length of time you need to 
avoid pregnancy or abstain. Natural family planning and the rhythm method will not be 
permissible means of avoiding pregnancy during study participation. If you have questions 
about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor.  If your partner becomes pregnant during the research study, please tell the study doctor 
and your regular doctor immediately. 
 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While doctors hope that 
interferon will be more useful against cancer compared to the usual treatment, there is no proof 
of this yet. We do know that the information from this study will help doctors learn more about 
osteosarcoma.  This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
 
Instead of being on this study, you have these options: 
 
The standard treatment for osteosarcoma which is chemotherapy with doxorubicin, 
cisplatin and methotrexate (MAP) without being on this study. 
 
Another experimental treatment (if available) 


 
 
 
AOST0331 
 
 
Page 117 
 
Please talk about these options with your regular doctor as well as other trusted personal and 
family advisors.  
 
Will my medical information be kept private?  
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is attached at end of this consent. 
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance and data analysis include: 
 
 
The Children's Oncology Group, 
 
Representatives of the National Cancer Institute (NCI), Food and Drug 
Administration (FDA), and other U.S. and international governmental regulatory 
agencies involved in keeping research safe for people, 
 
The Institutional Review Board (IRB) of this hospital, 
 
The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute, 
 
Representatives of Schering-Plough, the company that will be supplying pegylated 
interferon alfa-2b for this study, 
 
Representatives of the cooperating pediatric research groups. 
 
It is very unlikely that the research testing might uncover important information about you or 
your current or future health.  If this unlikely event occurs, the researchers may contact your 
doctor through Children’s Oncology Group about what the test results might mean.  Only your 
doctor will be notified and the information will remain confidential. Your doctor may discuss this 
unexpected finding with you, and may recommend consultation with a genetic counselor and/or 
repeat testing in a clinical (not research) laboratory if necessary.  It is possible that your doctor 
may recommend that no additional action is necessary. 
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost 
of getting regular cancer treatment.  
 
The drug company that produces Peg-Intron (pegylated interferon alfa-2b) will provide the drug 
free of charge for subjects randomized to get pegylated interferon alfa-2b therapy.  
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 


 
 
 
AOST0331 
 
 
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Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment. The study has no plans to pay for 
medical treatment.   
 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For 
questions 
about 
your 
rights 
while 
taking 
part 
in 
this 
study, 
call 
the 
________________________ [name of center] Institutional Review Board (a group of people who 
review the research to protect your rights) at __________________ (telephone number).  [Note to 
Local Investigator: Contact information for patient representatives or other individuals in a local 
institution who are not on the IRB or research team but take calls regarding clinical trial questions 
can be listed here.]    
 
 
Where can I get more information? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor can get you this Handbook, or you can get it at www.curesearch.org/. 


 
 
 
AOST0331 
 
 
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Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 1-800-4-
CANCER (1-800-422-6237) or TTY: 1-800-332-8615.  
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.   
I have read it or it has been read to me.  
 
 
I have reviewed the information and have had my questions answered.  I agree to take part in 
this study. 
 
 
Participant _______________________________  
Date_____________ 
 
Parent (or Guardian) _______________________  
Date_____________ 


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


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


 
 
 
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Risks and side effects related to methotrexate include those which are: 
Likely 
Less Likely 
Rare but Serious 
 
High levels of 
liver enzymes 
in the blood 
which may 
mean liver 
irritation or 
damage 
 
Nausea 
 
Vomiting 
 
Loss of appetite 
 
Diarrhea 
 
Chills and/or fever 
 
Inflammation and/or sores in 
the mouth, gums, throat 
and/or esophagus 
 
Inflammation of the 
intestines which may cause 
bleeding 
 
Sensitivity to sunlight and 
increased risk of sunburn 
 
Fewer white blood cells, red 
blood cells and platelets in 
the blood. 
○ 
A low number of red 
blood cells can make you 
feel tired and weak. 
○ 
A low number of white 
blood cells can make it 
easier to get infections. 
○ 
A low number of 
platelets causes you to 
bruise and bleed 
 
Learning disability 
 
Dizziness 
 
Sense of not feeling well or 
tiredness 
 
Drowsiness 
 
Blurred vision 
 
Rashes with itching and 
hives 
 
Hair loss, inflammation of 
the hair follicles 
 
Acne 
 
Tearing and inflammation of 
the eyes 
 
Darkening of the fingernails  
 
Severe allergic reaction which can be life 
threatening with shortness of breath, low 
blood pressure and a rapid heart rate 
 
The rapid death of large numbers of tumor 
cells which can cause the potassium and 
phosphate salts and the uric acid in the 
blood to rise quickly and this could lead 
to a life-threatening irregular heart beat or 
damage to the kidneys.  
 
Severe rashes which can cause loss of 
skin or damage to mucous membranes or 
which can cause peeling, redness and 
pain on the palms of the hands and soles 
of the feet  
 
Damage, inflammation and/or scarring of 
lung tissue which may make you short of 
breath and cough 
 
Seizures 
 
Temporary damage to the brain such that 
you may experience headaches, 
drowsiness, difficulty speaking or forming 
words, blurred vision or temporary 
blindness, and decreased reflexes 
 
Temporary loss of function or feeling in 
the lower part of the body (partial 
paralysis) 
 
Severe damage to brain tissue which over 
time could lead to difficulty carrying out 
normal daily tasks or could lead to a 
coma. 
 
Inflammation and scarring of the liver  
 
Damage to the bone which could lead to 
arthritis pain and weakness of the bone 
 
Inflammation of the heart 
 
Fluid buildup around the heart 
 
Damage to the kidney  
 
Leucovorin is given with methotrexate:  
 
Risks and side effects related to leucovorin include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
 
Rash with itching and/or 
hives 
 
 
Severe allergic reaction which can 
be life-threatening with shortness of 
breath, low blood pressure, rapid 
heart rate, chills and fever 
 
Convulsions 
 


 
 
 
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Sometimes dexrazoxane is given along with doxorubicin to help prevent heart damage.  
 
Side effects of dexrazoxane include those which are: 
Likely 
Less Likely 
Rare but serious 
 Fewer white blood cells, 
red blood cells and 
platelets in the blood. 
○ 
A low number of red 
blood cells can 
make you feel tired 
and weak 
○ 
A low number of 
white blood cells 
can make it easier 
to get infections 
○ 
A low number of 
platelets causes 
you to bruise and 
bleed more easily 
 
Mild nausea and/or 
vomiting 
 
Loss of appetite 
 
A feeling of extreme 
tiredness or not feeling 
well 
 
Diarrhea 
 
Increases in the blood of 
fats (triglycerides) and an 
enzyme made by the 
pancreas (amylase) 
 
Temporary increases in the 
blood of iron and 
decreases in the blood of 
calcium and zinc 
 
Damage to the skin if the 
medication leaks from a 
vein 
 
Thickening and hardening 
of the veins or pain in the 
vein through which the 
medication is given 
 
Temporary elevation in the 
blood of certain enzymes 
and bilirubin found in the 
liver 
 
It may take longer for the 
blood to clot 
 A new cancer or 
leukemia resulting 
from this treatment 
 
 


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


 
 
 
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This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Institutions should use the sections of this document which are 
in bold type in their entirety. Editorial changes to these sections may be made as long as they 
do not change information or intent. If the local IRB insists on making deletions or more 
substantive modifications to any of the sections in bold type, they must be justified in writing by 
the investigator at the time of the institutional audit.  
 
SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH  
 
AOST0331, A Randomized Trial of the European and American Osteosarcoma Study 
Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on 
Histologic Response to Pre-Operative Chemotherapy(EURAMOS 1) 
 
PART 2 – For subjects with a poor tumor response to Induction Therapy 
 
 
Why is this part of the study being done? 
Now that you have finished Part 1 of therapy you are being asked to continue on Part 2 of the 
study. Because your tumor had a poor response to induction chemotherapy (less than 90% of 
the tumor cells have been killed) you are eligible for more treatment with MAP chemotherapy or 
MAP chemotherapy plus ifosfamide and etoposide. 
 
Continuing with MAP therapy may still result in a good outcome, but study doctors would like to 
know if adding two other commonly used anti-cancer drugs (ifosfamide and etoposide) to MAP 
will improve the outcome and prevent the disease from returning later. Adding ifosfamide and 
etoposide to the MAP chemotherapy treatment is experimental. 
 
How many people will take part in the study? 
There will be about 615 subjects with a poor tumor response continuing on to Part 2 of the 
study. 
 
What will happen if I take part in this part of the research study? 
You will be assigned to one of the two treatments by randomization.  Randomization means that 
you are being put into a group by chance.  It is like flipping a coin. Which group you are put in is 
done by a computer. Neither you nor the study doctor will choose which group you will be put in.  
You will have an equal chance of being placed in any group.  You will be randomized to get 
continued standard treatment with MAP alone or treatment with MAP and the addition of 
ifosfamide and etoposide (MAPIE). This is called maintenance therapy. 
 
If you join in Part 2, you will also continue to have common medical tests to help your doctor find 
out about your health and how the treatment is going.  These tests are part of regular cancer 
care and may be done even if you do not join in this study: 
 
History and physical examination 
 
Blood tests 
 
Urine tests 
 
Echocardiogram (picture of the heart in motion) 
 
MRI (magnetic resonance imaging) of disease sites  
 
X-ray of disease sites and the chest 
 
CT scan (an X-ray procedure) of disease sites and the chest 


 
 
 
AOST0331 
 
 
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Bone Scan (picture of the bones) 
 
Audiogram (hearing test) 
 
Nuclear Medicine Scans  
 
Methods for Giving Drugs 
Various methods will be used to give the drugs to you (your child). Some drugs may be given by 
tablet or liquid through the mouth (oral).  Some drugs may be given using a needle inserted just 
under the skin (subcutaneous). Other drugs may be given using a needle inserted into a vein (IV 
or intravenous). 
 
The drugs for the study are given in this way: 
MAP 
Week 
Day Drug  
Method 
12, 17  
1,2 
1,2 
Doxorubicin* 
Cisplatin 
Given as a continuous infusion through a vein 
over 48 hours 
Given by vein over 4 hours 
22, 26 
1,2 
Doxorubicin 
Given as a continuous infusion through a vein 
over 48 hours 
15,16,20,21,24,25,28,29 1 
2 
Methotrexate 
Leucovorin# 
Given by vein over 4 hours 
Given by vein 24 hours after the start of 
Methotrexate, every 6 hours, until Methotrexate 
level has sufficiently cleared from the blood 
(determined by a blood test) 
 
* Dexrazoxane may be given with the doxorubicin. 
# Small doses may be given by mouth.  
 
MAPIE 
Week 
Day Drug  
Method 
12, 28  
1,2 
1,2 
Doxorubicin* 
Cisplatin 
Given as a continuous infusion through a vein 
over 48 hours 
Given by vein over 4 hours 
20,36 
1,2 
1-3 
1-3 
Doxorubicin 
Ifosfamide 
Mesna 
Given as a continuous infusion through a vein 
over 48 hours 
Given by vein over 4 hours 
Given by vein as a continuous infusion over 
24 hours, until at least 12 hours following the 
completion of the last Ifosfamide dose 
16,24,32 
1-5 
1-5 
1-5 
Ifosfamide 
Etoposide 
Mesna 
Given by vein over 4 hours 
Given by vein over 1 hour 
Given by vein as a continuous infusion over 
24 hours, until at least 12 hours following the 
completion of the last Ifosfamide dose 
15,19,23,27,31,35,39,40 1 
2 
Methotrexate 
Leucovorin# 
Given by vein over 4 hours 
Given by vein 24 hours after the start of 
Methotrexate, every 6 hours, until 
Methotrexate level has sufficiently cleared 
from the blood (determined by a blood test) 
* Dexrazoxane may be given with the doxorubicin 
# Small doses may be given by mouth.


 
 
 
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Central Line 
For drugs to be given by vein, your study doctor will likely recommend that you (your child) have 
a central venous line placed. A central line is a type of tubing inserted into a large vein in the 
chest by a surgeon during a short operation. The central line is used to administer 
chemotherapy drugs and to withdraw small amounts of blood for testing during treatment. How 
the tubing is inserted and all the risks associated with central lines will be explained to you, and 
all of your questions about the central line will be answered, when you sign a separate consent 
for the central line. 
 
 
How long will I be in the study? 
 
We think you will be treated for about 7 months if randomized to MAP therapy alone, and about 
10 months if randomized to get MAP plus ifosfamide and etoposide. The study doctors may 
decide to take you off the study if your cancer gets worse or you have side effects from the 
treatment that are too bad. After treatment, subjects will have follow-up examinations and 
medical tests. We will continue to collect some medical information about how you are doing for 
10 years after you start the study  
 
The study doctors may decide to take you off the study if your cancer gets worse or you have 
side effects from the treatment that are too bad. 
 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
therapy can be evaluated by your doctor. Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
 
What risks or side effects can I expect from being in the study? 
 
While on this study you are at risk for the side effects listed in Appendix I for MAP therapy as 
you were in Part 1 of the study. You should discuss these with the researcher and/or your 
regular doctor.  
 
If you are randomized to get ifosfamide and etoposide, there may also be other side effects that 
we cannot predict when MAP therapy is used together with ifosfamide and etoposide.  Adding 
ifosfamide and etoposide to MAP therapy will cause additional side effects and prolong the 
length of treatment and may not improve the chance that the disease will go away.  You will be 
watched closely and the ifosfamide and etoposide will be stopped if bad side effects develop. 
 


 
 
 
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Risks and side effects related to etoposide include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Nausea and vomiting 
 
Hair Loss 
 
A feeling of weakness or 
tiredness 
 
fewer red and white 
blood cells and platelets 
in the blood  
o 
a low number of red 
blood cells can make 
you feel tired and 
weak 
o 
a low number of 
white blood cells can 
make it easier to get 
infections 
o 
a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
 
 
Loss of appetite 
 
Decreased blood 
pressure during the 
infusion which may 
require treatment 
 
Rashes 
 
Diarrhea 
 
Pain in the abdomen 
 
Mouth sores 
 
Tingling sensation or 
loss of sensation in 
fingers or toes 
 
A feeling of extreme 
tiredness or weakness 
 
The finger or toe nails 
may loosen from their 
nail beds 
 
Inflammation of the vein 
through which the 
medication was given 
 
Chest pain 
 Damage to the liver 
 Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate, chills and fever 
 A new cancer or leukemia 
resulting from this treatment 
 Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes 
 Absence or decrease of 
monthly periods which may 
be temporary or permanent 
and which may decrease the 
ability to have children 
 Damage to the heart muscle 
which may make you feel 
tired, weak, feel short of 
breath, and retain fluid 
 
 
 
Risks and side effects related to ifosfamide include those which are: 
Likely 
Less Likely 
Rare but serious 
 
Nausea 
 
Vomiting 
 
Hair loss 
 
Fewer white blood cells 
in the blood. 
○ 
A low number of 
white blood cells 
may make it easier to 
get infections. 
 
Decreased ability of the 
body to fight infection  
 
Absence or decrease in 
the number of sperm 
which may be temporary 
or permanent which may 
decrease the ability to 
have children 
 
Slight decrease in kidney 
function 
 Drowsiness 
 Confusion  
 Depression 
 Loss of appetite 
 Diarrhea or constipation 
 Fewer red blood cells and 
platelets in the blood 
○ 
A low number of red 
blood cells may make 
you feel tired and weak. 
○ 
A low number of 
platelets may cause you 
to bruise and bleed 
more easily. 
 
Seizures 
 
Abnormal hormone 
function affecting levels of 
salt in the blood and urine 
 
Abnormal heart beat or 
rhythm. 
 
Blood in the urine that is 
only seen under the 
microscope 
 
Body loss of certain 
important salts and 
 
Damage to brain tissue 
with very high doses that 
may lead to coma 
 
Kidney failure or damage 
 
Damage to the bladder 
which can lead to large 
amounts of blood in the 
urine, pain and the urge to 
urinate frequently and also 
scarring of the bladder 
 
A new cancer or leukemia 
resulting from this 
treatment 
 
Damage to heart muscle 
which may make you tired, 
weak, feel short of breath, 
and retain fluid 
 
Abnormal bone growth and 
development 
 
 


 
 
 
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minerals (such as sodium, 
potassium, phosphate and 
bicarbonate) and retention 
of acids in the blood 
 
Failure of the ovaries to 
function normally which 
may be permanent and 
which may decrease the 
ability to have children 
 
Inflammation and burning 
along the vein where the 
medicine is given 
 
Elevation in the blood of 
certain enzymes found in 
the liver which may mean  
liver irritation or damage 
 
Structures in the kidney 
that remove acid from the 
blood are impaired which 
may lead to a build up of 
acid levels in the blood 
and affect the balance of 
electrolytes in the blood 
 
Subjects who get ifosfamide will also get a drug called mesna to protect the bladder from 
bleeding: 
 
 
Risks and side effects related to mesna include those which are: 
 
Likely 
Less Likely 
Rare but serious 
 
 
Nausea 
 
Vomiting 
 
Stomach pain 
 
Headache 
 
Pain in arms, legs and joints 
 
Tired feeling 
 
Rash 
 
Temporary low blood pressure 
 
Diarrhea 
 
Fever 
 
Facial flushing with red cheeks 
 
Nervousness 
 
Dizziness 
 
Confusion 
 
Swelling around the eyes 
 
Coughing 
 
Rapid heart rate 
 
Severe allergic reaction 
which can be life 
threatening with 
shortness of breath, low 
blood pressure, rapid 
heart rate, chills and 
fever 
 
 


 
 
 
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Reproductive Risks 
For Women: 
The treatment on this study can affect an unborn child.  You should not become pregnant 
or breast feed your baby while being treated on this study.  If you are sexually active and are at 
risk of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex.  The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study.  You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctors about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation.  If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor.  If you 
become pregnant during the research study, please tell the study doctor and your regular doctor 
immediately. 
 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctors about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage sperm.  You should not father a child while on this 
study as the treatment may indirectly affect an unborn child.  If you are sexually active and are 
at risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex.  The study doctor will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study.  You will 
have to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctors about the length of time you need to 
avoid pregnancy or abstain. Natural family planning and the rhythm method will not be 
permissible means of avoiding pregnancy during study participation. If you have questions 
about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor.  If your partner becomes pregnant during the research study, please tell the study doctor 
and your regular doctor immediately. 
 
Are there benefits to taking part in this study? 
Taking part in this study may or may not make your health better. While doctors hope that 
adding ifosfamide and etoposide to MAP will be more useful against cancer compared to the 
usual treatment, there is no proof of this yet. We do know that the information from this study 
will help doctors learn more about osteosarcoma. This information could help future cancer 
patients. 
 
What other choices do I have if I do not take part in this study? 
 
Instead of being on this study, you have these options: 
 
 
The standard treatment for osteosarcoma which is chemotherapy with doxorubicin, 
cisplatin and methotrexate (MAP) without being on this study. 
 
Another experimental treatment (if available) 
 


 
 
 
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Page 131 
Please discuss these options with your regular doctor as well as other trusted personal and 
family advisors.  
 
Will my medical information be kept private?  
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is attached at end of this consent. 
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance and data analysis include: 
 
 
The Children's Oncology Group, 
 
Representatives of the National Cancer Institute (NCI), Food and Drug 
Administration (FDA), and other U.S. and international governmental regulatory 
agencies involved in keeping research safe for people, 
 
The Institutional Review Board (IRB) of this hospital, 
 
The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute, 
 
Representatives of Schering-Plough, the company that will be supplying pegylated 
interferon alfa-2b for this study, 
 
Representatives of the cooperating pediatric research groups. 
 
It is very unlikely that the research testing might uncover important information about you or 
your current or future health.  If this unlikely event occurs, the researchers may contact your 
doctor through Children’s Oncology Group about what the test results might mean.  Only your 
doctor will be notified and the information will remain confidential. Your doctor may discuss this 
unexpected finding with you, and may recommend consultation with a genetic counselor and/or 
repeat testing in a clinical (not research) laboratory if necessary.  It is possible that your doctor 
may recommend that no additional action is necessary. 
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost 
of getting regular cancer treatment.  
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 


 
 
 
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What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment. The study has no plans to pay for 
medical treatment. 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.  
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For 
questions 
about 
your 
rights 
while 
taking 
part 
in 
this 
study, 
call 
the 
________________________ [name of center] Institutional Review Board (a group of people who 
review the research to protect your rights) at __________________ (telephone number).  [Note to 
Local Investigator: Contact information for patient representatives or other individuals in a local 
institution who are not on the IRB or research team but take calls regarding clinical trial questions 
can be listed here.]    
 
Where can I get more information? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor can get you this Handbook, or you can get it at www.curesearch.org/. 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615.  
 


 
 
 
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Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 
 
You will get a copy of this form. You will be given a copy of the protocol (full study plan) upon 
request.  If you want more information about this study, ask your study doctor. 
 
 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.   
I have read it or it has been read to me.  
 
I have reviewed the information and have had my questions answered.  I agree to take part in 
this study. 
 
 
Participant _______________________________  
Date_____________ 
 
Parent (or Guardian) _______________________  
Date_____________ 


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


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


 
 
 
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Risks and side effects related to methotrexate include those which are: 
Likely 
Less Likely 
Rare but Serious 
 
High levels of 
liver enzymes 
in the blood 
which may 
mean liver 
irritation or 
damage 
 
Nausea 
 
Vomiting 
 
Loss of appetite 
 
Diarrhea 
 
Chills and/or fever 
 
Inflammation and/or sores in 
the mouth, gums, throat 
and/or esophagus 
 
Inflammation of the 
intestines which may cause 
bleeding 
 
Sensitivity to sunlight and 
increased risk of sunburn 
 
Fewer white blood cells, red 
blood cells and platelets in 
the blood. 
○ 
A low number of red 
blood cells can make you 
feel tired and weak. 
○ 
A low number of white 
blood cells can make it 
easier to get infections. 
○ 
A low number of 
platelets causes you to 
bruise and bleed 
 
Learning disability 
 
Dizziness 
 
Sense of not feeling well or 
tiredness 
 
Drowsiness 
 
Blurred vision 
 
Rashes with itching and 
hives 
 
Hair loss, inflammation of 
the hair follicles 
 
Acne 
 
Tearing and inflammation of 
the eyes 
 
Darkening of the fingernails  
 
Severe allergic reaction which can be life 
threatening with shortness of breath, low 
blood pressure and a rapid heart rate 
 
The rapid death of large numbers of tumor 
cells which can cause the potassium and 
phosphate salts and the uric acid in the 
blood to rise quickly and this could lead 
to a life-threatening irregular heart beat or 
damage to the kidneys.  
 
Severe rashes which can cause loss of 
skin or damage to mucous membranes or 
which can cause peeling, redness and 
pain on the palms of the hands and soles 
of the feet  
 
Damage, inflammation and/or scarring of 
lung tissue which may make you short of 
breath and cough 
 
Seizures 
 
Temporary damage to the brain such that 
you may experience headaches, 
drowsiness, difficulty speaking or forming 
words, blurred vision or temporary 
blindness, and decreased reflexes 
 
Temporary loss of function or feeling in 
the lower part of the body (partial 
paralysis) 
 
Severe damage to brain tissue which over 
time could lead to difficulty carrying out 
normal daily tasks or could lead to a 
coma. 
 
Inflammation and scarring of the liver  
 
Damage to the bone which could lead to 
arthritis pain and weakness of the bone 
 
Inflammation of the heart 
 
Fluid buildup around the heart 
 
Damage to the kidney  
 
 
Leucovorin is given with methotrexate:  
 
Risks and side effects related to leucovorin include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
 
Rash with itching and/or 
hives 
 
 
Severe allergic reaction which can 
be life-threatening with shortness of 
breath, low blood pressure, rapid 
heart rate, chills and fever 
 
Convulsions 
 


 
 
 
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Sometimes dexrazoxane is given along with doxorubicin to help prevent heart damage.  
 
Side effects of dexrazoxane include those which are: 
Likely 
Less Likely 
Rare but serious 
 Fewer white blood cells, 
red blood cells and 
platelets in the blood. 
○ 
A low number of red 
blood cells can 
make you feel tired 
and weak 
○ 
A low number of 
white blood cells 
can make it easier 
to get infections 
○ 
A low number of 
platelets causes 
you to bruise and 
bleed more easily 
 
Mild nausea and/or 
vomiting 
 
Loss of appetite 
 
A feeling of extreme 
tiredness or not feeling 
well 
 
Diarrhea 
 
Increases in the blood of 
fats (triglycerides) and an 
enzyme made by the 
pancreas (amylase) 
 
Temporary increases in the 
blood of iron and 
decreases in the blood of 
calcium and zinc 
 
Damage to the skin if the 
medication leaks from a 
vein 
 
Thickening and hardening 
of the veins or pain in the 
vein through which the 
medication is given 
 
Temporary elevation in the 
blood of certain enzymes 
and bilirubin found in the 
liver 
 
It may take longer for the 
blood to clot 
 A new cancer or 
leukemia resulting 
from this treatment 
 
 


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