Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment
Phase: PHASE3
Conditions: PRETEXT I Hepatoblastoma, PRETEXT II Hepatoblastoma, PRETEXT III Hepatoblastoma, PRETEXT IV Hepatoblastoma
Sponsor: National Cancer Institute (NCI)

  
 
i 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
 
 
November 7, 2018 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #7 for protocol AHEP0731, Treatment of Children with All Stages 
of Hepatoblastoma with Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment, for 
CTEP review. 
 
This amendment is being submitted in response to a Request for Rapid Amendment (RRA) from 
Dr. L. Austin Doyle (doylela@mail.nih.gov), dated October 24, 2018. In this amendment, the revised 
CAEPR for temsirolimus (Version 2.6, August 19, 2018) has been inserted in the protocol, and the 
associated risk information in the informed consent document has been revised. Revisions to the 
protocol and consent documents are detailed in the pages below. 
 
The AHEP0731 study team looks forward to approval of this amendment. Please contact me with any 
questions or concerns. 
 
 
Sincerely, 
 
Christine Wang, PhD, Protocol Coordinator (for) 
 
Howard Katzenstein, MD, AHEP0731 Study Chair 
Carlos Rodriguez-Galindo, MD, COG Rare Tumor Committee Chair 
Peter Adamson, MD, Children’s Oncology Group Chair 
 
 

ii 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
 
# 
Section 
Page(s) 
Change 
1. 
Title Page 
1 
Updated version date and amendment number. 
2. 
6.1 
57-63 
Inserted revised CAEPR for temsirolimus (Version 2.6, August 19, 2018). 
Specific changes are as follows: 
 
• 
The section below utilizes CTCAE 5.0 language unless otherwise 
noted. 
 
• 
Added New Risk:  
• 
Rare but Serious: Nephrotic syndrome 
 
• 
Increase in Risk Attribution:  
• 
Changed to Rare but Serious from Also Reported on 
Temsirolimus Trials But With Insufficient Evidence for 
Attribution: Proteinuria 
 
 
 
SUMMARY OF CHANGES: INFORMED CONSENT DOCUMENTS 
In accordance with the above discussion, the following specific revisions have been made to the Informed Consent 
Documents. 
 
ICD-1: 
# 
Section 
Page(s) 
Change 
1. 
General 
All 
Updated version date in the footer to match the protocol version date. No 
other changes have been made to this consent as the risks of temsirolimus 
are not applicable. 
 
 
ICD-2: 
# 
Section 
Page(s) 
Change 
1. 
General 
All 
Updated version date in the footer. 
2. 
Possible Side 
Effects of 
Temsirolimus 
12-13 
• 
Provided Further Clarification: 
• 
Sore throat (under Occasional) is now reported as part of 
Sores in the mouth which may cause difficulty swallowing 
(under Common). 
 
• 
Removed codename for temsirolimus (CCI-779) from the risk 
tables for consistency with the NCI supplied risk profile. 
 
 
ICD-3: 
# 
Section 
Page(s) 
Change 
1. 
General 
All 
Updated version date in the footer to match the protocol version date. No 
other changes have been made to this consent as the risks of temsirolimus 
are not applicable. 
 
 

 
 
AHEP0731 
 
Page 1 
Version date: 11/07/18 
 
 
 
 
Activated: 
September 14, 2009 
Version Date: 11/07/18 
Closed: 
July 20, 2018 
Amendment: #7 
 
CHILDREN’S ONCOLOGY GROUP 
 
AHEP0731 
 
Treatment of Children with All Stages of Hepatoblastoma with Temsirolimus (NSC#683864) Added to 
High Risk Stratum Treatment  
 
A Phase III Study 
 
An Intergroup Study for Participation by COG and the Japanese Study Group for Pediatric Liver 
Tumors (JPLT) 
 
CTEP ID / JPLT Participating Institutions 
Investigator 
Investigator ID 
42067 / Fukushima Medical University Hospital 
Dr. Atsushi Kikuta  
48577 
42035 / Hiroshima University Hospital 
 
Dr. Eiso Hiyama 
 
48669 
42071 / Kagoshima University Medical and Dental Hospital 
Dr. Yasuhiro Okamoto 
48673 
42017 / National Cancer Center Hospital 
 
 
Dr. Chitose Ogawa  
55762 
42072 / Nihon University Itabashi Hospital 
 
Dr. Tsugumichi Koshinaga 55757 
42063 / Shizuoka Cancer Center 
 
Dr. Yuji Ishida 
 
48705 
 
NCI Supplied Agent: Temsirolimus (NSC#683864) 
 
IND sponsor for temsirolimus: DCTD, NCI 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC 
INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR 
CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE CHILDREN’S 
ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND SHOULD NOT BE 
USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, 
TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY 
FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER 
PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
STUDY CHAIR  
Howard Katzenstein, MD 
Nemours Children’s Clinic – Jacksonville 
Division of Hematology/Oncology 
807 Children’s Way 
Jacksonville, FL 32207 
Phone: 
(904) 697-3793 
Fax: 
(904) 697-3792 
E-mail: 
howard.katzenstein@nemours.org 
 
ATTENTION JPLT SITES: Please refer to the JPLT group specific appendix (Appendix VII) for important 
JPLT site specific protocol information.

 
 
AHEP0731 
 
Page 2 
Version date: 11/07/18 
 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Hypotheses 
11 
1.2 
Primary Aims 
11 
1.3 
Secondary Aims 
12 
2.0 
BACKGROUND 
12 
2.1 
Treatment Considerations 
12 
2.2 
Pathologic Considerations 
13 
2.3 
Risk-Stratified Treatment 
14 
2.4 
Prognostic Variables 
21 
2.5 
Surgical Considerations 
21 
2.6 
Significance 
25 
2.7 
Race and Gender Statement 
25 
2.8 
COG and Japanese Study Group for Pediatric Liver Tumors (JPLT) Collaboration 
25 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
26 
3.1 
Study Enrollment 
26 
3.2 
Patient Eligibility Criteria 
27 
4.0 
TREATMENT PLAN 
32 
4.1 
Overview of Treatment Plan 
32 
4.2 
General Therapy Guidelines 
33 
4.3 
Treatment for Very Low-Risk Patients (Stratum 1 – No further treatment) 
35 
4.4 
Treatment for Low-Risk Patients (Stratum 2 - Regimen T) 
35 
4.5 
Treatment for Intermediate-Risk Patients (Stratum 3 - Regimen F) 
37 
4.6 
Treatment for High-Risk Patients (Stratum 4) - Regimen H 
39 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
52 
5.1 
Myelosuppression 
52 
5.2 
Doxorubicin 
52 
5.3 
Cisplatin 
53 
5.4 
Vincristine 
53 
5.5 
Irinotecan 
53 
5.6 
Temsirolimus 
54 
6.0 
DRUG INFORMATION 
57 
6.1 
TEMSIROLIMUS 
57 
6.2 
Cisplatin 
66 
6.3 
Dexrazoxane 
68 
6.4 
Doxorubicin 
69 
6.5 
Fluorouracil 
71 
6.6 
Irinotecan 
73 
6.7  
Vincristine Sulfate 
74 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
76 
7.1 
Patients with low AFP levels 
76 

 
 
AHEP0731 
 
Page 3 
Version date: 11/07/18 
 
7.2 
Required Clinical, Laboratory and Disease Evaluations for Very Low Risk Patients-
Stratum 1 (Stage I PFH) 
76 
7.3 
Required Clinical, Laboratory and Disease Evaluations for Low-Risk Patients –      
Stratum 2 
77 
7.4 
Required Clinical, Laboratory and Disease Evaluations for Intermediate-Risk          
Patients –Stratum 3 
78 
7.5  
Required Clinical, Laboratory and Disease Evaluations for High-Risk Patients -      
Stratum 4 
79 
7.6 
Recommended Clinical, Laboratory and Disease Evaluations in Follow-up 
80 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
81 
8.1 
Criteria for Removal from Protocol Therapy 
81 
8.2 
Off Study Criteria 
81 
9.0 
STATISTICAL CONSIDERATIONS 
82 
9.1 
Patient Accrual and Expected Duration of Trial 
82 
9.2 
Statistical Analysis Methods 
82 
9.3 
Gender and Minority Accrual Estimates 
89 
10.0 
EVALUATION CRITERIA 
89 
10.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
89 
10.2 
PRETEXT GROUPING (See Appendix I) 
89 
10.3 
Response Criteria for Patients with Solid Tumors 
90 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
93 
11.1 
Purpose 
93 
11.2 
Determination of Reporting Requirements 
93 
11.3 
Steps to Determine if an Adverse Event is to be Reported in an Expedited Manner 
93 
11.4 
Reporting Methods 
94 
11.5 
When to Report An Event In An Expedited Manner 
94 
11.6 
Other Recipients of Adverse Event Reports 
95 
11.7 
Reporting of Adverse Events For Investigational Agents – CTEP-AERS 24-hour 
Notifications,  and Complete Report Requirements. 
95 
11.8 
Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
 
97 
11.9 
Routine Adverse Event Reporting 
98 
12.0 
RECORDS AND REPORTING 
98 
12.1 
Categories of Research Records 
98 
12.2 
CDUS 
98 
13.0 
SURGICAL GUIDELINES 
98 
13.1 
Surgical Resection Guidelines 
99 
13.2 
Central Surgical Review 
101 
13.3 
Surgical Management of Pulmonary Metastasis 
101 
13.4 
Liver Transplant or Extreme Liver Resection 
101 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
102 
14.1 
Pathology Evaluation 
103 
14.2 
Biology Studies 
105 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
105 
15.1 
Primary Site Imaging 
105 
15.2 
Metastatic Site Imaging 
106 
15.3 
Timing of Imaging 
106 

 
 
AHEP0731 
 
Page 4 
Version date: 11/07/18 
 
15.4 
Image Submission and Review 
108 
APPENDIX I:  PRETEXT SURGICAL RESECTION GUIDELINES 
109 
APPENDIX II:  YOUTH INFORMATION SHEET 
114 
APPENDIX III:  SURGICAL STAGING OF PRIMARY TUMOR AT TIME OF INITIAL 
SURGERY 
116 
APPENDIX IV: UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
117 
APPENDIX V:  CYP3A4 INDUCERS AND INHIBITORS 
118 
APPENDIX VI:  CTEP REGISTRATION PROCEDURES 
119 
APPENDIX VII:  JPLT SITE SPECIFIC INFORMATION 
120 
REFERENCES 
121 
 
 

 
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STUDY COMMITTEE 
 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Howard Katzenstein, MD 
Max Raymond Langham, MD 
Hematology/Oncology 
Surgery 
Nemours Children’s Clinic-Jacksonville 
St. Jude Children's Research Hospital 
Hematology/Oncology 
University of Tennessee Health Science Center, Surgery 
807 Children’s Way 
777 Washington Ave, Suite P230 
Jacksonville, FL 32207 
Memphis, TN 38106 
Phone: (904) 697-3793 
Phone: (901) 289-6300 
Fax: 
(904) 697-3792 
Fax: 
(901) 287-5191 
E-mail: howard.katzenstein@nemours.org 
E-mail:  mlangham@uthsc.edu 
 
 
STUDY VICE CHAIR 
Stephen P. Dunn, MD 
Marcio Malogolowkin, MD 
Surgery 
Hematology/Oncology 
A.I. duPont Hospital for Children 
University of California Davis Comprehensive Cancer  
Pediatric Surgery 
Center 
1600 Rockland Road 
Pediatric Hematology/Oncology 
Wilmington, DE 19803 
2516 Stockton Blvd., 2nd Fl. 
Phone: (302) 651-5999 
Sacramento. CA 95817 
Fax: 
(302) 651-5990 
Phone: (916) 734-2781 
E-mail:  sdunn@nemours.org 
Fax: 
(916) 451-3014 
 
E-mail: mmalogolowkin@ucdavis.edu 
Mary McCarville, MD 
 
Diagnostic Imaging  
STUDY STATISTICIAN 
St. Jude Children’s Research Hospital 
Mark Krailo, PhD 
Radiological Sciences 
Statistics 
262 Danny Thomas Place - MS 220 
Children’s Oncology Group - Operations Center 
Memphis, TN 38105-3678 
222 E. Huntington Dr. Suite 100 
Phone: (901) 595-2399 
Monrovia, CA 91016 
Fax: 
(901) 595-3981 
Phone: (626) 241-1529 
E-mail: beth.mccarville@stjude.org 
Fax: 
(626) 445-4334 
 
E-mail: mkrailo@childrensoncologygroup.org 
Christie Powell, MSN, CPNP 
 
Nursing 
STUDY COMMITTEE MEMBERS 
Children's Healthcare of Atlanta - Egleston 
Rebecka Meyers, MD 
Aflac Center for Cancer and Blood Disorders 
Surgery 
1405 Clifton Road NE 
Primary Children's Medical Center 
Atlanta, GA 30322 
Division of Pediatric Surgery 
Phone: (404) 785-1743 
100 North Mario Capecchi Drive, Suite 2600 
Fax: 
(404) 785-6288 
Salt Lake City, UT 84113 
E-mail: christie.powell@choa.org 
Phone: (801) 662-2950 
 
Fax: 
(801) 662-4707 
Alexander Justin Towbin, MD 
E-mail:  rebecka.meyers@hsc.utah.edu 
Diagnostic Imaging 
 
Cincinnati Children’s Hospital Medical Center  
Milton Finegold, MD 
Radiology 
Pathology 
3333 Burnet Ave 
Baylor College of Medicine  
Department of Radiology,  ML 5031 
Texas Children’s Hospital, MC1-2261 
Cincinnati, OH 45229 
6621 Fannin Street 
Phone:    (513) 636-5896 
Houston, TX 77030-2399 
Fax:        (513) 636-1388 
Phone: (832) 824-1856 
E-mail:   Alexander.towbin@cchmc.org 
Fax: 
(832) 825-1032 
 
E-mail: Mjfinego@TexasChildrens.org 
 

 
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STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
Wayne Furman, MD 
Rhonda Crutcher, CCRP 
Hematology/Oncology 
Clinical Research Associate 
St. Jude Children's Research Hospital 
Children’s Hospital of Los Angeles 
Department of Oncology 
Hematology/Oncology 
262 Danny Thomas Place - MS 260 
4650 Sunset Blvd. MS #54 
Memphis, TN 38105-3678 
Los Angeles, CA  90027 
Phone: (901) 595-2403 
Phone: (323)361-8659 
Fax: 
(901) 521-9005 
Fax: 
(323)361-1585 
E-Mail: wayne.furman@stjude.org 
E-mail:  rcrutcher@chla.usc.edu 
 
 
Anne Warwick, MD, MPH 
Gregory Tiao, MD 
Hematology/Oncology 
Surgery  
Walter Reed National Military Medical Center 
Cincinnati Children's Hospital Medical Center 
Pediatric Hematology/Oncology 
3333 Burnet Avenue 
8901 Wisconsin Avenue 
MLC - 2023 
Bethesda, MD 20889-5600 
Cincinnati, OH 45229 
Phone: (301) 400-1663 
Phone: (513) 636-4371 
Fax: 
(301) 400-1662 
Fax: 
(513) 636-7657 
E-mail: anne.warwick@usuhs.edu 
E-mail: Greg.Tiao@cchmc.org 
 
 
Sarangarajan Ranganathan, MD 
Christopher Bertero Weldon, MD PhD 
Pathology 
Surgery 
Children’s Hospital of Pittsburgh of UPMC 
Dana-Farber Cancer Institute 
Division of Pediatric Pathology  
Surgery 
One Children’s Hospital Drive 
Children’s Hospital Boston 
4401 Penn Avenue 
300 Longwood Avenue, Fegan 3 
Pittsburgh, PA 15224 
Boston, MA 02115 
Phone: (412) 692-5879 
Phone: (617) 355-4503 
Fax: 
(412) 692-6550 
Fax: 
(617) 730-0477 
E-mail: Sarangarajan.Ranganathan@chp.edu 
E-mail: Christopher.weldon@childrens.harvard.edu 
 
 
Eugene McGahren, MD 
PROTOCOL CONTACT 
Surgery 
Christine Wang 
University of Virginia  
Children’s Oncology Group - Operations Center 
Department of Surgery/Division of Pediatric Surgery 
Study Development Office 
University of Virginia Hospital 
222 E. Huntington Drive, Suite 100 
Box 800709  
Monrovia, CA 91016 
Charlottesville, VA 22908 
Phone: (626) 241-1626 
Phone: (434) 924-5643 
Fax: 
(626) 445-4334 
Fax: 
(434) 243-6129 
E-mail: cewang@childrensoncologygroup.org 
E-mail: edm6k@virginia.edu 
 
 
RESEARCH COORDINATOR 
Arun Atreiya Rangaswami, MD 
Justin Davis 
Hematology/Oncology 
Children's Oncology Group - Operations Center 
Lucile Packard Children’s Hospital Stanford University 
Statistics and Data Center 
1000 Welch Road, Suite 300 
222 E. Huntington Drive, Suite 100  
Palo Alto, CA 94304-1812 
Monrovia, CA 91016 
Phone: (650) 723-5535 
Phone: (626) 241-1509 
E-mail: atreiya@stanford.edu 
Fax: 
(626) 445-4334 
 
E-mail: jdavis@childrensoncologygroup.org 
 
 
 
 

 
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JPLT CONTACTS 
Eiso Hiyama, MD, PhD 
AGENT  
 
NSC#'s  
IND# 
Oncology/Surgery  
FLUOROURACIL 
19893 
 
Exempt 
Hiroshima University Hospital 
CISPLATIN 
 
119875  
Exempt 
1-2-3 Kasumi, Minami-ku  
DEXRAZOXANE  
169780  
Exempt 
Hiroshima 734-8551, Japan 
DOXORUBICIN  
123127  
Exempt 
Phone: 81 (82) 257-5951 
IRINOTECAN   
616348  
Exempt 
Fax: 
81 (82) 257-5416 
VINCRISTINE   
67574 
 
Exempt 
Email: eiso@hiroshima-u.ac.jp 
TEMSIROLIMUS 
683864  
 
 
 
Eriko Aotani, RN, MSN  
 
Director, Global Health Research Coordinating Center 
 
Kanagawa Academy of Science and Technology (KAST) 
 
KSP East 3F 309, 3-2-1, Sakado 
 
Takatsu-ku, Kawasaki-shi 
 
Kanagawa, 213-0012 Japan 
 
Phone: 81 (44) 850-1731 
 
Fax: 
81 (44) 850-1732 
 
Email: ahep0731@newkast.or.jp 
 
 
 
 
 
 
SEE SECTIONS 14.0 AND 15.0 FOR SHIPPING ADDRESSES 
 
 
 
 
 
 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will 
help us protect the privacy of our research subjects.  The Certificate protects against the involuntary release of 
information about your subjects collected during the course of our covered studies.  The researchers involved in the 
studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at 
the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings.   
However, the subject or the researcher may choose to voluntarily disclose the protected information under certain 
circumstances.  For example, if the subject or his/her guardian requests the release of information in writing, the 
Certificate does not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA 
request under the Food, Drug and Cosmetics Act.  The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others. 
 
ABSTRACT 
Hepatoblastoma is the most common malignant liver neoplasm in children. Although surgical resection is 
the mainstay of curative therapy for children with hepatoblastoma, only one-third to one-half of newly 
diagnosed patients with hepatoblastoma can be expected to have resectable disease at presentation. Patients 
who undergo a primary complete resection of their tumor have an excellent prognosis (90% event-free 
survival [EFS]). The use of chemotherapy has improved survival in patients with unresectable 
hepatoblastoma by increasing the number of patients whose tumors can be resected. However, more recent 
trials over the last decade have failed to significantly improve survival numbers. Therefore, the current EFS 
for the entire group of patients with non-metastatic, unresectable hepatoblastoma at diagnosis remains 
suboptimal (< 70%) and warrants novel treatment approaches. The survival of patients with metastatic 
disease at diagnosis remains poor (20-30%) and also requires consideration of novel therapeutic strategies. 
AHEP0731 builds on the results of the last 20 years of hepatoblastoma clinical trials and seeks to diminish 
toxicity in the approximately 30% of low-risk patients, increase survival in intermediate-risk patients and 
identify new agents(s) that may be used in high-risk and recurrent patients. Patients will be staged for risk 
classification and treatment at diagnosis using COG staging guidelines (see Appendix III). Study enrollment 
for patients with Stage I and II tumors is contingent on rapid central pathologic review of tumor specimens. 
All patients with Stage I pure fetal histology (PFH) hepatoblastoma will be classified as very low-risk and 
will be treated with surgery only. Patients with Stage I non-PFH, non-small cell undifferentiated (SCU) 
hepatoblastoma or with Stage II non-SCU hepatoblastoma will be classified as low-risk and will be treated 
on Regimen T with 2 adjuvant cycles of cisplatin, 5-flouorouracil, and vincristine (C5V), a reduction from 
the standard 4 cycles of chemotherapy used in previous COG trials.  Patients with Stage I SCU, Stage II 
SCU, or any Stage III hepatoblastoma will be classified as intermediate-risk and will be treated with 
Regimen F (intermediate risk, stratum 3, has been closed to accrual as of 03/12/12). This treatment regimen 
is based on previous COG trials which administered 6 cycles of C5V therapy plus surgical resection of the 
tumor. However, to improve resection and survival rates, doxorubicin, an agent with proven efficacy will 
be added to the C5V therapy (C5VD).  Surgical resection is necessary for cure and surgical resection 
whether by primary resection or orthotopic liver transplant (OLT) is intended after 4 cycles of intermediate-
risk therapy. This trial will assess the feasibility in a cooperative group setting of timely referral (by the 
completion of Cycle 2) for OLT in children with hepatoblastoma designated as potentially unresectable 
following central surgical review and staging according to the PRETEXT (Pretreatment Extent of Disease) 
grouping system. AHEP0731 also aims to determine if PRETEXT grouping can predict tumor resectability 
and to assess if institutional assessment of PRETEXT grouping is reliable by comparing to PRETEXT grouping 
as performed by central review. All patients with any Stage IV hepatoblastoma as well as patients with any 
stage of hepatoblastoma and initial AFP <100 ng/mL will be classified as high-risk and will be treated with 
the novel combination of vincristine, irinotecan and temsirolimus in Regimen H in order to estimate the 
response rate of this new combination of agents. This regimen includes 2 cycles of “up-front” vincristine, 
irinotecan and temsirolimus in the initial 6 weeks of therapy. Patients who respond to 
vincristine/irinotecan/temsirolimus (VIT) will continue to receive this combination. Responding patients 

 
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will receive a total of 6 cycles of C5VD therapy with 2 more cycles of VIT (total of 4). Non-responding 
patients will only receive the 6 cycles of C5VD following the “up-front” window therapy. The primary goal 
of AHEP0731 is to show that a risk-based treatment approach will maintain or improve EFS, decrease acute 
and long-term chemotherapy toxicity, and identify new agents for the treatment of children with 
hepatoblastoma. 
 
 

 
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EXPERIMENTAL DESIGN SCHEMA  
 
 
 
 
On Study 
Biopsy/Resection* 
Newly diagnosed 
hepatoblastoma 
 
Risk Stratification 
Stage I/II Hepatoblastoma 
RAPID CENTRAL PATHOLOGY 
REVIEW IS REQUIRED 
 
Stage III/IV 
Hepatoblastoma 
 
Very Low-Risk 
Stratum 1 
 
Low-Risk 
Stratum 2 
 
Intermediate-Risk 
Stratum 3 
 
High-Risk 
Stratum 4 
 
 
No further 
treatment 
 
 
Treatment 
Regimen T 
 
 
Treatment 
Regimen F 
 
 
Treatment 
Regimen H 
C5V 
2 adjuvant cycles 
C5VD 
6 cycles in total 
 
Surgical resection/ 
Transplant 
after 2 cycles with  
4 postoperative cycles 
OR  
Surgical 
resection/Transplant 
after 4 cycles with  
2 postoperative cycles 
 
Note: Stratum 3 is 
closed to accrual as of 
03/12/12 
2 cycles of “up-front” 
VIT window therapy 
followed by real time 
central review of 
response 
 
Responders will then 
receive 6 cycles of 
C5VD and 2 cycles of 
VIT  
 
Non-responders will 
then receive 6 cycles 
of C5VD 
 
Tumor resection or 
liver transplant should 
ideally occur after 4th 
cycle of C5VD with 2 
cycles of C5VD given 
postoperatively/ 
Post-transplant  
Very Low-Risk: Stage I PFH hepatoblastoma 
Low-Risk: Stage I non-PFH, non-SCU or Stage II 
non-SCU hepatoblastoma 
Intermediate-Risk: Stage I SCU, Stage II SCU, or 
any Stage III hepatoblastoma 
High-Risk: Any Stage IV or any stage hepatoblastoma 
with initial AFP < 100 ng/mL hepatoblastoma 
 
C5V: Cisplatin 5-Fluorouracil, Vincristine 
VIT: Vincristine, Irinotecan, Temsirolimus 
C5VD: Cisplatin, 5-Fluorouracil, Vincristine, 
Doxorubicin 
 
* Biopsy or complete tumor resection if deemed 
feasible at diagnosis 
 

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Hypotheses 
 
1.1.1  
A risk-based treatment approach will maintain or improve event-free survival (EFS), decrease acute and 
long-term chemotherapy toxicity, and identify new agents in the treatment of children with hepatoblastoma. 
 
1.1.2  
Stage I hepatoblastoma (non-pure fetal histology [PFH]), non-small cell undifferentiated [SCU]) and Stage 
II (non-SCU) is a highly curable disease with 2 cycles of adjuvant cisplatin, 5-fluorouracil, and vincristine 
(C5V). 
 
1.1.3  
The addition of doxorubicin to the chemotherapy regimen of C5V for children with intermediate-risk 
hepatoblastoma will be feasible and associated with acceptable levels of toxicity. 
 
1.1.4 
The use of vincristine, irinotecan and temsirolimus in an upfront window for children with high-risk, 
metastatic hepatoblastoma will improve the response rate in this group of children. 
 
1.1.5 
Referral for orthotopic liver transplant (OLT) is feasible in a cooperative group setting in children with 
hepatoblastoma designated as potentially unresectable following central surgical review and staging 
according to the PRETEXT (Pretreatment Extent of Disease) grouping system. 
 
1.2 
Primary Aims 
 
1.2.1 
To estimate the EFS in children with Stage I (non-PFH, non-SCU) and Stage II (non-SCU) hepatoblastoma 
treated with surgical resection followed by 2 cycles of C5V. 
 
1.2.2 
To determine the feasibility and toxicity of adding doxorubicin to the chemotherapy regimen of C5V for 
children with intermediate-risk hepatoblastoma. 
 
1.2.3 
To estimate the response rate to vincristine, irinotecan and temsirolimus in previously untreated children 
with high-risk, metastatic hepatoblastoma. 
 
1.2.4 
To determine whether timely (between diagnosis and end of second cycle of chemotherapy) consultation 
with a treatment center with surgical expertise in major pediatric liver resection and transplant can be 
achieved in 70% of patients with potentially unresectable hepatoblastoma. 
 
1.2.5 
To foster the collection of tumor tissue and biologic samples to facilitate translational research and to 
provide data that may aid in risk-adapted approaches for subsequent clinical trials.  
 
 

 
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1.3 
Secondary Aims 
 
1.3.1 
To estimate the EFS of patients with Stage I PFH treated with surgery alone. 
 
1.3.2 
To determine whether OLT can be accomplished after successful referral and completion of 4 cycles of 
initial chemotherapy. 
 
1.3.3 
To estimate the 2-year EFS for patients once identified as candidates for possible OLT, the 2-year EFS for 
patients referred to a transplant center that are resected without OLT, and the 2-year EFS for patients 
referred to a transplant center who receive OLT. 
 
1.3.4 
To register children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver Unresectable Tumor 
Observatory), an international cooperative registry for children transplanted for liver tumors. 
 
1.3.5 
To determine if PRETEXT grouping can predict tumor resectability. 
 
1.3.6 
To monitor the concordance between institutional assessment of PRETEXT grouping and PRETEXT grouping 
as performed by expert panel review. 
 
1.3.7 
To estimate the proportion of Stage IV patients who have surgical resection of metastatic pulmonary lesions. 
 
1.3.8 
To determine the proportion and estimate the EFS of patients with potentially poor prognostic factors including 
AFP < 100 ng/mL at diagnosis, microscopic positive surgical margins, surgical complications, multifocal 
tumors, microscopic vascular invasion, macrotrabecular histologic subtype, and SCU histologic subtype.  
 
 
2.0 
BACKGROUND  
 
2.1 
Treatment Considerations 
Hepatoblastoma is the most common malignant liver neoplasm in children. Although surgical resection is 
the mainstay of curative therapy for children with hepatoblastoma, only one-third to one-half of newly 
diagnosed patients with hepatoblastoma can be expected to have resectable disease at presentation.1,2 The 
main determinants of clinical outcome in patients with hepatoblastoma are the presence or absence of 
metastatic disease, and tumor resectability.3 In addition, unique histologic variants of hepatoblastoma, such 
as SCU histology, have also been shown to adversely affect survival.4,5  
 
Patients who undergo a primary complete resection of their tumor have an excellent prognosis (90% EFS) 
in several series.3,6,7 The use of chemotherapy has improved survival in patients with unresectable 
hepatoblastoma by increasing the number of patients whose tumors can be resected.6,8 Cisplatin (CDDP) 
has been identified as the most active agent for the treatment of hepatoblastoma.9,10 Doxorubicin (DOXO) 
appears to be the next most active agent. There is relatively little information on the efficacy of other single 
agents such as ifosfamide (IFOS), etoposide (ETOP), vincristine (VCR), 5-fluorouracil (FU), 

 
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cyclophosphamide (CPM), and carboplatin (CARBO) in the treatment of hepatoblastoma as most of these 
agents have been used in combination.2,11,12 Over the last 2 decades, the chemotherapeutic regimen 
CDDP/5-FU/VCR (C5V) has been utilized and studied within Children’s Oncology Group (COG) trials 
and has been adopted as the standard treatment regimen by COG because of its similar activity and 
favorable toxicity profile when compared to doxorubicin-containing regimens. 
 
Cooperative group studies from around the world performed in the late 1980s and early 1990s demonstrated 
the effectiveness of chemotherapy in increasing rates of surgical resection and survival in initially 
unresectable patients.13,14 However, more recent trials over the last decade have failed to significantly 
improve survival numbers. Therefore, the current EFS for the entire group of patients with non-metastatic, 
unresectable hepatoblastoma at diagnosis remains suboptimal (< 70%) and warrants novel treatment 
approaches.  The survival of patients with metastatic disease at diagnosis remains poor (20-30%) and also 
requires consideration of novel therapeutic strategies.2,15  
 
For patients without metastatic disease, delayed tumor resection has been associated with survival rates 
comparable to the survival rates observed in patients who undergo a primary resection at the time of 
diagnosis.2 However, only approximately two-thirds of patients with unresectable tumors at diagnosis 
become resectable with chemotherapy2 leaving too many children with gross residual disease. There is no 
good marker or method to predict which tumors initially considered unresectable will eventually become 
amenable to resection.  OLT is sometimes the only option that may result in complete tumor removal and 
increased chance for cure.  
 
In addition, biologic factors may be able to help predict tumor phenotype. These biologic variables may 
help to result in better identification of disease risk and therefore yield additional refinement criteria to risk-
stratified therapy. This could decrease toxicity for the most favorable groups by limiting therapy and 
maximize therapeutic options for the most aggressive tumor phenotypes. Hepatoblastoma has been 
characterized by several genetic markers, including chromosomal numerical and structural aberrations, in 
particular specific trisomies of chromosome 2, 8, and 20 and translocations with breakpoints at chromosome 
1q12.16-19 The correlation of these genetic markers in response to treatment and outcome has been only 
minimally studied. It has recently been determined that translocation of the NOTCH2 gene on chromosome 
1 may be an important component to the development of some cases of hepatoblastoma.20 As systematic 
evaluation of tumor biology may allow for refining risk stratification and for developing more targeted 
therapy for this childhood cancer, a goal for AHEP0731 is to characterize these genetic markers with respect 
to their association with outcome.  
 
2.2 
Pathologic Considerations 
The presence of SCU components in the resection specimen is an unfavorable histologic variant and has 
been previously associated with a trend towards an increased risk for an adverse event (P = 0.15). However, 
the number of patients with SCU tumors reported in the literature is relatively small.5  In the largest previous 
report, Haas and colleagues described the presence of SCU elements in 16 patients with Stage I tumors. A 
much higher than expected relapse rate for Stage I patients was observed in this cohort with recurrences in 
10 of the 16 patients.5 Relapses and death were seen even in patients with a small focus of SCU, including 
1 patient who ultimately died from disease and had only 1 microscopic SCU focus among 8 slides examined. 
These observations warrant further study.  The adverse prognostic impact of SCU in the reported cases 
warrants that the presence of any SCU elements must be considered as significant.  In an analysis of data 
from CCG trial CCG-881, survival was 70% in Stage I patients without SCU (n = 30) vs. 50% in Stage I 
patients with SCU (n = 4). In a similar analysis of the INT-0098 study, recurrence was observed in 9% of 
non-SCU, non-PFH Stage I patients (n = 35) compared to a 38% recurrence rate in Stage I patients with 
SCU (n = 8). The presence of SCU elements has also been recently identified and correlated with the 
presence of a low alphafetoprotein (AFP) level (< 100 ng/mL), another poor prognostic variable, and has 

 
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been observed in all stages of hepatoblastoma21. Previous cytogenetic reports have demonstrated that SCU 
hepatoblastomas have chromosome aberrations involving chromosome 22q11.22,23 A deletion of the 
rhabdoid associated gene, hSNF5/INI1 gene, has been observed in tumor tissue from 1 patient with SCU 
histology studied in the hepatoblastoma biology study POG 9346. A recent report summarizes similar 
findings in 11 patients with Stage III and IV disease with elements of SCU histology who often had low 
AFP and responded poorly to therapy. These patients clearly require novel therapeutic approaches.24 
 
2.3 
Risk-Stratified Treatment 
 
2.3.1 
Very Low-Risk Patients 
Very low-risk patients will include those patients who have grossly resected tumors (Stage I) with PFH 
AND have an elevated AFP level > 100 ng/mL. 
 
Patients with Stage I PFH hepatoblastoma have been considered as a “favorable” subtype and have been 
treated with surgical resection without adjuvant chemotherapy on the COG P9645 study. The rationale for 
this approach was based upon reports of selected patients who fared well with surgery alone.25 Stopping 
rules for the failure of this hypothesis have not been met on the current P9645 study and no events have 
been observed in the 18 patients enrolled on the study to date.26 All 18 patients enrolled onto P9645 study 
were alive and free of disease at the time of last contact, at a mean post-resection interval of 3.7 years 
(personal communication, Mark Krailo, PhD). This suggests that surgical resection alone provides adequate 
therapy for this selected subset of children with hepatoblastoma. Utilization of this approach limits 
unnecessary and harmful exposure to various chemotherapeutic regimens, such as cisplatin, vincristine, 5-
fluorouracil, and doxorubicin in the approximately 4% of all children with Stage I PFH hepatoblastoma.  
 
2.3.2 
Low-Risk Patients 
Low-risk patients will include those patients who have grossly resected tumors (Stages I and II) AND lack 
any unfavorable biologic feature (ie, any SCU elements or a low diagnostic AFP level < 100 ng/mL). 
 
Approximately 20-30% of children with hepatoblastoma can be expected to be classified as low-risk. In the 
POG 8696/8697, INT-0098, and P9645 studies, these patients received 4 adjuvant cycles of C5V. The 5-
year EFS was 84% and survival was 96% in patients treated with this approach.6 This approach has used 
the most active compound, cisplatin, as the integral component of therapy while avoiding exposure to 
anthracyclines and ifosfamide and their associated short- and long-term toxicities for the 15-30% of low-
risk patients diagnosed with hepatoblastoma and treated on COG studies. The 5-year EFS for Stage I 
patients with non-PFH is 91% and survival is 98% in patients treated with this approach.6 Cumulative Grade 
3-4 toxicities associated with 4 cycles of this regimen on P9645 include: anemia (45%), neutropenia (75%), 
thrombocytopenia (11%), anorexia (10%), vomiting (14%), febrile neutropenia (16%), and stomatitis (2%). 
Noticeable hearing loss (> 40 dB at any frequency from 3-5 kHz or > 20 but ≤ 40 dB at 2 kHz) as a measure 
of ototoxicity occurred in 2 of 21 evaluable patients (10%). This therapy has a significant impact on both 
the short-term and long-term quality of life in these children. Therefore, the history of the successful use of 
the C5V regimen within COG studies over the last 20 years has led to the point where a reduction in 
chemotherapy appears justified in the subset of patients with non-PFH, non-SCU hepatoblastoma who have 
an excellent prognosis.  In addition, the successful reduction in therapy for Stage I PFH patients treated 
with surgery alone helps to justify the reduction in therapy for this group of Stage I non-PFH, non-SCU 
patients who comprise about 20-25% of all hepatoblastoma patients. Strict monitoring criteria and stopping 
rules will be utilized to ensure patient safety and maintain excellent EFS. 

 
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While cisplatin has been the backbone of hepatoblastoma therapy, the additional agents used in combination 
with cisplatin have differed among the various cooperative groups. It is somewhat difficult to compare the 
results of COG studies with that of international groups as different staging criteria have been used and 
therefore comparison groups are not necessarily equivalent. COG and the German Cooperative Pediatric 
Liver Tumor Studies have used a surgical staging system. SIOPEL (International Childhood Liver Tumour 
Strategy Group) has classified patients using radiographic criteria as part of the PRETEXT (Pretreatment 
Extent of Disease) system and has categorized standard-risk patients as those with tumors that are either 
PRETEXT 1, 2, or 3.3 This standard-risk group is fairly similar to the Stage I and II COG patients classified 
in this trial as low-risk. The most recent published results of SIOPEL-2 have focused on the use of cisplatin 
monotherapy for these standard-risk patients who received a total of 6 cycles of cisplatin at 80 mg/m2 for a 
cumulative dose of 480 mg/m2.3  This is more than the total cumulative dose given during the 4 cycles of 
cisplatin at 100 mg/m2 used for resected Stage I and II patients on COG studies such as P9645.  In the 
German Cooperative Group HB studies, resected patients received 2 to 3 cycles of doxorubicin (60 mg/m2) 
and ifosfamide (3500 mg/m2) in addition to cisplatin (20mg/m2 x 5) exposing these patients to much more 
toxic chemotherapy than in resected Stage I and II COG patients.7,27 The further reduction in this study to 
2 cycles of cisplatin for low-risk patients should reduce both associated toxicity and medical costs. A 
comparison of survival rates in several recent studies is summarized in Table 1.  Survival rates among COG 
and SIOPEL groups are comparable with SIOPEL-2 standard-risk patients having a 3-year progression-free 
survival (PFS) of 89 ±7% compared to 88 ±6% for low-risk COG patients treated with C5V on INT-0098 
and 86 ±6% for COG patients treated with C5V without amifostine on P9645.3 However, results of the 
SIOPEL-2 trial must be interpreted with caution for several reasons: 1) the study uses any tumor shrinkage 
or decrease in AFP as a response, which is far less stringent than the 50% decrease in tumor size used as 
response criteria on COG studies; 2) of the 77 patients who were classified as standard-risk, 23 (30%) were 
not treated according to protocol and received additional, more intense therapy with doxorubicin and 
carboplatin, making the SIOPEL-2 results difficult to interpret. When chemotherapy administration in 
violation of protocol was considered as an event in the SIOPEL-2 study, the 3-year EFS was substantially 
inferior to COG studies at only 73 ± 11% for the standard-risk patients.3  
 
Table 1. Treatment and Survival of Resectable and Non-Metastatic Hepatoblastoma Patients in Recent 
Studies 
 
Study 
Treatment 
Number of Patients 
Stage 
EFS (%) 
S (%) 
P964526 
CDDP/5-FU/VCR 
55 
I/II 
84* 
96* 
INT-00986 
CDDP/5-FU/VCR 
CDDP/DOXO 
26 
24 
I/II 
I/II 
88* 
96* 
100* 
96* 
SIOPEL-23 
CDDP 
6 
36 
25 
I/II/III 
(PRETEXT) 
73# 
91# 
SIOPEL-114 
CDDP/DOXO 
6 
52 
45 
I 
II 
III 
(PRETEXT) 
100& 
83& 
56& 
100& 
91& 
68& 
HB-947 
CDDP/DOXO/IFOS 
27 
3 
I 
II 
89 
100 
96 
100 
HB-8927 
CDDP/DOXO/IFOS 
21 
6 
I 
II 
100 
50 
Not provided 
* = 4-year EFS or S; & = 5-year EFS and S; # = 3-year EFS and S  
 
While the roles of vincristine and 5-fluorouracil used in COG studies are not entirely clear, indirect evidence 
suggests that these 2 agents are active against hepatoblastoma and may be synergistic with cisplatin. COG 
results compare favorably with those reported in the SIOPEL studies using the PLADO regimen (CDDP 
and DOXO) and with the 3 drug IPA regimen (IFOS, CDDP, DOXO) used in the HB (German Cooperative 

 
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Pediatric Liver Tumor) studies. If vincristine and 5-fluorouracil were entirely inactive, then it would be 
expected that both the PLADO and IPA regimens should be superior to C5V. However, the results of 
SIOPEL and HB trials have been either equivalent or inferior to COG studies (see Table 1) despite more 
intense chemotherapy exposure in the international studies. In addition, in the most recent COG study, 
P9645, the experimental arm of intensified platinum-based therapy with cisplatin and carboplatin that was 
administered to advanced-stage patients proved to be inferior to the C5V regimen, suggesting that the 
addition of vincristine and 5-fluorouracil may add to the activity of single-agent cisplatin. Since cisplatin 
is the main cause of chemotherapy-related toxicity in low-risk patients, the best strategy to decrease toxicity 
may be to decrease the total dose of cisplatin that is administered.  The continued use of vincristine and 5-
fluorouracil and their potential synergy with cisplatin may be a significant contributor to the safe reduction 
in the total cumulative dose of cisplatin delivered to low-risk patients. The toxicity associated with 
vincristine and 5-fluorouracil is mild with little to no expected long-term toxicity as compared to the 
significant short- and long-term toxicities often associated with doxorubicin, ifosfamide, or etoposide. 
 
These data demonstrate that low-risk COG patients (Stage I non-PFH, Stage II patients) have:  
• excellent survival with the current COG standard therapy C5V,  
• equivalent, if not better, survival with C5V when compared to other cooperative group 
regimens;  
• potential for diminished toxicity when using regimen C5V compared with other regimens by 
avoiding the use of anthracyclines and ifosfamide; and 
• potential for salvage in the event of relapse with the administration of doxorubicin when it is 
excluded from initial treatment.  
For these reasons, C5V is the optimal treatment for the 20-25% of patients with non-PFH, low-risk disease. 
 
2.3.3 
Intermediate-Risk Patients 
Enrollment to stratum 3 was suspended on 12 March 2012 at the completion of the required number of 
patients to address study aim 1.1.3. Enrollment to this particular stratum will not reopen. 
 
Intermediate-risk patients will include those patients with: 1) gross residual disease/unresectable disease; 
or 2) grossly-resected disease with any SCU elements but who do not have metastatic disease and do not 
have a low diagnostic AFP level < 100 ng/mL. 
 
The Pediatric Intergroup Study INT-0098 randomized patients with hepatoblastoma to receive treatment 
with either C5V [cisplatin (90 mg/m2), 5-fluorouracil (600 mg/m2), and vincristine (1.5 mg/m2)], or CD 
[cisplatin and doxorubicin (80 mg/m2)]. Resected patients received 4 cycles whereas initially unresected 
patients received 6 or 8 cycles to a maximum total of 720 mg/m2 of cisplatin and 640 mg/m2 of doxorubicin.6 
Three patients treated with CD developed congestive heart failure, 2 of whom died. No significant renal 
toxicity was reported and information on ototoxicity was not specifically measured or reported. Five-year 
EFS was 64% for 83 Stage III patients and 25% for 40 Stage IV patients. Survival for children with localized 
hepatoblastoma was approximately 70%, while for those with metastatic disease at diagnosis, survival was 
approximately 35%. Although there was no significant difference in outcome between the 2 treatment arms, 
they differed with regards to the types of events observed. Tumor progression accounted for 86% of the 
events among patients treated with C5V, but only 50% of the events for those treated with CD.  
Consequently, COG adopted treatment with C5V as the standard for the treatment of patients with 
hepatoblastoma. While the doxorubicin arm was associated with a greater number of toxic events and 
deaths, these results do suggest some improved tumor response for patients receiving doxorubicin. 
AHEP0731 will evaluate whether the addition of doxorubicin can improve EFS in children with 
intermediate- and high-risk disease. In patients with unresectable and metastatic disease at diagnosis, no 
published treatment regimen has demonstrated clearly superior results (see Table 2). Therefore, it is 
reasonable to consider the use of C5VD as a novel therapeutic strategy to improve EFS for intermediate- 

 
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and high-risk patients. The addition of doxorubicin to the C5V regimen in this trial will intensify the 
regimen in an attempt to improve the outcome for intermediate-risk patients.  A goal of AHEP0731 is to 
determine the feasibility and toxicity of adding doxorubicin to the chemotherapy regimen of C5V for 
children with intermediate-risk hepatoblastoma. 
 
The administration of doxorubicin in the majority of previous trials has been by continuous infusion.6,14,27 
However, there are no data that establish continuous infusion doxorubicin as more efficacious than bolus 
administration. Prolonged administration of doxorubicin requires hospitalization and results in more 
mucositis and myelosuppression. Additionally, there is no documented evidence that continuous infusion 
doxorubicin results in diminished cardiac toxicity.28-30 The incidence of significant cardiac toxicity in INT-
0098 was relatively small with 3 patients (4%) developing congestive heart failure among 81 patients who 
were intended to receive either 320 mg/m2 (n = 24) or 640 mg/m2 (n = 57) of doxorubicin.6 In an older 
study, CCG-823F, > 400 mg/m2 of doxorubicin was given to 30 patients with no cardiac dysfunction 
reported.13 Cisplatin was also given in that study at 100 mg/m2 for a total of 4 or 8 courses depending upon 
the timing of resection. Magnesium wasting occurred in 13% of patients but no other permanent renal 
dysfunction was reported. Since the EFS in patients with Stages III and IV disease is less than desirable at 
64% and 25% respectively,6 the relatively small risk of cardiac toxicity with a maximum cumulative dose 
of 360 mg/m2 is reasonable. No data have been established to suggest that the administration of dexrazoxane 
(DXRZ) has impaired survival in pediatric malignancies. Therefore, the cardioprotectant dexrazoxane will 
be incorporated into AHEP0731 treatment postoperatively for all patients (when the doxorubicin dose has 
exceeded 240 mg/m2). In this trial, doxorubicin will be administered over 15 minutes on 2 consecutive days.  
 
The HB studies from the German Cooperative Pediatric Liver Group have used a slightly different treatment 
strategy and have incorporated ifosfamide and etoposide along with cisplatin and carboplatin.  In HB-89, 
patients were treated with ifosfamide (3500 mg/m2), doxorubicin (60 mg/m2), and cisplatin (20 mg/m2 x 5) 
per cycle. Twenty-one Stage I patients received 3 cycles and had 100% disease-free survival (DFS) while 
6 Stage II patients received 4 cycles and had only 50% DFS. DFS was 71% in 38 Stage III patients and 
only 9% for the 7 Stage IV patients.27 A separate report from the HB-89 study reported on a total of 37 
patients with unresectable or metastatic disease. However, the number of chemotherapy courses was not 
standardized as 21 patients received 2 courses, 5 patients received 3 courses, 7 patients received 4 courses, 
3 patients received 5 courses, and 1 patient received 6 courses.31 Thus, the efficacy of the IPA regimen in 
inducing resectability and survival is not assessable because it was not administered in a consistent manner. 
In HB-94, a total of 69 patients with hepatoblastoma were treated according to a complex treatment schema 
with CDDP/DOXO/IFOS and with additional carboplatin and etoposide administered to 46% of patients 
with poor response. Again, it is difficult to discern the number of cycles different patients received, but EFS 
was 89% for 27 Stage I patients, 100% for 3 Stage II patients, 68% for 25 Stage III patients, and 21% for 
14 Stage IV patients. These results are no different and no better than that observed in COG studies.7  
 
A summary review of the results from the most recent COG, SIOPEL, and HB studies is shown in Table 2. 
These results demonstrate that there is no clearly superior regimen when comparing the largest international 
trials. Overall survival for patients treated on P9645 was greater than that observed in SIOPEL-2 and may 
reflect the ability to salvage patients with the use of doxorubicin. 
 
 
 

 
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Table 2. Treatment and Survival of Unresectable and Metastatic Hepatoblastoma Patients in Recent Studies 
 
Study 
Treatment 
Number of Patients 
Stage 
EFS (%) 
S (%) 
P964526 
CDDP/5-FU/VCR 
38 
10 
III 
IV 
63* 
50#   
88* 
67# 
INT-00986 
CDDP/5-FU/VCR 
 
 
CDDP/DOXO 
45 
21 
 
38 
19 
III 
IV 
 
III 
IV 
60* 
14* 
 
68* 
37*           
68* 
33* 
 
71* 
42*       
SIOPEL-23 
CDDP/DOXO/CARBO 
21 
25 
IV 
Metastatic 
(PRETEXT) 
48# 
(combined) 
 
61# 
44# 
SIOPEL-114 
CDDP/DOXO/IFOS 
39 
31 
IV 
Metastatic 
(PRETEXT) 
46& 
28& 
57& 
57& 
HB-947 
CDDP/DOXO/IFOS 
VP/CARBO 
25 
14 
III 
IV 
68 
21 
76 
36 
HB-8927 
CDDP/DOXO/IFOS 
38 
7 
III 
IV 
71 
29 
Not provided 
SIOPEL-
3HR32 
CDDP/DOXO/CARBO 
70 
IV 
56# 
62# 
SIOPEL-4 
CDDP/DOXO/CARBO 
39 
M+/IV 
 
77# (95% CI 
63-90) 
79# 
* = 4-year EFS or S; & = 5-year EFS and S; # = 3-year EFS and S  
 
Xenograft studies have been performed using doxorubicin, cisplatin, carboplatin, etoposide, and 
ifosfamide.32 Reduction in tumor size and declines in AFP values were only seen following cisplatin and 
doxorubicin.  Ifosfamide, carboplatin, and etoposide caused a slightly lower rate of tumor growth when 
compared to controls. Based on this xenograft study it was concluded that as single agents, cisplatin and 
doxorubicin are most effective, ifosfamide is effective in some, carboplatin is moderately effective, and 
etoposide is ineffective. This xenograft report followed the completion of HB-94 which incorporated all of 
these agents. Previous phase 2 studies have evaluated the response of ifosfamide in 3 patients with 
hepatoma. None of the 3 patients showed a response. 
 
2.3.4 
High-Risk Patients 
High-risk patients include: 1) any patient with metastatic disease; 2) any patient with a low diagnostic AFP 
level < 100 ng/mL, regardless of stage (see Section 7.1). 
 
Based on multiple cooperative group studies, the 40-70% EFS for unresectable patients and 20-40% EFS 
for metastatic patients remain suboptimal (see Table 2). The optimal dose of cisplatin to administer to 
patients with unresectable and metastatic disease is unclear. However, as cisplatin is the most active agent 
for hepatoblastoma, intensification of cisplatin therapy may be beneficial. The dose of cisplatin proposed 
for intermediate- and high-risk patients in this trial exceeds doses used in other trials. SIOPEL administers 
an additional 3 grams of platin-based therapy with carboplatin to patients who receive 320 mg/m2 of 
cisplatin. SIOPEL-4, the current study for high-risk patients includes cisplatin (570 mg/m2), doxorubicin 
(300-350 mg/m2) and 2-3 courses of carboplatin. The HB studies administer 12,000 mg/m2 of ifosfamide. 
Table 3 provides a dose comparison of the cumulative chemotherapy dosing for intermediate- and high-risk 
patients being used in current studies. 
 
 
 

 
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Table 3. Cumulative Dosage* of Chemotherapy in Advanced-Stage Patients According to Treatment 
Regimen 
 
Study 
CDDP 
DOXO 
IFOS 
CARBO 
VCR 
FU 
AHEP0731 
600 
360 
0 
0 
33-39 
3600 
P9645 
600 
0 
0 
0 
0 
0 
SIOPEL-2 
320 
360 
0 
3000 
0 
0 
SIOPEL-4 
570 
300-350 
0 
2-3 courses 
0 
0 
HB-GPOH 
400 
240 
12000 
0 
0 
0 
*Chemotherapy dosing is mg/m2 
 
Chemotherapy is an important part of the treatment for patients with hepatoblastoma. However, since the 
introduction of platinum agents as part of the chemotherapy for hepatoblastoma, no new agents with 
significant activity have been identified. As most pediatric phase 1 and 2 studies usually include less than 
2 patients with liver tumors, identification of new effective agents against these tumors has been and will 
continue to be a challenge. Children with metastatic hepatoblastoma account for 25% of all cases of this 
disease. The outcome for these patients over the last 30 years has remained poor, despite intensive 
chemotherapy with the best available agents including cisplatin and doxorubicin (PLADO) as given by 
SIOPEL or COG, or with C5V as developed by POG and compared in INT-0098.6 All of these studies show 
similar unacceptable outcomes with < 40% 5-year EFS.3,6,7 Although patients often respond well initially, 
these early responses have not translated into cures. For example, Katzenstein, et al observed initial partial 
responses (PRs) to carboplatin alone in 55% of advanced-stage patients, but the 5-year EFS of Stage IV 
patients was still only 27%.2  New agents for this high-risk group of children are urgently needed. 
 
Irinotecan (IRIN) is a topoisomerase I inhibitor with significant anti-tumor activity against human tumor 
xenografts.33-35 Irinotecan, with or without doxorubicin, is currently being administered to relapsed patients 
in a SIOPEL trial which has been accruing patients slowly and has yet to release results. Anecdotal data in 
the literature36,37 and from members of the Liver Tumor committee exist for a total of more than 10 patients 
with recurrent or progressive hepatoblastoma who have been treated with irinotecan using different 
administration schedules (personal communication, Dr. O Beaty and Dr. H Katzenstein). Of these patients, 
6 achieved a PR lasting 3 to 12 months. Two patients with lung metastases had complete disappearance of 
the lung nodules and normalization of AFP levels (6 and 11 months). Two other patients showed no 
response to therapy. Overall therapy was well tolerated with myelosuppression and diarrhea as the most 
common side effects. PRs in 6 of these very heavily pretreated patients suggest that irinotecan may be an 
active drug in this disease and justifies its evaluation in a group of patients who have a 70% chance of 
eventually succumbing to their disease with “standard therapy”. 
 
In the initial window therapy arm (Regimen W) of AHEP0731, vincristine was given with irinotecan. 
Outcome information remains blinded but sufficient responses were seen to evaluate a full cohort of 30 
patients. This provides scientific rationale to attempt to build upon this potentially active novel 
combination. The regimen was well tolerated and suitable to be considered as a backbone for the addition 
of other agents. 
 
2.3.4.1 Rationale for Addition of Temsirolimus to Irinotecan/Vincristine 
The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that is a component of the TORC1 
complex that senses nutritional status of cells (e.g., amino acids, oxygen tension, glucose, and in 
mammalian cells, growth factor signaling), and regulates entry from G1 phase into S phase.38,39 mTOR also 
regulates protein synthesis of HIF (hypoxia inducible factors) proteins40-42 These proteins regulate tumor 
angiogenesis and survival pathways that permit tumor growth in the hypoxic conditions common in many 
solid tumors, suggesting that inhibition of mTOR would be detrimental to the survival of many solid tumors. 

 
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In fact, inhibition of mTOR with rapamycin results in decreased proliferation of human neuroblastoma cells 
in vitro,43,44 and synergistically enhances chemotherapy-induced cytotoxicity to a number of standard 
chemotherapy agents including: paclitaxel, carboplatin, vinorelbine, cisplatin, as well as camptothecin in 
human breast cancer cells45 and medulloblastoma cells.46 In animal studies with subcutaneously implanted 
rhabdomyosarcoma, and neuroblastoma xenografts, tumor bearing mice received intravenous irinotecan 
(1.25 mg/kg) daily for 5 days on 2 consecutive weeks. Cycles of therapy were repeated at 21 days for a 
total of 3 cycles [designated [(dx5)2]3]. Rapamycin (5 mg/kg) was administered by intraperitoneal injection 
daily for 5 days for up to 12 consecutive weeks. There was superior activity for the combination against 
both rhabdomyosarcoma and neuroblastoma xenografts. Irinotecan induced a maintained complete 
response as did the combination, with no evidence of drug antagonism and combination treatment appeared 
to be additive in effect. These results suggest that rapamycin does not abrogate the activity of irinotecan, 
but may in some models potentiate its antitumor activity (Peter Houghton, unpublished data). Recently, the 
use of rapamycin has been shown to induce apoptosis in HB cells in vitro and to decrease HB growth in 
mouse xenografts.47  
 
2.3.4.2 Temsirolimus in Children with Cancer 
Temsirolimus is an mTOR inhibitor approved by the FDA for the treatment of renal cell carcinoma. It is an 
ester of sirolimus (rapamycin) and a recommended Phase II dosage as a single agent has been determined 
in children, although no maximum tolerated dosage was determined. Nineteen patients were enrolled on 
study. Dose limiting toxicities at 150 mg/m2 included Grade 4 thrombocytopenia and Grade 3 anorexia. 
Other Grade 3 or 4 toxicities included leukopenia (17%), anemia (11%), neutropenia (22%) and elevated 
ALT. A dose of 75 mg/m2 weekly IV was recommended for study in the Phase II pediatric setting.48 In this 
Phase I study in children with refractory solid tumors, no patients with hepatoblastoma were entered. 
However there was one CR in a heavily pretreated neuroblastoma patient and three other patients (one each 
with an ependymoma, germ cell tumor and adrenocortical carcinoma) had disease stabilization for more 
than 4 months.48   
 
In a study of newly diagnosed children with high-risk neuroblastoma at St. Jude Children’s Research 
Hospital, 3 children were treated with 50 mg/m2 of temsirolimus weekly x 6 with irinotecan at 20 mg/m2/day 
x 5 x 2 repeated every 21 days for 2 courses. Three patients received 5 courses without significant 
chemotherapy related side effects. Two of these patients went on to receive weekly temsirolimus x 2 with 
each additional induction chemotherapy combination without significant increased toxicity (W. Furman, 
unpublished data). Additionally, the Children’s Oncology Group has a Phase I study (ADVL0918) of 
temsirolimus in combination with irinotecan and temozolomide which completed accrual and has 
determined temsirolimus at a dose of 35 mg/m2/dose d 1 and 8 to be tolerable in combination with irinotecan 
(90 mg/m2/dose) d 1-5, and temozolomide (100 mg/m2/dose) d 1-5 in children with refractory solid tumors  
 
Thus temsirolimus is safe as a single agent, in children at dosages up to 150 mg/m2 weekly IV and has 
evidence of single agent efficacy in heavily pretreated children with a variety of solid tumors. Also, there 
are data in a number of preclinical cancer models suggesting that an mTOR inhibitor in combination with 
several commonly used chemotherapeutic agents, including irinotecan49 is at least additive.45,46 Finally, 
temsirolimus has minimal systemic toxicity in humans and these untoward effects do not significantly 
overlap with the adverse effects seen with irinotecan or vincristine. In addition, since mTOR inhibitors are 
used to prevent solid organ rejection, mTOR inhibitor use in children with high-risk hepatoblastoma, some 
of whom may need liver transplantation, is intriguing in that if it is proven to have antitumor efficacy it 
may then be preferentially used as part of post-graft prophylaxis to preventing graft rejection and treat 
minimal residual disease at the same time. 
Temsirolimus was tolerated at 35 mg/m2 weekly x 2 with 90 mg/m2 of irinotecan daily x5 and 
temozolomide 100 mg/m2/d 1-5 in ADVL0918 50, therefore we are proposing to use that same dose of 
temsirolimus with 50 mg/m2/d, qd x5 of irinotecan and 1.5 mg/m2/ dose of vincristine. Because of the young 

 
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age of hepatoblastoma patients, the oral agent temozolomide (as used in ADVL0918) will not be used and 
IV temsirolimus will be given in combination with IV irinotecan and vincristine. As noted above toxicities 
of vincristine and temsirolimus are non-overlapping and should be well tolerated.  
 
AHEP0731 will estimate the response rate associated with 2 cycles of vincristine, irinotecan and 
temsirolimus (VIT) when administered as “up-front” window therapy for the treatment of high-risk children 
with metastatic hepatoblastoma (Stage IV).  
 
Patients who develop frank progression after the first course of VIT will proceed directly to therapy with 
C5VD. Responders will continue treatment with VIT and C5VD and will receive a total of 4 cycles of VIT 
(Cycles 1, 2, 7 and 10) and 6 cycles of C5VD. All patients, with the exception of patients enrolled in Japan 
(where dexrazoxane is currently unavailable), will receive dexrazoxane with the final 2 cycles of C5VD.  
 
2.4 
Prognostic Variables 
The decline of AFP levels after 4 cycles of chemotherapy and prior to surgical resection of the tumor has 
been shown to have prognostic value.51 However, no data have been reported to suggest that the initial rate 
of decline or the magnitude of decline of AFP after each cycle can be used to guide therapy. Data analyzed 
from INT-0098 and P9645 do not support AFP decline as a useful tool in low-risk patients (personal 
communication, Dr. M Malogolowkin). Initial AFP < 100 ng/mL has been described as being associated 
with an adverse outcome. While older reports of liver tumors with low AFP levels may include some 
misdiagnoses with other malignant liver disorders, recent reports continue to suggest that AFP < 100 ng/mL 
is associated with worse prognosis in hepatoblastoma. Data from SIOPEL evidenced 3-year EFS of 13% in 
patients with a low AFP regardless of stage.21 As a result, patients in AHEP0731 with a low AFP at the 
time of initial diagnosis regardless of stage will be considered to be high-risk and treated accordingly (see 
Section 7.1). 
 
Additional risk factors including histologic subtype, especially macrotrabecular and small cell 
undifferentiated,52,53 PRETEXT group,54 surgical margin,55,56 surgical complications,57,58 and diffuse 
multifocal tumors59 have been reported to have potential prognostic value in hepatoblastoma and should be 
further investigated in a prospective, multigroup setting. Collaboration among international colleagues 
would be particularly advantageous for the collection of these potential prognostic variables, thereby 
enabling the data to be pooled into a cooperative database and allowing increased statistical power to make 
subtle, or rare, observations. 
 
2.5 
Surgical Considerations 
When the proportion of Stage I patients in INT-0098 is compared with P9645, it appears that over the 
1990’s there was a trend away from upfront surgical resection. Stage I patients accounted for 28% (51/182) 
of the total in INT-0098 and 23% (40/175) of the total in P9645. However, as the data below suggest, this 
phenomenon occurred prior to the start of P9645 and is now static. Recent anecdotal trends in 
hepatoblastoma treatment within COG institutions have hinted at a possible decrease in the numbers of 
Stage I patients and an increase in the number of Stage III patients. This situation reflects a possible 
paradigm shift towards the SIOPEL strategy using pre-operative chemotherapy to shrink tumors, increase 
resectability, and decrease surgical morbidity associated with resection. However, one potential result of 
this practice is an overall increase in the amount of chemotherapy that patients receive. In the most recent 
COG study, P9645, patients who only had an initial biopsy performed received a total of 6 cycles of therapy 
which is 2 cycles more of chemotherapy than patients who underwent primary resection and received a 
total of 4 cycles of treatment. These additional cycles of chemotherapy result in increased short-term and 
long-term toxicity. In addition, “extra” cycles of chemotherapy are often administered by treating 
physicians and surgeons to make a tumor resectable. In spite of this, a review of data from INT-

 
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0098 indicates that 4 extra cycles of therapy did not increase the likelihood of tumor resectability in patients 
who were not resected after the initial 4 cycles of chemotherapy. 
 
The reported incidence of surgical morbidity and mortality on previously conducted COG studies has 
historically been extremely low. Yet, as a recent retrospective analysis of INT-0098 revealed (personal 
communication, Drs R Meyers and M Malogolowkin), this issue has not been rigorously investigated in 
prior studies.  With the advanced surgical and radiological techniques currently available, it would be 
expected that surgical morbidity and mortality rates could be even lower. In an attempt to minimize surgical 
risk, specific surgical guidelines using PRETEXT criteria have been developed. It is expected that these 
guidelines will maximize the number of patients with localized PRETEXT 1 and 2 tumors that are most 
appropriately resected at diagnosis (Stage I), and minimize the number of patients with PRETEXT 3 and 4 
tumors where attempts at resection at diagnosis would lead to increased surgical risk. It is interesting and 
important to note that the most recent publication of SIOPEL-2 reported 4 surgery-related deaths in patients 
treated preoperatively with chemotherapy.3 This is more than reported in any previous COG study. A 
surgery-related death was reported in only 1 of the 182 patients with hepatoblastoma treated on INT-00986 
In the HB-89 study, surgical complications occurred in 15% of patients who had a primary resection and 
21% of patients who had a resection following chemotherapy, failing to validate the hypothesis that 
preoperative chemotherapy will diminish the incidence of surgical morbidity.27 Although these numbers 
might suggest that upfront resection carries less risk of surgical morbidity, it is important to note that the 
PRETEXT classification of these tumors is not known. It is to be expected that much greater surgical 
morbidity would be observed in PRETEXT 3 and 4 tumors, the very tumors that are most likely to have 
been treated with neoadjuvant chemotherapy. The ultimate question is whether the risk of upfront surgical 
morbidity and mortality exceeds that of the additional chemotherapy administered to patients who have 
delayed resections. Various cooperative groups have established different criteria for diagnoses in part 
because of concerns with biopsy-related surgical morbidity. The SIOPEL group has treated patients on 
study without a diagnostic biopsy as was done in nearly 20% of patients on SIOPEL-1. Within COG, up to 
this point in time, a diagnostic sample has been required for all patients treated on study.  
 
Specific guidelines for surgical approaches to hepatoblastoma are provided in AHEP0731 since surgery is 
the critical component necessary for obtaining a cure. Patients with PRETEXT 1 and 2 tumors that have a 
clear radiographic 1 cm margin on CT or MRI imaging at diagnosis should have a resection performed as 
soon as possible after the diagnosis of hepatoblastoma is confirmed. The surgical strategy for patients with 
more advanced PRETEXT-group disease is described in the surgical guidelines section of the protocol (see 
Section 13.0).  
 
No patient with Stage IV disease will be offered a liver transplant unless all metastatic extra-hepatic disease 
has been radiographically documented to either have disappeared as a result of neoadjuvant chemotherapy 
or has been surgically removed.  
 
The historical barrier of “unresectability” can be redefined with the concept of “total liver resection” and 
salvage OLT.  Interestingly, although 1 of the first long-term survivors of liver transplantation was a child 
with hepatoblastoma, the role of liver transplantation in the treatment of pediatric hepatoblastoma has never 
been fully defined. Because liver transplant has not historically been offered to these children as part of a 
planned treatment algorithm, the optimal timing of transplantation and the potential role of post transplant 
adjuvant chemotherapy remain unclear. Largely due to negative experience with liver transplant in the 
treatment of adult hepatocellular carcinoma, liver transplant for the treatment of hepatic malignancy 
developed an early reputation as a dreaded, heroic last resort, and even potentially ethically-inappropriate 
intervention. But the biology of pediatric hepatoblastoma has proven to be very different from that of adult 
hepatocellular carcinoma, and experience with liver transplantation for hepatoblastoma has been far more 
favorable.  

 
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In study after study, complete surgical resection has been the most important predictor of survival.6,51,60-62  
Eleven studies reporting outcome after liver transplantation for unresectable hepatoblastoma have been 
published in the past decade.63,64 All but 1 of these studies are single-institution studies, with small numbers 
of highly selected patients. Factors thought to contribute to improved survival rates include complete 
resection as soon as possible after completing planned Induction chemotherapy (usually 4 cycles), avoiding 
excessive cycles (> 4-6) of pre-transplant chemotherapy, and a favorable response to chemotherapy. In 
Birmingham, England, 5-year DFS was 100% when primary transplant was performed in patients with a 
good response to chemotherapy, 60% with primary transplantation in patients having a poor response to 
chemotherapy, only 50% in patients with transplant as a second option or “rescue transplantation”, and 0% 
in patients not undergoing surgery.65 In SIOPEL-1, overall survival at 10 years was 85% with a primary 
transplant, but only 40% for the children who underwent a rescue transplant.66 In a collaborative report of 
the world experience of liver transplantation for hepatoblastoma,64 overall survival rate at 6 years was 82% 
for 106 patients who received a “primary transplant”, but only 30% for 41 patients who underwent a rescue 
transplant. These data stress the importance of facilitating primary transplant as it is far superior to rescue 
transplant in yielding long-term survival. 
 
The current United Network of Organ Sharing (UNOS) policy for liver allograft allocation in children with 
pediatric hepatoblastoma gives the patient an automatic Pediatric End Stage Liver Disease (PELD) priority 
score of 30. The PELD system is used to determine allograft distribution priority in children. A similar 
scoring system called MELD is used for adults. A PELD/MELD score of 30 places the patient at the top of 
the list and takes priority over all other listed patients, except Status I. For non-cancer patients, Status I 
means the patient is dying from liver failure, in an intensive care unit (ICU), with a life expectancy < 7 
days. Cancer patients are allowed to be listed as Status I, even though they are not in liver failure in an ICU, 
under the condition that they have not received a liver allograft within 30 days at the top of the PELD 
system. Average waiting time as a Status I patient is 3-7 days. The verbatim policy is quoted below: 
 
UNOS Policy 3.6.4.4.1, November 19, 2004. Pediatric Liver Transplant Candidates with 
Hepatoblastoma: A pediatric patient with non-metastatic hepatoblastoma who is otherwise a 
suitable candidate for liver transplantation may be assigned a PELD (less than 12 years old) or 
MELD (12-17 years old) score of 30. If the candidate does not receive a transplant within 30 days 
of being listed with a PELD/MELD of 30, then the candidate may be listed Status I.  
 
Hepatoblastoma patients who are determined to be candidates for liver transplant and identified to UNOS, 
have a good chance of receiving a donor liver. This modality may present a viable method of obtaining 
complete extirpation of the tumor when conventional surgery is not possible. AHEP0731 will assess the 
feasibility of identifying appropriate hepatoblastoma patients in the context of the current healthcare 
system. 
 
SIOPEL-1 introduced the PRETEXT system to the pediatric liver tumor community as an anatomic 
definition of the extent of liver involvement by the tumor, and the PRETEXT system depends upon accurate 
radiologic imaging and review.67 The PRETEXT system aims to predict surgical resectability and 
prognosis. However, the PRETEXT system has not been fully validated. Results published on PRETEXT 
in the SIOPEL-1 study showed that preoperative PRETEXT grouping was accurate in only 51% of patients, 
and that 37% of patients were overstaged while 12% of patients were understaged using PRETEXT.54 While 
this recent report claimed that PRETEXT was superior to the COG staging system, the validity of this 
conclusion is in question as the study excluded patients who failed neoadjuvant therapy and only included 
the select group of patients whose tumors were resectable. The number of surgically-staged metastatic 
patients in the study who survived was > 90%.54 This result leads to questions about the reliability of this 
study as the survival of this cohort is so significantly superior and discordant from all other series in the 

 
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literature. The more recent SIOPEL-2 study did not fully validate PRETEXT either, as patients were 
categorized and treated as either high- or low-risk.3 These high- and low-risk groups were each made up of 
several PRETEXT groups. No EFS data was provided for patients according to individual PRETEXT 
groups as is indicated in Tables 1 and 2 above. In addition, PRETEXT IV was not predictive of overall 
survival. So while the PRETEXT system has shown potential utility as a tool to compare treatment results 
between different multicenter trials, objectively quantify response to neoadjuvant chemotherapy, and 
predict surgical resectability, defining its precise role and validating its use is still required. Data to be 
collected for AHEP0731 will allow exploration of this issue. 
 
In order to validate PRETEXT, central review of surgical and radiology CT scans must be performed to 
validate the PRETEXT grouping done at the local institutions. In AHEP0731, this review will be performed 
on an annual basis. CT scans will be repeated after the second cycle of chemotherapy in patients with Stage 
III and Stage IV tumors to determine potential surgical resectability. PRETEXT after the second cycle of 
chemotherapy will be denoted as POST-TEXT. The PRETEXT definition of potential need for a transplant 
is defined as:  
• PRETEXT 3 extensive multifocal;  
• PRETEXT 3 +V;  
• PRETEXT 3 +P; or  
• PRETEXT 4 extensive multifocal  
 
Recent studies have shown long-term survival and cure in patients with known microscopic residual 
disease. For example, SIOPEL-166 evidenced that microscopic margins had no effect on the rate of 
survival.57,66 The implications of microscopic margins are thus poorly understood and have never been 
evaluated prospectively in any hepatoblastoma trial. Microscopic positive margins have been repeatedly 
shown to increase the risk of local relapse, metastatic relapse, and death in patients with hepatocellular 
carcinoma. However, the implications of microscopically-positive margins on the recurrence and survival 
of patients with hepatoblastoma remains unclear. Data to be collected for AHEP0731 will allow exploration 
of this issue. 
 
The most common site of metastasis for hepatoblastoma is the lung. The therapeutic approach and prognosis 
for patients with pulmonary metastases remains somewhat uncertain. A recent review of the INT-0098 data 
revealed that 18 patients who had previously achieved complete tumor clearance, experienced subsequent 
pulmonary relapse of their tumor (12 Stage I/II/III, 6 Stage IV). All 18 pulmonary relapse patients had 
salvage chemotherapy, 11 also had thoracotomy and pulmonary metastectomy (7) or thoracotomy and 
tumor biopsy (4). Only 2/11 were long-term survivors, both were Stage I relapse patients. For the 38 patients 
with metastatic disease at diagnosis, 9 underwent thoracotomy and pulmonary metastectomy either before 
(2), simultaneous with (5), or after (2) resection of their primary liver tumor. Six of these 9 patients with 
metastectomy were long-term survivors. These data demonstrate that there is much variation in the surgical 
approach to pulmonary metastasis in hepatoblastoma and that thoracotomy may have limited utility in the 
management of pulmonary relapse, but appears to be important in the management of metastases that persist 
following neoadjuvant chemotherapy. Other reports indicate that patients with metastatic disease, who are 
rendered free of gross disease by resection of the primary tumor, as well as resection of pulmonary 
metastases, may experience cure or long-term survival.66,68 In SIOPEL-1, all 4 of the 22 patients with 
pulmonary metastases at diagnosis, in whom a metastectomy was performed, survived without residual 
disease.66 Results were not as promising in SIOPEL-2 in which 8 out of 25 patients had surgery for lung 
metastases and only 3 of these patients survived.3 The difference in outcomes for patients who achieve a 
clinical remission of pulmonary metastases as a result of surgical resection and for those who achieve 
clinical remission in response to chemotherapy remains unknown and needs to be defined. A better 
understanding of hepatoblastoma metastases isolated to the lung(s) would help guide therapy and predict 
prognosis more appropriately and reliably. Thus, adoption of a uniform strategy to pulmonary metastatic 

 
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lesions is critical.  Data to be collected for AHEP0731 will allow exploration of the impact of surgical 
resection of metastatic pulmonary lesions on survival.  
 
Because of the known potential side effects of impaired wound healing and thrombosis that could 
complicate primary tumor resection or orthotopic transplant, the protocol has been written to allow some 
latitude in the order of administration of chemotherapy cycles to optimally result in a 6 week temsirolimus 
free period prior to definitive resection. While theoretically possible, it is not expected that the order of 
therapy administration should affect outcome and that the total amount of delivered therapy for all window 
responders should be identical. 
 
2.6 
Significance 
This study builds on the results of the last 20 years of hepatoblastoma clinical trials. AHEP0731 functionally 
divides patients into low-, intermediate-, and high-risk cohorts. It seeks to diminish toxicity in the 
approximately 30% of low-risk patients, increase survival in intermediate-risk patients and identify new 
agents(s) that may be used in high-risk and recurrent patients.  
 
Since hepatoblastoma is a disease that is dependent upon surgical resection for curative potential, this study 
will ask several surgical questions that address key concepts in treatment and may be used to guide therapy 
in future trials. Survival rates are much better with primary transplant than after a rescue or salvage 
transplant. Unfortunately, too many children continue to be referred for transplant after having received 
additional undue chemotherapy and/or after a failed initial attempt at resection. Further concepts that remain 
unclear are: what is the optimal timing of transplantation and what, if any, is the role of post-transplant 
chemotherapy? The COG Liver Tumor Subcommittee would ultimately like to study these questions with 
a randomized protocol. However, unless appropriate patients will be referred to transplant centers in a 
timely fashion, embarking upon a randomized trial is likely doomed to failure. Thus, it must first be 
determined whether it is possible to capture at least 70% of eligible (potentially unresectable) patients and 
ensure that they can be referred in a timely fashion to a surgical center that offers surgical expertise in major 
pediatric liver resection and transplantation. 
 
2.7 
Race and Gender Statement 
Previous studies completed and published by COG and others show no differences in outcome by race 
and/or gender when such parameters were analyzed.  
 
2.8 
COG and Japanese Study Group for Pediatric Liver Tumors (JPLT) Collaboration 
The high-risk stratum on this protocol (Stratum 4) will be a collaborative effort between COG and JPLT. 
We believe that this collaboration is necessary for two reasons. First, institutions in Japan have extensive 
experience in the management of hepatoblastoma patients and have an excellent track record on clinical 
research. Given the rarity of the disease, a collaborative effort will facilitate good study accrual in a timely 
manner. Second, future studies of hepatoblastoma are intended to be performed as an international 
collaborative effort among COG, SIOPEL, GPOH, and JPLT. This is an opportunity to develop the working 
relationship with JPLT in anticipation of the successor(s) to this trial.  
 
 

 
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3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration  
Prior to enrollment on this study, patients must be assigned a COG patient ID number.  This number is 
obtained via the eRDE system once authorization for the release of protected health information (PHI) has 
been obtained. The COG patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help.  
 
In order for an institution to maintain COG membership requirements, every newly diagnosed patient needs to 
be offered participation in ACCRN07, Protocol for the Enrollment on the Official COG Registry, The 
Childhood Cancer Research Network (CCRN). Participation in ACCRN07 is limited to patients who are 
residents of the United States, Canada or Mexico. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be 
assigned only 1 BPC number per COG Patient ID. For additional information about the labeling of specimens 
please refer to the Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix VI for detailed CTEP Registration Procedures for Investigators and Associates. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB approval and supporting 
documentation to the Cancer Trials Support Unit (CTSU) Regulatory Office before they can be approved 
to enroll patients. Allow 3 business days for processing. The submission must include a fax coversheet (or 
optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB Certification 
Form may be submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on the 
CTSU web page (https://www.ctsu.org). Any other regulatory documents needed for access to the study 
enrollment screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.  
  
IRB/REB approval documents may be faxed (1-215-569-0206), 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. 
 
Study centers can check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ web site by entering credentials at 
https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically load to RSS. 
 
3.1.3 
Reservation Requirements for Stratum 4 Only 
Reservations are required for patients enrolled on High Risk Stratum 4 only. 
Investigators should refer to the COG website to determine if the study is currently open for accrual. If the 
study is listed as active, investigators should then access the Studies Requiring Reservations page to ensure 
that a reservation for the study is available. To access the Studies Requiring Reservations page:  
 
1. Log in to https://members.childrensoncologygroup.org.  
2. From the menu bar, click eRDES. The eRDES sub-menu appears. 

 
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3. Click Reservation. The Studies requiring Reservations page appears. 
 
Prior to obtaining informed consent and enrolling a patient on Stratum 4, a reservation must be made 
following the steps above. 
 
Reservations may be obtained 24-hours a day through the COG website. Please refer to the Reservation 
System eRDES User Guide that can be downloaded from:  
https://members.childrensoncologygroup.org/_files/Help/eRDES_ReservationSystem_UserGuide.pdf 
 
3.1.4 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study 
enrollment is accomplished by going to the Enrollment application in the RDE system. If you have problems 
with enrollment, refer to online help in the Applications area of the COG Website.  
 
3.1.5 
Timing 
All patients must be enrolled on AHEP0731 before protocol treatment begins. The date protocol therapy is 
projected to start must be no later than 42 days (28 days preferred) from biopsy or definitive surgery, 
whichever occurs latest, except in the case AHEP0731 therapy is started in an emergent situation (see 
Section 3.2.2.b below). Investigators are strongly encouraged to enroll patients immediately following 
histological diagnosis and begin protocol therapy within 28 days of the initial surgical procedure.  
 
Patients with Stage I and II tumors (see Appendix III) require rapid central pathologic review and 
enrollment of these patients on AHEP0731 must not occur until the results of rapid central pathologic 
review are known. Stage I and II tumor specimens are to be submitted immediately following histological 
diagnosis. Pathology specimens MUST be submitted no later than 14 calendar days (7 days preferred) from 
definitive surgery and be accompanied by a Rapid Review Transmittal Form found on the AHEP0731 
protocol page of the COG website. If Stage I and II diagnostic specimens are not submitted within 14 days 
of initial surgery, the patient will not be eligible for this study. Enrollment of Stage I and II patients onto 
this study must not occur until the results of rapid central pathologic review are known and these 
results must be provided by the institutional investigator on the AHEP0731 Eligibility CRF.  
 
Retrospective central pathologic review is also required for all other biopsied/resected specimens (liver 
and/or lung).  Specimens must be submitted within 4 weeks from all biopsies/resections other than Stage I 
and II diagnostic procedures. These specimens will be submitted using the generic COG Specimen 
Transmittal form. See Section 14.1.1 for details. 
 
All clinical and laboratory studies to determine eligibility must be performed within 14 days prior to 
enrollment unless otherwise indicated in the eligibility section below. 
 
3.1.6 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per 
COG policy posted 5/11/01).  All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record which will serve 
as the source document for verification at the time of audit.  
 

 
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3.2.1 
Age 
Patients must be ≤ 21 years of age at the time of diagnosis. 
 
3.2.2.a Diagnosis  
Patients must be newly diagnosed with histologically-proven hepatoblastoma, except as noted in Section 
3.2.2.b below.  
 
3.2.2.b Emergent Treatment 
In emergency situations when a patient meets all other eligibility criteria and has had baseline required 
observations as outlined in Section 7.4 or 7.5, but is too ill to undergo a biopsy safely, the patient may be 
enrolled on AHEP0731 without a biopsy.  
 
Clinical situations in which such emergent treatment may be indicated include, but are not limited to, the 
following circumstances: 
a. Anatomic or mechanical compromise of critical organ function by tumor (eg, respiratory distress/failure, 
abdominal compartment syndrome, urinary obstruction, etc) 
b. Uncorrectable coagulopathy 
 
For a patient to maintain eligibility for AHEP0731 when emergent treatment is given, the following 
must occur: 
• 
The patient must have a clinical diagnosis of hepatoblastoma, including an elevated 
alphafetoprotein, and must meet all AHEP0731 eligibility criteria at the time of emergent treatment. 
• 
Patient must be enrolled on AHEP0731 prior to initiating protocol therapy. Per protocol Section 
3.2.9, a patient will be ineligible if any chemotherapy is administered prior to AHEP0731 
enrollment.  
 
• 
If the patient receives AHEP0731 chemotherapy PRIOR to undergoing a diagnostic biopsy, 
pathologic review of material obtained in the future during either biopsy or surgical resection must 
either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be 
included in the analysis of the study aims.   
 
PATIENTS WILL BE STAGED FOR RISK CLASSIFICATION AND TREATMENT AT DIAGNOSIS 
USING COG STAGING GUIDELINES, as listed in Appendix III. 
 
At the time of study enrollment, the patient’s treatment regimen must be identified. If the patient’s primary 
tumor was resected prior to the day of enrollment and a blood specimen for the determination of serum 
alphafetoprotein was not obtained prior to that surgery, the patient will be considered to have 
alphafetoprotein of greater than 100 ng/mL for the purpose of treatment assignment. If tumor samples 
obtained prior to the date of enrollment were not sufficient to determine whether small cell undifferentiated 
(SCU) histology was present, treatment assignment will be made assuming SCU is not present in the tumor.  
 
For patients with Stage I or II disease, specimens for rapid central review have been submitted and the rapid 
central review diagnosis and staging must be available to be provided on the AHEP0731 Eligibility CRF.  
 
3.2.3 
Performance Level  
(See 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
under 
Standard 
Material for Protocols.) 
Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients 
> 16 years of age and Lansky for patients ≤ 16 years of age. 
 

 
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3.2.4 
Prior Therapy 
Patients may have had surgical resection of some or all sites of hepatoblastoma prior to enrollment.  
 
3.2.5 
Organ Function Requirements 
Organ function requirements are not required for enrolled patients who are Stage I, PFH and will not be 
receiving chemotherapy.  
 
3.2.5.1  
Adequate renal function defined as: 
 
- 
Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 OR 
 
- 
A serum creatinine based on age/gender as follows: 
 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 
3.2.5.2  
For patients who will be assigned to protocol chemotherapy, adequate liver function defined as: 
 
 
- 
Total bilirubin  < 1.5 x upper limit of normal (ULN) for age, and 
 
 
- 
SGOT (AST) or SGPT (ALT) < 10 x ULN for age. 
3.2.5.3  
For patients who will be assigned to protocol chemotherapy, adequate bone marrow function defined as: 
 
- 
Absolute neutrophil count (ANC) > 750/µL 
 
- 
Platelet count > 75,000/µL 
 
3.2.5.4  
For intermediate- and high-risk patients who will be assigned to protocol chemotherapy, adequate cardiac 
function defined as: 
 
 
- 
Shortening fraction ≥ 27% by echocardiogram, or 
 
- 
Ejection fraction ≥ 47% by radionuclide angiogram (MUGA). 
 
Note: the echocardiogram (or MUGA) may be done within 28 days prior to enrollment.  
 

 
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3.2.6 
Additional Eligibility Criteria for High-Risk Patients 
 
3.2.6.1  
Serum triglyceride level ≤ 300 mg/dL (≤ 3.42 mmol/L) and serum cholesterol level ≤ 300 mg/dL 
(7.75 mmol/L) 
 
3.2.6.2  
Random or fasting blood glucose within the upper normal limits for age. If the initial blood glucose is a 
random sample that is outside of the normal limits, then a follow-up fasting blood glucose can be obtained 
and must be within the upper normal limits for age. 
 
3.2.6.3  Adequate Pulmonary Function Defined as: 
• 
Normal pulmonary function tests (including DLCO) if there is clinical indication for 
determination (e.g. dyspnea at rest, known requirement for supplemental oxygen).  
 
Note: For patients who do not have respiratory symptoms or requirement for supplemental oxygen, PFTs 
are NOT required. 
 
 
3.2.6.4 Adequate Neurologic Function Defined as: 
• 
Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and 
if seizures are well controlled. (See Appendix IV for a list of recommended non-enzyme 
inducing anticonvulsants). 
 
3.2.6.5 Adequate Clotting Function Defined as: 
• 
Prothrombin Time (PT) < 1.2 x ULN 
 
3.2.7 
Exclusion Criteria for All Patients  
 
3.2.7.1  
Patients with Stage I or II disease who do not have specimens submitted for rapid central pathology review 
by Day 14 after initial surgical resection. 
 
3.2.7.2 
Patients that have been previously treated with chemotherapy for hepatoblastoma or other hepatoblastoma-
directed therapy (eg, radiation therapy, biologic agents, local therapy [embolization, radiofrequency ablation, 
laser]) are not eligible. 
 
3.2.7.3 
Patients who have received any prior chemotherapy are not eligible. 
 
3.2.7.4 Investigational drugs  
Patients who are currently receiving another investigational drug are not eligible. 
 
3.2.7.5  Anti-Cancer Agents  
Patients who are currently receiving other anticancer agents are not eligible. 
 
3.2.7.6 Transplant 
Patients who have previously received a solid organ transplant are not eligible. 
 
3.2.7.7 Infection 

 
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Patients who have an uncontrolled infection are not eligible. 
 
3.2.7.8 Pregnancy and breast feeding 
3.2.7.8.1 
Females who are pregnant or breast feeding are not eligible for this study since fetal toxicities and 
teratogenic effects have been noted for several of the study drugs.  
 
3.2.7.8.2 
Female patients of childbearing potential are not eligible unless a negative pregnancy text result has been 
obtained. 
 
3.2.7.8.3 
Males and females of reproductive potential are not eligible unless they have agreed to use an effective 
contraceptive method.  
 
3.2.8 
 Additional Exclusion Criteria for High-Risk Patients 
 
3.2.8.1  Corticosteroids 
Patients receiving corticosteroids are not eligible. Patients must have been off corticosteroids for 7 days 
prior to start of chemotherapy. 
 
3.2.8.2  Enzyme-Inducing Anticonvulsants:  
Patients who are currently receiving enzyme inducing anticonvulsants are not eligible. (See Appendix IV 
for a list of unacceptable enzyme inducing anticonvulsants.) 
 
3.2.8.3  CYP3A4 Active Agents  
Patients must not be receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, 
clarithromycin, azithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit juice or 
St. John’s wort. A list of other known CYP3A4 inducers and inhibitors that should be avoided during study 
therapy is included in Appendix V. 
 
 
3.2.8.4 Anticoagulants  
Patients who are currently receiving therapeutic anticoagulants (including aspirin, low molecular weight 
heparin, warfarin and others) are not eligible. 
 
3.2.8.5 Angiotensin-Converting Enzyme (ACE) Inhibitors  
Patients who are currently receiving ACE inhibitors are not eligible due to the development of angioneurotic 
edema-type reactions in some subjects who received concurrent treatment with temsirolimus + ACE 
inhibitors. 
 
 
3.2.8.6 Surgery 
Patients must not have had major surgery within 6 weeks prior to enrollment on the high risk stratum. 
Patients with history of recent minor surgical procedures (vascular catheter placement, bone marrow 
evaluation, laparoscopic surgery, liver tumor biopsy) will be eligible. 
 
3.2.9 
Regulatory 
 
3.2.9.1 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 

 
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3.2.9.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
4.0 
TREATMENT PLAN 
 
4.1 
Overview of Treatment Plan 
AHEP0731 builds on the results of the last 20 years of hepatoblastoma clinical trials and seeks to diminish 
toxicity in the approximately 30% of low-risk patients, increase survival in intermediate-risk patients and 
identify new agents(s) that may be used in high-risk and recurrent patients.  
 
All patients with Stage I PFH hepatoblastoma will be classified as very low-risk (Stratum 1) and will be 
treated with surgery only. Patients with Stage I non-PFH, non-SCU hepatoblastoma or with Stage II non-
SCU hepatoblastoma will be classified as low-risk (stratum 2)and will be treated on Regimen T with 2 
adjuvant cycles of cisplatin, 5-flouorouracil, and vincristine (C5V), a reduction from the standard 4 cycles 
of chemotherapy given on previous COG trials. Patients with Stage I SCU, Stage II SCU, or any Stage III 
hepatoblastoma will be classified as intermediate-risk (stratum 3) and will be treated with Regimen F 
(intermediate risk, stratum 3, has been closed to accrual as of 03/12/12). This treatment regimen is based 
on previous COG trials that administered 6 cycles of C5V therapy plus surgical resection of the tumor. 
However, to improve resection and survival rates, doxorubicin, an agent with proven efficacy will be added 
to the C5V therapy (C5VD). All patients with any Stage IV hepatoblastoma as well as patients with any 
stage of hepatoblastoma and initial AFP < 100 ng/mL will be classified as high-risk (stratum 4). 
 
Initial Treatment Plan for High-Risk Patients (Stratum 4): Regimen W 
Initially, high-risk (Stratum 4) patients were treated on Regimen W. This regimen included 2 cycles of “up-
front” VI window therapy. Patients who respond to VI were considered as responders. Responder patients 
then received a total of 6 cycles of C5VD therapy with 1 cycle of VI in between each 2-cycle block of 
C5VD. Non-responder patients only received 6 cycles of C5VD following the “up-front” window therapy.  
 
As of Amendment # 3B, Regimen W has been replaced by Regimen H 
As of Amendment # 3B, patients in the high-risk group (Stratum 4) will be treated with experimental 
treatment consisting of vincristine, irinotecan and temsirolimus (VIT) in Regimen H in order to identify a 
new active combination. Patients assigned to Regimen H will receive 2 cycles of “up-front” VIT. Patients 
who respond to VIT will be considered responders. Responding patients will then receive a total of 6 cycles 
of C5VD (Cycles 3, 4, 5, 6, 8, 9) therapy with 4 total cycles of VIT (Cycles 1, 2, 7 and 10). Non-responding 
patients will only receive the 6 cycles of C5VD following the “up-front” window therapy. All patients, with 
the exception of those patients enrolled in Japan, will receive dexrazoxane with the final 2 cycles of C5VD. 
The table below illustrates the treatment plan overview. 
 
 
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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Stage 
Histology 
AFP 
Risk Stratification 
Regimen 
VIT Response 
Total Chemo 
Cycles  
I 
PFH 
> 100 ng/mL 
Very Low-Stratum 
1 
Surgery 
Only 
- 
0 
I 
Non-PFH 
Non-SCU 
> 100 ng/mL 
Low-Stratum 2 
T 
- 
2 (C5V) 
I 
SCU 
> 100 ng/mL 
Intermediate-
Stratum 3 
F 
- 
6 (C5VD) 
II 
Non-SCU 
> 100 ng/mL 
Low-Stratum 2 
T 
- 
2 (C5V) 
II 
SCU 
> 100 ng/mL 
Intermediate-
Stratum 3 
F 
- 
6 (C5VD) 
III 
Any 
> 100 ng/mL 
Intermediate-
Stratum 3 
F 
- 
6 (C5VD) 
IV 
Any 
Any 
High-Stratum 4 
H 
Yes 
4 (VIT) + 6 
(C5VD) 
IV 
Any 
Any 
High-Stratum 4 
H 
No 
2 (VIT) + 6 
(C5VD) 
Any 
Any 
< 100 ng/mL 
High-Stratum 4 
H 
Yes 
4 (VIT) + 6 
(C5VD) 
Any 
Any 
< 100 ng/mL 
High-Stratum 4 
H 
No 
2 (VIT) + 6 
(C5VD) 
 
Response to the initial 2 cycles of VIT treatment will be assessed by central review to determine if these 
patients will be considered as responders and treated accordingly, see Section 4.6. The assessment of 
response is based on central review of imaging, the alphafetoprotein values and sampling dates. The results 
of the central review will be returned to the institutional investigator within 3 weeks of submission of the 
imaging and AFP material. If there is a discrepancy between the assessment by central review and by 
institutional assessment, the study PI will discuss with the treating physician to resolve the discrepancy. If 
the investigator selects a post-induction regimen that is not indicated by the central review of response, the 
patient will be considered off protocol therapy as of the start date of consolidation therapy.  
 
4.2 
General Therapy Guidelines 
 
4.2.1 
Staging 
PATIENTS WILL BE STAGED FOR RISK CLASSIFICATION AND TREATMENT AT DIAGNOSIS 
USING COG STAGING GUIDELINES as listed in Appendix III. PRETEXT grouping of the patient’s 
disease prior to any surgical intervention will also be performed as detailed in Section 10.2 and Appendix I. 
PRETEXT grouping will not be used for risk classification but it will be used to guide the surgical approach 
and specifically which patients should be considered unresectable at diagnosis. PRETEXT grouping will 
be done at diagnosis and also at any time subsequent abdominal scans are performed preoperatively (called 
POST-TEXT if assigned after chemotherapy).  
 
Based on staging and risk classification at diagnosis, patients will receive therapy as outlined in Section 
4.1. Throughout the protocol, staging refers to COG staging (Appendix III) and grouping refers to 
PRETEXT/POST-TEXT grouping (Section 10.2).  
 
4.2.2 
Chemotherapy 
 
4.2.2.1 
Each cycle of chemotherapy should only be initiated if the absolute neutrophil count is ≥750/µL and the 
platelet count is ≥ 75,000/µL. 

 
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4.2.2.2 
Patients < 10 kg will have dosing in mg/kg for all agents. 
 
4.2.2.3 
Filgrastim (G-CSF) should not be given initially and should only be administered prophylactically if there 
is either a 1 week delay in the administration of chemotherapy because of neutropenia or if the patient 
requires hospitalization for fever and neutropenia or for sepsis.  
 
4.2.3 
Concomitant Medications Restrictions 
 
4.2.3.1 Cytochrome P450 interactions 
Clinically significant drug interactions have been reported when using irinotecan or vincristine with strong 
CYP450 3A4 inhibitors and inducers. Selected strong inhibitors of cytochrome P450 3A4 (such as the azole 
antifungals, fluconazole, voriconazole, itraconazole, ketoconazole and posaconazole) and strong inducers 
of cytochrome P450 3A4 (e.g. rifampin, phenytoin, phenobarbital, carbamazepine, and St. John’s wort) 
should be avoided while the patient is receiving vincristine, irinotecan or temsirolimus.  Aprepitant also 
interacts with CYP3A4 and should be used with caution with vincristine, irinotecan or temsirolimus. For a 
list of CYP3A4 inhibitors and inducers see Appendix V. 
 
Fluorouracil may increase the level and effect or CYP2C9 substrates like phenytoin and warfarin. Phenytoin 
levels and international normalized ratio (INR) should be closely monitored. 
 
The clinical outcome and significance of CYP450 interactions with doxorubicin is less clear. CYP450 3A4 
stimulators or inhibitors should be avoided or used with great caution. Additional inducers or inhibitors of 
CYP450 enzymes can be found at http://medicine.iupui.edu/clinpharm/ddis. 
 
4.2.3.2 Anticonvulsant levels (phenytoin, valproic acid and carbamazepine) should be monitored during 
concurrent use with doxorubicin and cisplatin and phenytoin levels should be monitored in patients 
receiving cisplatin alone. Patients who are currently receiving enzyme inducing anticonvulsants are not 
eligible for Stratum 4 (see Section 3.2.8.2). See Appendix IV for a list of unacceptable enzyme inducing 
anticonvulsants. 
 
4.2.4 
Supportive Care 
For general Supportive Care Guidelines see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for 
Protocols. 
 
4.2.5 
Radiation Therapy 
Since the role of radiation therapy in the treatment of hepatoblastoma is not clearly defined and not typically 
part of standard care, radiation therapy is not permitted on this study. 
 
4.2.6 
Treatment Initiation 
 
4.2.6.1 
Please note: It is recommended that patients who have had > 75% of their liver resected wait at least 
2 weeks prior to beginning protocol therapy to allow liver regeneration.  
 
4.2.6.2 
Also note: Stage I or II patients cannot be enrolled on study or begin protocol treatment until rapid central 
pathology review is complete. 

 
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4.3 
Treatment for Very Low-Risk Patients (Stratum 1 – No further treatment) 
Patients who have had their tumor completely resected at diagnosis must have tumor specimens submitted 
for rapid central pathology review prior to enrollment onto this study (see Section 14.0 for details). Patients 
must sign consent giving permission to submit tumor specimens prior to shipment and cannot be enrolled 
on study until the results of rapid review are known. Patients classified as very low-risk will have their 
tumor completely resected at diagnosis and then be observed with no further therapy. See Section 7.6.1 for 
recommended follow-up.  
 
4.4 
Treatment for Low-Risk Patients (Stratum 2 - Regimen T) 
Patients classified as low-risk must have tumor specimens submitted for rapid central pathology review 
prior to enrollment onto this study (see Section 14.0 for details). Patients must sign consent giving 
permission to submit tumor specimens prior to shipment and cannot be enrolled on study or start treatment 
until the results of rapid review are known. Low risk patients will have the tumor completely resected at 
diagnosis and then receive 2 cycles (each cycle is 21 days) of adjuvant C5V. Patients must begin protocol 
therapy within 42 days of definitive surgery to allow for recovery from any surgical complications. 
However, it is strongly encouraged that patients begin protocol therapy within 28 days of the initial 
surgical procedure. Begin each cycle of Regimen T only when the absolute neutrophil count is ≥ 
750/µL and the platelet count is ≥ 75,000/µL. Note: All patients < 10 kg will have dosing in mg/kg.  
 
4.4.1 
CISplatin: IV over 6 hours 
100 mg/m2/dose (3.3 mg/kg/dose for patients < 10 kg) on Day 1. 
 
Recommended hydration and administration guidelines:  
Urine specific gravity should be < 1.010 prior to starting CISplatin.  
Hours -2 to 0:  Prehydrate with 300 mL/m2 D5 ½ NS + MgSO4 8 mEq/L + KCL 20 mEq/L. 
Hours 0-6: Infuse CISplatin + mannitol 8000 mg/m2 in 750 mL/m2 NS @ 125 mL/m2/hr.  
Hours 6-24: D5½NS+ MgSO4 8 mEq/L + KCL 20 mEq/L to run at 125 mL/m2/hr.   
 
4.4.2 
5-Fluorouracil: Slow IV Push over 2-4 minutes 
600 mg/m2/dose (20 mg/kg/dose for patients < 10 kg) on Day 2. 
 
4.4.3 
VinCRIStine: IV Push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (0.05 mg/kg/dose for patients < 10 kg) [Maximum dose: 2 mg] on Days 2, 9 and 16. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the statement 
“Do not remove covering until moment of injection. For intravenous use only - Fatal if given by other 
routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. VinCRIStine is 
available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI, Marqibo®). Use 
conventional vincristine only; the conventional and liposomal formulations are NOT interchangeable. 
 
See Section 5.0 for Dose Modifications based on Toxicities. The therapy delivery map (TDM) for 
Regimen T is on the next page (see Section 4.4.4).  
 
 

 
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4.4.4 
Regimen T – Low-Risk Patients (Stratum 2) Cycles 1 & 2   
Low-risk patients receive 2 adjuvant cycles of C5V. Tumor tissue is strongly encouraged for 
banking: see ABTR01B1 or other appropriate study for details. This therapy delivery map relates 
to 2 cycles of C5V therapy. Each cycle lasts 21 days. One cycle is described on this TDM. This 
TDM is on 1 page. Use a copy of this page once for each cycle (please note cycle number below). 
 
 
 
____________________________  
____________ 
 
Patient name or initials 
 
         DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and the platelet count is ≥ 75,000/µL. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin   
(CDDP) 
IV over 
6 hours 
100 mg/m2/dose OR 
(3.3 mg/kg/dose for < 10 kg) 
1 
Recommended administration guidelines: Urine S.G. 
should be < 1.010 prior to starting CDDP. See Section 
4.4.1 for pre- and post- hydration & mannitol guidelines.  
a. History, physical, ht/wt, BSA, VS (Start 
of each cycle & end of therapy) 
b. CBC (diff/plt) (Weekly & end of therapy) 
c. Electrolytes, Ca++, Mg++, PO4, creatinine, 
ALT/AST, bilirubin, total protein/albumin, 
AFP (Start of each cycle & end of 
therapy) 
d. Tumor disease evaluation (End of therapy 
only), see Section 7.3. 
e. Audiogram (End of therapy only) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
5-Fluorouroracil 
(FU) 
Slow IV 
push over 2-
4 minutes 
600 mg/m2/dose OR 
(20 mg/kg/dose for < 10 kg) 
2 
 
VinCRIStine 
(VCR) 
IV push over 
1 minute**  
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for < 10 kg) 
2, 9 & 16 
Maximum dose: 2 mg 
** or infusion via minibag as per institutional policy 
 
Circle Cycle #:  1 (Weeks 1-3) 
2 (Weeks 4-6) 
 
Ht__________cm 
 
Wt_________kg  
BSA__________m2 
 
Date Due 
Date 
Given 
Day 
CDDP 
_________mg 
FU 
_________mg 
VCR 
_________mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_________mg 
 
 
a, b, c 
 
 
 
2 
 
_________mg 
_________mg 
 
 
 
 
9 
 
 
_________mg 
b 
 
 
 
16 
 
 
_________mg 
b 
 
 
 
21 
Repeat cycle or (End therapy after Cycle 2) 
(a, b ,c, d, e)* 
* End of therapy 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols. 

 
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4.5 
Treatment for Intermediate-Risk Patients (Stratum 3 - Regimen F)  
 
Note: Stratum 3 has been closed to accrual as of 03/12/12. 
 
All patients with Stage I SCU, Stage II SCU, and Stage III disease will be treated with Regimen F (C5VD). 
Patients will receive 4 cycles of therapy repeated every 21 days, followed by surgical resection of the tumor 
or liver transplant (OLT). Patients whose tumors are removed surgically or by OLT after Cycle 4 will 
receive 2 post-operative cycles of chemotherapy. Patients may have their tumor removed if deemed feasible 
after 2 cycles of chemotherapy but will then receive 4 cycles of post-operative chemotherapy. All 
intermediate-risk patients will receive a total of 6 cycles of chemotherapy. Patients whose tumors 
remain unresectable after 4 cycles will be considered off protocol therapy, but will continue to be followed 
on the AHEP0731 off protocol therapy follow-up CRF. These patients can at the discretion of the primary 
physician. Additional pre-operative cycles of chemotherapy after Cycle 4 are NOT permitted in an attempt 
to make the tumor resectable or if a liver is not available for transplantation. Patients with progressive 
disease at any time are off-protocol therapy.  
 
Tumors that are unresectable at diagnosis should be referred to a surgical center with expertise in pediatric 
liver transplant and “extreme” liver resection as soon as possible. Optimally for planning purposes, this 
liver transplant consultation should be obtained but at the latest it should be done following the first 2 cycles 
of neoadjuvant chemotherapy. The consent for the PLUTO registry should be obtained within one month 
of undergoing liver transplant and is usually obtained by the liver transplant team.  
 
For the purposes of this study, consultation will be defined and may be accomplished in one of two ways: 
• 
The FIRST TIME the patient is seen face to face by the transplant physician/team in the same 
institution or another institution. 
• 
The FIRST TIME radiographic films and referral material are sent to the transplant physician/team 
at the same or another institution and are formally reviewed by the transplant physician/team.  
The transplant physician/team will communicate the result of this consultation back to the referring 
physician.  
 
Resection planning is to be completed before completion of the 4th cycle of chemotherapy. Transplant or 
“extreme” resection is intended to occur within 4 weeks of the completion of the 4th cycle of chemotherapy. 
Chemotherapy should resume as soon as possible after surgical resection. In most circumstances this can 
typically be achieved within 3 weeks following surgery. Patients who do not resume post resection 
chemotherapy within 42 days of resection will be considered off protocol therapy. Further treatment will 
be at the discretion of the treating physician.  
 
Patients classified as intermediate-risk will receive 6 cycles of C5VD. Surgical resection of tumor or liver 
transplant will occur following Cycle 2 (if feasible) or Cycle 4. All patients < 10 kg will have dosing in 
mg/kg.  
 
4.5.1 
CISplatin: IV over 6 hours 
100 mg/m2/dose (3.3 mg/kg/dose for patients < 10 kg) on Day 1. 
 
Recommended hydration and administration guidelines:  
Urine specific gravity should be < 1.010 prior to starting cisplatin.  
Hours -2 to 0:  Prehydrate with 300 mL/m2 D5 ½ NS + MgSO4 8 mEq/L + KCL 20 mEq/L. 
Hours 0-6:  Infuse CISplatin + mannitol 8000 mg/m2 in 750 mL/m2 NS @ 125 mL/m2/hr.  
Hours 6- 24:  D5½NS+ MgSO4 8 mEq/L + KCL 20 mEq/L to run at 125 mL/m2/hr.   

 
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4.5.2 
5-Fluorouracil: Slow IV Push over 2-4 minutes 
600 mg/m2/dose (20 mg/kg/dose for patients < 10 kg) on Day 2. 
 
4.5.3 
VinCRIStine: IV Push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (0.05 mg/kg/dose for patients < 10 kg) [Maximum dose: 2 mg] on Days 2, 9 and 16. 
 
4.5.4 
 DOXOrubicin: IV over 15 minutes 
30 mg/m2/dose (1 mg/kg/dose for patients < 10 kg) on Days 1 and 2. 
It is suggested that DOXOrubicin be administered through the tubing of rapidly infusing solution of D5W 
or 0.9% NaCl and that it is infused into a large vein.  
 
 
4.5.5 
Dexrazoxane: Slow IV Push over 5-15 minutes immediately prior to DOXOrubicin dose 
300 mg/m2/dose (10 mg/kg/dose for patients < 10 kg) on Days 1 and 2 in Cycles 5 and 6 ONLY. 
The elapsed time from the beginning of the dexrazoxane dose to the end of the DOXOrubicin infusion 
should be 30 minutes or less.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 

 
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4.6 
Treatment for High-Risk Patients (Stratum 4) - Regimen H 
 
All high-risk patients will receive 2 cycles of vinCRIStine, irinotecan and temsirolimus (VIT), using a 5 day 
irinotecan schedule, as “up-front” window therapy on Regimen H. Each cycle lasts 21 days and cycles will 
start on Weeks 1 and 4. Antibiotics will be given to patients receiving irinotecan who develop 
chemotherapy-related diarrhea. See “Diarrhea Secondary to Irinotecan” in the Supportive Care Guidelines 
at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
under 
Standard 
Sections for Protocols. 
 
Following 2 cycles of VIT, patients will be evaluated for response (see Section 10.3). The assessment of 
response is based on central review of imaging, the alphafetoprotein values and sampling dates. The results 
of the central review will be returned to the institutional investigator within 3 weeks of submission of the 
imaging and AFP material. If there is a discrepancy between the assessment by central review and by 
institutional assessment, the study PI will discuss with the treating physician to resolve the discrepancy. If 
the investigator selects a post-induction regimen that is not indicated by the central review of response, the 
patient will be considered off protocol therapy as of the start date of consolidation therapy. 
 
Patients who respond (demonstrate a complete or partial response) to VIT will then receive a total of 6 
cycles of C5VD therapy and 2 more cycles of VIT. Following first 2 cycles of VIT, no further VIT should 
be given until after surgical resection/liver transplant to avoid potential surgical complications of 
thrombosis and wound dehiscence. Each cycle lasts 21 days. A total of 10 cycles of chemotherapy (6 cycles 
of C5VD and 4 cycles of VIT, including the “up-front” window therapy) will be given. VIT is intended to 
be given during Cycles 7 and 10. However, the order of chemotherapy cycles can be switched at the 
discretion of the treating oncologists and surgeons to optimize surgical outcomes and minimize 
complications.   
 
Patients who do not respond to VIT will continue with 6 cycles of C5VD repeated every 21 days and receive 
no further VIT. A total of 8 cycles of chemotherapy (6 cycles of C5VD and 2 cycles of VIT, including the 
“up-front” window therapy) will be given.  
 
Tumors that are unresectable at diagnosis, even if metastatic disease is present, should be referred to a 
surgical center with expertise in pediatric liver transplant and “extreme” liver resection should be done as 
soon as possible. Optimally for planning purposes, this liver transplant consultation should be obtained at 
diagnosis and no later than the FIRST DAY of the 3rd cycle of C5VD chemotherapy. The consent for the 
PLUTO registry should be obtained within one month of liver transplant and usually is obtained by the liver 
transplant team.  
 
For the purposes of this study, consultation will be defined and may be accomplished in one of two ways: 
• 
The FIRST TIME there is documented telephone or email/letter contact and a request for 
consultation between the treating oncologist and the liver specialty/transplant team. 
• 
The FIRST TIME radiographic films and referral material are sent to the transplant physician/team 
at the same or another institution and are formally reviewed by the transplant physician/team.  
The liver specialty/transplant physician/team will communicate the result of this consultation back to the 
referring physician.  
 
Resection planning is to be completed before completion of the 4th cycle of C5VD chemotherapy. See 
Surgical Guidelines in Section 13.0. 
 
Patients will be evaluated after every 2 cycles of C5VD chemotherapy that occur prior to resection. Patients 
may have their primary tumor removed whenever it is feasible. It is the intent of the treatment that patients 
should have their tumors removed surgically or by OLT at the latest after Cycle 6 in both responders and 

 
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non-responders (ie, after the 4th cycle of C5VD) so that they can receive post-operative cycles of 
chemotherapy. 
 
Chemotherapy should resume as soon as possible after surgical resection. In most circumstances this can 
typically be achieved within 3 weeks following surgery. Patients who do not resume post resection 
chemotherapy within 42 days of resection will be considered off protocol therapy but not off study. 
Further treatment will be at the discretion of the treating physician. Patients will continue to be followed 
on the AHEP0731 off protocol therapy follow-up CRF.  
 
Regardless of the timing of surgery, patients should receive the total number of cycles as described above. 
 
Patients whose tumors remain unresectable at the completion of planned therapy will be considered 
to have experienced an adverse EFS event. No further protocol therapy is planned for such patients. 
These patients can be treated at the discretion of the primary physician.   
 
Patients with pulmonary metastases will receive the first 2 cycles of Regimen H chemotherapy described 
above. If metastases disappear with chemotherapy, no pulmonary surgical intervention will be performed. 
If metastases are persistent after 4 total cycles of C5VD chemotherapy and the patient is considered a 
candidate for liver transplant at that time, metastases are to be resected to render the patient free of 
extrahepatic disease prior to transplant. Transplant may then be undertaken. If the liver tumor can be 
primarily resected after either 2 or 4 cycles of C5VD chemotherapy without transplant, this should be 
performed and the final cycles of chemotherapy should be administered. If the metastases are still present, 
they should then be resected. Pulmonary metastectomy may be performed earlier in the course of therapy 
if it can be done without resulting in delays in the administration of scheduled chemotherapy.   
 
Regimen H for Responders 
 
Cycle 
1 
2 
Eval 
3 
4 
5 
6 
7 
8 
9 
10 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 
Chemotherapy 
VIT 
VIT 
C5VD 
C5VD 
C5VD 
C5VD 
VIT 
C5VD+ 
DXRZ* 
C5VD+ 
DXRZ* 
VIT  
Responders will receive a total of 8 cycles post VIT window.  
 
Regimen H for Non-Responders 
Cycle 
1 
2 
Eval 3 
4 
5 
6 
7 
8 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
Chemotherapy VIT VIT 
C5VD C5VD C5VD C5VD C5VD+ 
DXRZ* 
C5VD+ 
DXRZ* 
Non responders will receive 6 total cycles of C5VD post VIT window.  
 
*Dexrazoxane administration is not required for patients enrolled in Japan. 
 
NOTE: For high-risk patients being assessed at the end of Cycle 2, the central review assessment will 
be returned to the institutional investigator and will indicate the post-induction treatment regimen.  
 
4.6.1 
Criteria to Start Cycle 1 of Regimen H and Subsequent Cycles 
 
4.6.1.1 Criteria to Start Cycle 1 of Regimen H for All High-Risk Patients 
Begin Cycle 1 of Regimen H, when ANC ≥ 750/µL and the platelet count is ≥ 75,000/µL and all 
the eligibility criteria have been met.  

 
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4.6.1.2 Criteria to Start Cycle 2 of Regimen H for All High-Risk Patients and Cycles 3-10 of Regimen H 
for All High-Risk Responders 
• 
ANC ≥ 750/µL and the platelet count is ≥ 75,000/µL. 
• 
Total Cholesterol ≤ 400 mg/dL OR ≤ 500 mg/dL and on lipid lowering medication, AND 
triglycerides ≤ 300 mg/dL OR ≤ 500 mg/dL and on lipid lowering medication. If cholesterol or 
triglyceride parameters are not met based on testing performed in a non-fasting patient, these 
tests should be repeated after fasting. 
 
4.6.1.3 Criteria to Start Cycles 3-8 of Regimen H for All High-Risk Non-Responder Patients 
• 
ANC ≥ 750/µL and the platelet count is ≥ 75,000/µL. 
Note: Beyond Cycle 2, the cholesterol and triglyceride parameters to start a cycle of therapy are 
not applicable for non-responders, as they will not receive any further VIT therapy.  
 
Note: All patients < 10 kg will have dosing in mg/kg 
 
4.6.2 
VinCRIStine: IV Push over 1 minute or infusion via minibag as per institutional policy 
During ‘Upfront’ Window Therapy for All High-Risk Patients 
1.5 mg/m2/dose (0.05 mg/kg/dose for patients < 10 kg) [Maximum dose: 2 mg] on Days 1 and 8 
of Cycles 1 and 2.  
 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
1.5 mg/m2/dose (0.05 mg/kg/dose for patients < 10 kg) [Maximum dose: 2 mg] on Days 2, 9 and 
16 of Cycles 3-6, 8-9 and Days 1 and 8 of Cycles 7 and 10. 
 
During Post ‘Upfront’ Window Therapy for All High-Risk Non-responder Patients 
1.5 mg/m2/dose (0.05 mg/kg/dose for patients < 10 kg) [Maximum dose: 2 mg] on Days 2, 9 and 
16 of Cycles 3-8.  
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the 
statement “Do not remove covering until moment of injection. For intravenous use only - Fatal if 
given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate liposomal injection, 
VSLI, Marqibo®). Use conventional vincristine only; the conventional and liposomal formulations 
are NOT interchangeable. 
 
 
4.6.3 
Irinotecan: IV over 90 minutes 
 
During ‘Upfront’ Window Therapy for All High-Risk Patients 
50 mg/m2/dose (1.67 mg/kg/dose for patients < 10 kg) [Maximum dose: 100 mg] on Days 1-5 of 
Cycles 1 and 2. 
 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
50 mg/m2/dose (1.67 mg/kg/dose for patients < 10 kg) [Maximum dose: 100 mg] on Days 1-5 of 
Cycles 7 and 10. 
 
See: https://members.childrensoncologygroup.org/prot/reference_materials.asp   

 
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Under Standard Sections for Protocols – Supportive Care Guidelines for prophylactic antibiotics 
and treatment recommendation for diarrhea secondary to irinotecan.  
 
4.6.4 
Temsirolimus: IV over 30 minutes  
During ‘Upfront’ Window Therapy for All High-Risk Patients  
35 mg/m2/dose (1.2 mg/kg/dose for patients < 10 kg) on Days 1 and 8 of Cycles 1 and 2. 
 
On Day 1 
Administer diphenhydramine (1 mg/kg, max 50 mg) immediately upon completion of 
irinotecan infusion. Begin temsirolimus infusion 30 minutes after administration of 
diphenhydramine. 
 
On Day 8 
Administer diphenhydramine (1 mg/kg, max 50 mg) immediately upon completion of 
vinCRIStine. Begin temsirolimus infusion 30 minutes after administration of 
diphenhydramine.  
 
 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
35 mg/m2/dose (1.2 mg/kg/dose for patients < 10 kg) on Days 1 and 8 of Cycles 7 and 10. 
 
On Day 1 
Administer diphenhydramine (1 mg/kg, max 50 mg) immediately upon completion of 
irinotecan infusion. Begin temsirolimus infusion 30 minutes after administration of 
diphenhydramine. 
 
On Day 8 
Administer diphenhydramine (1 mg/kg, max 50 mg) immediately upon completion of 
vinCRIStine. Begin temsirolimus infusion 30 minutes after administration of 
diphenhydramine.  
 
4.6.5 
CISplatin: IV over 6 hours 
 
Recommended hydration and administration guidelines:  
Urine specific gravity should be < 1.010 prior to starting CISplatin.  
Hours -2 to 0:  Prehydrate with 300 mL/m2 D5 ½ NS + Magnesium sulfate 8 mEq/L + KCL 
20 mEq/L.  
Hours 0-6:  Infuse CISplatin + mannitol 8000 mg/m2 in 750 mL/m2 NS @ 125 mL/m2/hr.  
Hours 6- 24:  D5½NS+ Magnesium sulfate 8 mEq/L + KCL 20 mEq/L to run at 125 mL/m2/hr.   
 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
100 mg/m2/dose (3.3 mg/kg/dose for patients < 10 kg) on Day 1 of Cycles 3-6 and 8-9.  
 
During Post ‘Upfront’ Window Therapy for All High-Risk Non-responder Patients  
100 mg/m2/dose (3.3 mg/kg/dose for patients < 10 kg) on Day 1 of Cycles 3-8. 
 
4.6.6 
5-Fluorouracil: Slow IV Push over 2-4 minutes 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
600 mg/m2/dose (20 mg/kg/dose for patients < 10 kg) on Day 2 of Cycles 3-6 and 8-9. . 
 
During Post ‘Upfront’ Window Therapy For All High-Risk Non-responder Patients 

 
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600 mg/m2/dose (20 mg/kg/dose for patients < 10 kg) on Day 2 of Cycles 3-8. 
 
4.6.7 
Dexrazoxane: Slow IV Push over 5-15 minutes immediately prior to doxorubicin dose 
The elapsed time from the beginning of the dexrazoxane dose to the end of the DOXOrubicin 
infusion should be 30 minutes or less.   
Note: Dexrazoxane administration is not required for patients enrolled in Japan. 
 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
300 mg/m2/dose (10 mg/kg/dose for patients < 10 kg) on Days 1 and 2 beginning 15 minutes prior 
to DOXOrubicin dose in Cycles 8-9 ONLY. 
 
During Post ‘Upfront’ Window Therapy For All High-Risk Non-responder Patients 
300 mg/m2/dose (10 mg/kg/dose for patients < 10 kg) on Days 1 and 2 beginning 15 minutes 
prior to DOXOrubicin dose of Cycles 7-8 ONLY 
 
4.6.8 
DOXOrubicin: IV over 15 minutes 
During Post ‘Upfront’ Window Therapy for All High-Risk Responder Patients 
30 mg/m2/dose (1 mg/kg/dose for patients < 10 kg) on Days 1 and 2 of Cycles 3- 6 and 8-9. 
 
 
During Post ‘Upfront’ Window Therapy For all High-Risk Non-responder Patients 
30 mg/m2/dose (1 mg/kg/dose for patients < 10 kg) on Days 1 and 2 of Cycles 3-8.  
 
Medication errors have occurred due to confusion between DAUNOrubicin and DOXOrubicin. 
DOXOrubicin is available in a liposomal formulation. Use conventional DOXOrubicin only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
The therapy delivery maps (TDMs) for Regimen H are on the next 8 pages (see Sections 4.6.9-4.6.11.b)  

 
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4.6.9 
Regimen H – All High-Risk Patients (Stratum 4) (‘Upfront’ Window Therapy) Cycles 1 & 2 
All High-Risk patients receive 2 cycles of “upfront” VIT window therapy, with subsequent treatment dependent upon 
response to “upfront” cycles. This therapy delivery map relates to the first 2 cycles of VIT therapy (Cycles 1& 2). Each 
cycle lasts 21 days. One cycle is described on this TDM. This TDM is on 1 page. Tumor tissue is strongly encouraged 
for banking: see ABTR01B1 or other appropriate study for details. Use a copy of this page once for each cycle (please 
note cycle number below).  
 
 
_____________________________________________  
Patient name or initials   
 
 
____________________________ 
                          
 DOB 
Criteria to start Cycle 1 see Section 4.6.1.1. Criteria to start Cycle 2 see Section 4.6.1.2 
 
DRUG 
ROUTE 
DOSAGE 
DAY
S 
IMPORTANT 
NOTES 
OBSERVATIONS 
VinCRIStine  
(VCR) 
IV push over 
1 minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for < 10 kg) 
1 and 
8 
Maximum dose:  2 mg 
**or infusion via 
minibag as per 
institutional policy 
a. History, physical, ht/wt, BSA, VS  
b. CBC (diff/plt) (Weekly) 
c. Electrolytes, Ca++, Mg++, PO4, creatinine, ALT/AST, bilirubin, 
total protein/albumin, AFP^, triglycerides & cholesterol^ 
d. Bilirubin 
e. Urine glucose^  
f. Tumor disease evaluation (End of Cycle 2 only)^ 
g. Liver transplant consult should be obtained ASAP post diagnosis 
but no later than end of Cycle #4.  
h. POST-TEXT grouping (End of Cycle 2 only)^ 
^ See Section 7.5 for details 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
PATIENT CARE 
Irinotecan 
(IRIN) 
IV over 
90 minutes 
50 mg/m2/dose OR 
(1.67 mg/kg/dose for < 10 kg)     
1-5 
Maximum dose: 
100 mg 
 
Temsirolimus 
(TORI) 
 
IV over 30 
minutes 
35 mg/m2/dose OR  
(1.2 mg/kg/dose for < 10 kg ) 
1 and 
8  
See Section 4.6.4 for 
diphenhydramine 
premedication 
administration details 
 
Circle Cycle #:  1 (Weeks 1-3) 
2 (Weeks 4-6) 
 
 
 
Ht_________cm         Wt_________kg 
         BSA__________m2 
 
Date 
Due 
Date 
Given 
Day 
VCR 
_________mg 
IRIN 
_________mg 
TORI 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_________mg 
_________mg 
_________mg 
a, b, c*, d, e 
 
 
 
2 
 
_________mg 
 
 
 
 
 
3 
 
_________mg 
 
 
 
 
 
4 
 
_________mg 
 
 
 
 
 
5 
 
_________mg 
 
 
 
 
 
8 
_________mg 
 
_________mg 
b, d, e 
 
 
 
15 
 
 
 
b, e 
 
 
 
21 
Start post window therapy at the end of Cycle 2. Responders will receive 6 cycles of 
C5VD with 2 cycles of VIT (see Sections 4.6.10.a–4.6.10.d). Non-responders will 
receive 6 cycles of C5VD and no further VIT (see Section 4.6.11.a and 4.6.11.b). 
f, g, h 
 
* The AFP obtained post Cycle 2/prior to Cycle 3 must be submitted for central review assessment of response in Reporting Period 1. For details see Section 10.3. 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols 
Page 1 of 1 

 
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4.6.10.a  Regimen H – Continuation for High-Risk Patients(Stratum 4): Window Therapy for Responders Cycles 3, 4, 
 
5 and 6 (C5VD) 
 
Responders to “upfront” VIT window therapy will next receive C5VD and VIT chemotherapy: a total of 6 cycles of C5VD and 2 more cycles 
of VIT. This therapy delivery map relates to 4 cycles of C5VD therapy (Cycles 3-6). Each cycle lasts 21 days. One cycle is described on this 
TDM. This TDM is on 1 page. Use a copy of this page once for each cycle (please note cycle number below). 
Tumor resection or liver transplant should occur whenever feasible BUT ideally by the end of Cycle 6 (4th C5VD cycle) and prior to any 
further VIT. Patients should resume chemotherapy as soon as possible following surgical resection and within 42 days of surgery or will be 
off protocol therapy.  
 
 
 
_____________________________ 
Patient name or initials 
 
 
____________________________ 
                            DOB 
 
Criteria to start each cycle: see Section 4.6.1.2 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin   
(CDDP) 
IV over 
6 hours 
100 mg/m2/dose OR 
(3.3 mg/kg/dose for 
< 10 kg) 
1  
 
Recommended administration 
guidelines: Urine S.G. should 
be < 1.010 prior to starting CDDP. 
See Section 4.6.5 for pre- and post- 
hydration & mannitol guidelines.  
a. History, physical, ht/wt, BSA, VS  
b. CBC (diff/plt) (Weekly) 
c. Electrolytes, Ca++, Mg++, PO4, creatinine, ALT/AST, bilirubin, total 
protein/albumin, AFP^, triglycerides & cholesterol^, urine glucose^ 
d. Tumor disease evaluation (End of Cycles 4 and 6 only)^ 
e. Liver transplant consult should be performed ASAP post diagnosis but 
no later than FIRST day of Cycle 5. 
f.   Consent for PLUTO registry should be obtained within one month of 
liver transplant, see (See Section 13.4) 
g.  See Section 14.0 for details regarding pathology slides/tumor tissue. 
h.  POST-TEXT grouping (when scans are  performed - End of Cycles 4 
and 6 if appropriate)^ 
i.   Audiogram (End of Cycle 6 only) 
j.  Echocardiogram or MUGA (End of Cycle 6 only) 
 
^ See Section 7.5 for details 
 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD PATIENT 
CARE 
5-Fluorouroracil 
(FU) 
Slow IV 
push over 
2-4 minutes 
600 mg/m2/dose OR 
(20 mg/kg/dose for 
< 10 kg) 
2 
 
 
VinCRIStine 
(VCR) 
IV push 
over 1 
minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose 
for < 10 kg) 
2, 9 and 16  
Maximum dose: 2 mg 
**or infusion via minibag as per 
institutional policy 
DOXOrubicin 
(DOXO) 
IV over 
15 minutes 
30 mg/m2/dose OR 
(1 mg/kg/dose for 
 < 10 kg) 
1 & 2   
 
 
Circle Cycle #:  
3 (Wks 7-9)   4 (Wks 10-12)     5 (Wks 13-15)     6 (Wks 16-18)      Ht________cm 
        Wt_________kg          BSA_________m2 
 
Date Due 
Date 
Given 
Day 
CDDP 
_________mg 
FU 
_________mg 
VCR 
_________mg 
DOXO 
_________mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_________mg 
 
 
_________mg 
a, b, c*, e 
 
 
 
2 
 
_________mg 
_________mg 
_________mg 
 
 
 
 
9 
 
 
_________mg 
 
b 
 
 
 
16 
 
 
_________mg 
 
b 
 
 
 
21 
If feasible, proceed to tumor resection or transplant at the end of Cycle 6. 
See Section 4.6.10.b. to start Cycle 7.  
d, f, g, h, i, j  
 
* The AFP obtained post Cycle 2/prior to Cycle 3 must be submitted for central review assessment of response in Reporting Period 1. For details see Section 10.3. 
Note: If an AFP was obtained post Cycle 2, do not repeat prior to Cycle 3. 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols 
   
 
Page 1 of 4 

 
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4.6.10.b Regimen H – Continuation for High-Risk Patients (Stratum 4): Window Therapy Responders 
 
Cycle 7 (VIT) 
 
This therapy delivery map relates to 1 cycle of VIT therapy and will last 21 days. One cycle is described on this TDM. 
This TDM is on 1 page. Tumor resection or liver transplant should have occurred prior to any additional post Cycle 2 VIT 
therapy. Patients should resume chemotherapy as soon as possible following surgical resection and within 42 days of 
surgery or will be off protocol therapy. The order of chemotherapy cycles can be switched at the discretion of the treating 
oncologists and surgeons to optimize surgical outcomes and minimize complications (see Section 4.6 for details). 
 
______________________________________ 
Patient name or initials 
 
 
______________________ 
 
      DOB 
 
Criteria to start each cycle: See Section 4.6.1.2 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 
1 minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for < 10 kg) 
1 & 8  
Maximum dose: 2 mg 
**or infusion via minibag as per 
institutional policy 
a. History, physical, ht/wt, BSA, VS  
b. CBC (diff/plt) (Weekly) 
c. Electrolytes, Ca++, Mg++, PO4, creatinine, 
ALT/AST, bilirubin, total protein/albumin, 
AFP , triglycerides & cholesterol^, urine 
glucose^ 
d. Bilirubin 
 
^ See Section 7.5 for details 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Irinotecan 
(IRIN) 
IV over 
90 minutes. 
50 mg/m2/dose OR 
(1.67 mg/kg/dose for < 10 kg) 
1-5   
Maximum dose: 100 mg 
 
Temsirolimus 
(TORI) 
 
IV over 30 
minutes 
35 mg/m2/dose OR  
(1.2 mg/kg for < 10 kg) 
1& 8 
See Section 4.6.4 for diphenhydramine 
premedication administration details 
 
Enter Cycle #:  
 
 
 
Ht_________cm         Wt_________kg 
         BSA_________m2 
 
Date Due 
Date 
Given 
Day 
VCR 
_________mg 
IRIN 
_________mg 
TORI 
_________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_________mg 
_________mg 
_________mg 
a, b, c, d 
 
 
 
2 
 
_________mg 
 
 
 
 
 
3 
 
_________mg 
 
 
 
 
 
4 
 
_________mg 
 
 
 
 
 
5 
 
_________mg 
 
 
 
 
 
8 
_________mg 
 
_________mg 
b, d 
 
 
 
15 
 
 
 
b 
 
 
 
21 
See Section 4.6.10.c to start Cycle 8.  
 
 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols. 
 
 
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4.6.10.c  Regimen H – Continuation for High-Risk Patients (Stratum 4): Window Therapy Responders Cycles 8 and 9  
 
 (C5VD + DXRZ) 
 
This therapy delivery map relates to 2 Cycles of C5VD + DXRZ therapy (Cycles 8 and 9). Each Cycle lasts 21 days. One cycle is 
described on this TDM. This TDM is on 1 page. Patients should resume chemotherapy as soon as possible following surgical resection 
and within 42 days of surgery or will be off protocol therapy. The order of chemotherapy cycles can be switched at the discretion of 
the treating oncologists and surgeons to optimize surgical outcomes and minimize complications (see Section 4.6 for details).Use a 
copy of this page once for each cycle (please note cycle number below).  
 
_____________________________ 
Patient name or initials 
 
____________________________ 
                            DOB 
 
Criteria to start each cycle: See Section 4.6.1.2 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin   
(CDDP) 
IV over 
6 hours 
100 mg/m2/dose OR 
(3.3 mg/kg/dose for < 10 kg) 
1  
Recommended administration guidelines: 
Urine S.G. should be <1.010 prior to starting 
CDDP. See Section 4.6.5 for pre- and post- 
hydration & mannitol guidelines.  
a. 
History, physical, ht/wt, BSA, VS  
b. 
CBC (diff/plt)  
c. 
Electrolytes, Ca++, Mg++, PO4 creatinine, 
ALT/AST, bilirubin, total protein/albumin, AFP, 
triglycerides & cholesterol^, urine glucose^  
 
^ See Section 7.5 for details 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
5-Fluorouroracil 
(FU) 
Slow IV push 
over 2-4 
minutes 
600 mg/m2/dose OR 
(20 mg/kg/dose for < 10 kg) 
2 
 
VinCRIStine 
(VCR) 
IV push over 1 
minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for < 10 kg) 
2, 9 and 16  
Maximum dose: 2 mg 
**or infusion via minibag as per institutional 
policy 
Dexrazoxane$ 
(DXRZ) 
Slow IV push 
over  
5-15 minutes# # 
300 mg/m2/dose OR 
(10 mg/kg/dose for < 10 kg) 
1 & 2  
Give immediately prior to DOXO . The 
elapsed time from the beginning of the 
DXRZ to the end of the DOXO infusion 
should be 30 minutes or less.  
DOXOrubicin 
(DOXO) 
IV over 
15 minutes 
30 mg/m2/dose OR  
(1 mg/kg/dose for < 10 kg) 
1 & 2  
 
 
Enter Cycle #:  
 
 
 
Ht_________cm 
        Wt_________kg 
         BSA__________m2 
 
Date Due 
Date Given 
Day 
CDDP 
________mg 
FU 
________mg 
VCR 
________mg 
DXRZ$ 
________mg 
DOXO 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
________mg 
 
 
________mg 
________mg 
a, b, c 
 
 
 
2 
 
________mg 
________mg 
________mg 
________mg 
 
 
 
 
9 
 
 
________mg 
 
 
b 
 
 
 
16 
 
 
________mg 
 
 
b 
 
 
 
21 
See Section 4.6.10.d to start Cycle 10. 
 
 
$Dexrazoxane administration is not required for patients enrolled in Japan. 
 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols 
 
 
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4.6.10.d Regimen H – Continuation for High-Risk Patients (Stratum 4): Window Therapy Responders 
 
Cycle 10 (VIT) 
 
This therapy delivery map relates to 1 Cycle of VIT therapy and will last 21 days. One cycle is described on this TDM. 
This TDM is on 1 page. Tumor resection or liver transplant should have occurred prior to any additional post Cycle 2 VIT 
therapy. Patients should resume chemotherapy as soon as possible following surgical resection and within 42 days of 
surgery or will be off protocol therapy. The order of chemotherapy cycles can be switched at the discretion of the treating 
oncologists and surgeons to optimize surgical outcomes and minimize complications (see Section 4.6 for details). 
 
______________________________________ 
Patient name or initials 
 
 
______________________ 
 
      DOB 
 
Criteria to start each cycle: See Section 4.6.1.2 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push 
over 
1 minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for < 10 kg) 
1 & 8  
Maximum dose: 2 mg 
**or infusion via minibag as per 
institutional policy 
a. History, physical, ht/wt, BSA, VS  
b. CBC (diff/plt) (Weekly) 
c. Electrolytes, Ca++, Mg++, PO4, creatinine, 
ALT/AST, total protein/albumin, AFP , 
triglycerides & cholesterol^, urine glucose^ 
d. Bilirubin 
e. Tumor disease evaluations  
f.  Echocardiogram or MUGA  
g. Audiogram  
 
^ See Section 7.5 for details 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Irinotecan 
(IRIN) 
IV over 
90 minutes. 
50 mg/m2/dose OR 
(1.67 mg/kg/dose for < 10 kg) 
1-5   
Maximum dose: 100 mg 
 
Temsirolimus 
(TORI) 
 
IV over 30 
minutes 
35 mg/m2/dose OR  
(1.2 mg/kg for < 10 kg)  
1& 8 
See Section 4.6.4 for 
diphenhydramine premedication 
administration details 
 
Cycle #: 10 (Wks 28-30) 
 
 
Ht_________cm         Wt_________kg 
         BSA_________m2 
 
Date Due 
Date 
Given 
Day 
VCR 
_________mg 
IRIN 
_________mg 
TORI 
_________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_________mg 
_________mg 
_________mg 
a, b, c, d 
 
 
 
2 
 
_________mg 
 
 
 
 
 
3 
 
_________mg 
 
 
 
 
 
4 
 
_________mg 
 
 
 
 
 
5 
 
_________mg 
 
 
 
 
 
8 
_________mg 
 
_________mg 
b, d 
 
 
 
15 
 
 
 
b 
 
 
 
21 
Completion of Cycle 10 is the end of therapy for High-Risk 
(Stratum 4) Responders  
a, b, c, e, f, g 
 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols. 
 
 
 
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4.6.11.a Regimen H – High-Risk Patients (Stratum 4): Window Therapy Non-responders Cycles 3-6  
 
 (C5VD) 
This therapy delivery map relates to 4 Cycles of C5VD therapy (Cycles 3-6). Each Cycle lasts 21 days. One cycle is described 
on this TDM. This TDM is on 1 page. Use a copy of this page once for each cycle (please note cycle number below.) 
Tumor resection or liver transplant should occur whenever feasible BUT ideally by the end of Cycle 6 (4th C5VD cycle). Patients 
should resume chemotherapy as soon as possible and within 42 days of surgery or will be off protocol therapy.  
 
_____________________________ 
Patient name or initials 
 
____________________________ 
                            DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and the platelet count is ≥ 75,000/µL. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin   
(CDDP) 
IV over 6 hours 
100 mg/m2/dose OR 
(3.3 mg/kg/dose for < 10 kg) 
1  
Recommended administration 
guidelines: Urine S.G. should 
be < 1.010 prior to starting 
CDDP. See Section 4.6.5 for 
pre- and post- hydration & 
mannitol guidelines.  
a. History, physical, ht/wt, BSA, VS 
b. CBC (diff/plt) (Weekly) 
c. Electrolytes, Ca++, Mg++, PO4, creatinine, 
ALT/AST, bilirubin, total protein/albumin, AFP^, 
triglycerides & cholesterol^, urine glucose^  
d. Tumor disease evaluation (End of Cycles 4 & 
6,Only)^ 
e. Audiogram (End of Cycle 6 only) 
f. Echocardiogram or MUGA (End of Cycle 6 only) 
g. Liver transplant consult should be performed 
ASAP post diagnosis but no later than FIRST day 
of Cycle 5. 
h.  Consent for PLUTO registry should be obtained 
within one month of liver transplant, see Section 
13.4 
i.   POST-TEXT grouping (when scans are performed 
- End of Cycle 4 & 6 if appropriate)^ 
j.   See Section 14.0 for details regarding pathology 
slides/tumor tissue. 
^ See Section 7.5 for details 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
5-Fluorouroracil 
(FU) 
Slow IV push 
over 2-4 minutes 
600 mg/m2/dose OR 
(20 mg/kg/dose for < 10 kg) 
2  
 
VinCRIStine 
(VCR) 
IV push over 1 
minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for < 10 kg) 
2, 9 and 16  
Maximum dose: 2 mg 
**or infusion via minibag as 
per institutional policy 
DOXOrubicin 
(DOXO) 
IV over 15 
minutes 
30 mg/m2/dose OR  
(1 mg/kg/dose for < 10 kg) 
1 & 2   
 
 
Circle Cycle #:  
3 (Wks 7-9) 
4 (Wks 10-12) 
5 (Wks 13-15) 
6 (Wks 16-18) 
 
Ht_________cm 
      Wt________kg       BSA________m2 
 
Date Due 
Date 
Given 
Day 
CDDP 
_________mg 
FU 
_________mg 
VCR 
_________mg 
DOXO 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_________mg 
 
 
_________mg 
a, b, c*, h 
 
 
 
2 
 
_________mg 
_________mg 
_________mg 
 
 
 
 
9 
 
 
_________mg 
 
b 
 
 
 
16 
 
 
_________mg 
 
b 
 
 
 
21 
If feasible, proceed to tumor resection or transplant at the end of Cycle 6. See 
Section 4.6.10.b. to start Cycle 7.  
d, e, h, i , j 
 
* The AFP obtained post Cycle 2/prior to Cycle 3 must be submitted for central review assessment of response in Reporting Period 1. For details see Section 10.3. 
Note: If an AFP was obtained post Cycle 2, do not repeat prior to Cycle 3. 
Page 1 of 2 

 
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See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols. 
 
 
 

 
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4.6.11.b Regimen H – High-Risk Patients (Stratum 4) (Window Therapy Non- responders) Cycles 7 and 8   
 
 (C5VD + DXRZ) 
This therapy delivery map relates to 2 Cycles of C5VD + DXRZ therapy (Cycles 7 and 8). Each Cycle lasts 21 days. One 
cycle is described on this TDM. This TDM is on 1 page. Patients should resume chemotherapy as soon as possible and 
within 42 days of surgery or will be off protocol therapy. Use a copy of this page once for each cycle (please note cycle 
number below).  
 
 
_____________________________ 
Patient name or initials 
 
 
____________________________ 
                                DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and the platelet count is ≥ 75,000/µL.   
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CISplatin   
(CDDP) 
IV over 6 hours 
100 mg/m2/dose OR 
(3.3 mg/kg/dose for 
< 10 kg) 
1 
Recommended administration guidelines: 
Urine S.G. should be < 1.010 prior to starting 
CDDP. See Section 4.6.5 for pre- and post- 
hydration & mannitol guidelines  
a. History, physical, ht/wt, BSA, 
VS, performance status 
b. CBC (diff/plt) (Weekly) 
c. Electrolytes, Ca++, Mg++, PO4, 
creatinine, ALT/AST, bilirubin, 
total protein/albumin, AFP, 
triglycerides & cholesterol^, 
urine glucose^  
d. Tumor/ disease evaluations^ 
(End of therapy only),  
e. Audiogram (End of therapy 
only) 
f. Echocardiogram or MUGA (End 
of therapy only) 
^ See Section 7.5 for details 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
5-
Fluorouroracil 
(FU) 
Slow IV push 
over  
2-4 minutes 
600 mg/m2/dose OR  
(20 mg/kg/dose for < 10 kg) 
2 
 
VinCRIStine 
(VCR) 
IV push over 
1 minute** 
1.5 mg/m2/dose OR 
(0.05 mg/kg/dose for 
< 10 kg) 
2, 9 & 
16 
Maximum dose: 2 mg 
**or infusion via minibag as per institutional 
policy 
Dexrazoxane$ 
(DXRZ) 
Slow IV push 
over 5-
15 minutes## 
300 mg/m2/dose OR 
(10 mg/kg/dose for < 10 kg) 
1 & 2 
Give immediately prior to DOXO. The 
elapsed time from the beginning of the 
DXRZ to the end of the DOXO infusion 
should be 30 minutes or less.    
DOXOrubicin 
(DOXO) 
IV over 
15 minutes 
30 mg/m2/dose OR 
(1 mg/kg/dose for < 10 kg) 
1 & 2 
 
 
Circle Cycle #:    7 (Wks 19-21) 
8 (Wks 22-24)                                             Ht__________cm 
        Wt__________kg 
         BSA_________m2 
 
Date Due 
Date 
Given 
Day 
CDDP 
_________mg 
FU 
_________mg 
VCR 
_________mg 
DXRZ$ 
_________mg 
DOXO 
_________mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_________mg 
 
 
_________mg 
_________mg 
a, b, c 
 
 
 
2 
 
_________mg 
_________mg 
_________mg 
_________mg 
 
 
 
 
9 
 
 
_________mg 
 
 
b 
 
 
 
16 
 
 
_________mg 
 
 
b 
 
 
 
21 
Completion of Cycle 8 is the end of therapy for High-Risk (Stratum 4) Non-responders.  
(a, b ,c, d, e, f)* 
* End of therapy only 
$Dexrazoxane administration is not required for patients enrolled in Japan. 
 
See Section 5.0 for Dose Modifications for Toxicities and for general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for Protocols
Page 2 of 2 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Myelosuppression 
 
5.1.1 
Myeloid Growth Factor Support 
If the patient is due to begin a cycle of chemotherapy and the ANC < 750/μL and/or platelet count is 
< 75,000/μL on Day 1, delay the next cycle until recovery occurs. If the patient recovers to ANC > 750/μL 
and platelets > 75,000/μL within 7 days proceed to next cycle. Consider holding Bactrim. If the delay of 
therapy is more than 7 days due to neutropenia or if the patient requires hospitalization for fever and 
neutropenia or sepsis, then the patient should receive myeloid growth factors prophylactically starting 24 
hours post chemotherapy in subsequent cycles. Cytokine support need not be limited to filgrastim; 
pegfilgrastim is also permitted according to institutional standard guidelines. Note: The use of 
erythropoietin is discouraged.  
 
If filgrastim is used, continue it for at least 7 days and until ANC ≥ 5,000/μL after nadir. Filgrastim should 
be discontinued at least 24 hours before the start of the next chemotherapy cycle but may be given on days 
when vincristine is administered. Filgrastim should be given subcutaneously if possible, as it is less 
effective when given intravenously. If pegfilgrastim is used, the next chemotherapy cycle should start at 
least 14 days after pegfilgrastim administration. 
 
5.2 
Doxorubicin 
 
5.2.1 
Mucositis 
If the patient develops Grade 3 or 4 mucositis that resolves to < Grade 2 by Day 1 of the next cycle, no dose 
adjustments will be made in chemotherapy. If the patient develops Grade 3 or 4 mucositis that is NOT 
attributable to infectious etiology AND recovery to < Grade 2 does not occur by Day 1 of any cycle, reduce 
the dose of doxorubicin in the next cycle by 25% to 22.5 mg/m2/dose (0.75 mg/kg/dose). If subsequent 
chemotherapy is tolerated without the recurrence of Grade 3 or 4 toxicity, then resume full dose in the next 
cycle. 
 
If the patient receives the 25% reduced dose and again has Grade 3 or 4 mucositis that is NOT attributable 
to infectious etiology AND recovery to < Grade 2 does not occur by Day 1 of the next cycle, further reduce 
the dose of doxorubicin in the next cycle to 15 mg/m2/dose (0.5 mg/kg/dose). If subsequent chemotherapy 
is 
tolerated 
without 
the 
recurrence 
of 
Grade 
3 
or 
4 
toxicity, 
then 
escalate 
to 
22.5 mg/m2/dose (0.75 mg/kg/dose). If subsequent chemotherapy is tolerated without the recurrence of 
Grade 3 or 4 toxicity, then resume full dose in the next cycle.  
 
If the patient experiences Grade 3 or 4 toxicity with the 50% dose reduction, the doxorubicin should be 
omitted from subsequent cycles. 
 
5.2.2 
Change In Ejection/Shortening Fraction 
If the cardiac ejection fraction falls below 47% or shortening fraction below 27% and the patient is 
asymptomatic following a cycle of doxorubicin, repeat the study in 1 week. If the ejection fraction or 
shortening fraction remains abnormal 1 week later, omit doxorubicin. 
 
If doxorubicin is held from a cycle of therapy, repeat the study prior to the next cycle.  If the cardiac ejection 
fraction returns to normal and is ≥ 47% and shortening fraction is ≥ 27%, resume doxorubicin at full dose. 
 
5.2.3 
Symptomatic Congestive Heart Failure (CHF) 
If at any time, the patient develops Grade 3 CHF or other cardiac disorders or any Grade 4 cardiac toxicity 
not related to underlying infection or metabolic abnormality, omit doxorubicin from all subsequent cycles.  
 
 

 
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5.2.4 
Hepatotoxicity 
If direct bilirubin is > 3 mg/dL prior to chemotherapy, omit doxorubicin. If direct bilirubin is > 1.5 mg/dL 
but ≤ 3 mg/dL (Grade 2 toxicity) prior to chemotherapy, reduce doxorubicin dose by 50% [15 mg/m2/dose 
(0.5 mg/kg/dose)].  If doxorubicin is dose reduced because of direct hyperbilirubinemia, subsequent doses 
should be based on above criteria, ie, if direct bilirubin returns to < Grade 2 toxicity, the full dose of 
doxorubicin is to be given.  
 
5.3 
Cisplatin 
 
5.3.1 
Hearing Loss 
Do not modify cisplatin dose based upon audiologic reports/loss of hearing. 
 
5.3.2 
Change in Renal Function 
If the serum creatinine increases to greater than the maximum serum creatinine for age (see Section 3.2.5.1 
for threshold creatinine values table), check a creatinine clearance or GFR.  
 
No dose reductions in cisplatin will be made for a decrease in the baseline GFR or creatinine clearance as 
long as the value remains > 60 mL/min/1.73 m². Omit cisplatin therapy from a cycle of therapy if GFR or 
creatinine clearance is < 60 mL/min/1.73 m².  If cisplatin is held for a cycle of therapy, repeat the study 
prior to next cycle. Resume therapy at full dose if GFR or creatinine clearance > 60 mL/min/1.73 m². 
 
5.4 
Vincristine 
 
5.4.1 
Peripheral Neuropathy 
If severe peripheral neuropathy (vocal cord paralysis, inability to walk or perform usual motor functions) 
or ileus develops from vincristine, vincristine therapy should be stopped or withheld until the ileus resolves 
or the peripheral neuropathy improves. Restart vincristine at 50% dose [0.75 mg/m2/dose 
(0.025 mg/kg/dose)] and escalate to 75% of full dose [1.125 mg/m2/dose (0.0375 mg/kg/dose)], if tolerated, 
with the next cycle. If tolerated then resume full dose with the next cycle. If neuropathy recurs on escalating 
dose, return to previously tolerated dose once neuropathy has improved. 
 
5.4.2 
Hepatotoxicity 
If direct bilirubin is > 3 mg/dL prior to a cycle of chemotherapy, omit vincristine. If direct bilirubin 
is > 1.5 mg/dL but ≤ 3 mg/dL (Grade 2 toxicity) prior to chemotherapy, reduce vincristine dose by 50%.  If 
vincristine is dose reduced because of direct hyperbilirubinemia, subsequent doses should be based on 
above criteria, ie, if direct bilirubin returns to < Grade 2 toxicity, the full dose of vincristine is to be given.  
 
5.5 
Irinotecan 
 
5.5.1 
Diarrhea 
See Supportive Care Guidelines posted in 'Standard Sections for Protocols' on the COG Website 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
for 
recommendations 
concerning early and late diarrhea secondary to irinotecan.  
 
If Grade 3 or 4 irinotecan-associated diarrhea is experienced by a patient despite maximal use of anti-
diarrheal medications and cefixime/cefpodoxime, the dose of irinotecan should be reduced by 25% to 37.5 
mg/m2/dose (1.25 mg/kg/dose) for subsequent cycles. If Grade 3 or 4 diarrhea occurs despite maximal use 
of anti-diarrheals, cefixime/cefpodoxime and the 25% dose reduction in irinotecan, no further irinotecan 
should be administered. If irinotecan is discontinued, proceed with subsequent cycles of chemotherapy 
(C5VD) omitting the VI cycles.  
 
 

 
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5.6 
Temsirolimus 
 
Note: If temsirolimus therapy needs to be discontinued as detailed below, the patient can remain on study 
and continue with planned therapy while omitting all subsequent doses of temsirolimus. 
 
5.6.1 
Hyperglycemia 
Therapy modifications for patients who develop hyperglycemia (based on random, non-fasting glucose 
levels) should be: 
 
• 
Grade 1-2: Continue temsirolimus 
 
• 
Grade 3 
o Initiate insulin therapy or oral diabetic agent* as indicated. Hold temsirolimus until 
resolves to ≤ Grade 2. Resume temsirolimus at same dose IF patient is asymptomatic, AND 
serum glucose is consistently < 250 mg/dL (≤ Grade 2) without glycosuria. The patient 
may continue to receive concomitant insulin or an oral diabetic agent for the management 
of hyperglycemia while receiving temsirolimus. 
 
o If Grade 3 hyperglycemia recurs despite a stable dose of insulin an oral diabetic agent 
should be used, as the effect of temsirolimus on glucose transport into cells may make 
patients refractory to insulin. Oral diabetic agents should be tried before declaring a 
patient’s hyperglycemia refractory to therapy. If hyperglycemia recurs despite the use of 
an oral diabetic agent, temsirolimus therapy should be discontinued. 
 
o If a patient experiences Grade 3 hyperglycemia despite insulin, and an oral diabetic agent, 
patient should be taken off temsirolimus therapy. 
 
• 
Grade 4 
o Initiate insulin therapy or an oral diabetic agent* as indicated. Hold temsirolimus until 
resolves to ≤ Grade 2. Resume temsirolimus at same dose IF patient is asymptomatic AND 
serum glucose is consistently < 250 mg/dL (≤ Grade 2) without glycosuria. The patient 
may continue to receive concomitant insulin or an oral diabetic agent for the management 
of hyperglycemia while receiving temsirolimus.   
 
o If Grade 4 hyperglycemia recurs despite a stable dose of insulin, or an oral diabetic agent, 
the patient should be taken off temsirolimus therapy. 
 
*Recommended guidelines for use of oral diabetic agents: 
Initiation of treatment for hyperglycemia should occur under the guidance of a pediatric 
endocrinologist at the local institution. Metformin or other oral antihyperglycemia agent may be used per 
local endocrinologist’s recommendations. Insulin therapy should be directed by specialists in pediatric 
diabetes, with the goal of normal fasting blood sugars < 126 mg/dL and HgbA1C < 8%. 
 
5.6.2 
Dose Modification for Infusional Reactions to Temsirolimus 
Therapy modifications for patients who develop infusional reactions to temsirolimus are: 
 
• 
Grade 1-2: Only dose interruption/discontinuation, but not dose reduction is required for 
allergic/infusional reactions. 
o If a patient develops a hypersensitivity reaction despite diphenhydramine pretreatment, 
stop the infusion and wait 30 to 60 minutes (depending upon the reaction severity). At the 

 
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physician’s discretion, it may be possible to resume treatment by administering an H2 
blocker approximately 30 minutes before restarting the infusion. The manufacturer 
recommends famotidine 0.5 mg/kg IV maximum dose 20 mg, rather than cimetidine, 
because it lacks reported drug interactions. If famotidine is unavailable, administer 
ranitidine 1-2 mg/kg IV maximum dose 50 mg. Re-attempt infusion at a slower rate, 
possibly over 60 minutes. 
 
o If Grade 1-2 infusion reactions recur with subsequent dose, add dexamethasone 0.2 mg/kg 
(max 10mg) IV or equivalent to premedications above. 
 
• 
Grade 3: Stop infusion immediately and remove the infusion tube. Administer diphenhydramine 
hydrochloride 1 mg/kg IV (max 50 mg), dexamethasone 0.2 mg/kg (max 10 mg) IV (or equivalent), 
bronchodilators for bronchospasms, and other medications as medically indicated. Hospital 
admission should be considered. Discontinue temsirolimus treatment. 
 
• 
Grade 4: Stop infusion immediately and remove the infusion tube. Administer diphenhydramine 
hydrochloride 1 mg/kg (max 50 mg) IV, dexamethasone 0.2 mg/kg (max 10mg) IV (or equivalent), 
and other anaphylaxis medications as indicated. Epinephrine or bronchodilators should be 
administered as indicated. Hospital admission for observation may be indicated. Discontinue 
temsirolimus treatment. 
 
5.6.3 
 Dose Modifications for Pneumonitis 
For patients who develop pneumonitis (cough, dyspnea, fever), temsirolimus should be held 
pending investigation. If events are considered at least possibly due to treatment, discontinue 
temsirolimus therapy. If the treating clinician determines that respiratory symptoms are not related 
to drug therapy, the patient should be retreated with the same doses of temsirolimus, irinotecan, 
and vincristine. 
 
5.6.4 
Dose Modifications for Mucositis or Rash 
The following guidelines should be used for patients who develop mucositis, or rash. In addition, 
stomatitis, mucositis, and/or mouth ulcers due to temsirolimus (inflammation or ulcers in the 
mouth) should be treated using local supportive care.  
 
• 
Grade 1-2: Continue temsirolimus 
 
• 
Grade 3-4 
o 
Hold temsirolimus until recovery to ≤ Grade 1. If recovery takes ≤ 7 days, resume 
treatment with the same dose of temsirolimus. Upon retreatment, if Grade 3 or 4 toxicity 
recurs and persists >7 days, discontinue temsirolimus. 
o 
If recovery takes > 14 days, discontinue temsirolimus therapy. 
 
5.6.5  Dose Modifications for Elevated Fasting Cholesterol 
The following guidelines should be used for patients who develop elevated fasting cholesterol. 
 
• 
Grade 2 
Continue temsirolimus; consider treatment with an HMG-CoA reductase inhibitor 
depending upon recommendations of institutional hyperlipidemia consultants 
 
• 
Grade 3 

 
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An HMG-CoA reductase inhibitor should be started, and dosages adjusted based upon 
recommendations of institutional hyperlipidemia consultants. It is expected that optimal 
effects of the lipid lowering medication will be observed 2-4 weeks after its initiation. 
Treatment with temsirolimus can continue during this time provided that 
hypercholesterolemia remains ≤ Grade 3. 
 
• 
Grade 4 
Hold temsirolimus. An HMG-CoA reductase inhibitor should be started, and dosages 
should be adjusted based upon recommendations from institutional hyperlipidemia 
consultants. It is expected that optimal effect of the lipid lowering medication will be 
observed 2-4 weeks after initiation. Temsirolimus is to be restarted at the same dose level 
when recovery to ≤ Grade 3 cholesterol is observed. Upon retreatment with temsirolimus 
concurrent with an HMGCoA reductase inhibitor, if Grade 4 elevations recurs, 
temsirolimus should be discontinued. 
 
Note: There is a potential drug interaction between mTOR inhibitors and cholesterol lowering agents, 
particularly atovastatin.  This should be considered when prescribing a cholesterol lowering 
agent. 
 
 
5.6.6 
 Dose Modifications for Elevated Fasting Triglycerides 
The following guidelines should be used for patients who develop elevated fasting triglycerides. 
 
• 
Grade 2 
Continue temsirolimus; if triglycerides are between 301 and 400 mg/dL consider treatment 
with an HMG-CoA reductase inhibitor depending upon recommendations of institutional 
hyperlipidemia consultants. HMG-CoA reductase inhibitor is recommended if 
triglycerides are between 401 and 500. 
 
• 
Grade 3-4 
Hold temsirolimus until recovery to ≤ Grade 2. An HMG-CoA reductase inhibitor should 
be started, and dosages should be adjusted based upon recommendations from institutional 
hyperlipidemia consultants. Upon retreatment at the same dose level, if Grade 3 or 4 
toxicity recurs, lipid lowering medication should be adjusted in consultation with 
institutional hyperlipidemia consultants. Temsirolimus should be held until recovery to 
≤ Grade 2. Upon retreatment with temsirolimus concurrent with an HMGCoA reductase 
inhibitor, if Grade 3 or 4 elevations recur, temsirolimus should be discontinued. 
 
Note: There is a potential drug interaction between mTOR inhibitors and cholesterol lowering agents, 
particularly atovastatin.  This should be considered when prescribing a cholesterol lowering agent. 
 
5.6.7 
Dose Modifications for Hyperbilirubinemia 
 
• 
If bilirubin is ≥ Grade 2 toxicity (> 1.5×ULN) prior to chemotherapy, omit temsirolimus 
dose. If temsirolimus dose is omitted because of hyperbilirubinemia, subsequent doses 
should be based on above criteria, ie. if bilirubin returns to < Grade 2 toxicity, the full dose 
of temsirolimus is to be given. 
If the temsirolimus dose has to be omitted twice due to hyperbilirubinemia, temsirolimus 
should be discontinued permanently. 
 

 
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6.0 
DRUG INFORMATION  
 
6.1 
TEMSIROLIMUS   
 
 
 
 
 
 
 
 
 
(Torisel®, CCI-779, rapamycin analog, WAY-130779) NSC# 683864 
 
 
 
 
 
 
 
 
 
(10/24/18) 
Source and Pharmacology: Temsirolimus is an ester of the immunosuppressive compound sirolimus 
(rapamicin, Rapamune®). Its chemical name is rapamycin 42-[2,2-bis(hydroxymethyl)propionate]. 
Temsirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR), an enzyme that regulates 
cell growth and proliferation. Temsirolimus binds to an intracellular protein FK506 binding protein (FKBP) 12 
and the protein-drug complex inhibits the activity of mTOR and controls cell division. Inhibition of mTOR 
prevents progression from G1 to S phase of the cell cycle. In vitro studies show that inhibition of the activity of 
mTOR resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha and the vascular 
endothelial growth factor.  
 
Pharmacokinetic studies of a single intravenous (IV) dose of temsirolimus in adults showed that over a dose 
range of 1 mg to 25 mg, the drug exposure increased with increasing doses in a less than proportional 
fashion. After a single 25 mg IV dose, the volume of distribution was large (172 L) with preferential 
partitioning into blood, the mean clearance was 16.2 L/h, and the terminal half-life was 17.3 hours.  
 
The pharmacokinetics of temsirolimus was assessed in 19 pediatric subjects with relapsed or refractory 
advanced solid tumors. The typical subject was an 11-year-old male child, with a body weight of 44.4 kg 
and a body surface area of 1.38 m2. Subjects received doses of 10, 25, 75, and 150 mg/m2 once weekly. 
Comparisons of exposure with adult subjects show that temsirolimus Cmax and AUCsum (sum of 
temsirolimus and sirolimus area under the concentration vs time curve) in the pediatric subjects was 
comparable to adult subjects, while temsirolimus AUC was higher in the pediatric subjects. This greater 
exposure to parent drug in the pediatric population was balanced by the shorter half-lives of sirolimus 
metabolite and corresponding lower AUCs. 
 
The safety and pharmacokinetics of temsirolimus were evaluated in a dose escalation phase 1 study in 110 
patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin > 1.5× the 
upper limit of normal (ULN) experienced greater toxicity than patients with baseline bilirubin ≤ 1.5×ULN 
when treated with temsirolimus. The overall frequency of ≥ Grade 3 adverse reactions and deaths, including 
deaths due to progressive disease, were greater in patients with baseline bilirubin > 1.5×ULN due to 
increased risk of death. Caution should be used when treating patients with hepatic impairment. 
Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST 
or bilirubin levels. Temsirolimus is contraindicated in patients with bilirubin > 1.5 X ULN.  
 
Temsirolimus is metabolized extensively in the liver mainly by the isoenzyme cytochrome (CYP) P450 3A4. 
The main active metabolite is sirolimus and the other four metabolites account for less than 10% of the parent 
drug. The activity of temsirolimus is dictated both by the parent drug and by the equipotent metabolite 
sirolimus. Sirolimus half life is longer (54.6 hours) and after a single 25 mg IV dose its AUC is 2.7-fold that of 
temsirolimus AUC due to mainly the longer half-life of sirolimus. Temsirolimus elimination occurs primarily 
in the liver with only minor amounts of drug-related products eliminated in the urine. Multiple doses of 25 mg 
administered once weekly exhibited little or no substantial accumulation. 
 
Since the primary oxidative metabolism of temsirolimus is via CYP3A4, inhibitors and inducers of the 
CYP3A4 enzyme system may alter the metabolism of temsirolimus; however, temsirolimus does not induce 
CYP3A4. Temsirolimus may inhibit the metabolic clearance of substrates of CYP3A4/5 or CYP2D6, but not 
CYP2C9 or CYP2C8. Caution should be used when administering strong CYP3A4 inhibitors or strong 

 
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CYP3A4/5 inducers with temsirolimus IV. In Phase I drug interaction studies, coadministration of IV 
temsirolimus with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus, but 
increased the major metabolite sirolimus exposure. Coadministration of temsirolimus with rifampin, a potent 
CYP3A4 inducer, had no significant effect on temsirolimus, but decreased sirolimus exposure.  
 
In vitro studies showed that temsirolimus is subject to P-gp-mediated efflux; additionally temsirolimus 
inhibited the transport of digoxin, a P-gp substrate. These results indicate that temsirolimus has the potential 
to alter the transport of agents that are P-gp substrates as well as to be altered by P-gp inhibitors. Clinical 
implications related to concomitant administration of P-gp substrates are unknown and dose modifications 
for co-administration with P-gp substrates or inhibitors are not provided in the drug package insert. 
 
The combination of temsirolimus and angiotensin converting enzyme (ACE) inhibitors resulted in 
angioedema-type reactions (including delayed reactions occurring up to 2 months after initiation of 
therapy). Coadministration of sunitinib and temsirolimus resulted in increase toxicity. During temsirolimus 
treatment, the coadministration of sunitinib or ACE inhibitors should be avoided. Prothrombin time and 
INR should be monitored if warfarin is added or discontinued. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Temsirolimus (CCI-779, NSC 683864) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 1927 patients. Below is the CAEPR for temsirolimus (CCI-779). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents 
and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 
         
 
 
Version 2.6, August 19, 20181 
 
 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
ENDOCRINE DISORDERS 
  
 
Testosterone deficiency 
 
 Testosterone deficiency (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 

 
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 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Anal mucositis2 
 
 Anal mucositis2 (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
 
Gastrointestinal fistula3 
  
 
 
Gastrointestinal perforation4  Gastrointestinal perforation4 (Gr 4) 
Mucositis oral2 
 
 
 Mucositis oral2 (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis2 
 
 Rectal mucositis2 (Gr 2) 
 
Small intestinal mucositis2 
 
 Small intestinal mucositis2 (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
 Edema face (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction5 
 
 Allergic reaction5 (Gr 2) 
INFECTIONS AND INFESTATIONS6 
  
 
Infection7 
 
 Infection7 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Wound dehiscence8 
 
 Wound dehiscence8 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased  
(Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased 
(Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Cholesterol high9 
 
 
 Cholesterol high9 (Gr 4) 
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
Fibrinogen decreased 
 
 Fibrinogen decreased (Gr 2) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased  
(Gr 4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased10  
 
 Platelet count decreased10 (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  

 
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 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Acidosis 
 
 Acidosis (Gr 2) 
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Glucose intolerance11 
 
 Glucose intolerance11 (Gr 2) 
 
Hyperglycemia11 
 
 Hyperglycemia11 (Gr 3) 
 
Hyperlipidemia9 
 
 Hyperlipidemia9 (Gr 4) 
 
Hypertriglyceridemia9 
 
 Hypertriglyceridemia9 (Gr 4) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 4) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of 
consciousness 
 
 Depressed level of consciousness 
(Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
 Depression (Gr 2) 
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Libido decreased 
 
 Libido decreased (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury12 
  
 
 
Nephrotic syndrome 
  
 
 
Proteinuria 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Erectile dysfunction 
 
 Erectile dysfunction (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Laryngeal mucositis2 
 
 Laryngeal mucositis2 (Gr 2) 
 
Pharyngeal mucositis2 
 
 Pharyngeal mucositis2 (Gr 2) 
 
Pleural effusion 
 
 Pleural effusion (Gr 3) 
 
Pneumonitis13 
 
 Pneumonitis13 (Gr 3) 
 
Sinus disorder 
 
 Sinus disorder (Gr 2) 
 
Tracheal mucositis2 
 
 Tracheal mucositis2 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes14 
 
 Nail changes14 (Gr 1) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform Gr 2) 

 
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 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Hypotension 
 
 Hypotension (Gr 3) 
 
 
Thromboembolic event 
 Thromboembolic event (Gr 4) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Mucositis/stomatitis:  Gingivitis, mucositis/stomatitis, ulcers in mouth and throat, pharyngitis, and 
dysphagia have been reported in subjects receiving temsirolimus. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation 
under the GASTROINTESTINAL DISORDERS SOC.  GI perforation (including fatal outcome) has been 
observed in subjects who received temsirolimus. 
 
5Hypersensitivity /infusion reactions (including some life threatening and rare fatal reactions), including and 
not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity, 
and anaphylaxis, have been associated with the administration of temsirolimus.  These reactions can occur 
very early in the first infusion but may also occur with subsequent infusions.  Patients should be monitored 
early during infusion and appropriate supportive care should be available.  Temsirolimus infusion should 
be interrupted in all patients with severe infusion reactions and appropriate medical care administered.  A 
risk-benefit assessment should be done prior to the continuation of temsirolimus therapy in patients with 
severe life-threatening reactions. 
 
6Infections:  Bacterial and viral infections including opportunistic infections have been reported in subjects. 
Infections may originate in a variety of organ systems/body regions and may be associated with normal or 
grade 3-4 neutropenia. Bacterial and viral infections have included cellulitis, herpes zoster, herpes simplex, 
bronchitis, abscess, pharyngitis, urinary tract infection (including dysuria hematuria, cystitis, and urinary 
frequency), rhinitis folliculitis, pneumonia, and upper respiratory tract infection. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
8Wound Dehiscence:  The use of temsirolimus has been associated with abnormal wound healing. 
Therefore, caution should be exercised with the use of temsirolimus in the perisurgical period. 
 
9Cholesterol High: The use of temsirolimus in subjects has been associated with increases in serum levels 
of triglycerides and cholesterol. This may require initiation of or increase in the dose of lipid-lowering agents. 

 
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10Thrombocytopenia and Neutropenia: Grades 3 and 4 thrombocytopenia and/or neutropenia have been 
observed at higher frequency in subjects with mantle cell lymphoma (MCL). 
 
11Hyperglycemia/Glucose Intolerance: The use of temsirolimus in subjects was associated with increases 
in serum glucose level. This may result in the need for an increase in the dose of, or initiation of, insulin 
and/or oral hypoglycemic agent therapy.  
 
12Acute Kidney Injury: Renal failure (including fatal outcome) has been observed in subjects receiving 
temsirolimus for advanced RCC and/or with pre-existing renal insufficiency. 
 
13Interstitial Lung Disease: There have been cases of nonspecific interstitial pneumonitis, including rare 
fatal reports. Some subjects were asymptomatic with pneumonitis detected on computed tomography scan 
or chest radiograph. Others presented with symptoms such as dyspnea, cough, and fever. Some subjects 
required discontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while some 
subjects continued treatment without additional intervention. 
 
14Nail Changes includes Nail discoloration, Nail loss, and Nail ridging under the SKIN AND 
SUBCUTANEOUS TISSUE DISORDERS SOC. 
 
15Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal 
hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, 
Rectal 
hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
 
 Adverse events reported on temsirolimus (CCI-779) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that temsirolimus (CCI-779) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(coagulopathy); Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Left ventricular systolic dysfunction; Myocardial infarction; Pericardial effusion; Right ventricular 
dysfunction; Sinus tachycardia; Supraventricular tachycardia; Ventricular fibrillation; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Cushing's syndrome); Endocrine disorders - 
Other (diabetes mellitus) 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Eye disorders - Other (diplopia); Eye pain; Flashing 
lights; Photophobia; Retinopathy 
GASTROINTESTINAL DISORDERS - Anal fissure; Anal pain; Anal ulcer; Ascites; Bloating; Colitis; Colonic 
obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal 
pain; Esophageal ulcer; Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other 
(gastroenteritis); Gastrointestinal hemorrhage15; Hemorrhoids; Ileus; Oral pain; Pancreatitis; Periodontal 
disease; Proctitis; Rectal pain; Small intestinal obstruction; Stomach pain; Typhlitis; Visceral arterial 
ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Facial pain; Gait 
disturbance; Injection site reaction; Localized edema; Malaise; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Postoperative 
hemorrhage; Vascular access complication; Wound complication 

 
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INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Blood 
lactate dehydrogenase increased; CD4 lymphocytes decreased; INR increased (potential interaction with 
Coumadin); Investigations - Other (BUN increased); Lipase increased; Lymphocyte count increased; Serum 
amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (albuminuria); Metabolism and nutrition disorders 
- Other (blood urea increased); Metabolism and nutrition disorders - Other (hypoproteinemia)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; Bone 
pain; Chest wall pain; Generalized muscle weakness; Joint effusion; Muscle cramp; Muscle weakness lower 
limb; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (carcinoma of the lung); Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (lymphoma); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Dysesthesia; 
Hydrocephalus; Lethargy; Neuralgia; Paresthesia; Peripheral motor neuropathy; Peripheral sensory 
neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; Somnolence; Spasticity; 
Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Mania; Psychiatric disorders - Other (bipolar 
disorder); Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Cystitis noninfective; Hematuria; Hemoglobinuria; 
Renal hemorrhage; Urinary frequency; Urinary retention; Urinary tract pain; Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx; Irregular menstruation; 
Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Reproductive system and breast disorders - 
Other (female genital tract fistula); Spermatic cord hemorrhage; Testicular disorder; Testicular hemorrhage; 
Testicular pain; Uterine hemorrhage; Vaginal discharge; Vaginal dryness; Vaginal fistula; Vaginal 
hemorrhage; Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Bronchopulmonary hemorrhage; Bronchospasm; Hiccups; Hypoxia; Nasal congestion; 
Pharyngolaryngeal pain; Pleuritic pain; Productive cough; Pulmonary edema; Pulmonary fibrosis; 
Pulmonary hypertension; Respiratory failure; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Hyperhidrosis; Pain 
of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous tissue 
disorders - Other (angioneurotic edema); Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Phlebitis; Superficial thrombophlebitis 
 
 
Note:  Intracerebral Bleeding: Subjects with central nervous system (CNS) tumors (primary CNS tumors or 
metastases) and/or receiving anticoagulation therapy may be at an increased risk of intracerebral bleeding 
(including fatal outcomes) while receiving therapy with temsirolimus (CCI-779). 
 
Note: Temsirolimus (CCI-779) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
Effect in pregnancy: 
Temsirolimus is Pregnancy Category D. It can cause fetal harm. Female of childbearing potential should 
be advised to avoid becoming pregnant throughout treatment and for three months after temsirolimus 
therapy has stopped. Male with partners of childbearing potential should use reliable contraception 
throughout treatment and are recommended to continue this for three months after the last dose of 
temsirolimus. 
 

 
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Formulation and Stability: 
Temsirolimus (Torisel®) is supplied as the commercially labeled kit consisting of a concentration solution 
and a diluent. The kit components are: 
• 
Temsirolimus injection (25 mg/mL), 1.2 mL  
• 
DILUENT vial that includes a deliverable volume of 1.8 mL. 
 
Temsirolimus injection 25 mg/mL is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile 
solution. The inactive ingredients include dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol, propylene 
glycol, and anhydrous citric acid. The diluent is a sterile, non-aqueous solution that includes polysorbate 
80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v). After the 
temsirolimus injection vial has been diluted with the provided diluent, the solution contains 35.2% alcohol. 
The two-vial kit must be stored at 2°-8°C (36°-46°F) protected from light. 
 
During handling and preparation of admixtures, temsirolimus should be protected from excessive room 
light and sunlight. In order to minimize the patient exposure to the plasticizer di-2-ethylhexyl phthalate 
(DEHP) which may be leached from polyvinyl chloride (PVC) infusion bags, the final temsirolimus dilution 
for infusion should be prepared in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin). 
The preparation of the solution for administration requires two-step dilution process in an aseptic manner. 
These mixing instructions apply to the commercial Torisel kit that is provided for this study. 
 
 
Step 1: 
• 
The temsirolimus injection vial contains 30 mg temsirolimus in 1.2 mL (25 mg/mL).  
• 
Inject 1.8 mL of the provided diluent into the vial of temsirolimus injection (25 mg/mL). The 
resulting drug concentration is 10 mg/mL and the total volume is 3 mL.  
• 
Mix well by inversion of the vial. DO NOT SHAKE. Allow sufficient time for air bubbles to 
subside. The solution is clear to slightly turbid, colorless to yellow, and free from visual 
particulates.  
• 
The 10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at controlled room 
temperature. This 10 mg/mL drug solution/diluent mixture must be further diluted as described in 
Step 2 below.  
 
Step 2: 
• 
Withdraw the amount of temsirolimus required for the dose from the 10 mg/mL drug 
solution/diluent mixture prepared in Step 1.  
• 
For doses less than 10 mg, filter the concentrate/diluents mixture using a syringe filter unit before 
measuring required volume. 
• 
Further dilute with 0.9% sodium chloride injection immediately in non-DEHP container (see 
above) to a final concentration between 0.04 mg/mL and 1 mg/mL.  
• 
Mix by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming.  
• 
The diluted solution for administration is stable at controlled room temperature for up to six hour 
from the time of the final dilution. Protect the bag/bottle from light. 
 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration.  
 
Route of administration: Intravenous with an appropriate in-line filter (i.e. 0.2 to 5 micron) for all 
temsirolimus doses equal to or greater than 10 mg. To avoid drug loss, prepare doses less than 10 mg by 
filtering the concentrate/diluent mixture as noted above in step 2 using a syringe filter unit. 

 
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Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
To prevent hypersensitivity reaction, an H1 antihistamine (eg, diphenhydramine) should be administered 
before the start of the temsirolimus infusion. 
 
For doses less than 10 mg, filter the concentrate/diluents mixture using a syringe filter unit before measuring 
required volume as noted above in step 2. 
 
Avoid contact of the diluted product with polyvinyl chloride (PVC) equipment or devices that are 
plasticized with di- (2-ethylhexyl)pthalate (DEHP) to prevent DEHP leaching. Store diluted temsirolimus 
solutions in bottles (glass) or plastic bags (polyolefin or polypropylene). Infusion sets containing polyvinyl 
chloride should not be used to administer temsirolimus to avoid leaching of plasticizer. 
 
The following are examples of in-line filters that are compatible with temsirolimus: 
•IV 6200 Disposable I.V. Filter 0.2 micron by EPS®, Inc  
•IV 6120 Disposable I.V. Filter 1.2 micron by EPS®, Inc  
•LV 5000 Large Volume 5 micron Conical Filter by B. Braun  
•Baxter Paclitaxel Set with 0.22 micron filter  
•Codan 5 micron monofilter 
 
Other polyethersulfone filters may be used.  
 
Supplier: Supplied by Pfizer and distributed by the NCI DTCD. Do not use commercially available drug. 
 
Agent Ordering 
NCI supplied agent may be requested by the Principal Investigator (or their authorized designee) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped 
directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained). The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission of FDA form 
1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead investigator at 
that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees must submit agent requests through the PMB Online Agent Order Processing (OAOP) application 
< https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to OAOP requires the establishment of 
a CTEP Identity and Access Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the 
maintenance of an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI 
Drug 
Accountability 
Record 
Form 
(DARF). 
(See 
the 
CTEP 
home 
page 
at 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs for the Procedures for Drug 

 
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Accountability and Storage and http://ctep.cancer.gov/forms/default.htm to obtain a copy of the DARF and 
Clinical Drug Request form.) 
 
Agent Returns 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI clinical 
repository as soon as possible when: the agent is no longer required because the study is completed or 
discontinued and the agent cannot be transferred to another DCTD sponsored protocol; the agent is outdated 
or the agent is damaged or unfit for use. Regulations require that all agents received from the DCTD, NCI 
be returned to the DCTD, NCI for accountability and disposition. Return only unused vials/bottles. Do NOT 
return opened or partially used vials/bottles unless specifically requested otherwise in the protocol. See the 
CTEP 
web 
site 
for 
Policy 
and 
Guidelines 
for 
Investigational 
agent 
Returns 
at: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate forms may be 
obtained at: http://ctep.cancer.gov/forms/docs/return_form.pdf. 
 
 
6.2 
Cisplatin 
(Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC #119875 
(05/06/11) 
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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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 (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. 
(L) Toxicity may also occur later. 
 
 
Formulation and Stability:  
Available as an aqueous solution containing 1 mg/mL of cisplatin and 9 mg (1.54 mEq)/mL of sodium 
chloride in 50 mL, 100 mL, 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 >0.3% 
sodium chloride.  The final infusion solution should contain ≥ 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. 

 
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Accidental extravasation with solutions that are > 0.5 mg/mL may result in significant tissue toxicity.   
 
Supplier: Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
6.3 
Dexrazoxane  (ICRF-187, ADR-529, ZINECARD, Totect) NSC #169780 
(10/28/11) 
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 receiving 
drug 
 
Pain on injection, phlebitis, transient 
increases in triglycerides and amylase, 
increase in SGPT (ALT)/ SGOT (AST) and 
bilirubin, mild nausea, vomiting, diarrhea, 
increase in serum iron, decrease in serum 
zinc and calcium  
Anorexia, malaise, 
extravasation (rare) but 
if 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:  
Three products are available: 
1. Dexrazoxane for Injection (generic)  

 
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a. 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.  
b. Store protected from light at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Available in as a sterile, pyrogen-free lyophilized powder in 250 mg and 500 mg single use 
vials. Hydrochloric Acid, NF is added to the vials for pH adjustment. 
b. Intact vials should be stored at 25°C (77°F); excursions are permitted to 15° to 30°C (59° 
to 86°F). 
3. Totect® (dexrazoxane for anthracycline extravasation only)   
a. Totect is packaged as an emergency treatment carton for single patient use. Each carton 
contains 10 vials of Totect (dexrazoxane for injection) 500 mg and 10 vials of 50 mL 
diluent, which provides a complete three day treatment. 
Reconstitution and dilution requirements and expiration dating vary based on the product used. 
Refer to package insert for additional details.   
1. Dexrazoxane (generic) 
a. Dexrazoxane (250 mg or 500 mg vials) must be reconstituted with a sufficient quantity of 
0.167 Molar (M/6) Sodium Lactate Injection, USP, to a concentration of 10 mg 
dexrazoxane for each mL of sodium lactate.  
b. Further dilute solution in either D5W or NS to a final concentration of 1.3 to 5 mg/mL.  
c. The final solution is stable for up to 6 hours at room temperature, 15°C to 30°C (59°F to 
86°F), or under refrigeration, 2°C to 8°C (36°F to 46°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Reconstitute with Sterile Water for Injection, USP as follows:  
• 
For 250 mg vials, reconstitute with 25 mL.  
• 
For 500 mg vials, reconstitute with 50 mL.  
• 
The resultant reconstituted solutions will have a concentration of 10 mg/mL.  
b. Following initial reconstitution, ZINECARD is stable for 30 minutes at room temperature 
or up to 3 hours when stored under refrigeration, 2° to 8°C (36° to 46°F).  
c. The pH of the resultant solution is 1.0 to 3.0.  Further dilution with Lactated Ringer’s 
Injection, USP is required to achieve a final concentration range of 1.3 to 3 mg/mL in 
intravenous infusion bags. The infusion solution has a pH of 3.5 to 5.5.  
d. The infusion solution is stable for one (1) hour at room temperature or if storage is 
necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). 
 
Supplier: Commercially available. See package insert for further information. 
 
6.4 
Doxorubicin (Adriamycin®) NSC #123127  
 
 
 
 
(05/09/11) 
 
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 

 
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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. 
 
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 50 mg¹vials and 
a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 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. 
 

 
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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 NS 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 and 15 days under refrigeration, 2°-8°C (36°-46°F) when protected 
from light. Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is stable for up to 48 hours at room 
temperature (25°C) when protected from light. 
 
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. 
 
6.5 
Fluorouracil (5-Fluoruracil, 5-FU, 5-fluoro-2, 4 (1H, 3H)-pyrimidinedione, Adrucil®, Fluoro-
Uracil®) NSC# 19893  
 
 
 
 
 
 
 
(05/06/11) 
 
Source and Pharmacology:  
Fluorouracil, an analogue of the pyrimidine uracil, is an antimetabolite antineoplastic that requires 
intracellular activation to exert its cytotoxic effects. 5-FU is converted to FUdR by thymidine 
phosphorylase. Subsequent phosphorylation of FUdR by thymidine kinase results in formation of the active 
metabolite 5-fluoro-2 -deoxyuridine monophosphate (FdUMP). In the presence of the reduced folate 
cofactor 5,10-methylenetetrahydrofolate, FdUMP forms a stable covalent complex with thymidylate 
synthetase (TS). TS catalyzes the sole intracellular de novo formation of thymidine-5 -monophosphate 
from dUMP. Inhibition of TS leads to depletion of deoxythymidine triphosphate (dTTP), thus interfering 
with DNA biosynthesis and repair. 5-FU is also metabolized to fluorouridine monophosphate and further 
to fluorouridine diphosphate and then to the triphosphate form (FUTP), which is subsequently incorporated 
into RNA, thereby also interfering with RNA synthesis. Since DNA and RNA are essential for cell division 
and growth, the effect of fluorouracil may be to create a thymine deficiency which provokes unbalanced 
growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells 
which grow more rapidly and which take up fluorouracil at a more rapid rate. Following intravenous 
injection, fluorouracil distributes into tumors, intestinal mucosa, bone marrow, liver and other tissues 
throughout the body. Seven to twenty percent of the parent drug is excreted unchanged in the urine in 
6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose 
is metabolized, primarily in the liver. The catabolic metabolism of fluorouracil results in degradation 
products (e.g., CO2, urea and α-fluoro- β-alanine) which are inactive. The inactive metabolites are excreted 
in the urine over the next 3 to 4 hours. Following intravenous administration of fluorouracil, the mean half-
life of elimination from plasma is approximately 16 minutes, with a range of 8 to 20 minutes, and is dose 
dependent. No intact drug can be detected in the plasma 3 hours after an intravenous injection. In spite of 
its limited lipid solubility, fluorouracil diffuses readily across the blood-brain barrier and distributes into 
cerebrospinal fluid and brain tissue.  
 
 

 
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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, 
metallic taste, anorexia 
 
 
Hypotension, angina, ECG changes (rare 
cases of sudden death reported), anaphylaxis 
Prompt: 
Within 2-3 
weeks, prior to 
next course 
Myelosuppression, 
alopecia 
 
Diarrhea, stomatitis, 
esophagopharyngitis, 
photosensitivity, 
palmar-plantar 
erythrodysesthesia 
syndrome 
Tearing, conjunctivitis and blurred vision, 
rashes, GI ulceration and inflammation, 
hypo/hyper calcemia 
 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
Hyperpigmentation of 
the skin including the 
vein through which the 
drug is given, dry skin 
 
Nail changes (including: diffuse blue 
superficial pigment, onycholysis, dystrophy, 
pain and thickening of the nail bed, transverse 
striations), headache, visual disturbances, 
cerebellar ataxia, leukoencephalopathy 
(symptoms of which may include: ataxia, 
speech disturbances, memory loss, confusion, 
aphasia, seizures, coma), proctitis, elevated 
transaminases, hepatic necrosis (1 patient), 
MI (2 patients), ascites (4 patients with 
cancers metastatic to the liver) 
Unknown 
Frequency and 
Timing: 
Fetal and teratogenic toxicities: Fetal toxicities and teratogenic effects of 5-FU have been noted 
in animals. Malformations included cleft palates, skeletal defects and deformed appendages, 
paws and tails. The dosages which were teratogenic in animals are 1 to 3 times the maximum 
recommended human therapeutic dose. It is unknown whether the drug is excreted in breast milk. 
*Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-
fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity. A few patients have been 
rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with 
worse morbidity. Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil. 
 
Formulation and Stability:  
Fluorouracil injection is a sterile, nonpyrogenic injectable solution for intravenous administration. 
Fluorouracil 50 mg/mL is available in 10 mL, 50 mL and 100 mL vials; pH is adjusted to approximately 
9.2 with sodium hydroxide. Store at room temperature 15°-30°C (59°-86°F). Protect from light. Retain in 
carton until time of use. 
 
Although the fluorouracil solution may discolor slightly during storage, the potency and safety are not 
adversely affected. If a precipitate occurs due to exposure to low temperatures, resolubilize by gently 
heating to 60°C and shaking vigorously; allow to cool to body temperature before using. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
IV: For administration by IV push or by short infusion, no further dilution is required. 
 
IV Continuous Infusion: For administration by continuous infusion, fluorouracil can be diluted in 
50 – 1000 mL D5W or NS.  
 
Supplier:  
Commercially available from various manufacturers. See package insert for further information. 
 

 
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6.6 
Irinotecan  
[CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-
carbonyloxy-camptothecin), Camptosar®], NSC #616348 
 
 
(05/09/11) 
 
Source and Pharmacology:  
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant alkaloid isolated from 
Camptotheca acuminata). Irinotecan is a prodrug that requires conversion, by the carboxylesterase enzyme 
to the topoisomerase-I inhibitor, SN-38 in order to exert anti-tumor activity. SN-38 is approximately 
1000 times more potent than irinotecan. Camptothecins interact specifically with the enzyme topoisomerase 
I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its 
active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-
strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA 
damage produced during DNA synthesis when replication enzymes interact with the ternary complex 
formed by topoisomerase I, DNA, and either irinotecan or SN-38. Renal excretion is a minor route of 
elimination of irinotecan. The majority of the drug is metabolized in the liver. SN-38 is conjugated to 
glucuronic acid and this metabolite has no anti-tumor activity. The extent of conversion of SN-38 to its 
glucuronide has been inversely correlated with the risk of severe diarrhea, because the other major route of 
SN-38 excretion is biliary excretion by canalicular multispecific organic anion transporter (cMOAT) which 
presumably leads to mucosal injury. In addition, APC and NPC are oxidative metabolites of irinotecan 
dependent on the CYP3A4 isoenzyme. After intravenous infusion of irinotecan in humans, irinotecan 
plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of 
about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 
10 to 20 hours. Irinotecan is 30% to 68% bound to albumin and SN-38 is approximately 95% bound to 
albumin. 
 
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, fever, 
asthenia, cholinergic symptoms: 
(rhinitis, increased salivation, miosis, 
lacrimation, diaphoresis, flushing, and 
intestinal hyperperistalsis that can 
cause abdominal cramping and early 
diarrhea)  
Constipation, 
headache, diarrhea (L)  
Anaphylaxis, dehydration 
with dizziness & hypotension, 
bradycardia, dyspnea and 
cough, 
disorientation/confusion, 
somnolence, pain at infusion 
site 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Neutropenia, alopecia, eosinophilia, 
elevations in transaminases, alkaline 
phosphatase, bilirubin, mucositis, 
infection 
Anemia, rash, 
dyspepsia, 
thrombocytopenia 
Colitis, renal failure 
(secondary to severe 
dehydration), 
thromboembolic events, ileus 
Delayed: 
Any time later 
during therapy 
 
 
Pneumonitis 
Late: 
Any time after 
completion of 
treatment 
 
 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at doses similar 
or less than those used in humans. Toxicities include: decreased skeletal ossification, multiple 
anomalies, low birth weight and increased fetal mortality. It is not known if irinotecan is 
excreted into breast milk but it is excreted into rat milk. 
(L) Toxicity may also occur later. 
 

 
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Formulation & Stability:  
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the trihydrate salt), 45 mg 
sorbitol, and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium 
hydroxide or hydrochloric acid. Irinotecan is available in single-dose amber glass vials in 40 mg 
(2 mL),100 mg (5 mL), 300 mg (15 mL), and 500 mg (25 mL). Store at controlled room temperature 15°-
30°C (59°-86°F). Protect from light. It is recommended that the vial (and backing/plastic blister) should 
remain in the carton until the time of use.  
 
Guidelines for Administration:  See Treatment and Dose Modifications sections of the protocol. 
Irinotecan must be diluted prior to infusion. Irinotecan should be diluted in D5W, (preferred) or NS to a 
final concentration range of 0.12-2.8 mg/mL. The solution is physically and chemically stable for up to 
24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions diluted 
in D5W and stored at refrigerated temperatures (approximately 2°-8°C), and protected from light are 
physically and chemically stable for 48 hours. Refrigeration of admixtures using NS is not recommended 
due to a low and sporadic incidence of visible particulates. Care should be taken to avoid extravasation; the 
use of a central line is suggested. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more detailed information. 
 
6.7  
Vincristine Sulfate (Oncovin®, VCR, LCR) NSC #67574 
 
 
(08/16/12) 
 
Source and Pharmacology:  
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, disrupting 
microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. The initial, middle, and 
terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of the terminal 
half-life in humans is from 19 to 155 hours. The liver is the major excretory organ in humans and animals; 
about 80% of an injected dose of vincristine sulfate appears in the feces and 10% to 20% can be found in 
the urine. The p450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to 30 minutes 
after injection, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but 
not irreversibly bound. It is excreted in the bile and feces. There is poor CSF penetration.  
 
 

 
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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 
 
Jaw pain, headache 
Extravasation (rare) but if occurs = 
local ulceration, shortness of breath, 
and bronchospasm 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Alopecia, constipation 
Weakness, abdominal 
pain, mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia) 
Paralytic ileus, ptosis, diplopia, 
night blindness, hoarseness, vocal 
cord paralysis, SIADH, seizure, 
defective sweating 
Delayed: 
Any time later during 
therapy 
Loss of deep tendon reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
foot drop, abnormal gait  
Difficulty walking or inability to 
walk; sinusoidal obstruction 
syndrome (SOS, formerly VOD) (in 
combination); blindness, optic 
atrophy; urinary tract disorders 
(including bladder atony, dysuria, 
polyuria, nocturia, and urinary 
retention); autonomic neuropathy 
with postural hypotension; 8th 
cranial nerve damage with 
dizziness, nystagmus, vertigo and 
hearing loss 
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with 
other antineoplastic agents) have been noted in humans. The toxicities include: chromosome 
abnormalities, malformation, pancytopenia, and low birth weight. It is unknown whether the 
drug is excreted in breast milk. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate 1 mg 
(1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are added for pH control. The pH of 
vincristine sulfate injection, USP ranges from 3.5 to 5.5. This product is a sterile, preservative free solution. 
Store refrigerated at 2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton until time of use. 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the Safety and 
Quality Council (Australia) all support the use of minibag rather than syringe for the infusion of vincristine. 
The delivery of vincristine via either IV slow push or minibag is acceptable for COG protocols. Vincristine 
should NOT be delivered to the patient at the same time with any medications intended for central nervous 
system administration. Vincristine is fatal if given intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. Vincristine sulfate must 
be administered via an intact, free-flowing intravenous needle or catheter. Care should be taken to ensure 
that the needle or catheter is securely within the vein to avoid extravasation during administration. The 
solution may be injected either directly into a vein or into the tubing of a running intravenous infusion. 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   

 
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The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the statement: 
“Do not remove covering until moment of injection. For intravenous use only - Fatal if given by other 
routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. VinCRIStine is 
available in a liposomal formulation (vinCRIStine sulfate liposomal injection, VSLI, Marqibo®). Use 
conventional vincristine only; the conventional and liposomal formulations are NOT interchangeable. 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
 
 
 
 
 
 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below.  
 
7.1 
Patients with low AFP levels 
On rare occasions, laboratory assays have been described to be falsely low in patients whose true AFP 
levels are so high that they create a “hook” effect and overwhelm the methods of the assay. In patients 
with low AFP levels, discussion with the laboratory should be considered to determine if serial dilutions 
can be performed to verify whether an AFP level is truly low. As noted in the background, small cell 
undifferentiated phenotype is often associated with a truly low AFP level.69  
 
7.2 
Required Clinical, Laboratory and Disease Evaluations for Very Low Risk Patients-
Stratum 1 (Stage I PFH) 
 
See Section 7.6.1 for details. 
  
 
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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7.3 
Required Clinical, Laboratory and Disease Evaluations for Low-Risk Patients – Stratum 2  
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
Obtain prior to start of each treatment cycle unless otherwise indicated. 
 
 
STUDIES TO BE OBTAINED 
Baseline 
Each Cycle 
End of Therapy 
History 
X 
X 
X 
Physical exam (Ht, Wt, BSA, VS) 
X 
X 
X 
CBC, differential, platelets 
X 
Weekly 
X 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
X 
X 
Creatinine, ALT/AST, bilirubin 
X 
X 
X 
Total protein/albumin 
X 
X 
X 
Primary tumor evaluation (CT and/or MRI)4 
X1 
 
X 
Metastatic tumor evaluation (CT chest)4 
X1 
 
X 
Abdominal ultrasound4 
X1 
 
 
PRETEXT Grouping5 
X 
 
 
Audiogram 
X1 
 
X 
AFP6 
X 
X 
X 
Pathology slides 
X2 
 
 
Tumor tissue 
X 3 
 
 
Pregnancy test for females of childbearing potential 
X 
 
 
1 Tumor evaluation, ultrasound and audiogram may be done within 28 days prior to enrollment.  
2 Pathology slides required for rapid review of all Stage I and II patient’s diagnostic specimens (see Section 14.0). 
3 Tumor tissue is strongly encouraged to be submitted and can be submitted if consent has been obtained and patient is enrolled 
on ABTR01B1 or other appropriate study (see protocol for details). 
4 See Section 15.0 for details.  
5 PRETEXT grouping should be done by radiologist, surgeon and oncologist on diagnostic scans (see Section 10.2 and 
Appendix I). 
6 Following resection, a repeat AFP should be obtained immediately prior to beginning chemotherapy (the same day). 
 
 
This table only includes evaluations necessary to answer the primary and secondary aims.  Obtain 
other studies as required for good patient care. 
  
 

 
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7.4 
Required Clinical, Laboratory and Disease Evaluations for Intermediate-Risk Patients –
Stratum 3 
 
Note: Stratum 3 has been closed to accrual as of 03/12/12 
 
Obtain prior to start of each treatment cycle unless otherwise indicated. 
 
STUDIES TO BE OBTAINED 
Baseline 
Each 
cycle 
End of 
Cycle 2 
End of 
Cycle 4 
End of 
Therapy 
History 
X 
X 
 
 
X 
Physical exam (Ht, Wt, BSA, VS) 
X 
X 
 
 
X 
CBC, differential, platelets 
X 
Weekly 
 
 
X 
Urinalysis 
X 
 
 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
X 
 
 
X 
Creatinine, ALT/AST, bilirubin 
X 
X 
 
 
X 
Total protein/albumin 
X 
X 
 
 
X 
Primary tumor evaluation (CT and/or MRI)5 
X1 
 
X 
X 
X 
Metastatic tumor evaluation (CT chest)5 
X1 
 
 
X 
X 
Abdominal ultrasound5 
X1 
 
X 
X 
 
PRETEXT/POST-TEXT Grouping6 
X 
 
X 
X 
 
Echocardiogram or MUGA7 
X1 
 
 
X 
X 
Audiogram 
X1 
 
 
X 
X 
AFP 
X 
X 
 
 
X 
Liver transplant consultation 
X2 
 
X2 
 
 
PLUTO registry consent 
 
 
X8 
 
 
Pathology slides 
X3 
 
X3 
X3 
 
Tumor tissue 
X4 
 
X4 
X4 
 
Pregnancy test for females of childbearing 
potential 
X 
 
 
 
 
1 
Tumor evaluation, ultrasound, echocardiogram (or MUGA) and audiogram may be done within 28 days prior to enrollment.  
It is highly recommended that patients have echocardiogram (or MUGA) and audiogram prior to treatment, but if  patient is 
emergently treated (see Section 3.2.2) these may be deferred until clinically stable, but must be done before beginning Cycle 
2.  
2 
A liver transplant consult should be performed as soon as possible after diagnosis but no later than after Cycle #2 (see Section 
13.1.3). 
3 
Pathology slides required for rapid central review of all Stage I and II patient’s diagnostic specimens. Pathology slides required 
for patients following all surgical (biopsy/resection) procedures (see Section 14.0). 
4 
Tumor tissue is strongly encouraged to be submitted and can be submitted if consent has been obtained and patient is enrolled 
on, ABTR01B1 or other appropriate study (see protocol for details). 
5 
See Section 15.0 for details. Ultrasound only needs repeating if initial U/S showed tumor thrombus & does not need to be 
performed once thrombus has resolved or surgery performed.  
6 
PRETEXT/POST-TEXT grouping should be done by radiologist, surgeon and oncologist on all scans performed at diagnosis 
and pre-operatively (see Section 10.2 and Appendix I). 
7 
The same modality is to be used each time for consistency. 
8 
Consent for PLUTO registry should be obtained within one month of liver transplant, see Section 13.4  
 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as required for good patient care. 
  
 

 
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7.5  
Required Clinical, Laboratory and Disease Evaluations for High-Risk Patients - Stratum 4 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
Obtain prior to start of each treatment cycle unless otherwise indicated. 
 
STUDIES TO BE OBTAINED 
Baseline 
Each cycle 
End 
of 
Cycl
e 2  
End of 
Cycle 4 
End of Cycle 6 
(Responders and 
Non-responders) 
End of 
Therapy 
History 
X 
X 
 
 
 
X 
Physical exam (Ht, Wt, BSA, VS) 
X 
X 
 
 
 
X 
CBC, differential, platelets 
X 
Weekly 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
X 
 
 
 
X 
Creatinine, ALT/AST, bilirubin 
X 
X 
 
 
 
X 
Bilirubin 
X 
Day 1 of 
each cycle 
and Day 8 
of VIT 
cycles 
 
 
 
 
Total protein/albumin 
X 
X 
 
 
 
X 
Urine glucose 
X 
X1 
 
 
 
 
Triglycerides, Cholesterol (Total, HDL,LDL) 
X2 
X2 
 
 
 
 
Primary tumor evaluation (CT and/or MRI)8 
X3 
 
X 
X5 
X5 
X 
Metastatic tumor evaluation (CT chest)8 
X3 
 
X 
X5 
X5 
X 
Abdominal ultrasound8 
X3 
 
X 
X 
X 
 
PRETEXT/POST-TEXT Grouping9 
X 
 
X 
X 
X 
 
Echocardiogram or MUGA10 
X3 
 
 
 
X 
X 
Audiogram 
X3 
 
 
 
X 
X 
AFP12 
X 
X13 
X13 
 
 
X 
Liver transplant consult 
X4 
 
X4 
X4 
 
 
PLUTO registry consent 
 
 
 
X11 
 
 
Pathology slides 
X6 
 
 
X6 
 
 
Tumor tissue 
X7 
 
 
X7 
 
 
Pregnancy test for females of childbearing 
potential 
X 
 
 
 
 
 
 
1 If patients at baseline have ≥ Grade 2 hyperglycemia or polyuria or polydipsia, obtain urine glucose weekly during Cycle 1. 
Obtain at the start of each cycle and as clinically indicated ONLY in patients who develop ≥ Grade 2 hyperglycemia or polyuria 
or polydipsia on protocol therapy. 
2 If Grade 3 or 4 hypercholesterolemia or Grade 3 or 4 hypertriglyceridemia is detected when routine (non-fasting) laboratory 
studies are performed, the tests should be repeated within 3 days in the fasting state to permit accurate grading 
3 Tumor evaluation, ultrasound, echocardiogram (or MUGA), and audiogram may be done within 28 days prior to enrollment. It 
is highly recommended that patients have echocardiogram (or MUGA) and audiogram prior to treatment, but if  patient is 
emergently treated (see Section 3.2.2) these may be deferred until clinically stable, but must be done before beginning Cycle 2.  
4 A liver transplant consult should be performed as soon as possible after diagnosis but no later than first day of 3rd C5VD Cycle. 
(i.e. no later than first day of Cycle 5,) (See Section 13.1.5).  
5 Tumor disease evaluation performed after VIT Cycle 2 for all patients and after Cycles 4, 6 & 8 for non-responders and after 
Cycles 4, 6 and 10 for responders until tumor removed. No scans required once all tumor has been removed or resolved until 
the end of therapy (see Section 15.3). 
6 Pathology slides required for patients following all surgical (biopsy/resection) procedures (see Section 14.0). 
7 Tumor tissue is strongly encouraged to be submitted and can be submitted if consent has been obtained and patient is enrolled 
on ABTR01B1 or other appropriate study (See protocol for details.) 
8 See Section 15.0 for details. Ultrasound only needs repeating if initial U/S showed tumor thrombus & does not need to be 
performed once thrombus has resolved or surgery performed.  

 
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9 PRETEXT/POST-TEXT grouping should be done by radiologist, surgeon and oncologist on all scans performed at diagnosis 
and pre-operatively as appropriate. (See Section 10.2 and Appendix I). 
10 The same modality is to be used each time for consistency. 
11 Consent for PLUTO registry should be obtained within one month of liver transplant, see Section 13.4. 
12 If a biopsy is performed to make diagnosis, a repeat AFP should be obtained immediately prior to beginning chemotherapy 
(the same day). 
13 The AFP obtained at the end of Cycle 2/prior to Cycle 3 must be recorded on the Reporting Period 1 CRF and submitted for 
central review assessment of response. If an AFP was obtained post Cycle 2, do not repeat prior to Cycle 3. Note: The Reporting 
Period 1 CRF must be submitted without delay, see the Data Submission Schedule for details. 
 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as required for good patient care. 
 
7.6 
Recommended Clinical, Laboratory and Disease Evaluations in Follow-up 
 
7.6.1 
Recommended Follow-up Evaluations for Patients with Stage I PFH Tumors (Very low-risk-
Stratum 1) 
History/Physical exam, AFP and other studies as required for good patient care 
• 
Year 1 (Months 1, 2, 4, 6, 8, 10 and 12)  
• 
Year 2 (Months 15, 18, 21 and 24)  
• 
Year 3 (Months 28, 32 and 36)  
• 
Year 4 (Months 42 and 48) 
 
No specific imaging is required. CT (abdomen/chest), abdominal ultrasound and/or chest X-ray can be 
performed at the discretion of the treating physician. 
 
7.6.2 
Recommended Follow-up Evaluations for Patients Who Receive Chemotherapy 
History/Physical exam, CBC, AFP, Electrolytes, creatinine (until normal) 
• 
Year 1 off therapy (Months 1, 2, 4, 6, 8, 10 and 12) 
• 
Year 2 (Months 15, 18, 21 and 24)  
• 
Year 3 (Months 28, 32 and 36)  
• 
Year 4 (Months 42 and 48) 
 
Follow up in Year 5 and beyond is at the discretion of the treating physician. See COG Late Effects 
Guidelines for recommended post treatment follow-up at: 
http://www.survivorshipguidelines.org 
 
No specific imaging is required for patients who presented with elevated AFP (> 100 ng/mL) at diagnosis.  
CT (chest), CT or MRI (abdomen), abdominal ultrasound, and/or chest X-ray can be performed at the 
discretion of the treating physician.  
 
For patients with a low AFP (< 100 ng/mL) at diagnosis, imaging studies (CT [chest], CT or MRI 
[abdomen] and/or chest X-ray) should be performed every 3 months during the first year off therapy, and 
then at the times of follow-up as listed above.  
 
Audiograms should be performed when the patient is one year off therapy. Further audiograms can then be 
performed at the discretion of the treating physician. Patients who have evidence of hearing loss should be 
considered for yearly follow up audiograms. 
 
Echocardiograms (or MUGAS) should be performed for patients who received doxorubicin yearly for the 
first 4 years off therapy, and can then be performed at the discretion of the treating physician. 
 

 
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If relapse is suspected, then CBC, AST, ALT, AFP, and CT (abdomen/chest) should be performed. A rise 
in AFP by itself will not be considered as progressive disease. If an AFP level is elevated compared to a 
previous level then weekly AFP measurements should be considered. Radiographic studies (CT chest and 
CT or MRI abdomen) should be considered in patients with an elevated AFP in an attempt to try and 
identify progressive disease. 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
 
a) 
Progressive disease. 
b) 
Unresectability of tumors following 4 cycles of chemotherapy in intermediate-risk patients. 
c) 
Unresectability of tumors following 10 cycles of chemotherapy in high-risk patients who 
responded (RECIST CR or PR) to “up-front” window therapy. 
d) 
Unresectability of tumors following 8 cycles of chemotherapy in high-risk patients who did not 
respond to “up-front” window therapy. 
e) 
Inability to have a liver transplant by the specified protocol timepoints for reasons unrelated to 
hepatoblastoma. 
f) 
Failure to begin protocol therapy within 42 days of initial biopsy or definitive surgery whichever 
occurs last. 
g) 
Failure to resume post resection chemotherapy within 42 days of resection in intermediate- or 
high-risk patients. 
h) 
Refusal of further protocol therapy by patient/parent/guardian. 
i) 
Completion of planned therapy.  
j) 
Physician determines it is in patient’s best interest. 
k) 
Development of a second malignant neoplasm. 
l) 
For high-risk patients, if the investigator selects a post-induction regimen that is not 
indicated by the central review of response. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below). 
Follow-up data will be required unless consent was withdrawn.  
 
8.2 
Off Study Criteria 
 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Tenth anniversary of the date the patient was enrolled on this study. 
f) Definitive surgery does not confirm the diagnosis of hepatoblastoma or reveals another 
pathological diagnosis in patient who was enrolled emergently without initial biopsy because too 
sick. 
 

 
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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Patient Accrual and Expected Duration of Trial 
Patients will be enrolled for five (5) years and analyses to address the primary study aims will be conducted 
with one more year of follow-up.  The projected annual enrollment rates for each of the categories of 
patients are: 
 
Stratum 
Patient Category 
Estimated Annual Accrual 
1 
Stage I PFH with initial AFP ≥100 ng/mL or AFP not 
obtained prior to initial resection 
3 patients per year 
2 
Stage I, non-PFH, non-SCU, Stage II, non-SCU 
9.2 patients per year 
3 
Intermediate risk 
41.6 patients per year 
4 
Stage IV or patients with AFP <100 ng/mL at 
diagnosis 
16 patients per year 
 
 
9.2 
Statistical Analysis Methods 
Statistical Considerations 
Patients will be enrolled to the study for Five years and followed for an additional year, by which time we 
expect most disease-related analytic events will have occurred. The design objectives will be different for 
the four subgroups: (1) Stage I PFH patients (stratum 1) with AFP ≥ 100 ng/mL or AFP not obtained prior 
to surgical resection of tumor; (2) low risk patients (stratum 2) defined as patients with Stage I non-PFH, 
non-SCU; Stage II non-SCU (3) intermediate risk patients (stratum 3); and (4) Stage IV patients or patients 
with AFP < 100 ng/mL at diagnosis (stratum 4). EFS will be the time from patient enrollment until last 
follow-up or an analytic event is observed, whichever comes first. Analytic events are: (1) progression of 
existing disease or occurrence of disease at new sites; (2) treatment failure defined as the presence of disease 
after four cycles of chemotherapy and post-induction surgery (if attempted) for patients enrolled with Stage III 
disease or presence of disease after planned chemotherapy (eight cycles for non-responders, ten cycles for 
responders) for patients enrolled with Stage IV disease (3) death from any cause prior to disease progression 
or diagnosis of a second malignant neoplasm; or (4) diagnosis of a second malignant neoplasm. Survival 
will be the time from enrollment until death from any cause or last follow-up, whichever comes first. 
Section 3 requires that planned start of systemic therapy for patients whose protocol prescribed therapy 
includes chemotherapy must be within 42 days of enrollment. Experience from prior COG studies of 
hepatoblastoma demonstrates that this can be accomplished in most patients. All patients who die within 
42 days of enrollment will be considered in the analytic plans below. All patients who survive more than 
42 days after enrollment and whose protocol therapy prescribes chemotherapy but who do not have such 
systemic therapy started by the 43rd day after enrollment will be excluded from the analyses below. 
A patient enrolled without histological confirmation (see Section 3.2.2.b) will be considered evaluable for 
all study analyses unless the tumor tissue obtained in a future surgical procedure is not consistent with 
hepatoblastoma or reveals another pathological diagnosis. If histological confirmation is not confirmed in 
the future for these patients by a biopsy or surgical resection, they will be considered off study.  
 
The statistical analysis will include an assessment of the influence of the exclusion of cases for whom there 
is a discrepancy in diagnosis between institutional and central review, or for whom there is an atypical 
histological presentation. The influence will be assessed by comparing the EFS and survival, as estimated 
by the method of Kaplan and Meier70 with and without such cases. This will provide an ad hoc assessment 
of the effect of such cases on outcome characterization. Formal statistical quantification of such effects will 
not be straightforward. 
 
Surgical resection followed by observation was first tested on COG trial P9645 and has been demonstrated 
to be a successful approach for patients with stage I PFH. These patients will be enrolled on the trial, since 

 
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it will be necessary to submit all Stage I and II patients to mandatory central review to determine the 
appropriate analytic strategy.  The results of this review will be returned for information to the relevant 
institutional investigator.  Individuals considered Stage I PFH and treated with surgery only will be 
considered for the analysis described in the paragraph below.  Individuals considered Stage I non-PFH, 
non-SCU, Stage II, non-SCU patients and treated with the chemotherapy for such patients will be 
considered in the analysis described in “Hypothesis 1.1” below.  
 
Nine (9) stage I PFH patients will be required for AHEP0731. We may enroll up to 12 patients to account 
for patients who are determined later to be ineligible. These patients will be followed closely for disease 
and life status. The outcome of these patients will be summarized through survival and EFS curves 
estimated by the method of Kaplan and Meier70 If 2or more analytic events are observed, the strategy of 
surgery without any further therapy will identify enrollment to this strategy for possible termination because 
of insufficient disease control. If this strategy is associated with a long-term event-free survival of 65%, the 
probability of accepting it is 0.12. If this strategy is associated with a long-term event-free survival of 93%, 
the probability of accepting it is 0.89.  
 
Toxicity will be reported using CTCAE criteria (version 4). All Grade 3 or 4 or greater non-hematological 
toxicities as well as any toxicity that requires submission of an CTEP-AERS report as outlined in protocol 
section 11.3, Table B, will be reported while the patient is on protocol therapy. The frequency of each 
toxicity type will be quantified as the percent of reporting periods on which the toxicity of the relevant 
grade is reported. All reporting periods where the patient receives at least one dose of each of the agents in 
the therapeutic plan for that individual will be included in the denominator for the rate calculation.  
 
Follow-up data will be obtained on all patients considered eligible for the protocol. As part of the study 
design, slides sufficient to confirm the histological subtype of hepatoblastoma (PFH v. SCU v. neither PFH 
nor SCU) of all Stage I patients will be submitted to mandatory central review according to the time lines 
described above. Patients for whom the central review supports the therapeutic approach of the institutional 
investigator will constitute the analytic subgroup for each of the analyses planned for Stage I patients. The 
results of this review will be returned for information to the relevant institutional investigator as soon as 
the assessment becomes available in the COG data system. 
 
Hypothesis 1.1: (Stage I, non-PFH, non- SCU, Stage II, non-SCU [Stratum 2]): Expected Annual Accrual: 
9.2 patients per year. Total: 51 patients. We may enroll up to 60 patients to account for patients who are 
determined later to be ineligible.    
 
If 7 or more analytic events are observed the strategy of surgery with reduced chemotherapy will identify 
enrollment to this strategy for possible termination because of insufficient disease control. If this strategy 
is associated with a long-term event-free survival of 78%, it will be rejected with probability 0.90. If this 
strategy is associated with a long-term event-free survival of 89%, it will be accepted with probability 0.81.  
The graph below describes the probability of accepting the strategy as a function of its long-term EFS: 
 

 
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Hypothesis 1.2 (Intermediate-risk patients [Stratum 3]): As of Amendment #3B enrollment to stratum 3 is 
terminated because sufficient patients have been enrolled to address the hypothesis. The total enrollment to 
stratum 3 was 105 patients. 
 
Feasibility of Delivery of C5VD: The primary measure of feasibility will be rate of death as a first analytic 
event.  All patients who receive at least one dose of the C5VD regimen will be considered evaluable for 
this endpoint. Any patient who dies on protocol therapy or within 30 days of the termination of protocol 
therapy of a cause considered possibly, probably or likely related to systemic chemotherapy will be 
considered to have experienced an on-protocol-therapy death. If five or fewer of the 99 patients experience 
on-protocol-therapy death, the regimen will be considered feasible for further development.  If the regimen 
is associated with a death-event rate of 3%, that observed for patients who were assigned to chemotherapy 
on P9645, the regimen will be considered feasible with probability 0.92.  If the regimen is associated with 
a death-event rate of 10%, the regimen will be considered not feasible with probability 0.94. If the sixth on-
protocol-therapy death is reported, study enrollment will be suspended. In addition to this, at each report to 
the DSMC the estimated on-protocol-therapy death rate and its 95% confidence interval will be reported to 
the phase III DSMC as the cumulative incidence of on-treatment death and the 95% confidence intervals at 
four and six months.  
 
 
Since the addition of doxorubicin to C5V may affect the delivery of all the agents in the combination, we 
will characterize the amount of each agent that can be delivered during the first four cycles of therapy and 
the actual amount of doxorubicin delivered on protocol therapy. During the first four cycles, the total dose 
of each agent administered will be collected, along with the patient’s height and weight. The average 
amount of each drug, calculated as dose per meter squared will be calculated and a lower 95% confidence 
bound on the true average dose delivered will be calculated assuming a normal distribution of delivered 
dose. In addition the total doxorubicin dose, in milligrams per meter squared will be calculated for each 
patient as well as the average and the 95% confidence interval for this amount. This will be used in planning 
subsequent trials. 
 

 
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Hypothesis 1.3: (Stage IV [Stratum 4]): Expected Annual Accrual: 16 patients per year. Total: 43 patients 
(to account for patients who may be later determined to be ineligible.) 
 
Prior to Amendment 3B, VI therapy was evaluated in stage IV patients. No patient assigned to VI 
experienced early progression. All patients evaluated for the VIT combination, therefore, will be evaluated 
only for response as defined in Section 10 of the protocol. 
 
Disease status at the end of two cycles of therapy (or earlier in the case of early progressive disease) will 
be the endpoint for evaluable patients.  
 
A patient will be considered evaluable if the individual is eligible, receives at least one dose of each agent 
in the combination being tested and is not removed from protocol therapy for reasons other than toxicity or 
disease progression. Any evaluable patient who has a CR or PR according the criteria prescribed Section 
10 of the protocol will be considered a ‘responder’. All other evaluable patients will be considered non-
responders. Patients will be enrolled in two stages according to the design specified below: 
 
 
Number of Evaluable 
Patients Enrolled 
Results 
Decision 
Stage I: 22 Evaluable 
Patients 
9 or fewer responders  
Terminate the trial with the conclusion 
the regimen does not demonstrate 
sufficient disease control 
10 or more responders 
Continue to the next stage and enroll 19 
more patients 
Stage II:  19 Evaluable 
Patients (Total of 41) 
Cumulatively 22 or fewer responders  
Terminate the trial with the conclusion 
the regimen does not demonstrate 
sufficient disease control 
23 or more responders 
Terminate the trial with the conclusion 
the regimen demonstrates sufficient 
disease control for further investigation 
 

 
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The statistical characteristic of this rule are presented in the figure below: 
 
 
If the regimen is associated with a true response rate of 45%, which is approximately the maximum 
likelihood estimate of the response rate associated with VI, the design will identify the regimen as not 
sufficiently effective for further development with probability 0.90. If the regimen is associated with a true 
response rate of 65%, the regimen will be considered of sufficient efficacy to warrant further development 
with probability 0.90. The probability enrollment will be terminated at the first stage of accrual if the true 
response rate is 45% is 0.435. 
 
The response status used for the application of the statistical rule will be that obtained from the central 
review of RECIST response and the alphafetoprotein values and sampling dates provided by the 
institutional investigator. If there is a discrepancy between the assessment by central review and by 
institutional assessment, the study PI will discuss with the treating physician to resolve the discrepancy. 
 If the investigator selects a post-induction regimen that is not indicated by the central review of response, 
the patient will be considered off protocol therapy as of the start date of consolidation therapy.  
 
Hypothesis 2.0:  Referral Feasibility:  
All patients enrolled on the planned COG phase III study of hepatoblastoma (AHEP0731) and who have 
Stage III or IV disease and whose tumor is PRETEXT classified as PRETEXT 3-4 extensive multifocal; 
Probability of Acceptance
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Response Probability 
0.44 
0.46 
0.48 
0.50
0.52 
0.54 
0.56
0.58
0.60
0.62 
0.64 
0.66 
Statistical Characteristics of the Two Stage Design 

 
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PRETEXT 3 +V; PRETEXT 3 +P; or PRETEXT 4 extensive multifocal will be evaluable for this portion 
of the study (‘referable extent of disease’). A recent retrospective analysis of the data from INT-0098 looked 
at the PRETEXT grouping of tumors in patients with Stage III and Stage IV disease. In the years since INT-
0098 the PRETEXT system has been increasingly employed by the European SIOPEL studies of pediatric 
hepatoblastoma in an attempt to define resectability.   
 
INT-0098 was a POG/CCG cooperative trial enrolling 182 children with hepatoblastoma in the early 
1990’s. In our retrospective review, detailed surgical and pathology reports enabling accurate retrospective 
PRETEXT grouping were available for 155 of the initial 182 patients. By the proposed definition of 
resectability in this study, INT-0098 included 32 patients with potentially unresectable tumors who might 
have been referred early for potential transplantation. The precise breakdown from INT-0098 is as follows: 
 
Stage III: 
PRETEXT 2 multifocal = 1 
PRETEXT 3 multifocal or +V or +P = 8 
PRETEXT 4 = 13 
Stage IV: 
PRETEXT 2 multifocal = 0 
PRETEXT 3 multifocal or +V or +P = 2 
PRETEXT 4 = 8 
Total = 32 
 
INT-0098 was open for enrollment for 4 years. As a conservative estimate, using the 32 patients as the 
projected number of patients for whom referral is appropriate, we expect referral will be appropriate for 
approximately 25 patients enrolled to AHEP0731. 
 
Patients enrolled on this study will be considered candidates for referral provided the patient has a referable 
stage of disease and receives two cycles of chemotherapy and is still considered on protocol therapy at the 
end of the second cycle. A patient will be considered a referral success if: (1) the patient is enrolled on 
regimen F or regimen H and referred for transplant prior to the start of the third cycle of chemotherapy; or 
(2) the patient is enrolled on regimen H or W and is referred for transplant by the start of the third cycle of 
C5VD. Otherwise the patient will be considered a referral failure. In particular, a patient who has a referable 
stage of disease, is treated on regimen H or W and has protocol therapy terminated after the completion of 
cycle 2 but before the completion of cycle 4 without being referred for transplant will be considered a 
referral failure. 
 
The feasibility of referral will be evaluated for each of the expected 25 patients who would be amenable to 
OLT. A patient for whom referral is considered appropriate who receives a consultation after enrollment 
will be considered a success with respect to feasibility. If referral is accomplished for 16 or more patients, 
the strategy will be considered successful and identified for possible incorporation into a randomized study.  
The characteristics of this rule as a function of the true ‘success’ probability are: 
 
True Probability of Successful Referral 
Chance Referral Will be Identified 
as Feasible 
0.50 
11% 
0.55 
24% 
0.60 
42% 
0.65 
63% 
0.70 
81% 
0.75 
93% 
 
If more than 25 patients are identified as candidates for referral, the number of patients for whom referral 

 
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is accomplished required to consider referral “feasible” will be increased in such a way as to yield “Chance 
Referral Will be Identified as Feasible” probabilities of greater than 80% for the scenarios identified by the 
last two lines in the table above. 
 
All patients who are referred for OLT evaluation and considered candidates for such a surgery will 
contribute to the evaluation of secondary aim 1.3.2. If we conclude referral is feasible, we estimated 
conservatively 16 patients would be referred. We estimate that 2 such patients will not be candidates for 
OLT because of technical reasons. If 8 or more of the 14 patients considered candidates for OLT receive 
such a procedure, OLT will be considered a candidate for possible incorporation into a randomized trial. 
The characteristics of this rule as a function of the true ‘success’ probability is: 
 
Probability of OLT Performed on a Potential 
Candidate 
Chance OLT will be Identified for Possible 
Incorporation Into a Randomized Trial 
0.50 
0.40 
0.55 
0.55 
0.60 
0.69 
0.65 
0.82 
0.70 
0.90 
0.75 
0.96 
 
If more than 14 patients are successfully referred for OLT the current cutoff of 8 noted in the paragraph 
above will be increased in a manner similar to that described for the analysis of feasibility of referral. 
 
Any patient from this secondary endpoint analysis population that receives an OLT will be considered a 
success with respect to the secondary aim 1.3.3. All patients in this cohort will be further subdivided into 
one of four outcome-of-transplant attempt groups: (a) proven to be resectable with a conventional 
surgery; (b) remain unresectable, primary transplant performed after a good initial response to 
chemotherapy; (c) remain unresectable, no surgery performed due to persistent metastatic disease 
unresponsive to chemotherapy or surgical resection; or (d) do not proceed to surgery because of refusal or 
deteriorating patient condition.   
 
Two years after the last patient is enrolled we will calculate the 95% confidence interval for the 2-year EFS. 
If OLT is considered for possible incorporation into a randomized trial, we estimate conservatively that 8 
patients will have undergone an OLT.  The expected width of the 95% confidence interval is: 
 
Expected 95% Confidence Interval Widths as a Function of the True 2-Year EFS 
 
True 2-Year EFS 
Expected 95% Confidence Interval 
for 2-Year EFS 
0.50 
0.17-0.83 
0.60 
0.24-0.88 
0.70 
0.32-0.93 
0.80 
0.42-0.97 
0.90 
0.54-0.99 
 

 
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9.3 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
24 
37 
61 
Not Hispanic or Latino 
89 
103 
192 
Ethnic Category: Total of all subjects 
113 
140 
*253 
Racial Category 
 
American Indian or Alaskan Native 
3 
0 
3 
Asian 
2 
10 
12 
Black or African American 
8 
8 
16 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
100 
122 
222 
Racial Category: Total of all subjects 
113 
140 
*253 
* These totals must agree 
 
This distribution was derived from P9645 and accounts for an aggregate ineligibility and inevlauability rate 
of 10%. 
 
 
 
10.0 
EVALUATION CRITERIA  
 
10.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting beginning July 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 website (http://ctep.cancer.gov). 
  
10.2 
PRETEXT GROUPING (See Appendix I) 
PRETEXT will be assessed at diagnosis and at the time of all subsequent abdominal scans performed. PRE-
OPERATIVELY. The group assigned after the second cycle of chemotherapy and where applicable, after 
the 4th cycle of chemotherapy, will be referred to as POST-TEXT.   
 
The number of affected liver sections determines the PRETEXT group as shown in Appendix I. The 
assignment of PRETEXT will be established by the consensus of the treating oncologist, radiologist, and 
surgeon at the local institution. Pre-operative abdominal scans will also be submitted for central radiologic 
and surgical review to assess concordance of local and central PRETEXT grouping.  
 

 
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The patient’s liver tumor will be assigned PRETEXT (and/or POST-TEXT) according to the guidelines 
below. These guidelines are shown graphically in Appendix I.  
 
PRETEXT/POST-
TEXT Group 
Number of Affected Liver Sections  
1 Tumor involves only 1 liver section; 3 adjoining sections are free of tumor. 
2 Tumor involves 2 adjoining liver sections; 2 adjoining sections are free of tumor. 
3 Tumor involves 3 adjoining sections or 2 nonadjoining sections; 1 section or 2 
nonadjoining sections are free of tumor. 
4 Tumor involves all 4 liver sections; there is no section free of tumor. 
Any PRETEXT/POST-TEXT Group can be annotated with the following:  
+V Tumor ingrowth of vena cava or ALL THREE hepatic veins 
+P Tumor ingrowth of main portal vein bifurcation or both right and left portal veins 
+C Tumor ingrowth of caudate lobe 
+E Extrahepatic contiguous tumor ingrowth of diaphragm, abdominal wall, bowel 
+M Distant metastatic disease 
 
10.3 
Response Criteria for Patients with Solid Tumors  
This study will evaluate response using the Response Evaluation Criteria in Solid Tumor (RECIST) from 
the NCI for the evaluation of radiographic response. Response will also be evaluated using the tumor 
marker alphafetoprotein for patients with initial serum elevation of that marker. Patients who did not have 
an alphafetoprotein level obtained prior to initial therapeutic intervention will not be able to use AFP as a 
response criteria.  
 
For high-risk patients being assessed at the end of Cycle 2, the assessment of response is based on central 
review of imaging, the alphafetoprotein values and sampling dates. The results of the central review will 
be returned to the institutional investigator within 3 weeks of submission of the imaging and AFP material. 
If there is a discrepancy between the assessment by central review and by institutional assessment, the study 
PI will discuss with the treating physician to resolve the discrepancy. If the investigator selects a post-
induction regimen that is not indicated by the central review of response, the patient will be considered off 
protocol therapy as of the start date of consolidation therapy.  
 
10.3.1 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 should be 
used to characterize each identified and reported lesion at baseline and during follow-up. 
 
 
Quantification of Disease Burden 
The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the disease 
measurement. 
 
Complete Response (CR)  
Disappearance of all target lesions. Serum alphafetoprotein is normal for age for patients with initially 
elevated markers and for patients for whom markers were not obtained prior to initial therapy. 
 

 
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Partial Response (PR) 
Either 
At least a 30% decrease in the disease measurement, taking as reference the disease measurement done to 
confirm measurable disease at study entry.  
 
OR 
Serum alphafetoprotein concentration decline of at least 90% of the highest AFP prior to the initiation of 
therapy (≥ 1 log10) for patients with initially elevated markers in the absence of disease progression.  
 
RECIST Measurement (% decline) = 
Sum of longest diameter of each measurable lesion at diagnosis – Sum of longest diameter of each measurable lesion after chemotherapy x100% 
Sum of longest diameter of each measurable lesion at diagnosis 
 
 
To be included in RECIST calculation liver lesions must be > 20 mm and pulmonary lesions must be > 10 
mm at the time of diagnosis.   
 
 
% AFP decline = (Maximum AFP prior to beginning chemotherapy – Maximum AFP following chemotherapy) x100% 
Maximum AFP Prior to beginning chemotherapy 
 
 
For evaluation of window response 
Maximum AFP prior to beginning chemotherapy should be used. If a biopsy is performed to make 
diagnosis, a repeat AFP should be obtained immediately prior to beginning chemotherapy (the same day). 
AFP following window chemotherapy should be drawn at the end of Cycle 2 (Week 6/7) just prior to 
beginning Cycle 3. 
 
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, or the appearance of one or more new lesions.  
 
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. Serum alpha fetoprotein concentration does 
not increase for patients with initially elevated markers. 
 
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. 
 
10.3.2 Non-measurable Metastatic Disease 
Non-target lesions:  Includes all lesions that do not qualify as measurable disease at diagnosis. These lesions 
should be noted and recorded and response indicated as improved, no change or worse. These lesions should 
not be included as part of RECIST calculations. 
 

 
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10.3.3 Overall response assessment 
The overall response assessment takes into account response in the measurable and non-measurable disease, 
and the appearance of new lesions, where applicable, and decline of alphafetoprotein according to the 
criteria described in the table below. 
 
Target 
Lesions 
Non-target 
Lesions 
New Lesions Tumor Markers 
Overall 
Response 
CR 
CR 
No 
Normalized1 
CR1 
CR 
Incomplete 
response/SD 
No 
Decreased 
PR 
PR 
Non-PD 
No 
Decreased 
PR 
NON-PD 
Non-PD 
No 
≥ 90% decrease 
from highest AFP 
prior to treatment 
(1 log10 decreased) 
PR 
SD 
Non-PD 
No 
Stable 
SD 
PD 
Any 
Yes or No 
Any 
PD 
Any 
PD 
Yes or No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
 
1 An overall response of CR MUST include a normal AFP. Until the AFP has normalized, a patient can be 
considered PR at best. 
 
It is not uncommon for a patient to complete therapy and have an AFP that remains minimally elevated. If 
there is no evidence of persistent clinical or radiographic disease, these patients can be followed as in 
Section 7.6  
 
A rise in AFP by itself will not be considered as progressive disease. If an AFP level is elevated compared 
to a previous level then weekly AFP measurements should be considered. Radiographic studies (CT chest 
and CT or MRI abdomen) should be considered in patients with an elevated AFP in an attempt to try and 
identify progressive disease. 
 
 
 

 
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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. 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. 
 
11.2 
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. 
 
11.3 
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  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Step 2: Grade the event using the NCI CTCAE. 
 
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 

 
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Expected events for a CTEP IND agent are defined as those listed in the SPEER (Specific Protocol 
Exceptions to Expedited Reporting), a subset of the CAEPR (Comprehensive Adverse Event and 
Potential Risks). For investigational agents that are not commercially available and are being 
studied under a company’s IND, expected AEs are usually based on the Investigator’s Brochure.  
 
Unexpected events for a CTEP IND agent are defined as those NOT listed in the SPEER. 
 
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. 
  
11.4 
Reporting Methods 
• 
Use the NCI’s CTEP Adverse Event Reporting System (CTEP-AERS). The NCI’s guidelines 
for CTEP-AERS can be found at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
 
 
An CTEP-AERS report must be submitted by the following method: https://eapps-
ctep.nci.nih.gov/ctepaers 
 
Electronically submit the report via the CTEP-AERS Web-based application located at  
 
• 
Fax supporting documentation for AEs related to investigational agents to: 
o  The NCI for agents supplied under a CTEP IND only (fax # 301-230-0159).  
o and 
to 
COG 
for 
all 
studies 
(fax 
# 
310-640-9193; 
email: 
COGAERS@childrensoncologygroup.org; Attention: COG CTEP-AERS Coordinator).  
 
• 
DO NOT send the supporting documentation for AEs related to commercial agents to 
the NCI. Fax or email this material to COG (fax # 310-640-9193; email: 
COGAERS@childrensoncologygroup.org; Attention: COG AERS 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. 
 
11.5 
When to Report An Event In An Expedited Manner 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via the 
web based application and/or by telephone call to the Study Chair. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be made to the 
NCI for agents supplied under a CTEP IND by telephone call to 301-897-7497. 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned in 
must be entered into the electronic CTEP-AERS system by the original submitter of the report 
at the site.   

 
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• 
Submit the report within 5 calendar days of learning of the event. 
 
11.6 
Other Recipients of Adverse Event Reports 
COG will forward reports and supporting documentation to the Study Chair, to the FDA (when COG 
holds the IND) and to the pharmaceutical company (for industry sponsored trials).  
 
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. 
 
11.7 
Reporting of Adverse Events For Investigational Agents – CTEP-AERS 24-hour 
Notifications,  and Complete Report Requirements. 
 
Reporting requirements are provided in Table A. The investigational agent used in this study is 
Temsirolimus. 
 
 

 
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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: CTEP-AERS Expedited Reporting Requirements for Adverse Events That Occur 
Within 30 Days1 of the Last Dose of the Investigational Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. This 
 
does not include hospitalizations which are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
 
312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional Special Situations as 
Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have an 
attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
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 
CTEP-AERS for CTEP IND agents; via e-mail to COG AE Coordinator for agents 
in  non-CTEP IND studies) within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
 
“5 calendar days” - A complete CTEP-AERS 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. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
 
• 
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 CTEP-AERS requirements, are to 
be entered in the COG remote data entry system.   
 
Additional Instructions or Exceptions to CTEP-AERS 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 CTEP-AERS for an 
agent under a CTEP IND [and via CTEP-AERS for non-CTEP IND agent] per the timelines 
outlined in the table above. 
 
Grades 1- 4 myelosuppression do not require expedited reporting unless unexpected.  
 
• As of August 25, 2010 all secondary malignancies should be reported via CTEP-AERS.   
 
11.8 
Reporting of Adverse Events for commercial agents – CTEP-AERS 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 CTEP-AERS 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.  
 

 
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CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy With a 
Commercial Agent or Within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, 
regardless of attribution. Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent which can be attributed (possibly, probably, or definitely) 
to the agent and is not due to cancer recurrence must be reported via CTEP-AERS. 
 
 
As of August 25, 2010 all secondary malignancies should be reported via CTEP-AERS. 
 
 
11.9 
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 CTEP-AERS reporting.  
 
The NCI defines both routine and expedited AE reporting.  Routine reporting is accomplished via the 
Adverse Event (AE) Case Report Form (CRF) within the study database.  For this study, routine reporting 
will include non-hematological adverse events of Grade 3 or higher (any attribution), as well as any toxicity 
that required submission of an CTEP-AERS report as outlined above in Sections 11.7, Table A and 11.8, 
Table B.  
 
 
12.0 
RECORDS AND REPORTING 
 
12.1 
Categories of Research Records 
Research records for this study can be divided into 3 categories:  
Non-computerized information: Pathology Narrative Reports and Surgical Reports.  These forms are 
submitted through the Document Imaging System in eRDES.  
1. Reference Labs’ required reports and IROC RI (QARC) data. These data accompany submissions 
to these centers which forward their review data electronically to the COG Statistics and Data 
Center. 
2. Computerized Information Electronically Submitted: All other computerized data will be entered 
in the COG Remote Data Entry System with the aid of schedules and Case Report Forms (paper 
copies of the RDE screens) provided in the data form packet. The packet is posted on the COG 
Website with each protocol under “Data Collection/Specimens”.  
 
12.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be 
submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 
31.  This is not a responsibility of institutions participating in this trial. 
 
 
 
13.0 
SURGICAL GUIDELINES  
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 

 
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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).  
 
13.1 
Surgical Resection Guidelines 
Surgical resection guidelines will be determined according to the PRETEXT grouping system, which was 
designed specifically for patients with liver tumors. See Section 10.2 and Appendix I for PRETEXT 
guidelines.  Terminology for PRETEXT grouping at diagnosis is “PRETEXT”. PRETEXT assignment 
AFTER chemotherapy is referred to as “POST-TEXT”. Please refer to Appendix I for diagram of resection 
guidelines. 
 
 
13.1.1a Tumors Considered Resectable at Diagnosis  
Non-Extreme Resection 
• 
PRETEXT 1. 
• 
PRETEXT 2 with >1 cm radiographic margin on the middle hepatic vein, the retrohepatic IVC 
and the portal bifurcation. 
 
13.1.1b Tumor Biopsy Only at Diagnosis (Stage III)  
• 
PRETEXT 2 with less than 1 cm radiographic margin on the middle hepatic vein, the 
retrohepatic IVC, and the portal bifurcation. 
• 
PRETEXT 3. 
• 
PRETEXT 4. 
• 
Biopsy technique at the discretion of the treating institution may be a percutaneous tru-cut, 
laparoscopic tru-cut or wedge, or open biopsy. Minimum biopsy size is 3 tru-cut cores of tissue. 
Larger biopsies, however, are strongly recommended where feasible to evaluate for the 
possibility of heterogenous foci of small-cell undifferentiated (SCU) tumor. (See Section 14.0 
for Pathology specimen requirements.) 
 
13.1.2 Tumors Considered Resectable After First 2 Cycles of C5VD Neoadjuvant Chemotherapy  
Non-Extreme Resection 
See Section 14.0 for Pathology specimen requirements. 
• 
Tumors with POST-TEXT 1. 
• 
Tumor with POST-TEXT 2 with > 1 cm radiographic margin on the middle hepatic vein, the 
retrohepatic IVC, or the portal bifurcation.  
 
13.1.3 Tumors With Potential Need for Liver Transplant or Extreme Resection 
• 
Definition of potential candidate for liver transplant or extreme resection based upon 
radiographic imaging obtained at diagnosis (PRETEXT) and after the SECOND cycle of C5VD 
chemotherapy (POST-TEXT): 
- 
Major Venous Invasion: Unifocal PRETEXT/POST-TEXT 3 with tumor ingrowth of all 3 
hepatic veins or the retrohepatic vena cava (+V), or portal vein or both right and left (+P).  
The distinction between major venous “ingrowth” by tumor vs major venous 
“displacement” or “extrinsic compression” by tumor can be radiographically very difficult. 
Clinicians are encouraged to err on the side of “possible invasion” and refer patient for 
transplant evaluation if this distinction is very difficult to make. 

 
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- 
Unifocal PRETEXT/POST-TEXT 4  
 
- 
Multifocal PRETEXT/POST-TEXT 3 and 4  
 
• 
Refer to surgical center with expertise in pediatric liver transplant and “extreme” liver 
resection at diagnosis if possible and no later than the first day of the 3rd cycle of C5VD 
neoadjuvant chemotherapy. Resection planning is to be completed before completion of the 
4th cycle of chemotherapy. Transplant or “extreme” resection is to occur within 4 weeks of 
completing the 4th cycle of chemotherapy. 
 
13.1.4 Tumors Considered Resectable Within 4 weeks of Completing 4th Cycle of Chemotherapy  
Non-Extreme Resection 
See Section 14.0 for Pathology specimen requirements.  
• 
Tumors with POST-TEXT 3 and no major venous invasion. The surgeon must anticipate the 
ability to achieve a negative surgical margin on the right/left hepatic vein, retrohepatic IVC, or 
portal bifurcation. Margin may be less than 1 cm if the surgeon feels a complete resection will 
be feasible without transplant and patient has completed 4 cycles of C5VD chemotherapy. 
 
13.1.5 Tumors Presenting with Metastatic Disease (Stage IV)  
See Section 14.0 for Pathology specimen requirements. 
• 
Complete 2 cycles of upfront experimental window chemotherapy. 
• 
Repeat radiographic imaging after completing upfront window therapy 
- 
Resect (non-extreme) tumors POST-TEXT 1 or 2 with > 1 cm radiographic margin on the 
middle hepatic vein, retrohepatic IVC, and portal bifurcation 
- 
For all others, proceed with 2 cycles of C5VD 
• 
Repeat radiographic imaging after completing first 2 cycles of C5VD 
- 
Resect (non-extreme) tumors downstaged to POST-TEXT Group 1, 2, or 3 tumors with 
> 1 cm radiographic margin on right/left hepatic vein, retrohepatic IVC, and portal 
bifurcation. 
- 
For patients potentially needing liver transplant/extreme resection (see definition in Section 
13.1.3), refer to surgical center with expertise in pediatric liver transplant and “extreme” 
liver resection at diagnosis if possible and no later than the FIRST DAY of the 3rd cycle of 
C5VD chemotherapy. Resection planning is to be completed before completion of Cycle 7 
in high risk responders and before completion of Cycle 6 in high risk non-responders. 
Transplant or “extreme” resection is to occur within 4 weeks of completing the 7th cycle of 
chemotherapy in high risk responders and the 6th cycle of chemotherapy in high-risk non-
responders.  
- 
Repeat chest CT scan must demonstrate complete clearance of pulmonary metastatic 
disease within 1 week prior to liver transplant. 
- 
Those patients with persistent extrahepatic disease, may be resected (not transplanted) at 
the discretion of the surgical center with expertise in pediatric liver transplant and 
“extreme” liver resection. 
- 
Those patients with persistent extrahepatic disease who are not anatomically resectable 
without transplantation will continue chemotherapy. 

 
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13.1.6 Optional Central Assistance to Aid in Determination of Tumor Resectability 
If the treating physicians/surgeons desire assistance with their clinical decision making this will be available 
from one of the study surgeons on the Surgical Review Committee with expertise in the treatment of 
pediatric liver tumors.  Clinical consultation is NOT REQUIRED. However, at least one of these surgeons 
will be available AT ALL TIMES for emergent consultation. The local treating institution is ultimately 
responsible for making the treatment decision regarding resectability with the full backup of the 
OPTIONAL consultation. The consulting surgeon on call can be reached by contacting the surgical study 
chair or the study chair.  
 
 
13.2 
Central Surgical Review 
For purposes of evaluating clinical predictive value and reproducibility of the PRETEXT system, central 
review will be completed for all scans obtained at diagnosis (PRETEXT) and after neoadjuvant 
chemotherapy (POST-TEXT). The central surgical review will be performed on an ongoing basis by the 
team of study surgeons by web access to imaging coordinated through IROC RI (QARC) and completed 
by the team of surgeons and radiologists. A bi-annual group review of imaging will be held to achieve 
consensus on imaging where central review is divergent amongst the reviewers 
 
13.3 
Surgical Management of Pulmonary Metastasis 
Patients presenting with pulmonary metastatic disease (Stage IV) will receive the “up-front” window 
chemotherapy described above for high-risk patients. If metastases disappear with chemotherapy, no 
pulmonary surgical intervention will be performed. If metastases are persistent after 4 total cycles of C5VD 
chemotherapy and the patient is considered a candidate for liver transplant at that time, metastases are to 
be resected to render the patient free of extrahepatic disease prior to transplant. Transplant may then be 
undertaken.  
 
If the liver tumor can be primarily resected after either Cycles 4 or 7 in high risk responders and after Cycles 
4 or 6 in high-risk non-responders without transplant, this should be performed and the final cycles of 
chemotherapy should be administered. If the metastases are still present, they should then be resected. 
Pulmonary metastectomy may be performed earlier in the course of therapy if it can be done without 
resulting in delays in the administration of scheduled chemotherapy. 
 
13.4 
Liver Transplant or Extreme Liver Resection  
Two distinct cohorts of unresectable patients are expected.  Patients identified as potentially unresectable 
based on preoperative radiographic imaging that are either: 1) successfully referred for evaluation at a 
transplant center in a timely fashion, or 2) not successfully referred for evaluation at a transplant center in 
a timely fashion. Within the first cohort there are further possible subgroups: 1a) prove to be resectable at 
the time of surgery; 1b) remain unresectable and primary transplant performed, 1c) remain unresectable, no 
surgery performed due to persistent metastatic disease unresponsive to chemotherapy or surgical resection, 
or 1d) do not proceed to surgery because of refusal or deteriorating patient condition.  
 
Post surgery/transplant chemotherapy will be based on the chemotherapy received preoperatively. For 
patients with disease confined to the liver, 2 additional post operative/transplant cycles of the same 
chemotherapy given preoperatively (4 cycles) will be given postoperatively for a total of 6 cycles. For 
patients with metastatic disease, additional cycles of the same chemotherapy given pre-operatively will be 
given post-operatively. The number of post operative cycles may vary depending upon the point in 
treatment during which resection occurred for a total of 8 cycles for patients who did not respond to window 
therapy and a total of 10 cycles for patients who did respond to window therapy.  
 

 
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Patient management guidelines will follow the same format that has been discussed and agreed upon by an 
international committee of liver transplant surgeons in the preparation of the Pediatric Liver Unresectable 
Tumor Observatory (PLUTO). All patients treated by liver transplantation will be asked to sign a consent 
within one month (optimally) post transplant giving permission for registration on the PLUTO multi-center 
international cooperative database for children who receive a liver transplant for hepatoblastoma or 
hepatocellular carcinoma. The consent is usually obtained by the liver transplant team, but may also be 
obtained by the oncology team. Medical information is entered via a secure internet connection with a 
remote data entry system accessible at www.pluto.cineca.org. The organization called CINECA is an 
information management organization with a contract with SIOPEL (the liver tumor study group of the 
Societe International Oncologie Pediatric (SIOP)) to collect and manage the information. Other children’s 
liver study groups that participate in the registry include the Children’s Oncology Group (COG), the 
German Pediatric Oncology Group (GPOH), the Study Pediatric Liver International Transplant group 
(SPLIT), and several independent liver transplant centers throughout the USA, Europe, South America, and 
Japan.  
 
The database collects information about type of liver tumor, tumor size, number and location of tumors in 
and outside of the liver, involvement of blood vessels, chemotherapy medications used, lymphocyte blood 
count, immunosuppression medications used after transplant, side effects of the medications, at what point 
in the treatment was the transplant performed, complications from the transplant surgery, and outcome of 
the transplant and the disease free survival. The registry plans to enroll patients for a minimum of ten years 
with an enrollment of approximately 300. The registry currently plans to keep the entered data indefinitely.  
If subjects do not want to continue participating in the database, their data will be removed upon request. 
This database can be accessed via the PLUTO Registry Website: http://pluto.cineca.org/access.htm. In 
order to be authorized to use the transplant database, it is necessary to register with PLUTO. The link to the 
required participation form is found using the same PLUTO access link provided above.  
 
The registry on the internet has a home page with basic information about what it is and about the 
organizations that have cooperated to make the registry possible. Access to the main part of the registry 
where the patient information is collected and stored is strictly controlled and requires a secure password 
which is available only to the research doctors approved by the registry. The registry is maintained by 
CINECA (www.cineca.it), a nonprofit consortium made up of 32 Italian Universities, the Italian National 
Institute of Oceanography and Experimental Geophysics, the Italian National Research Council, and the 
Italian Ministry of University and Research. CINECA supports the research activities of the scientific 
community through supercomputing and its applications. By contract with SIOPEL (International 
Childhood Liver Tumour Strategy Group), CINECA serves as the data management group for all SIOPEL 
studies. The PLUTO registry data are available to scientists/clinicians whose centers regularly contribute 
to PLUTO. Data can be used to perform scientific studies which have been approved by the PLUTO steering 
committee.  To obtain access to data, a written request is addressed to the chairperson of PLUTO steering 
committee serving as custodian of the registry. The request must contain title, objectives and description of 
study, supporting letter of program director, name and affiliation of investigator, and a disclosure statement 
disclosing any potential conflicts of interest.  
 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS  
Before entering patients on this trial, clinicians should discuss this protocol with their pathologist and 
provide them with pathology section of the protocol and list of the required materials that will need to be 
submitted. (Requirements are listed on the Data Submission Schedule in the CRF packet.) 
 

 
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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 AHEP0731 and to request that patients’ materials be forwarded to the COG 
Biopathology Center (BPC), as required. The BPC will NOT request materials. 
 
14.1 
Pathology Evaluation 
The pathologic classification of liver tumors is becoming increasingly complex. Because of limited biopsy 
specimens for review, the diagnosis of hepatoblastoma is sometimes difficult to make. Central review is 
therefore critical to ensuring that the diagnosis is accurate and that patients are treated appropriately. Central 
pathologic review will be performed on all diagnostic specimens (whether resected or biopsied). Results of 
the review will only be given to the treating institution for Stage I and II patients who receive rapid central 
pathology review.  
 
If there is a discrepancy between the institutional diagnosis and the diagnosis on the central review of a 
Stage I or II patient, then a discussion between the local and study pathologists will take place to attempt 
to reach a consensus. If a consensus cannot be reached, then the institutional diagnosis will be accepted. An 
assessment of the influence of the exclusion of cases for whom there is a discrepancy in diagnosis between 
institutional and central review, or for whom there is an exceptional or unusual histological presentation 
will be addressed statistically.  
 
Please label all materials with the patient’s COG Patient Identification Number and the surgical pathology 
number and block number from the corresponding institutional pathology report(s). 
 
There are 2 study pathologists: Drs. Milton Finegold and Sarangarajan Ranganathan. 
There are 2 JPLT study pathologists: Drs. Yukichi Tanaka and Takeshi Inoue. 
 
14.1.1 Central Pathology Review 
Central pathologic review will be performed for all resected/biopsied specimens (liver and/or lung) to assess 
for the presence of positive surgical margins, microscopic satellite nodules, and microscopic venous 
invasion. Specimens should be submitted at the time of diagnosis and from all subsequent biopsies or 
resections or explants.   
 
• 
Stage I and II Specimens at Diagnosis 
Rapid central pathology review of all Stage I and II patient specimens is required. Rapid central pathology 
review was utilized on the P9645 study and was shown to be feasible. Two sets of duplicate slides of the 
entire specimen must be SUBMITTED to the COG Biopathology Center (BPC) no later than 14 calendar 
days from resection (7 days preferred). The BPC will immediately forward one set to one of the study 
pathologists. Enrollment on this study of Stage I or II patients must not occur until results of rapid 
central pathologic review are known. The study pathologists will review all slides and will communicate 
results to the contact person noted on the Rapid Review Transmittal Form for Stage I and II patients. If 
there is > 1 week delay from submission of specimens for rapid review and receipt of pathology review, 
the study chair should be contacted. 
 
Required materials for Stage I and II are:  
Paraffin-embedded blocks are preferred; if all blocks with tumor are not available, then send 2 H&E and 2 
unstained slides per block.  
 
• 
A minimum of 1 block of tissue for each 1 cm of maximum tumor diameter should be sampled 
• 
Sections of tumor should measure approximately 2.5 x 1.5 cm per paraffin block 
• 
Include the surgical margin (1 section for each cm of resection margin) 
• 
Include the peri-or intra-hilar portal vein and hepatic vein at margin of resection  

 
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• 
Include any well-defined encapsulated circular foci of tumor suggestive of intravenous growth 
• 
Representative sections of grossly diverse appearing areas (most closely resembling normal liver 
and moderately firm to capture 'fetal" histology; softer more pale, pinkish and moist areas for 
'embryonal' or 'small cell' components; more firm and even calcified areas for fibrous and 'osteoid' 
mesodermal derivatives; dark brown foci for melanotic 'teratoid' elements). Some or all of these 
sections may also meet the requirement for marginal material. It is very desirable to photograph the 
gross specimen and to diagram {map} the precise source of the samples.  
 
Special Instructions: It should be noted on the AHEP0731 Rapid Review Transmittal Form for Stage I 
and II patients that the specimen is for a Stage I or II rapid review at diagnosis.  
 
• 
All Other Specimens (all surgeries except initial Stage I and II surgery)  
Histologic sections of all remaining pathology specimens will be sent to the BPC (see address below). 
Slides must be submitted following all other surgical biopsies/resections including: 
- 
Non-Stage I or II diagnostic biopsy 
- 
Primary upfront resection 
- 
Delayed surgical resection 
- 
Liver explant at time of orthotopic liver transplant 
- 
Pulmonary metastectomy 
 
Slides must be submitted within 4 weeks of surgical procedure.  Required materials for all surgeries 
(except initial Stage I and II surgery) are: 
Paraffin-embedded blocks are preferred; if all blocks with tumor are not available, then send 2 H&E 
and 2 unstained slides per block.  
• A minimum of 1 block for each 1 cm of maximum tumor diameter  
• Sections of tumor should measure approximately 2.5 x 1.5 cm per paraffin block  
• Include the surgical margin (1 section for each cm of resection margin) 
• 
Include the peri- or intra-hilar portal vein and hepatic vein at margin of resection 
• Include any well-defined encapsulated circular foci of tumor suggestive of intravenous growth  
• Representative sections of grossly diverse appearing areas (most closely resembling normal 
liver and moderately firm to capture 'fetal' histology; softer more pale, pinkish and moist areas 
for 'embryonal' or 'small cell' components; more firm and even calcified areas for fibrous and 
'osteoid' mesodermal derivatives; dark brown foci for melanotic 'teratoid' elements). Some or 
all of these sections may also meet the requirement for marginal material. It is very desirable to 
photograph the gross specimen and to diagram {map} the precise source of the samples.  
 
14.1.2 Pathology Submission Requirements 
All materials must be submitted with the following identification: 
• 
COG Registration Number 
• 
Surgical Pathology ID (SPID) Number  
• 
Block Number  
 
The following items from each surgical procedure must also be submitted:   
Pathology Report 
Pathology Checklist 
Operative report 
Specimen Transmittal Form (Stage I & II tumors use specific form for rapid review submission 
available on AHEP0731 protocol page on COG website; all other submissions use the COG 
Generic Specimen Transmittal form) 
Any gross image with mapping if performed 

 
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14.1.3 Shipping Addresses 
Please see the link below for guidelines on which courier account to use when sending rapid central pathology 
review materials: https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf. All other 
materials should be sent by regular mail or using your own courier account. 
 
BPC Shipment Address: 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, Room WA 1340 
Columbus, OH 43205 
Phone: (614) 722-2894 
Email:BPCParaffinTeam@nationwidechildrens.org 
 
Shipping address for JPLT Institutions Only: 
Japanese Children Cancer Group (JCCG) Pathology Center 
National Center for Child Health and Development 
National Medical Center for Children and Mothers Research Institute 
2-10-1 Okura Setagaya-ku Tokyo, 157-8535 Japan 
Phone: 03-3416-0181 
Email: nakagawa-a@ncchd.go.jp 
 
 
14.2 
Biology Studies 
The submission of diverse tumor and corresponding normal tissue for biologic studies is strongly 
encouraged. Please submit biology specimens using ABTR01B1 or other appropriate study.  
 
 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
 
15.1 
Primary Site Imaging 
The same modality used at baseline should be used for all follow-up imaging.  
 
15.1.1 Primary Site Computed Tomography 
1.  All CT scans should be done with technical factors using the lowest radiation exposure possible 
(ALARA principle) that allow optimal image quality.  
2. CT slice acquisition thickness should be 1.5 mm or less. 
3. Post-contrast IV enhanced portal venous phase abdominal and pelvic CT should be performed from 
just above the diaphragm to the symphysis pubis. Dual phase (arterial and portal venous) abdominal 
CT is strongly recommended.  
4. Oral contrast is strongly recommended. 
 
15.1.2 Primary Site Magnetic Resonance Imaging 
Axial images and coronal images of the liver tumor should be acquired with at least two pulse sequences, 
including T1 and either fat-suppressed T2, STIR, or fat-suppressed fast/turbo imaging. Gadolinium should 
be given if appropriate and if there is normal renal function. After contrast administration T1W, fat-
suppressed, axial images should be obtained. Based on patient age, images may be non-breath-hold or 
breath-hold, including respiratory triggered or respiratory gated. 
 
Dual phase MRI may be performed at the discretion of the local radiologist. To perform dual phase MR, 
gadolinium-enhanced imaging is performed in combination with dynamic gradient echo sequences. After 

 
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contrast agent injection, images are obtained through the liver during the arterial phase (20 to 30 seconds 
post injection), portal venous phase (60 to 80 seconds after injection), and at equilibrium (3 to 5 minutes 
after injection). Delayed images can be obtained if needed for further lesion characterization.  
 
15.2 
Metastatic Site Imaging 
Chest CT is required to evaluate metastatic disease. Chest CT may be performed without intravenous 
contrast material. The diameter of a "measurable" nodule should be at least twice the reconstructed slice 
thickness. Smaller nodules are considered detectable, but will be counted as "non-measurable. Bone scan 
is not required but should be considered in symptomatic patients with bone pain or bone lesions. Metastatic 
disease to bone and bone marrow is extremely rare and should only be considered if the patient is 
symptomatic with unexplained bone pain or unexplained cytopenias. 
 
15.3 
Timing of Imaging 
Real Time Review: 
• 
The Stratum 4 (upfront window therapy) patients will have a real-time central review of 
response using RECIST by one of the study committee radiologists.  This review will be 
performed after Cycle 2. Baseline and post cycle 2 images must be submitted to IROC RI 
(QARC) as soon as the post Cycle 2 imaging is acquired.  Baseline imaging can be submitted 
when performed or included with the post Cycle 2 imaging. 
 
Retrospective Reviews: 
• 
PRETEXT at diagnosis for all patients (to establish concordance between local and central 
grouping) will be performed by a panel of pediatric surgeons and radiologists. 
• 
POST-TEXT for Stage III and IV patients after window therapy and after all subsequent 
imaging (to compare concordance between local and central grouping and compare with 
surgical/pathologic staging) will be performed by a panel of pediatric surgeons and 
radiologists. 
 
All patients with tumors that are only biopsied initially will have CT and/or MRI scans performed at the 
time points noted below. Patients will all have abdominal ultrasounds performed at diagnosis (to evaluate 
the IVC and portal vein) if reconstructed CT MIP or VRT images of the portal vein are inadequate to 
exclude thrombus. Patients with tumor/thrombus in blood vessels at diagnosis should have repeat 
examinations using the same confirmatory imaging modality after Cycles 2 and 4 of C5VD.  
 
Imaging studies as noted below for all Stratum 4 patient (high risk) should be submitted immediately after 
acquisition of the post Cycle 2 scans as further treatment will be determined by central review. Results of 
the central review will be entered into the COG eRDE system.  
 
All other imaging studies should be submitted to IROC RI (QARC) within 1 month of obtaining the scans. 
These scans will be reviewed retrospectively.  Therapy decisions at these time points are not based on 
central review.  
 
 
 
 

 
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The following imaging studies with the corresponding radiology reports should be submitted as noted 
below:   
 
Stratum 1 Radiologic Studies  to be 
Submitted 
Baseline 
Primary tumor evaluation (CT and/or 
MRI)1 
X3 
Metastatic tumor evaluation (CT 
chest) 
X3 
Abdominal ultrasound2 
X3 
 
Stratum 2 Radiologic Studies  to be 
Submitted 
Baseline 
End of 
Therapy 
Primary tumor evaluation (CT and/or 
MRI)1 
X3 
X 
Metastatic tumor evaluation (CT 
chest) 
X3 
X 
Abdominal ultrasound2 
X3 
 
 
Stratum 3 Radiologic Studies  to be 
Submitted 
Baseline 
End of 
Cycle 2  
End of 
Cycle 4 
End of 
Therapy 
Primary tumor evaluation (CT and/or 
MRI)1 
X3 
X4 
X4 
X 
Metastatic tumor evaluation (CT 
chest) 
X3 
 
X4 
 
Abdominal ultrasound2 
X3 
X2 
X2 
 
 
All Stratum 4 patients 
Radiologic Studies  to be 
Submitted 
Baseline 
End of Cycle 2  
(submitted for real 
time review of 
response) 
Primary tumor evaluation 
(CT and/or MRI)1 
X3 
X4 
Metastatic tumor evaluation 
(CT chest) 
X3 
X4 
Abdominal ultrasound2 
X3 
X2 
 
Stratum 4 Non Responders 
Additional Radiologic Studies  to be 
Submitted 
End of 
Cycle 4  
End of 
Cycle 6 
End of 
Therapy 
Primary tumor evaluation (CT and/or 
MRI)1 
X4 
X4 
X4 
Metastatic tumor evaluation (CT 
chest) 
X4 
X4 
X4 
Abdominal ultrasound2 
X2 
X2 
X2 
 
Stratum 4 Responders Additional 
Radiologic Studies  to be Submitted 
End of 
Cycle 4  
End of 
Cycle 6 
End of 
Therapy 
Primary tumor evaluation (CT and/or 
MRI)1 
X4 
X4 
X4 
Metastatic tumor evaluation (CT 
chest) 
X4 
X4 
X4 
Abdominal ultrasound2 
X2 
X2 
X2 
1 The same modality should be used each time for consistency. 
2 Ultrasound only needs to be repeated if initial U/S showed tumor thrombus & does not need to be performed once 
thrombus has resolved or surgery performed.  

 
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3 Tumor evaluation, including ultrasound, may be done within 28 days prior to enrollment and must be submitted within 
one month from diagnosis. 
4 Tumor disease evaluation performed after VIT Cycle 2 and after Cycles 4, 6 & 8 for non-responders and after Cycles 4, 
6, and 10 for responders until tumor removed. No scans required once all tumor has been removed or resolved until the 
end of therapy. Scans should be submitted immediately after VIT Cycle 2 for central review while all other timepoints 
should be submitted within 1 month of each set of scans 
 
15.4 
Image Submission and Review 
Submission of Diagnostic Imaging data in digital format is required. Digital files must be in DICOM format. 
These files can be submitted via sFTP. Information for obtaining an sFTP account and submission 
instructions can be found at www.QARC.org. Follow the link labeled digital data. Alternatively, if sFTP is 
not feasible, the imaging may be burned to a CD and mailed to IROC RI (QARC). Multiple studies for the 
same patient may be submitted on one CD; however, please submit only one patient per CD. Sites using 
DICOMmunicator may submit imaging via that application. Contact IROC RI (QARC) with questions or 
for additional information. Diagnostic Imaging reports may be submitted with the scans or electronically. 
 
Note for JPLT sites: do not submit material directly to IROC-RI, instead send materials to the _JPLT 
Center shipping address provided below. 
 
If submitted via CD send to: 
IROC Rhode Island QA Center 
Building B, Suite 201 
640 George Washington Highway 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 or E-mail to DataSubmission@QARC.org 
 
Shipping address for JPLT Institutions Only: 
JPLT Center 
National Center for Basic Research and Development (NBRAD) 
Hiroshima University 
1-2-3, Kasumi, Minami-ku Hiroshima, 734-8551 Japan 
Phone: 082-257-5416 
Email: jplt@hiroshima-u.ac.jp 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX I:  PRETEXT SURGICAL RESECTION GUIDELINES 
 
 
 
 
 
 
 
1     3 contiguous free sections
2     2 contiguous free sections
3     1 contiguous free section
4     no free sections
Any group may have 
involvement of:
V  vena cava or all 3 hepatic veins
P  main portal or portal bifurcation vein
C  caudate 
E  extrahepatic, contiguous
M distant  metastatic
PRETEXT 
or 
POST-TEXT if assigned after 
chemotherapy
4
3
2
1

 
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Resect at Diagnosis 
Easy lobectomy with > 1 cm 
margin:   
-
PRETEXT 1 
-
PRETEXT 2
Diagnosis CT shows unifocal 
tumor with at least 1cm clear 
radiographic margin from middle 
hepatic vein and portal bifurcation 
AHEP 0731 Surgical Resection Guidelines
4
3
2
1

 
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Biopsy and 
Refer at Diagnosis 
Tumor expected to require liver 
transplantation  or extreme, 
complex liver resection 
- multifocal PRETEXT 3 or 4 
- PRETEXT 3  +V, +P
- PRETEXT 4
Consultation with liver program to 
complete transplant evaluation 
and listing with goal of transplant 
on or before completion of four 
cycles neoadjuvant
chemotherapy 
AHEP 0731 Surgical Resection Guidelines
4
3
2
1

 
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Biopsy at Diagnosis 
Neoadjuvant Chemotherapy
POST-TEXT => Repeat CT Scan 
after 2nd cycle chemotherapy
* Resect after 2nd cycle chemo 
- POST-TEXT 1    
- POST-TEXT 2 if there is > 1cm 
radiographic margin on middle 
hepatic vein and portal bifurcation
* * Resect after 4th cycle chemo 
- POST-TEXT 2 < 1 cm margin
- POST-TEXT 3
*** Refer to liver center
-
POST-TEXT 3  +V, +P
Consultation with liver program to complete transplant 
evaluation and listing with goal of transplant on or before 
completion of four cycles neoadjuvant chemotherapy 
AHEP 0731 Surgical Resection Guidelines
4
3
2
1

 
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Statistical 
office: 
Berne, 
Switzerland
PLUTO Project 
Director Jean-
Bernard Otte, 
Brussels, 
Belgium
CINECA
WEB System 
headquarter: 
Bologna, Italy
*
*
*
*
*
Liver Transplant for Tumor
Data Base - Registry
http://pluto.cineca.org

 
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APPENDIX II:  YOUTH INFORMATION SHEET 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AHEP0731 
(for children from 7 through 12 years of age) 
 
Special Studies to Learn More About a Liver Tumor called Hepatoblastoma and How to Treat It 
 
1. We have been talking with you about hepatoblastoma. Hepatoblastoma is a type of cancer (tumor) 
that grows in the liver, which is on the upper right side of your belly area. After doing tests, we 
have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have hepatoblastoma. A research 
study is when doctors work together to try out new ways to help people who are sick. This study is 
trying to safely change the amount of treatment that children with hepatoblastoma need. This is 
why we are doing this study.  
 
3. Some children, who have surgery to remove their entire tumor, may not need any further treatment. 
Other children will need treatment with chemotherapy. (Chemotherapy is a type of strong medicine 
that destroys cancer cells). If the cancer cannot be removed when it is first discovered or has spread 
to other organs you may need more chemotherapy medicines over a longer period of time.  
 
4. Some children who are part of this study will have surgery and then will need blood tests 
occasionally to make sure they are doing OK. Some children will be treated with chemotherapy.  
The chemotherapy may be given for 6 to 36 weeks, depending on the features of your cancer.  If 
the tumor cannot be removed when it is first discovered you will be treated with chemotherapy and 
have frequent blood tests and scans to see if the tumor is getting smaller.  
 
5. Sometimes good things can happen to people when they are in a research study.  These good things 
are called “benefits”. We hope that being part of this study may have benefits for you.  
 
6. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks”. Other things may happen to you that we don’t yet know about. Depending on 
the kind of tumor you have, your study doctors may give you less or more treatment than has been 
normally given to adolescents and children with hepatoblastoma. It is possible that giving less 
treatment may not work as well at getting rid of your cancer. It is possible that giving more 
treatment may cause more side effects. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness.  Your doctor 
can tell you about them. Ask your doctors any questions that you have. 
 
 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY AHEP0731 
(for teens from 13 through 17 years of age) 
 
Special Studies to Learn more About a Liver Tumor called Hepatoblastoma and How to Treat It 
 
 
1. We have been talking with you about hepatoblastoma. Hepatoblastoma is a type of cancer that 
grows in the liver, which is on the upper right side of your abdomen. After doing tests, we have 
found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have hepatoblastoma. A research 
study is when doctors work together to try out new ways to help people who are sick. This study is 
trying to safely reduce the amount of treatment that children and teens with low-risk 
hepatoblastoma need. This study is also trying to improve the treatment for children and teens with 
high-risk hepatoblastoma by adding a new medication to the regular treatment. The term, risk, 
refers to the chance of the cancer coming back after treatment This is why we are doing this study.  
 
3. Some children and teens, who have surgery to remove their entire tumor, may not need any further 
treatment.  Other children will need treatment with chemotherapy. (Chemotherapy is a type of 
strong medicine that destroys cancer cells). If the cancer cannot be removed when it is first 
discovered or has spread to other organs you may need more chemotherapy medicines over a longer 
period of time. If all of the tumor could not be removed when you were diagnosed, you may need 
a second surgery or maybe even a liver transplant. You may need to go to another hospital, where 
there are doctors who specialize in liver surgery or liver transplant.  
 
4. Some children and teens who are part of this study will have surgery and then will need blood tests 
occasionally to make sure they are doing OK.  Some teens and children will be treated with 
chemotherapy. The chemotherapy may be given for about 6 to 36 weeks, depending on the features 
of your cancer.  If the tumor cannot be removed when it is first discovered you will be treated with 
chemotherapy and have frequent blood tests and scans to see if the tumor is getting smaller.   
  
5. Sometimes good things can happen to people when they are in a research study.  These good things 
are called “benefits”. We hope that being part of this study may have benefits for you.  We don’t 
know for sure if there is any benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks”. Things may happen to you that we don’t yet know about. Depending on the 
kind of tumor you have, your study doctors may give you less or more treatment than has been 
normally given to adolescents and children with hepatoblastoma. It is possible that giving less 
treatment may not work as well at getting rid of your cancer. It is possible that giving more 
treatment may cause more side effects.  
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Ask your doctors any questions that you have. 
 
 

 
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APPENDIX III:  SURGICAL STAGING OF PRIMARY TUMOR AT TIME OF INITIAL 
SURGERY 
 
Patients are staged for risk classification and treatment using COG staging guidelines as listed below: 
 
Stage I: 
completely resected tumors.    
Note:  all Stage I tumors require rapid pathology review prior to enrollment. 
 
Stage II: 
grossly resected tumors with evidence of microscopic residual.  
Resected tumors with microscopic positive margins or pre-operative (intra-operative) rupture.  
Note:  all Stage II tumors require rapid pathology review prior to enrollment. 
 
Stage III: 
unresectable tumors  
Partially resected tumors with measurable tumor left behind or patients with abdominal lymph 
node involvement.    
 
Stage IV:  
metastatic disease to lungs, other organs or sites distant from the abdomen.   
 
PFH tumors are entirely composed of a purely fetal histologic pattern with a low mitotic index defined as 
≤ 2 mitoses/10 high power fields 
 
SCU tumors are tumors with any amount of small cell undifferentiated cells detected.  
 
 

 
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APPENDIX IV: UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
 
Note:  This concomitant medication restriction is applicable only for Stratum 4 (High Risk) patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recommended Non-enzyme inducing 
anticonvulsants 
 
Generic Name 
U.S. Trade Name 
Gabapentin 
Neurontin 
Lamotrigine 
Lamictal 
Levetiracetam  
Keppra 
Tigabine 
Gabitril 
Topiramate 
Topamax 
Valproic Acid 
Depakote, Depakene 
Zonisamide 
Zonegran 
 
Unacceptable Enzyme inducing anticonvulsants 
 
Generic Name 
U.S.Trade Name 
Carbamazepine 
Tegretol 
Felbamate 
Felbatol 
Phenobarbital 
Phenobarbital 
Phenytoin 
Dilantin 
Primidone 
Mysoline 
Oxcarbazepine 
Trileptal 
 

 
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APPENDIX V:  CYP3A4 INDUCERS AND INHIBITORS 
 
Note:  This concomitant medication restriction is applicable only for Stratum 4 (High Risk) patients.  
 
The use of the following medications should be discontinued prior to initiation of protocol therapy and 
should be avoided during protocol therapy if reasonable alternatives exist. This list may not be 
comprehensive. Additional information about this list can be found at the following site: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
 
 
Strong 
Inhibitors 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Other 
Inhibitors 
Inducers 
Clarithromycin 
Indinavir 
Itraconazole 
Ketoconazole 
Posaconazole 
Nefazodone 
Nelfinavir 
Ritonavir 
Saquinavir 
Telithromycin 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit 
Juice 
Verapamil 
Cimetidine 
Amiodarone 
Boceprevir 
Chloramphenicol 
Ciprofloxacin 
Delaviridine 
Fluvoxamine 
Imatinib 
Norfloxacin 
Norfluoxetine 
(fluoxetine) 
Starfruit 
Telaprevir 
Voriconazole 
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids 
Modanfinil 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
Troglitazone 
 
 
 
 

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

 
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APPENDIX VII:  JPLT SITE SPECIFIC INFORMATION 
 
Japanese Data Safety Committee 
Serious Adverse Reaction (SAR) Reports will be reviewed by the Japanese Data Safety Committee (DSC) 
for patients enrolled on AHEP0731 in Japan. Review of SAR reports is in addition to COG Data Safety 
Committee review of Serious Adverse Events (SAE) Reports. The Japanese DSC serves as a local advisory 
committee to ensure Japanese patient safety according to the Independent Data Monitoring Guideline in 
Japan. 
 

 
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REFERENCES 
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2. 
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Zsiros J, Maibach R, Brock P, et al: Initial low AFP level predicts a bad prognosis in high-risk 
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Hansen K, Bagtas J, Mark HF, et al: Undifferentiated small cell hepatoblastoma with a unique 
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