Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT00980460

Collaborator

(none)

236

Enrollment

209

Locations

Arms

1.1

Patients Per Site

Study Details

Study Description

Brief Summary

This phase III trial studies the side effects and how well risk-based therapy works in treating younger patients with newly diagnosed liver cancer. Surgery, chemotherapy drugs (cancer fighting medicines), and when necessary, liver transplant, are the main current treatments for hepatoblastoma. The stage of the cancer is one factor used to decide the best treatment. Treating patients according to the risk group they are in may help get rid of the cancer, keep it from coming back, and decrease the side effects of chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
PRETEXT Stage 1 Hepatoblastoma PRETEXT Stage 2 Hepatoblastoma PRETEXT Stage 3 Hepatoblastoma PRETEXT Stage 4 Hepatoblastoma	Drug: Cisplatin Drug: Dexrazoxane Drug: Doxorubicin Hydrochloride Drug: Fluorouracil Drug: Irinotecan Hydrochloride Other: Laboratory Biomarker Analysis Procedure: Liver Transplantation Drug: Temsirolimus Procedure: Therapeutic Conventional Surgery Drug: Vincristine Sulfate	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

To estimate the event-free survival (EFS) in children with stage I (non-pure fetal histology [PFH], non-small cell undifferentiated [SCU]) and stage II (non-SCU) hepatoblastoma treated with surgical resection followed by 2 cycles of cisplatin, fluorouracil, and vincristine sulfate (C5V).
To determine the feasibility and toxicity of adding doxorubicin (doxorubicin hydrochloride) to the chemotherapy regimen of C5V for children with intermediate-risk hepatoblastoma.
To estimate the response rate to vincristine (vincristine sulfate), irinotecan (irinotecan hydrochloride), and temsirolimus in previously untreated children with high-risk, metastatic hepatoblastoma.
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.
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.

SECONDARY OBJECTIVES:

To estimate the EFS of patients with stage I PFH treated with surgery alone. II. To determine whether orthotopic liver transplantation (OLT) can be accomplished after successful referral and completion of 4 cycles of initial chemotherapy.
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.
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.
To determine if pretreatment extent of disease (PRETEXT) grouping can predict tumor resectability.
To monitor the concordance between institutional assessment of PRETEXT grouping and PRETEXT grouping as performed by expert panel review.
To estimate the proportion of stage IV patients who have surgical resection of metastatic pulmonary lesions.
To determine the proportion and estimate the EFS of patients with potentially poor prognostic factors including alpha fetoprotein (AFP) < 100 ng/mL at diagnosis, microscopic positive surgical margins, surgical complications, multifocal tumors, microscopic vascular invasion, macrotrabecular histologic subtype, and SCU histologic subtype.

OUTLINE: Patients are assigned to 1 of 4 treatment groups according to risk group.

VERY LOW-RISK GROUP: Patients undergo surgery and receive no further treatment.

LOW-RISK GROUP: (regimen T) Patients undergo surgery and then receive adjuvant cisplatin intravenously (IV) over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

INTERMEDIATE-RISK GROUP: (regimen F) (closed to accrual as of 3/12/2012) Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6.

HIGH-RISK GROUP: (regimen W) (regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity.

HIGH-RISK GROUP: (regimen H) Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6.

After completion of study therapy, patients who receive chemotherapy are followed up periodically for at least 4 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

236 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment

Actual Study Start Date :

Sep 14, 2009

Actual Primary Completion Date :

Jun 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High-risk group (regimen H) Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Fluorouracil Given IV Other Names: 5 Fluorouracil 5 Fluorouracilum 5 FU 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-Fu 5FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757 Drug: Irinotecan Hydrochloride Given IV Other Names: Campto Camptosar Camptothecin 11 Camptothecin-11 CPT 11 CPT-11 Irinomedac Irinotecan Hydrochloride Trihydrate Irinotecan Monohydrochloride Trihydrate U-101440E Other: Laboratory Biomarker Analysis Correlative studies Procedure: Liver Transplantation Undergo liver transplant Other Names: Hepatic Transplantation Liver Grafting Liver Transplant Transplantation of Liver Drug: Temsirolimus Given IV Other Names: CCI-779 CCI-779 Rapamycin Analog Cell Cycle Inhibitor 779 Rapamycin Analog Rapamycin Analog CCI-779 Torisel Procedure: Therapeutic Conventional Surgery Undergo surgery Drug: Vincristine Sulfate Given IV Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate
Experimental: High-risk group (regimen W) (regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Fluorouracil Given IV Other Names: 5 Fluorouracil 5 Fluorouracilum 5 FU 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-Fu 5FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757 Drug: Irinotecan Hydrochloride Given IV Other Names: Campto Camptosar Camptothecin 11 Camptothecin-11 CPT 11 CPT-11 Irinomedac Irinotecan Hydrochloride Trihydrate Irinotecan Monohydrochloride Trihydrate U-101440E Other: Laboratory Biomarker Analysis Correlative studies Procedure: Therapeutic Conventional Surgery Undergo surgery Drug: Vincristine Sulfate Given IV Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate
Experimental: Intermediate-risk group (regimen F) Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012)	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Dexrazoxane Given IV Other Names: 2, 6-Piperazinedione, 4,4'-propylenedi-, (P)- (8CI) 2,6-Piperazinedione, 4, 4'-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI) ADR-529 ICRF-187 Razoxane (+)-form Soluble ICRF (L-isomer) Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Fluorouracil Given IV Other Names: 5 Fluorouracil 5 Fluorouracilum 5 FU 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-Fu 5FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757 Other: Laboratory Biomarker Analysis Correlative studies Procedure: Liver Transplantation Undergo liver transplant Other Names: Hepatic Transplantation Liver Grafting Liver Transplant Transplantation of Liver Procedure: Therapeutic Conventional Surgery Undergo surgery Drug: Vincristine Sulfate Given IV Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate
Experimental: Low-risk group (regimen T) Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Fluorouracil Given IV Other Names: 5 Fluorouracil 5 Fluorouracilum 5 FU 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-Fu 5FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757 Other: Laboratory Biomarker Analysis Correlative studies Procedure: Therapeutic Conventional Surgery Undergo surgery Drug: Vincristine Sulfate Given IV Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate
Experimental: Very low-risk group Patients undergo surgery and then receive no further treatment.	Other: Laboratory Biomarker Analysis Correlative studies Procedure: Therapeutic Conventional Surgery Undergo surgery

Outcome Measures

Primary Outcome Measures

Event-free Survival [Time from patient enrollment to progression, treatment failure, death from any cause, diagnosis of a second malignant neoplasm, or last follow-up, assessed up to 5 years]
Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
Number of Cycles on Which Grade 3 or Higher Adverse Events Coded According to CTC AE Version 5 Were Observed [During protocol therapy up to 1 year after enrollment]
All grade 3 or 4 or greater non-hematological toxicities. The frequency of each toxicity type will be quantified as the number of reporting periods on which the toxicity of the relevant grade is reported. This measure does not apply to patients enrolled in the VERY LOW RISK group.
Number of Deaths [During protocol therapy or within 30 days of the termination of protocol therapy up to 1 year after enrollment]
Number of patients who experience on-protocol-therapy death possibly, probably or likely related to systemic chemotherapy. This outcome measure applies to INTERMEDIATE RISK patients only.
Disease Status at the End of 2 Courses of Therapy [First two cycles of therapy- up to 42 days after enrollment]
RECIST v 1.1 and serum alphafetoprotein responses are evaluated separately. RECIST v 1.1 complete response (CR) is defined as disappearance of all target lesions and partial response (PR) is defined as reduction of at last 30% in the sum of the longest dimension of all target lesions (CR and PR measured by CT or MRI) between enrollment. Serum alphafetoprotein response is a decrease of at least 90% from the last serum alphafetoprotein measurement from the baseline prior to the start of chemotherapy to the end of cycle 2. This is calculated for HIGH RISK regimen W and HIGH RISK regimen H only.

Secondary Outcome Measures

Feasibility of Referral for Liver Transplantation [3 cycles of therapy - up to 3 months after enrollment]
A patient for whom referral is considered appropriate who receives a consultation after enrollment will be considered a success with respect to feasibility.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must be newly diagnosed with histologically-proven hepatoblastoma
In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, 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:
Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc)
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 alpha fetoprotein, and must meet all AHEP0731 eligibility criteria at the time of emergent treatment
Patient must be enrolled on AHEP0731 prior to initiating protocol therapy; 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 Children's Oncology Group (COG) staging guidelines
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 alpha fetoprotein was not obtained prior to that surgery, the patient will be considered to have alpha fetoprotein 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 case report form (CRF)
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
Patients may have had surgical resection of some or all sites of hepatoblastoma prior to enrollment
Organ function requirements are not required for enrolled patients who are stage I, PFH and will not be receiving chemotherapy
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR serum creatinine based on age/gender as follows:
1 month to < 6 months: 0.4 mg/dL
6 months to < 1 year: 0.5 mg/dL
1 to < 2 years: 0.6 mg/dL
2 to < 6 years: 0.8 mg/dL
6 to < 10 years: 1 mg/dL
10 to < 13 years: 1.2 mg/dL
13 to < 16 years: 1.5 mg/dL (male) or 1.4 mg/dL (female)
= 16 years: 1.7 mg/dL (male) or 1.4 mg/dL (female)
Total bilirubin < 1.5 x upper limit of normal (ULN) for age
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN for age
Absolute neutrophil count (ANC) > 750/uL
Platelet count > 75,000/uL
Shortening fraction >= 27% by echocardiogram
Ejection fraction >= 47% by radionuclide angiogram (multi gated acquisition scan [MUGA]); Note: the echocardiogram (or MUGA) may be done within 28 days prior to enrollment
Serum triglyceride level =< 300 mg/dL (=< 3.42 mmol/L)
Serum cholesterol level =< 300 mg/dL (7.75 mmol/L)
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
Normal pulmonary function tests (including diffusing capacity of the lungs for carbon monoxide [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, pulmonary function tests (PFTs) are NOT required
Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and if seizures are well controlled
Prothrombin time (PT) < 1.2 x ULN
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

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
Patients that have been previously treated with chemotherapy for hepatoblastoma or other hepatoblastoma-directed therapy (e.g., radiation therapy, biologic agents, local therapy [embolization, radiofrequency ablation, laser]) are not eligible
Patients who have received any prior chemotherapy are not eligible
Patients who are currently receiving another investigational drug are not eligible
Patients who are currently receiving other anticancer agents are not eligible
Patients who have previously received a solid organ transplant are not eligible
Patients who have an uncontrolled infection are not eligible
Females who are pregnant or breast feeding are not eligible for this study
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
Males and females of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method
Patients receiving corticosteroids are not eligible; patients must have been off corticosteroids for 7 days prior to start of chemotherapy
Patients who are currently receiving enzyme inducing anticonvulsants are not eligible
Patients must not be receiving any of the following potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors: erythromycin, clarithromycin, azithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit juice or St. John's wort
Patients who are currently receiving therapeutic anticoagulants (including aspirin, low molecular weight heparin, warfarin and others) are not eligible
Patients who are currently receiving angiotensin-converting enzymes (ACE) inhibitors are not eligible
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
3	USA Health Strada Patient Care Center	Mobile	Alabama	United States	36604
4	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
5	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
6	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
7	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
8	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
9	Loma Linda University Medical Center	Loma Linda	California	United States	92354
10	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
11	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
12	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
13	Valley Children's Hospital	Madera	California	United States	93636
14	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
15	Kaiser Permanente-Oakland	Oakland	California	United States	94611
16	Children's Hospital of Orange County	Orange	California	United States	92868
17	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
18	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
19	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
20	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
21	Naval Medical Center -San Diego	San Diego	California	United States	92134
22	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
23	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
24	Santa Barbara Cottage Hospital	Santa Barbara	California	United States	93102
25	Children's Hospital Colorado	Aurora	Colorado	United States	80045
26	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
27	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
28	Yale University	New Haven	Connecticut	United States	06520
29	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
30	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
31	Children's National Medical Center	Washington	District of Columbia	United States	20010
32	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
33	Lee Memorial Health System	Fort Myers	Florida	United States	33901
34	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
35	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
36	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
37	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
38	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
39	Nicklaus Children's Hospital	Miami	Florida	United States	33155
40	Miami Cancer Institute	Miami	Florida	United States	33176
41	AdventHealth Orlando	Orlando	Florida	United States	32803
42	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
43	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
44	Orlando Health Cancer Institute	Orlando	Florida	United States	32806
45	Nemours Children's Hospital	Orlando	Florida	United States	32827
46	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
47	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
48	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
49	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
50	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
51	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
52	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
53	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
54	Tripler Army Medical Center	Honolulu	Hawaii	United States	96859
55	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
56	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
57	University of Illinois	Chicago	Illinois	United States	60612
58	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
59	Loyola University Medical Center	Maywood	Illinois	United States	60153
60	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
61	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois	United States	60068
62	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
63	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
64	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
65	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
66	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
67	Blank Children's Hospital	Des Moines	Iowa	United States	50309
68	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
69	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
70	Norton Children's Hospital	Louisville	Kentucky	United States	40202
71	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
72	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
73	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
74	Eastern Maine Medical Center	Bangor	Maine	United States	04401
75	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
76	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
77	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
78	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
79	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
80	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts	United States	01655
81	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
82	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
83	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
84	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
85	Hurley Medical Center	Flint	Michigan	United States	48503
86	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
87	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
88	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
89	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
90	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
91	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
92	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
93	Columbia Regional	Columbia	Missouri	United States	65201
94	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
95	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
96	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
97	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
98	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
99	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
100	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
101	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
102	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
103	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada	United States	89169
104	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
105	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
106	Morristown Medical Center	Morristown	New Jersey	United States	07960
107	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
108	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
109	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
110	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
111	Overlook Hospital	Summit	New Jersey	United States	07902
112	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
113	Albany Medical Center	Albany	New York	United States	12208
114	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
115	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
116	NYU Winthrop Hospital	Mineola	New York	United States	11501
117	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
118	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
119	Mount Sinai Hospital	New York	New York	United States	10029
120	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
121	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
122	University of Rochester	Rochester	New York	United States	14642
123	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
124	New York Medical College	Valhalla	New York	United States	10595
125	Mission Hospital	Asheville	North Carolina	United States	28801
126	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
127	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
128	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
129	Duke University Medical Center	Durham	North Carolina	United States	27710
130	East Carolina University	Greenville	North Carolina	United States	27834
131	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
132	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
133	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
134	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
135	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
136	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
137	Dayton Children's Hospital	Dayton	Ohio	United States	45404
138	Mercy Children's Hospital	Toledo	Ohio	United States	43608
139	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
140	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
141	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
142	Oregon Health and Science University	Portland	Oregon	United States	97239
143	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
144	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
145	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
146	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
147	Rhode Island Hospital	Providence	Rhode Island	United States	02903
148	Medical University of South Carolina	Charleston	South Carolina	United States	29425
149	Prisma Health Richland Hospital	Columbia	South Carolina	United States	29203
150	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
151	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
152	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
153	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
154	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
155	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
156	The Children's Hospital at TriStar Centennial	Nashville	Tennessee	United States	37203
157	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
158	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
159	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
160	Medical City Dallas Hospital	Dallas	Texas	United States	75230
161	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
162	El Paso Children's Hospital	El Paso	Texas	United States	79905
163	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
164	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
165	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
166	UMC Cancer Center / UMC Health System	Lubbock	Texas	United States	79415
167	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
168	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
169	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
170	Scott and White Memorial Hospital	Temple	Texas	United States	76508
171	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
172	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
173	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
174	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
175	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
176	Carilion Children's	Roanoke	Virginia	United States	24014
177	Seattle Children's Hospital	Seattle	Washington	United States	98105
178	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
179	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
180	Madigan Army Medical Center	Tacoma	Washington	United States	98431
181	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
182	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
183	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
184	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
185	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales	Australia	2310
186	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
187	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia	Australia	5006
188	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
189	Instituto De Oncologia Pediatrica	Sao Paulo		Brazil	04023-062
190	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
191	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
192	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
193	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
194	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
195	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
196	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
197	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
198	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
199	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
200	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
201	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
202	Fukushima Medical University Hospital	Fukushima City	Fukushima Prefecture	Japan	960-1295
203	Kagoshima University Medical Dental Hospital	Kagoshima City	Kagoshima	Japan	890-8520
204	Shizuoka Cancer Center	Shizuoka City	Suntou	Japan	411-8777
205	Nihon University Itabashi Hospital	Itabashi-ku	Tokyo	Japan	173-8610
206	Hiroshima University Hospital	Hiroshima City		Japan	734-8551
207	National Cancer Center Hospital	Tokyo		Japan	104 0045
208	San Jorge Children's Hospital	San Juan		Puerto Rico	00912
209	University Pediatric Hospital	San Juan		Puerto Rico	00926

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator: Howard M Katzenstein, Children's Oncology Group

Study Documents (Full-Text)

Study Protocol and Statistical Analysis Plan - Nov 7, 2018

More Information

Additional Information:

Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Publications

None provided.

Responsible Party:

National Cancer Institute (NCI)

ClinicalTrials.gov Identifier:

NCT00980460

Other Study ID Numbers:

NCI-2011-01975
NCI-2011-01975
AHEP0731
10-00098
COG-AHEP0731
CDR0000654889
AHEP0731
AHEP0731
U10CA180886
U10CA098543
NCT02265692

First Posted:

Sep 21, 2009

Last Update Posted:

Jul 28, 2022

Last Verified:

Jul 1, 2022

Additional relevant MeSH terms:

Liposomal doxorubicin

3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione

Liver Extracts

Study Results

Participant Flow

Recruitment Details	Study opened for enrollment on 09/14/2009 and closed on 07/20/2018
Pre-assignment Detail

Arm/Group Title	Very Low-risk Group	Low-risk Group (Regimen T)	Intermediate-risk Group (Regimen F)	High-risk Group (Regimen W)	High-risk Group (Regimen H)
Arm/Group Description	Patients undergo surgery and then receive no further treatment. Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery	Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	(regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
Period Title: Overall Study
STARTED	8	51	105	32	40
COMPLETED	8	47	70	14	24
NOT COMPLETED	0	4	35	18	16

Baseline Characteristics

Arm/Group Title	Very Low-risk Group	Low-risk Group (Regimen T)	Intermediate-risk Group (Regimen F)	High-risk Group (Regimen W)	High-risk Group (Regimen H)	Total
Arm/Group Description	Patients undergo surgery and then receive no further treatment. Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery	Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	(regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Total of all reporting groups
Overall Participants	8	51	105	32	40	236
Age (Count of Participants)
<=18 years	8 100%	51 100%	105 100%	32 100%	40 100%	236 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.5 (2.56)	1.59 (1.71)	1.42 (2.61)	2.31 (2.4)	2.75 (2.9)	1.84 (2.5)
Sex: Female, Male (Count of Participants)
Female	1 12.5%	15 29.4%	43 41%	12 37.5%	13 32.5%	84 35.6%
Male	7 87.5%	36 70.6%	62 59%	20 62.5%	27 67.5%	152 64.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 12.5%	13 25.5%	27 25.7%	10 31.3%	16 40%	67 28.4%
Not Hispanic or Latino	7 87.5%	35 68.6%	73 69.5%	22 68.8%	23 57.5%	160 67.8%
Unknown or Not Reported	0 0%	3 5.9%	5 4.8%	0 0%	1 2.5%	9 3.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 12.5%	5 9.8%	8 7.6%	2 6.3%	6 15%	22 9.3%
Native Hawaiian or Other Pacific Islander	1 12.5%	0 0%	0 0%	0 0%	0 0%	1 0.4%
Black or African American	1 12.5%	6 11.8%	7 6.7%	6 18.8%	3 7.5%	23 9.7%
White	5 62.5%	29 56.9%	75 71.4%	20 62.5%	25 62.5%	154 65.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	11 21.6%	15 14.3%	4 12.5%	6 15%	36 15.3%
Region of Enrollment (participants) [Number]
United States	8 100%	50 98%	98 93.3%	30 93.8%	37 92.5%	223 94.5%
Canada	0 0%	1 2%	4 3.8%	2 6.3%	0 0%	7 3%
Australia	0 0%	0 0%	3 2.9%	0 0%	0 0%	3 1.3%
Japan	0 0%	0 0%	0 0%	0 0%	3 7.5%	3 1.3%

Outcome Measures

1. Primary Outcome

Title	Event-free Survival
Description	Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
Time Frame	Time from patient enrollment to progression, treatment failure, death from any cause, diagnosis of a second malignant neoplasm, or last follow-up, assessed up to 5 years

Outcome Measure Data

Analysis Population Description
Only eligible patients are considered in the calculation of this outcome measure.

Arm/Group Title	Very Low-risk Group	Low-risk Group (Regimen T)	Intermediate-risk Group (Regimen F)	High-risk Group (Regimen W)	High-risk Group (Regimen H)
Arm/Group Description	Patients undergo surgery and then receive no further treatment. Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery	Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	(regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
Measure Participants	8	49	102	31	36
Number (95% Confidence Interval) [Percent Probability]	100	87.21	87.03	43.61	46.38

2. Primary Outcome

Title	Number of Cycles on Which Grade 3 or Higher Adverse Events Coded According to CTC AE Version 5 Were Observed
Description	All grade 3 or 4 or greater non-hematological toxicities. The frequency of each toxicity type will be quantified as the number of reporting periods on which the toxicity of the relevant grade is reported. This measure does not apply to patients enrolled in the VERY LOW RISK group.
Time Frame	During protocol therapy up to 1 year after enrollment

Outcome Measure Data

Analysis Population Description
All eligible patients except for patients in the very low-risk group. Regimen T includes 49 cycles, Regimen F includes 269 cycles, Regimen W includes 107 cycles and Regimen H includes 124 cycles.

Arm/Group Title	Low-risk Group (Regimen T)	Intermediate-risk Group (Regimen F)	High-risk Group (Regimen W)	High-risk Group (Regimen H)
Arm/Group Description	Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	(regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
Measure Participants	51	105	32	40
Measure Cycles	49	269	107	124
Hearing impaired	1	20	4	4
Diarrhea	4	15	15	15
Enterocolitis	1	0	0	1
Nausea	1	10	10	3
Small intestinal obstruction	1	1	0	0
Vomiting	2	24	13	5
Abdominal distension	0	1	3	0
Abdominal pain	0	10	9	6
Colitis	0	3	1	1
Anal mucositis	0	1	0	0
Ascites	0	1	0	0
Malabsorption	0	1	0	0
Mucositis oral	0	44	8	6
Constipation	0	2	1	0
Dental caries	0	1	0	0
Typhlitis	0	2	2	1
Duodenal obstruction	0	1	0	0
Esophageal hemorrhage	0	1	0	0
Gastritis	0	1	1	0
Illeus	0	3	4	0
Oral pain	0	4	1	0
Small intestinal mucositis	0	1	0	0
Colonic hemorrhage	0	0	1	0
Dysphagia	0	0	1	0
Esophagitis	0	0	1	0
Gastroparesis	0	0	1	0
Gastric fistula	0	0	0	1
Gastrointestinal disorders - Other, specify	0	0	0	1
Obstruction gastric	0	0	0	1
Rectal mucositis	0	0	0	1
Fever	1	9	1	9
General disorders and administration site conditions - Other, specify	0	1	0	0
Pain	0	6	1	4
Multi-organ failure	0	1	0	2
Irritability	0	0	0	1
Infusion related reaction	0	0	0	1
Hypothermia	0	0	0	1
Catheter related infection	1	8	1	0
Infections and infestations - Other, specify	4	38	27	9
Mucosal infection	1	0	1	0
Otitis media	1	0	1	0
Urinary tract infection	1	3	0	3
Biliary tract infection	0	1	0	0
Abdominal infection	0	1	0	0
Bladder infection	0	2	0	0
Enterocolitis infectious	0	8	4	5
Duodenal infection	0	1	0	0
Upper respiratory infection	0	4	2	2
Eye infection	0	1	0	0
Wound infection	0	1	0	0
Sepsis	0	5	0	3
Lung infection	0	2	0	1
Peritoneal infection	0	1	0	0
Skin infection	0	1	1	7
Small intestine infection	0	1	0	0
Periorbital infection	0	0	0	1
Alanine aminotransferase increased	1	28	9	6
Aspartate aminotransferase increased	1	37	10	19
Activated partial thromboplastin time prolonged	0	2	3	1
Alkaline phosphatase increased	0	1	0	1
Blood bilirubin increased	0	7	2	5
Creatinine increased	0	3	0	1
GGT increased	0	7	1	6
Weight loss	0	6	4	6
Fibronogen decreased	0	2	0	1
Ejection fraction decreased	0	1	0	1
Investigations - Other, specify	0	1	0	0
White blood cell decreased	0	0	1	0
INR increased	0	0	1	0
CPK increased	0	0	0	1
Cholesterol high	0	0	0	1
Electrocardiogram QT corrected interval prolonged	0	0	0	1
Lipase increased	0	0	0	1
Serum amylase increased	0	0	0	1
Anorexia	1	30	20	17
Dehydration	3	13	3	12
Hyperglycemia	2	15	5	10
Hyperkalemia	2	12	3	5
Hypermagnesemia	2	4	0	0
Hypernatremia	2	1	0	3
Hypokalemia	4	48	12	29
Hyponatremia	1	22	6	10
Acidosis	0	4	0	1
Alkalosis	0	1	0	3
Hypocalcemia	0	7	4	2
Hypoalbuminemia	0	3	3	1
Hypomagnesemia	0	11	3	2
Hypophosphatemia	0	21	7	19
Tumor lysis syndrome	0	2	0	0
Hypercalcemia	0	0	1	0
Hypoglycemia	0	0	1	1
Hypertriglyceridemia	0	0	0	4
Metabolism and nutrition disorders - Other, specify	0	0	0	1
Peripheral sensory neuropathy	2	5	2	1
Oculomotor nerve disorder	0	3	0	0
Abducens nerve disorder	0	1	2	0
Peripheral motor neuropathy	0	7	3	2
Syncope	0	1	0	0
Dysphasia	0	0	1	0
Depressed level of consciousness	0	0	0	1
Seizure	0	0	0	1
Apnea	1	0	0	0
Atelectasis	0	2	0	0
Dyspnea	0	2	1	3
Bronchospasm	0	1	0	0
Hypoxia	0	10	2	6
Pleural effusion	0	2	2	1
Pulmonary edema	0	1	0	0
Stridor	0	1	0	0
Respiratory failure	0	2	0	1
Epistaxis	0	0	2	1
Wheezing	0	0	0	1
Hypertension	3	6	2	4
Hematoma	0	1	1	0
Hypotension	0	3	3	5
Vascular disorders - Other, specify	0	2	1	0
Thromboembolic event	0	0	1	1
Left ventricular systolic dysfunction	0	1	1	0
Cardiac arrest	0	1	3	0
Right ventricular dysfunction	0	2	0	0
Ventricular tachycardia	0	1	0	0
Cardiac disorders - Other, specify	0	0	1	0
Sinus tachycardia	0	0	1	4
Heart failure	0	0	1	1
Myocardial infarction	0	0	1	0
Biliary fistula	0	1	0	0
Hepatobiliary disorders - Other, specify	0	1	0	1
Hepatic hemorrhage	0	2	1	1
Portal vein thrombosis	0	1	0	0
Portal hypertension	0	0	1	0
Biliary anastomotic leak	0	1	1	0
Postoperative hemorrhage	0	1	1	0
Gastrointestinal anastomotic leak	0	0	2	0
Intraoperative hemorrhage	0	0	0	1
Arthralgia	0	1	0	0
Generalized muscle weakness	0	2	0	0
Back pain	0	1	0	0
Bone pain	0	1	0	0
Muscle weakness lower limb	0	1	0	0
Agitation	0	4	1	0
Hallucinations	0	1	0	0
Insomnia	0	0	0	1
Acute kidney injury	0	9	0	0
Renal and urinary disorders - Other, specify	0	3	1	0
Renal calculi	0	1	0	0
Proteinuria	0	0	0	1
Erythema multiforme	0	1	0	0
Skin and subcutaneous tissue disorders - Other, specify	0	2	0	1
Rash maculo-papular	0	3	1	2
Eye disorders - Other, specify	0	1	0	0
Surgical and medical procedures - Other, specify	0	1	0	0
Tumor pain	0	0	1	0
Allergic reaction	0	0	0	2
Anaphylaxis	0	0	0	2
Immune system disorders - Other, specify	0	0	0	1

3. Primary Outcome

Title	Number of Deaths
Description	Number of patients who experience on-protocol-therapy death possibly, probably or likely related to systemic chemotherapy. This outcome measure applies to INTERMEDIATE RISK patients only.
Time Frame	During protocol therapy or within 30 days of the termination of protocol therapy up to 1 year after enrollment

Outcome Measure Data

Analysis Population Description
Only eligible patients are considered in the calculation of this outcome measure.

Arm/Group Title	Intermediate-risk Group (Regimen F)
Arm/Group Description	Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
Measure Participants	102
Count of Participants [Participants]	1 12.5%

4. Primary Outcome

Title	Disease Status at the End of 2 Courses of Therapy
Description	RECIST v 1.1 and serum alphafetoprotein responses are evaluated separately. RECIST v 1.1 complete response (CR) is defined as disappearance of all target lesions and partial response (PR) is defined as reduction of at last 30% in the sum of the longest dimension of all target lesions (CR and PR measured by CT or MRI) between enrollment. Serum alphafetoprotein response is a decrease of at least 90% from the last serum alphafetoprotein measurement from the baseline prior to the start of chemotherapy to the end of cycle 2. This is calculated for HIGH RISK regimen W and HIGH RISK regimen H only.
Time Frame	First two cycles of therapy- up to 42 days after enrollment

Outcome Measure Data

Analysis Population Description
Thirty-two (32) patients were enrolled to Regiment W. Two were excluded from the analysis: (1)one was ineligible; and (2) one did not have an accurate report of initial AFP. Forty (40) patients were enrolled to Regiment H. Five were excluded from the analysis: (1)four were ineligible; and (2) one did not receive Temsirolimus.

Arm/Group Title	High-risk Group (Regimen W)	High-risk Group (Regimen H)
Arm/Group Description	(regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
Measure Participants	30	35
RECIST PR, no AFP response	3 37.5%	3 5.9%
AFP response, no RECIST response	5 62.5%	10 19.6%
RECIST response, AFP response	6 75%	4 7.8%
no AFP response, no RECIST response	16 200%	18 35.3%

5. Secondary Outcome

Title	Feasibility of Referral for Liver Transplantation
Description	A patient for whom referral is considered appropriate who receives a consultation after enrollment will be considered a success with respect to feasibility.
Time Frame	3 cycles of therapy - up to 3 months after enrollment

Outcome Measure Data

Analysis Population Description
Only eligible patients with COG surgical stage III or IV disease and whose tumor is PRETEXT classified as PRETEXT 3-4 extensive multifocal; PRETEXT 3 +V; PRETEXT 3 +P; or PRETEXT 4 extensive multifocal are evaluated for feasibility of transplant referral.

Arm/Group Title	Intermediate-risk Group (Regimen F)	High-risk Group (Regimen H)
Arm/Group Description	Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV	Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
Measure Participants	57	31
Count of Participants [Participants]	37 462.5%	16 31.4%

Adverse Events

	Very Low-risk Group		Low-risk Group (Regimen T)		Intermediate-risk Group (Regimen F)		High-risk Group (Regimen W)		High-risk Group (Regimen H)
Time Frame	AEs and OAEs: Up to 6 months post-treatment planned as 18 months; All-Cause Mortality: up to 10 years
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Arm/Group Title	Very Low-risk Group		Low-risk Group (Regimen T)		Intermediate-risk Group (Regimen F)		High-risk Group (Regimen W)		High-risk Group (Regimen H)
Arm/Group Description	Patients undergo surgery and then receive no further treatment. Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery		Patients undergo surgery and then receive adjuvant cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV		Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. (Closed to accrual as of 3/12/2012) Cisplatin: Given IV Dexrazoxane: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV		(regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV		Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. Cisplatin: Given IV Doxorubicin Hydrochloride: Given IV Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Liver Transplantation: Undergo liver transplant Temsirolimus: Given IV Therapeutic Conventional Surgery: Undergo surgery Vincristine Sulfate: Given IV
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		3/49 (6.1%)		7/102 (6.9%)		11/31 (35.5%)		13/36 (36.1%)
Serious Adverse Events
	Very Low-risk Group		Low-risk Group (Regimen T)		Intermediate-risk Group (Regimen F)		High-risk Group (Regimen W)		High-risk Group (Regimen H)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		2/31 (6.5%)		1/36 (2.8%)
Blood and lymphatic system disorders
Anemia	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Disseminated intravascular coagulation	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Febrile neutropenia	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Cardiac disorders
Cardiac arrest	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Cardiac disorders - Other, specify	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Heart failure	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Left ventricular systolic dysfunction	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Myocardial infarction	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Right ventricular dysfunction	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Gastrointestinal disorders
Abdominal pain	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Ascites	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Esophageal hemorrhage	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Typhlitis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
General disorders
Multi-organ failure	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Hepatobiliary disorders
Portal hypertension	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Portal vein thrombosis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Infections and infestations
Sepsis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Injury, poisoning and procedural complications
Postoperative hemorrhage	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Renal and urinary disorders
Acute kidney injury	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Pulmonary edema	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Respiratory failure	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		0/36 (0%)
Vascular disorders
Hypotension	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Thromboembolic event	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Very Low-risk Group		Low-risk Group (Regimen T)		Intermediate-risk Group (Regimen F)		High-risk Group (Regimen W)		High-risk Group (Regimen H)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		24/49 (49%)		91/102 (89.2%)		27/31 (87.1%)		32/36 (88.9%)
Blood and lymphatic system disorders
Anemia	0/8 (0%)		1/49 (2%)		2/102 (2%)		0/31 (0%)		1/36 (2.8%)
Disseminated intravascular coagulation	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Febrile neutropenia	0/8 (0%)		7/49 (14.3%)		50/102 (49%)		19/31 (61.3%)		14/36 (38.9%)
Cardiac disorders
Cardiac arrest	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		0/36 (0%)
Heart failure	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Left ventricular systolic dysfunction	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Right ventricular dysfunction	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Sinus tachycardia	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		2/36 (5.6%)
Ventricular tachycardia	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Ear and labyrinth disorders
Hearing impaired	0/8 (0%)		1/49 (2%)		18/102 (17.6%)		2/31 (6.5%)		4/36 (11.1%)
Eye disorders
Eye disorders - Other, specify	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Gastrointestinal disorders
Abdominal distension	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		0/36 (0%)
Abdominal pain	0/8 (0%)		0/49 (0%)		7/102 (6.9%)		3/31 (9.7%)		5/36 (13.9%)
Anal mucositis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Colitis	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		0/31 (0%)		1/36 (2.8%)
Colonic hemorrhage	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Constipation	0/8 (0%)		0/49 (0%)		2/102 (2%)		1/31 (3.2%)		0/36 (0%)
Dental caries	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Diarrhea	0/8 (0%)		4/49 (8.2%)		12/102 (11.8%)		8/31 (25.8%)		13/36 (36.1%)
Duodenal obstruction	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Enterocolitis	0/8 (0%)		1/49 (2%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Gastric fistula	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Gastritis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Gastrointestinal disorders - Other, specify	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Gastroparesis	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Ileus	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		1/31 (3.2%)		1/36 (2.8%)
Malabsorption	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Mucositis oral	0/8 (0%)		0/49 (0%)		30/102 (29.4%)		5/31 (16.1%)		6/36 (16.7%)
Nausea	0/8 (0%)		1/49 (2%)		8/102 (7.8%)		4/31 (12.9%)		3/36 (8.3%)
Obstruction gastric	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Oral pain	0/8 (0%)		0/49 (0%)		2/102 (2%)		1/31 (3.2%)		0/36 (0%)
Rectal mucositis	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Small intestinal mucositis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Small intestinal obstruction	0/8 (0%)		1/49 (2%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Typhlitis	0/8 (0%)		0/49 (0%)		1/102 (1%)		2/31 (6.5%)		1/36 (2.8%)
Vomiting	0/8 (0%)		2/49 (4.1%)		19/102 (18.6%)		9/31 (29%)		4/36 (11.1%)
General disorders
Fever	0/8 (0%)		1/49 (2%)		8/102 (7.8%)		0/31 (0%)		11/36 (30.6%)
General disorders and administration site conditions - Other, specify	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Hypothermia	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Infusion related reaction	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Irritability	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Multi-organ failure	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		1/36 (2.8%)
Pain	0/8 (0%)		0/49 (0%)		6/102 (5.9%)		1/31 (3.2%)		2/36 (5.6%)
Hepatobiliary disorders
Biliary fistula	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Hepatic hemorrhage	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		1/36 (2.8%)
Hepatobiliary disorders - Other, specify	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		1/36 (2.8%)
Immune system disorders
Allergic reaction	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		2/36 (5.6%)
Anaphylaxis	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		2/36 (5.6%)
Immune system disorders - Other, specify	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Infections and infestations
Abdominal infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Biliary tract infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Bladder infection	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		0/36 (0%)
Catheter related infection	0/8 (0%)		1/49 (2%)		5/102 (4.9%)		1/31 (3.2%)		0/36 (0%)
Duodenal infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Enterocolitis infectious	0/8 (0%)		0/49 (0%)		6/102 (5.9%)		2/31 (6.5%)		4/36 (11.1%)
Eye infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Infections and infestations - Other, specify	0/8 (0%)		4/49 (8.2%)		26/102 (25.5%)		16/31 (51.6%)		7/36 (19.4%)
Lung infection	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		1/36 (2.8%)
Mucosal infection	0/8 (0%)		1/49 (2%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Otitis media	0/8 (0%)		1/49 (2%)		0/102 (0%)		0/31 (0%)		0/36 (0%)
Periorbital infection	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Peritoneal infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Sepsis	0/8 (0%)		0/49 (0%)		4/102 (3.9%)		0/31 (0%)		3/36 (8.3%)
Skin infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		5/36 (13.9%)
Small intestine infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Upper respiratory infection	0/8 (0%)		0/49 (0%)		4/102 (3.9%)		2/31 (6.5%)		2/36 (5.6%)
Urinary tract infection	0/8 (0%)		1/49 (2%)		2/102 (2%)		0/31 (0%)		3/36 (8.3%)
Wound infection	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Injury, poisoning and procedural complications
Biliary anastomotic leak	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		0/36 (0%)
Gastrointestinal anastomotic leak	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Intraoperative hemorrhage	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Postoperative hemorrhage	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/8 (0%)		0/49 (0%)		2/102 (2%)		3/31 (9.7%)		1/36 (2.8%)
Alanine aminotransferase increased	0/8 (0%)		1/49 (2%)		21/102 (20.6%)		7/31 (22.6%)		6/36 (16.7%)
Alkaline phosphatase increased	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		1/36 (2.8%)
Aspartate aminotransferase increased	0/8 (0%)		1/49 (2%)		26/102 (25.5%)		7/31 (22.6%)		16/36 (44.4%)
Blood bilirubin increased	0/8 (0%)		0/49 (0%)		7/102 (6.9%)		2/31 (6.5%)		5/36 (13.9%)
Cholesterol high	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
CPK increased	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Creatinine increased	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		0/31 (0%)		1/36 (2.8%)
Ejection fraction decreased	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		1/36 (2.8%)
Electrocardiogram QT corrected interval prolonged	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		2/36 (5.6%)
Fibrinogen decreased	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		1/36 (2.8%)
GGT increased	0/8 (0%)		0/49 (0%)		6/102 (5.9%)		1/31 (3.2%)		5/36 (13.9%)
INR increased	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Investigations - Other, specify	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Lipase increased	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Neutrophil count decreased	0/8 (0%)		3/49 (6.1%)		4/102 (3.9%)		1/31 (3.2%)		0/36 (0%)
Platelet count decreased	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		0/36 (0%)
Serum amylase increased	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Weight loss	0/8 (0%)		0/49 (0%)		4/102 (3.9%)		3/31 (9.7%)		6/36 (16.7%)
White blood cell decreased	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Metabolism and nutrition disorders
Acidosis	0/8 (0%)		0/49 (0%)		4/102 (3.9%)		0/31 (0%)		1/36 (2.8%)
Alkalosis	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		2/36 (5.6%)
Anorexia	0/8 (0%)		1/49 (2%)		19/102 (18.6%)		9/31 (29%)		11/36 (30.6%)
Dehydration	0/8 (0%)		3/49 (6.1%)		8/102 (7.8%)		2/31 (6.5%)		10/36 (27.8%)
Hypercalcemia	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Hyperglycemia	0/8 (0%)		2/49 (4.1%)		14/102 (13.7%)		2/31 (6.5%)		7/36 (19.4%)
Hyperkalemia	0/8 (0%)		2/49 (4.1%)		9/102 (8.8%)		3/31 (9.7%)		4/36 (11.1%)
Hypermagnesemia	0/8 (0%)		2/49 (4.1%)		4/102 (3.9%)		0/31 (0%)		0/36 (0%)
Hypernatremia	0/8 (0%)		2/49 (4.1%)		1/102 (1%)		0/31 (0%)		2/36 (5.6%)
Hypertriglyceridemia	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		4/36 (11.1%)
Hypoalbuminemia	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		2/31 (6.5%)		1/36 (2.8%)
Hypocalcemia	0/8 (0%)		0/49 (0%)		7/102 (6.9%)		4/31 (12.9%)		2/36 (5.6%)
Hypoglycemia	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		1/36 (2.8%)
Hypokalemia	0/8 (0%)		4/49 (8.2%)		37/102 (36.3%)		7/31 (22.6%)		16/36 (44.4%)
Hypomagnesemia	0/8 (0%)		0/49 (0%)		11/102 (10.8%)		3/31 (9.7%)		2/36 (5.6%)
Hyponatremia	0/8 (0%)		1/49 (2%)		15/102 (14.7%)		4/31 (12.9%)		9/36 (25%)
Hypophosphatemia	0/8 (0%)		0/49 (0%)		18/102 (17.6%)		6/31 (19.4%)		13/36 (36.1%)
Metabolism and nutrition disorders - Other, specify	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Tumor lysis syndrome	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		0/36 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Back pain	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Bone pain	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Generalized muscle weakness	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Muscle weakness lower limb	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Nervous system disorders
Abducens nerve disorder	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Depressed level of consciousness	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Dysphasia	0/8 (0%)		0/49 (0%)		0/102 (0%)		1/31 (3.2%)		0/36 (0%)
Oculomotor nerve disorder	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		0/36 (0%)
Peripheral motor neuropathy	0/8 (0%)		0/49 (0%)		4/102 (3.9%)		2/31 (6.5%)		2/36 (5.6%)
Peripheral sensory neuropathy	0/8 (0%)		2/49 (4.1%)		4/102 (3.9%)		1/31 (3.2%)		1/36 (2.8%)
Seizure	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Syncope	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Psychiatric disorders
Agitation	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		1/31 (3.2%)		0/36 (0%)
Hallucinations	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Insomnia	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Renal and urinary disorders
Acute kidney injury	0/8 (0%)		0/49 (0%)		5/102 (4.9%)		0/31 (0%)		0/36 (0%)
Proteinuria	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Renal and urinary disorders - Other, specify	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		0/31 (0%)		0/36 (0%)
Renal calculi	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	0/8 (0%)		1/49 (2%)		0/102 (0%)		0/31 (0%)		0/36 (0%)
Atelectasis	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		0/36 (0%)
Bronchospasm	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Cough	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Dyspnea	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		3/36 (8.3%)
Epistaxis	0/8 (0%)		0/49 (0%)		0/102 (0%)		2/31 (6.5%)		1/36 (2.8%)
Hypoxia	0/8 (0%)		0/49 (0%)		7/102 (6.9%)		1/31 (3.2%)		6/36 (16.7%)
Pleural effusion	0/8 (0%)		0/49 (0%)		2/102 (2%)		2/31 (6.5%)		1/36 (2.8%)
Respiratory failure	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Stridor	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Wheezing	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Skin and subcutaneous tissue disorders
Erythema multiforme	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Rash maculo-papular	0/8 (0%)		0/49 (0%)		3/102 (2.9%)		0/31 (0%)		2/36 (5.6%)
Skin and subcutaneous tissue disorders - Other, specify	0/8 (0%)		0/49 (0%)		2/102 (2%)		0/31 (0%)		1/36 (2.8%)
Surgical and medical procedures
Surgical and medical procedures - Other, specify	0/8 (0%)		0/49 (0%)		1/102 (1%)		0/31 (0%)		0/36 (0%)
Vascular disorders
Hematoma	0/8 (0%)		0/49 (0%)		1/102 (1%)		1/31 (3.2%)		0/36 (0%)
Hypertension	0/8 (0%)		3/49 (6.1%)		4/102 (3.9%)		2/31 (6.5%)		4/36 (11.1%)
Hypotension	0/8 (0%)		0/49 (0%)		1/102 (1%)		2/31 (6.5%)		4/36 (11.1%)
Thromboembolic event	0/8 (0%)		0/49 (0%)		0/102 (0%)		0/31 (0%)		1/36 (2.8%)
Vascular disorders - Other, specify	0/8 (0%)		0/49 (0%)		2/102 (2%)		1/31 (3.2%)		0/36 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Name/Title	Results Reporting Coordinator
Organization	Children's Oncology Group
Phone	626-447-0064
Email	resultsreportingcoordinator@childrensoncologygroup.org

Responsible Party:

National Cancer Institute (NCI)

ClinicalTrials.gov Identifier:

NCT00980460

Other Study ID Numbers:

NCI-2011-01975
NCI-2011-01975
AHEP0731
10-00098
COG-AHEP0731
CDR0000654889
AHEP0731
AHEP0731
U10CA180886
U10CA098543
NCT02265692

First Posted:

Sep 21, 2009

Last Update Posted:

Jul 28, 2022

Last Verified:

Jul 1, 2022

Risk-Based Therapy in Treating Younger Patients With Newly Diagnosed Liver Cancer

Study Details

Study Description

Brief Summary

Detailed Description

PRIMARY OBJECTIVES:

SECONDARY OBJECTIVES:

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact