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

• ClinicalTrials.gov Identifier: NCT00980460
• Recruitment Status: Active, not recruiting
• First Posted: September 21, 2009
• Results First Posted: December 28, 2021
• Last Update Posted: June 28, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: PRETEXT Stage 1 Hepatoblastoma; PRETEXT Stage 2 Hepatoblastoma; PRETEXT Stage 3 Hepatoblastoma; PRETEXT Stage 4 Hepatoblastoma
• Interventions: 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
• Enrollment: 236

Participant Flow

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

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
Reason Not Completed
Death	0	0	1	2	1
Lack of Efficacy	0	0	10	6	8
Lost to Follow-up	0	0	0	1	0
Physician Decision	0	0	11	5	3
Withdrawal by Subject	0	0	1	0	0
Ineligible	0	2	3	1	4
Refusal of further therapy	0	2	3	2	0
No therapy within 42 days of resection	0	0	3	1	0
No transplant by protocol timepoints	0	0	3	0	0

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 Number of Baseline Participants		8	51	105	32	40	236
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	51 participants	105 participants	32 participants	40 participants	236 participants
	<=18 years	8 100.0%	51 100.0%	105 100.0%	32 100.0%	40 100.0%	236 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	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%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	8 participants	51 participants	105 participants	32 participants	40 participants	236 participants
		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; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	51 participants	105 participants	32 participants	40 participants	236 participants
	Female	1 12.5%	15 29.4%	43 41.0%	12 37.5%	13 32.5%	84 35.6%
	Male	7 87.5%	36 70.6%	62 59.0%	20 62.5%	27 67.5%	152 64.4%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	51 participants	105 participants	32 participants	40 participants	236 participants
	Hispanic or Latino	1 12.5%	13 25.5%	27 25.7%	10 31.3%	16 40.0%	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 0.0%	3 5.9%	5 4.8%	0 0.0%	1 2.5%	9 3.8%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	51 participants	105 participants	32 participants	40 participants	236 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	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 15.0%	22 9.3%
	Native Hawaiian or Other Pacific Islander	1 12.5%	0 0.0%	0 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%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	11 21.6%	15 14.3%	4 12.5%	6 15.0%	36 15.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	8 participants	51 participants	105 participants	32 participants	40 participants	236 participants
United States		8	50	98	30	37	223
Canada		0	1	4	2	0	7
Australia		0	0	3	0	0	3
Japan		0	0	0	0	3	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
Overall Number of Participants Analyzed	8	49	102	31	36
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percent Probability
	100; (100 to 100)	87.21; (73.67 to 94.06)	87.03; (78.71 to 92.26)	43.61; (25.79 to 60.16)	46.38; (29.47 to 61.68)

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
Overall Number of Participants Analyzed	51	105	32	40
Overall Number of Units Analyzed; Type of Units Analyzed: Cycles	49	269	107	124
Measure Type: Number; Unit of Measure: Cycles
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
Overall Number of Participants Analyzed	102
Measure Type: Count of Participants; Unit of Measure: Participants
	1 1.0%

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
Overall Number of Participants Analyzed	30	35
Measure Type: Number; Unit of Measure: participants
RECIST PR, no AFP response	3	3
AFP response, no RECIST response	5	10
RECIST response, AFP response	6	4
no AFP response, no RECIST response	16	18

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
Overall Number of Participants Analyzed	57	31
Measure Type: Count of Participants; Unit of Measure: Participants
	37 64.9%	16 51.6%

Adverse Events

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
	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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/8 (0.00%)	3/49 (6.12%)	7/102 (6.86%)	11/31 (35.48%)	13/36 (36.11%)
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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	2/31 (6.45%)	1/36 (2.78%)
Blood and lymphatic system disorders
Anemia †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Disseminated intravascular coagulation †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Febrile neutropenia †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Cardiac disorders
Cardiac arrest †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Cardiac disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Heart failure †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Left ventricular systolic dysfunction †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Myocardial infarction †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Right ventricular dysfunction †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Gastrointestinal disorders
Abdominal pain †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Ascites †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Esophageal hemorrhage †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Typhlitis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
General disorders
Multi-organ failure †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Hepatobiliary disorders
Portal hypertension †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Portal vein thrombosis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Infections and infestations
Sepsis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Injury, poisoning and procedural complications
Postoperative hemorrhage †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Renal and urinary disorders
Acute kidney injury †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Respiratory, thoracic and mediastinal disorders
Hypoxia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Pulmonary edema †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Respiratory failure †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	0/36 (0.00%)
Vascular disorders
Hypotension †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Thromboembolic event †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/8 (0.00%)	24/49 (48.98%)	91/102 (89.22%)	27/31 (87.10%)	32/36 (88.89%)
Blood and lymphatic system disorders
Anemia †	0/8 (0.00%)	1/49 (2.04%)	2/102 (1.96%)	0/31 (0.00%)	1/36 (2.78%)
Disseminated intravascular coagulation †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Febrile neutropenia †	0/8 (0.00%)	7/49 (14.29%)	50/102 (49.02%)	19/31 (61.29%)	14/36 (38.89%)
Cardiac disorders
Cardiac arrest †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	0/36 (0.00%)
Heart failure †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Left ventricular systolic dysfunction †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Right ventricular dysfunction †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Sinus tachycardia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	2/36 (5.56%)
Ventricular tachycardia †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Ear and labyrinth disorders
Hearing impaired †	0/8 (0.00%)	1/49 (2.04%)	18/102 (17.65%)	2/31 (6.45%)	4/36 (11.11%)
Eye disorders
Eye disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Gastrointestinal disorders
Abdominal distension †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	0/36 (0.00%)
Abdominal pain †	0/8 (0.00%)	0/49 (0.00%)	7/102 (6.86%)	3/31 (9.68%)	5/36 (13.89%)
Anal mucositis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Colitis †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	0/31 (0.00%)	1/36 (2.78%)
Colonic hemorrhage †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Constipation †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	1/31 (3.23%)	0/36 (0.00%)
Dental caries †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Diarrhea †	0/8 (0.00%)	4/49 (8.16%)	12/102 (11.76%)	8/31 (25.81%)	13/36 (36.11%)
Duodenal obstruction †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Enterocolitis †	0/8 (0.00%)	1/49 (2.04%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Gastric fistula †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Gastritis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Gastrointestinal disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Gastroparesis †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Ileus †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	1/31 (3.23%)	1/36 (2.78%)
Malabsorption †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Mucositis oral †	0/8 (0.00%)	0/49 (0.00%)	30/102 (29.41%)	5/31 (16.13%)	6/36 (16.67%)
Nausea †	0/8 (0.00%)	1/49 (2.04%)	8/102 (7.84%)	4/31 (12.90%)	3/36 (8.33%)
Obstruction gastric †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Oral pain †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	1/31 (3.23%)	0/36 (0.00%)
Rectal mucositis †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Small intestinal mucositis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Small intestinal obstruction †	0/8 (0.00%)	1/49 (2.04%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Typhlitis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	2/31 (6.45%)	1/36 (2.78%)
Vomiting †	0/8 (0.00%)	2/49 (4.08%)	19/102 (18.63%)	9/31 (29.03%)	4/36 (11.11%)
General disorders
Fever †	0/8 (0.00%)	1/49 (2.04%)	8/102 (7.84%)	0/31 (0.00%)	11/36 (30.56%)
General disorders and administration site conditions - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Hypothermia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Infusion related reaction †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Irritability †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Multi-organ failure †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	1/36 (2.78%)
Pain †	0/8 (0.00%)	0/49 (0.00%)	6/102 (5.88%)	1/31 (3.23%)	2/36 (5.56%)
Hepatobiliary disorders
Biliary fistula †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Hepatic hemorrhage †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	1/36 (2.78%)
Hepatobiliary disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	1/36 (2.78%)
Immune system disorders
Allergic reaction †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	2/36 (5.56%)
Anaphylaxis †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	2/36 (5.56%)
Immune system disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Infections and infestations
Abdominal infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Biliary tract infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Bladder infection †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	0/36 (0.00%)
Catheter related infection †	0/8 (0.00%)	1/49 (2.04%)	5/102 (4.90%)	1/31 (3.23%)	0/36 (0.00%)
Duodenal infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Enterocolitis infectious †	0/8 (0.00%)	0/49 (0.00%)	6/102 (5.88%)	2/31 (6.45%)	4/36 (11.11%)
Eye infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Infections and infestations - Other, specify †	0/8 (0.00%)	4/49 (8.16%)	26/102 (25.49%)	16/31 (51.61%)	7/36 (19.44%)
Lung infection †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	1/36 (2.78%)
Mucosal infection †	0/8 (0.00%)	1/49 (2.04%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Otitis media †	0/8 (0.00%)	1/49 (2.04%)	0/102 (0.00%)	0/31 (0.00%)	0/36 (0.00%)
Periorbital infection †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Peritoneal infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Sepsis †	0/8 (0.00%)	0/49 (0.00%)	4/102 (3.92%)	0/31 (0.00%)	3/36 (8.33%)
Skin infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	5/36 (13.89%)
Small intestine infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Upper respiratory infection †	0/8 (0.00%)	0/49 (0.00%)	4/102 (3.92%)	2/31 (6.45%)	2/36 (5.56%)
Urinary tract infection †	0/8 (0.00%)	1/49 (2.04%)	2/102 (1.96%)	0/31 (0.00%)	3/36 (8.33%)
Wound infection †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Injury, poisoning and procedural complications
Biliary anastomotic leak †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	0/36 (0.00%)
Gastrointestinal anastomotic leak †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Intraoperative hemorrhage †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Postoperative hemorrhage †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Investigations
Activated partial thromboplastin time prolonged †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	3/31 (9.68%)	1/36 (2.78%)
Alanine aminotransferase increased †	0/8 (0.00%)	1/49 (2.04%)	21/102 (20.59%)	7/31 (22.58%)	6/36 (16.67%)
Alkaline phosphatase increased †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	1/36 (2.78%)
Aspartate aminotransferase increased †	0/8 (0.00%)	1/49 (2.04%)	26/102 (25.49%)	7/31 (22.58%)	16/36 (44.44%)
Blood bilirubin increased †	0/8 (0.00%)	0/49 (0.00%)	7/102 (6.86%)	2/31 (6.45%)	5/36 (13.89%)
Cholesterol high †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
CPK increased †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Creatinine increased †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	0/31 (0.00%)	1/36 (2.78%)
Ejection fraction decreased †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	1/36 (2.78%)
Electrocardiogram QT corrected interval prolonged †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	2/36 (5.56%)
Fibrinogen decreased †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	1/36 (2.78%)
GGT increased †	0/8 (0.00%)	0/49 (0.00%)	6/102 (5.88%)	1/31 (3.23%)	5/36 (13.89%)
INR increased †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Investigations - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Lipase increased †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Neutrophil count decreased †	0/8 (0.00%)	3/49 (6.12%)	4/102 (3.92%)	1/31 (3.23%)	0/36 (0.00%)
Platelet count decreased †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	0/36 (0.00%)
Serum amylase increased †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Weight loss †	0/8 (0.00%)	0/49 (0.00%)	4/102 (3.92%)	3/31 (9.68%)	6/36 (16.67%)
White blood cell decreased †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Metabolism and nutrition disorders
Acidosis †	0/8 (0.00%)	0/49 (0.00%)	4/102 (3.92%)	0/31 (0.00%)	1/36 (2.78%)
Alkalosis †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	2/36 (5.56%)
Anorexia †	0/8 (0.00%)	1/49 (2.04%)	19/102 (18.63%)	9/31 (29.03%)	11/36 (30.56%)
Dehydration †	0/8 (0.00%)	3/49 (6.12%)	8/102 (7.84%)	2/31 (6.45%)	10/36 (27.78%)
Hypercalcemia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Hyperglycemia †	0/8 (0.00%)	2/49 (4.08%)	14/102 (13.73%)	2/31 (6.45%)	7/36 (19.44%)
Hyperkalemia †	0/8 (0.00%)	2/49 (4.08%)	9/102 (8.82%)	3/31 (9.68%)	4/36 (11.11%)
Hypermagnesemia †	0/8 (0.00%)	2/49 (4.08%)	4/102 (3.92%)	0/31 (0.00%)	0/36 (0.00%)
Hypernatremia †	0/8 (0.00%)	2/49 (4.08%)	1/102 (0.98%)	0/31 (0.00%)	2/36 (5.56%)
Hypertriglyceridemia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	4/36 (11.11%)
Hypoalbuminemia †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	2/31 (6.45%)	1/36 (2.78%)
Hypocalcemia †	0/8 (0.00%)	0/49 (0.00%)	7/102 (6.86%)	4/31 (12.90%)	2/36 (5.56%)
Hypoglycemia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	1/36 (2.78%)
Hypokalemia †	0/8 (0.00%)	4/49 (8.16%)	37/102 (36.27%)	7/31 (22.58%)	16/36 (44.44%)
Hypomagnesemia †	0/8 (0.00%)	0/49 (0.00%)	11/102 (10.78%)	3/31 (9.68%)	2/36 (5.56%)
Hyponatremia †	0/8 (0.00%)	1/49 (2.04%)	15/102 (14.71%)	4/31 (12.90%)	9/36 (25.00%)
Hypophosphatemia †	0/8 (0.00%)	0/49 (0.00%)	18/102 (17.65%)	6/31 (19.35%)	13/36 (36.11%)
Metabolism and nutrition disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Tumor lysis syndrome †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	0/36 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Back pain †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Bone pain †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Generalized muscle weakness †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Muscle weakness lower limb †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Nervous system disorders
Abducens nerve disorder †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Depressed level of consciousness †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Dysphasia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	1/31 (3.23%)	0/36 (0.00%)
Oculomotor nerve disorder †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	0/36 (0.00%)
Peripheral motor neuropathy †	0/8 (0.00%)	0/49 (0.00%)	4/102 (3.92%)	2/31 (6.45%)	2/36 (5.56%)
Peripheral sensory neuropathy †	0/8 (0.00%)	2/49 (4.08%)	4/102 (3.92%)	1/31 (3.23%)	1/36 (2.78%)
Seizure †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Syncope †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Psychiatric disorders
Agitation †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	1/31 (3.23%)	0/36 (0.00%)
Hallucinations †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Insomnia †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Renal and urinary disorders
Acute kidney injury †	0/8 (0.00%)	0/49 (0.00%)	5/102 (4.90%)	0/31 (0.00%)	0/36 (0.00%)
Proteinuria †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Renal and urinary disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	0/31 (0.00%)	0/36 (0.00%)
Renal calculi †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Respiratory, thoracic and mediastinal disorders
Apnea †	0/8 (0.00%)	1/49 (2.04%)	0/102 (0.00%)	0/31 (0.00%)	0/36 (0.00%)
Atelectasis †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	0/36 (0.00%)
Bronchospasm †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Cough †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Dyspnea †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	3/36 (8.33%)
Epistaxis †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	2/31 (6.45%)	1/36 (2.78%)
Hypoxia †	0/8 (0.00%)	0/49 (0.00%)	7/102 (6.86%)	1/31 (3.23%)	6/36 (16.67%)
Pleural effusion †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	2/31 (6.45%)	1/36 (2.78%)
Respiratory failure †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Stridor †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Wheezing †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Skin and subcutaneous tissue disorders
Erythema multiforme †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Rash maculo-papular †	0/8 (0.00%)	0/49 (0.00%)	3/102 (2.94%)	0/31 (0.00%)	2/36 (5.56%)
Skin and subcutaneous tissue disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	0/31 (0.00%)	1/36 (2.78%)
Surgical and medical procedures
Surgical and medical procedures - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	0/31 (0.00%)	0/36 (0.00%)
Vascular disorders
Hematoma †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	1/31 (3.23%)	0/36 (0.00%)
Hypertension †	0/8 (0.00%)	3/49 (6.12%)	4/102 (3.92%)	2/31 (6.45%)	4/36 (11.11%)
Hypotension †	0/8 (0.00%)	0/49 (0.00%)	1/102 (0.98%)	2/31 (6.45%)	4/36 (11.11%)
Thromboembolic event †	0/8 (0.00%)	0/49 (0.00%)	0/102 (0.00%)	0/31 (0.00%)	1/36 (2.78%)
Vascular disorders - Other, specify †	0/8 (0.00%)	0/49 (0.00%)	2/102 (1.96%)	1/31 (3.23%)	0/36 (0.00%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Trobaugh-Lotrario A, Katzenstein HM, Ranganathan S, Lopez-Terrada D, Krailo MD, Piao J, Chung N, Randazzo J, Malogolowkin MH, Furman WL, McCarville EB, Towbin AJ, Tiao GM, Dunn SP, Langham MR, McGahren ED, Feusner J, Rodriguez-Galindo C, Meyers RL, O'Neill AF, Finegold MJ. Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee. J Clin Oncol. 2022 Feb 10;40(5):459-467. doi: 10.1200/JCO.21.00803. Epub 2021 Dec 7.

Katzenstein HM, Langham MR, Malogolowkin MH, Krailo MD, Towbin AJ, McCarville MB, Finegold MJ, Ranganathan S, Dunn S, McGahren ED, Tiao GM, O'Neill AF, Qayed M, Furman WL, Xia C, Rodriguez-Galindo C, Meyers RL. Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):719-727. doi: 10.1016/S1470-2045(18)30895-7. Epub 2019 Apr 8. Erratum in: Lancet Oncol. 2019 May;20(5):e243.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00980460
• Obsolete Identifiers: NCT02265692
• Other Study ID Numbers: NCI-2011-01975; NCI-2011-01975 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); AHEP0731; 10-00098; COG-AHEP0731; CDR0000654889; AHEP0731 ( Other Identifier: Children's Oncology Group ); AHEP0731 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract ); U10CA098543 ( U.S. NIH Grant/Contract )
• First Submitted: September 18, 2009
• First Posted: September 21, 2009
• Results First Submitted: August 4, 2021
• Results First Posted: December 28, 2021
• Last Update Posted: June 28, 2022