OBJECTIVES:

Primary

- To estimate the event-free survival (EFS) in pediatric patients with stage I (non-PFH,
non-SCU) and stage II (non-SCU) hepatoblastoma treated with surgical resection followed
by 2 courses of cisplatin, fluorouracil, and vincristine (C5V).

- To determine the feasibility and toxicity of adding doxorubicin hydrochloride to the
chemotherapy regimen of C5V for pediatric patients with intermediate-risk
hepatoblastoma.

- To estimate the response rate to vincristine and irinotecan hydrochloride in previously
untreated pediatric patients with high-risk, metastatic hepatoblastoma.

- To determine whether timely (between diagnosis and end of second course 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

- To estimate the EFS of patients with stage I PFH treated with surgery alone.

- To determine whether liver transplantation (OLT) can be accomplished after successful
referral and completion of 4 courses 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 pediatric patients with hepatoblastoma who receive OLT with PLUTO
(Pediatric Liver Unresectable Tumor Observatory), an international cooperative registry
for pediatric patients transplanted for liver tumors.

- To determine if 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 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: This is a multicenter study. Patients are stratified according to risk (very low vs
low vs intermediate vs high). 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 IV over 6 hours on day 1, fluorouracil IV on day 2, and vincristine sulfate
IV 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): Patients receive C5VD chemotherapy comprising
cisplatin IV over 6 hours on day 1, fluorouracil IV on day 2, vincristine sulfate IV 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.

- High-risk group (regimen W): 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. Patients undergo tumor resection or liver
transplantation after course 4 of C5VD followed by 2 courses of adjuvant C5VD.

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