Trial Information

Treatment of Children With All Stages of Hepatoblastoma

PRIMARY OBJECTIVES:

I. 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).

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

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

IV. 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.

V. 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:

I. To estimate the EFS of patients with stage I PFH treated with surgery alone. II. To
determine whether liver transplantation (OLT) can be accomplished after successful referral
and completion of 4 courses of initial chemotherapy.

III. 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.

IV. 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.

V. To determine if PRETEXT grouping can predict tumor resectability. VI. To monitor the
concordance between institutional assessment of PRETEXT grouping and PRETEXT grouping as
performed by expert panel review.

VII. To estimate the proportion of stage IV patients who have surgical resection of
metastatic pulmonary lesions.

VIII. 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.