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

Official Title

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

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.

Trial Description

Primary Outcome:

• Event-free survival
• Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 4.0
• Rate of death
• Disease status at the end of 2 courses of therapy

Secondary Outcome:

• Feasibility of referral for liver transplantation

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 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 centre 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 tumour 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.
• 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 centre that are resected without OLT, and the 2-year EFS for patients referred to a transplant centre who receive OLT.
• To register children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver Unresectable Tumour Observatory), an international cooperative registry for children transplanted for liver tumours.
• To determine if PRETEXT grouping can predict tumour 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. VIII. 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 tumours, 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 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 H) Patients receive up front VIT chemotherapy comprising vincristine sulfate IV 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 tumour resection or liver transplant 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.

View this trial on ClinicalTrials.gov