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

Phase 3

Active, not recruiting

Conditions: PRETEXT IV Hepatoblastoma
PRETEXT II Hepatoblastoma
PRETEXT III Hepatoblastoma
PRETEXT I Hepatoblastoma

Interventions: Drug: Cisplatin
Procedure: Therapeutic Conventional Surgery
Drug: Doxorubicin Hydrochloride
Drug: Dexrazoxane
Drug: Fluorouracil
Drug: Irinotecan Hydrochloride
Other: Laboratory Biomarker Analysis
Procedure: Liver Transplantation
Drug: Temsirolimus
Drug: Vincristine Sulfate

Registration Number: NCT00980460

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: PRIMARY OBJECTIVES:

I. 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).

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

III. To estimate the response rate to vincristine (vincristine sulfate), irinotecan (irinotecan hydrochloride), and temsirolimus in previously untreated children with high-risk, metastatic hepatoblastoma.

IV. 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.

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 orthotopic liver transplantation (OLT) can be accomplished after successful referral and completion of 4 cycles 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 children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver Unresectable Tumor Observatory), an international cooperative registry for children transplanted for liver tumors.

V. To determine if pretreatment extent of disease (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 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 236

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intermediate-risk group (regimen F)	Vincristine Sulfate	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)
Very low-risk group	Therapeutic Conventional Surgery	Patients undergo surgery and then receive no further treatment.
High-risk group (regimen H)	Irinotecan Hydrochloride	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.
High-risk group (regimen H)	Therapeutic Conventional Surgery	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.
High-risk group (regimen H)	Vincristine Sulfate	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.
High-risk group (regimen H)	Liver Transplantation	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.
Intermediate-risk group (regimen F)	Laboratory Biomarker Analysis	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)
High-risk group (regimen H)	Laboratory Biomarker Analysis	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.
High-risk group (regimen W)	Laboratory Biomarker Analysis	(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 W)	Vincristine Sulfate	(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 W)	Therapeutic Conventional Surgery	(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.
Low-risk group (regimen T)	Therapeutic Conventional 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.
Low-risk group (regimen T)	Vincristine Sulfate	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.
Intermediate-risk group (regimen F)	Liver Transplantation	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)
Intermediate-risk group (regimen F)	Therapeutic Conventional Surgery	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)
Low-risk group (regimen T)	Laboratory Biomarker Analysis	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.
Very low-risk group	Laboratory Biomarker Analysis	Patients undergo surgery and then receive no further treatment.
High-risk group (regimen H)	Cisplatin	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.
High-risk group (regimen H)	Doxorubicin Hydrochloride	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.
High-risk group (regimen H)	Fluorouracil	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.
High-risk group (regimen H)	Temsirolimus	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.
High-risk group (regimen W)	Cisplatin	(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 W)	Doxorubicin Hydrochloride	(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 W)	Fluorouracil	(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 W)	Irinotecan Hydrochloride	(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.
Intermediate-risk group (regimen F)	Cisplatin	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)
Intermediate-risk group (regimen F)	Dexrazoxane	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)
Intermediate-risk group (regimen F)	Doxorubicin Hydrochloride	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)
Intermediate-risk group (regimen F)	Fluorouracil	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)
Low-risk group (regimen T)	Cisplatin	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.
Low-risk group (regimen T)	Fluorouracil	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.

Primary Outcome Measures

Name	Time	Method
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.
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.
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

Name	Time	Method
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.

Trial Locations

Locations (209): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Albany Medical Center
🇺🇸
Albany, New York, United States
NYU Langone Hospital - Long Island
🇺🇸
Mineola, New York, United States
Instituto De Oncologia Pediatrica
🇧🇷
Sao Paulo, Brazil
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
USA Health Strada Patient Care Center
🇺🇸
Mobile, Alabama, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸
Oakland, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Sutter Medical Center Sacramento
🇺🇸
Sacramento, California, United States
Naval Medical Center -San Diego
🇺🇸
San Diego, California, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Santa Barbara Cottage Hospital
🇺🇸
Santa Barbara, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Broward Health Medical Center
🇺🇸
Fort Lauderdale, Florida, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸
Gainesville, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸
Hollywood, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Nicklaus Children's Hospital
🇺🇸
Miami, Florida, United States
Miami Cancer Institute
🇺🇸
Miami, Florida, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸
Orlando, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸
Orlando, Florida, United States
Orlando Health Cancer Institute
🇺🇸
Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Saint Mary's Medical Center
🇺🇸
West Palm Beach, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸
Atlanta, Georgia, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
University of Hawaii Cancer Center
🇺🇸
Honolulu, Hawaii, United States
Kapiolani Medical Center for Women and Children
🇺🇸
Honolulu, Hawaii, United States
Tripler Army Medical Center
🇺🇸
Honolulu, Hawaii, United States
Saint Luke's Cancer Institute - Boise
🇺🇸
Boise, Idaho, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸
Oak Lawn, Illinois, United States
Advocate Children's Hospital-Park Ridge
🇺🇸
Park Ridge, Illinois, United States
Advocate Lutheran General Hospital
🇺🇸
Park Ridge, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸
Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Tulane University School of Medicine
🇺🇸
New Orleans, Louisiana, United States
Children's Hospital New Orleans
🇺🇸
New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
🇺🇸
New Orleans, Louisiana, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
Maine Children's Cancer Program
🇺🇸
Scarborough, Maine, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
UMass Memorial Medical Center - University Campus
🇺🇸
Worcester, Massachusetts, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Henry Ford Health Saint John Hospital
🇺🇸
Detroit, Michigan, United States
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸
Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
Kalamazoo Center for Medical Studies
🇺🇸
Kalamazoo, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
University of Missouri Children's Hospital
🇺🇸
Columbia, Missouri, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
University Medical Center of Southern Nevada
🇺🇸
Las Vegas, Nevada, United States
Sunrise Hospital and Medical Center
🇺🇸
Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸
Las Vegas, Nevada, United States
Nevada Cancer Research Foundation NCORP
🇺🇸
Las Vegas, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸
Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Saint Peter's University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸
New Hyde Park, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Rochester
🇺🇸
Rochester, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Mission Hospital
🇺🇸
Asheville, North Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
Mercy Children's Hospital
🇺🇸
Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Legacy Emanuel Hospital and Health Center
🇺🇸
Portland, Oregon, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Penn State Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Greenville Cancer Treatment Center
🇺🇸
Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
T C Thompson Children's Hospital
🇺🇸
Chattanooga, Tennessee, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
Saint Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸
Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸
El Paso, Texas, United States
Brooke Army Medical Center
🇺🇸
Fort Sam Houston, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
UMC Cancer Center / UMC Health System
🇺🇸
Lubbock, Texas, United States
Children's Hospital of San Antonio
🇺🇸
San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Scott and White Memorial Hospital
🇺🇸
Temple, Texas, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
University of Virginia Cancer Center
🇺🇸
Charlottesville, Virginia, United States
Inova Fairfax Hospital
🇺🇸
Falls Church, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Carilion Children's
🇺🇸
Roanoke, Virginia, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
West Virginia University Charleston Division
🇺🇸
Charleston, West Virginia, United States
West Virginia University Healthcare
🇺🇸
Morgantown, West Virginia, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
John Hunter Children's Hospital
🇦🇺
Hunter Regional Mail Centre, New South Wales, Australia
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Women's and Children's Hospital-Adelaide
🇦🇺
North Adelaide, South Australia, Australia
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
Alberta Children's Hospital
🇨🇦
Calgary, Alberta, Canada
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦
Kingston, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦
Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Saskatoon Cancer Centre
🇨🇦
Saskatoon, Saskatchewan, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦
Quebec, Canada
Fukushima Medical University Hospital
🇯🇵
Fukushima City, Fukushima Prefecture, Japan
Kagoshima University Medical Dental Hospital
🇯🇵
Kagoshima City, Kagoshima, Japan
Shizuoka Cancer Center
🇯🇵
Shizuoka City, Suntou, Japan
Nihon University Itabashi Hospital
🇯🇵
Itabashi-ku, Tokyo, Japan
Hiroshima University Hospital
🇯🇵
Hiroshima City, Japan
National Cancer Center Hospital
🇯🇵
Tokyo, Japan
San Jorge Children's Hospital
🇵🇷
San Juan, Puerto Rico
University Pediatric Hospital
🇵🇷
San Juan, Puerto Rico