Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Liver Neoplasms

Hepatoblastoma

Neoplasms by Histologic Type

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Hematinics

Cardiotonic Agents

Irinotecan

Doxorubicin

Liposomal doxorubicin

Fluorouracil

Vincristine

Cisplatin

Sirolimus

Camptothecin

Liver Extracts

Dexrazoxane

Razoxane

Temsirolimus

MTOR Inhibitors

3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Tubulin Modulators

Antimitotic Agents

Clotrimazole

Miconazole

Antifungal Agents

Protein Kinase Inhibitors

Protective Agents

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.

(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.

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)

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.

Patients undergo surgery and then receive no further treatment.

Doxorubicin Hydrochloride

Irinotecan Hydrochloride

Laboratory Biomarker Analysis

Liver Transplantation

Therapeutic Conventional Surgery

Vincristine Sulfate

Howard M Katzenstein

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.

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.

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

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

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.

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 patients who experience on-protocol-therapy death possibly, probably or likely related to systemic chemotherapy. This outcome measure applies to INTERMEDIATE RISK patients only.

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.

A patient for whom referral is considered appropriate who receives a consultation after enrollment will be considered a success with respect to feasibility.

National Cancer Institute (NCI)

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.

Patients undergo surgery and then receive no further treatment.

Laboratory Biomarker Analysis: Correlative studies

Therapeutic Conventional Surgery: Undergo surgery

Very Low-risk Group

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

Low-risk Group (Regimen T)

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

Intermediate-risk Group (Regimen F)

(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

High-risk Group (Regimen W)

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

High-risk Group (Regimen H)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Australia

Japan

Region of Enrollment

Results Reporting Coordinator

Only eligible patients are considered in the calculation of this outcome measure.

Event-free Survival

Hearing impaired

Diarrhea

Enterocolitis

Nausea

Small intestinal obstruction

Vomiting

Abdominal distension

Abdominal pain

Colitis

Anal mucositis

Ascites

Malabsorption

Mucositis oral

Constipation

Dental caries

Typhlitis

Duodenal obstruction

Esophageal hemorrhage

Gastritis

Illeus

Oral pain

Small intestinal mucositis

Colonic hemorrhage

Dysphagia

Esophagitis

Gastroparesis

Gastric fistula

Gastrointestinal disorders - Other, specify

Obstruction gastric

Rectal mucositis

Fever

General disorders and administration site conditions - Other, specify

Pain

Multi-organ failure

Irritability

Infusion related reaction

Hypothermia

Catheter related infection

Infections and infestations - Other, specify

Mucosal infection

Otitis media

Urinary tract infection

Biliary tract infection

Abdominal infection

Bladder infection

Enterocolitis infectious

Duodenal infection

Upper respiratory infection

Eye infection

Wound infection

Sepsis

Lung infection

Peritoneal infection

Skin infection

Small intestine infection

Periorbital infection

Alanine aminotransferase increased

Aspartate aminotransferase increased

Activated partial thromboplastin time prolonged

Alkaline phosphatase increased

Blood bilirubin increased

Creatinine increased

GGT increased

Weight loss

Fibronogen decreased

Ejection fraction decreased

Investigations - Other, specify

White blood cell decreased

INR increased

CPK increased

Cholesterol high

Electrocardiogram QT corrected interval prolonged

Lipase increased

Serum amylase increased

Anorexia

Dehydration

Hyperglycemia

Hyperkalemia

Hypermagnesemia

Hypernatremia

Hypokalemia

Hyponatremia

Acidosis

Alkalosis

Hypocalcemia

Hypoalbuminemia

Hypomagnesemia

Hypophosphatemia

Tumor lysis syndrome

Hypercalcemia

Hypoglycemia

Hypertriglyceridemia

Metabolism and nutrition disorders - Other, specify

Peripheral sensory neuropathy

Oculomotor nerve disorder

Abducens nerve disorder

Peripheral motor neuropathy

Syncope

Dysphasia

Depressed level of consciousness

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.

Number of Cycles on Which Grade 3 or Higher Adverse Events Coded According to CTC AE Version 5 Were Observed

Number of Deaths

RECIST PR, no AFP response

AFP response, no RECIST response

RECIST response, AFP response

no AFP response, no RECIST response

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.

Disease Status at the End of 2 Courses of Therapy

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.

Feasibility of Referral for Liver Transplantation

Overall Study

Spots Global Cancer Trial Database for pretext iii hepatoblastoma