Neoplasms

All Conditions

Digestive System Diseases

Symptoms and General Pathology

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Recurrence

Liver Neoplasms

Hepatoblastoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Neoplasms by Histologic Type

Childhood Hepatocellular Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Anti-Infective Agents

Carboplatin

Doxorubicin

Liposomal doxorubicin

Cisplatin

Liver Extracts

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

carboplatin

cisplatin

doxorubicin hydrochloride

conventional surgery

Giorgio Perilongo, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which chemotherapy regimen is more effective in treating children with liver cancer.

PURPOSE: Randomized phase III trial to study the effectiveness of cisplatin with or without doxorubicin and the effectiveness of combining cisplatin, carboplatin, and doxorubicin in treating children who have liver cancer.

OBJECTIVES:

* Compare the efficacy of cisplatin with or without doxorubicin in terms of tumor response, complete resection rate, overall survival, and event free survival in children with standard risk hepatoblastoma.
* Compare the toxicity of cisplatin with or without doxorubicin in this patient population.
* Evaluate whether an intensive multiagent regimen including carboplatin, cisplatin, and doxorubicin improves the response rate to chemotherapy and subsequent resection rate of children with high risk hepatoblastoma or hepatocellular carcinoma.

OUTLINE: This is a randomized, multicenter study. All hepatoblastoma patients are intended to be treated with primary chemotherapy. Hepatoblastoma patients are stratified by risk (standard vs high).

Patients receive cisplatin IV over 24 hours on day 1, beginning within 15 days of diagnosis. Standard risk patients are then randomized to one of two treatment arms. High risk hepatoblastoma patients and hepatocellular carcinoma patients receive a separate multiagent regimen.

* Arm I: Patients receive cisplatin IV over 24 hours and doxorubicin IV over 48 hours beginning on day 15. Treatment repeats every 21 days for a maximum of 5 courses. Tumor response is evaluated prior to the second course. Patients with responsive disease receive the remaining 2 courses of the preoperative phase, then undergo delayed primary surgery if their tumors are deemed resectable, prior to receiving 2 additional courses of chemotherapy. Patients whose tumors are still unresectable after 3 courses receive 2 more courses of chemotherapy, then undergo surgery if feasible. Patients with stable disease are considered for radical surgery or salvage chemotherapy. Patients with unresectable tumors after 5 courses may be considered for liver transplant or salvage chemotherapy.
* Arm II: Patients receive cisplatin IV over 24 hours every 15 days for a maximum of 5 additional courses. Tumor response is evaluated after the second course. Patients with responsive disease receive another 2 courses of cisplatin. Patients with resectable tumors after 4 courses undergo delayed primary surgery, then receive 2 more courses of cisplatin. Patients whose tumors are still unresectable after 4 courses receive 2 more courses of cisplatin, then undergo surgery if their tumors are resectable. Patients with stable disease may be moved to the high risk regimen or considered for radical surgery. Patients with unresectable tumors after 6 courses may be considered for liver transplant or salvage chemotherapy.

Patients with high risk hepatoblastoma or unresectable hepatocellular carcinoma receive cisplatin IV over 24 hours on days 29, 57, and 85, and carboplatin IV over 1 hour followed by doxorubicin IV over 48 hours on days 15, 43, and 71. Patients with responsive resectable disease undergo surgery either after day 43 or within 3 weeks of day 85 of preoperative chemotherapy, then receive another 2 courses of carboplatin and doxorubicin on days 1 and 29 post surgery, and one more course of cisplatin on day 15 post surgery, for a total of 5 courses each. Patients with responsive but unresectable disease after day 85 also receive 2 more courses of carboplatin and doxorubicin alternating with 1 course of cisplatin. Definitive surgery will be re-considered after these further courses of chemotherapy. Patients with stable disease at day 43 or a tumor that remains unresectable after completion of chemotherapy may be considered for liver transplant.

Patients with a resectable hepatocellular carcinoma have primary surgery followed by alternating courses of cisplatin, and carboplatin and doxorubicin for a total of 4 courses of cisplatin and 3 courses of carboplatin and doxorubicin.

Patients are followed every 2-3 months for 2 years, every 6 months for 1 year, then annually thereafter.

PROJECTED ACCRUAL: A total of 170-260 patients (85-130 patients per treatment arm) will be accrued for this study over 5.5 years.

Chemotherapy in Treating Children With Liver Cancer

Liver Tumour Studies - Hepatoblastoma and Hepatocellular Carcinoma

Societe Internationale d'Oncologie Pediatrique

Primary Liver Cancer

Antirheumatic Agents

Thalidomide

Cyclophosphamide

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Angiogenesis Inhibitors

Growth Inhibitors

cyclophosphamide

thalidomide

adjuvant therapy

neoadjuvant therapy

Bruce Morland, MD

RATIONALE: Drugs used in chemotherapy, such as cisplatin and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Thalidomide may stop the growth of liver cancer by blocking blood flow to the tumor. Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. Giving combination chemotherapy, thalidomide, and chemoembolization before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving thalidomide together with chemotherapy after surgery may kill any remaining tumor cells and prevent the tumor from coming back.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy and thalidomide together with chemoembolization works in treating younger patients undergoing surgery for newly diagnosed liver cancer.

OBJECTIVES:

Primary

* Determine the event-free and overall survival of younger patients undergoing surgery for newly diagnosed, noncirrhotic hepatocellular carcinoma (HCC) treated with neoadjuvant cisplatin, doxorubicin hydrochloride, and thalidomide (PLADOTH) followed by transarterial hepatic arterial chemoembolization comprising cisplatin and doxorubicin hydrochloride and adjuvant cyclophosphamide and thalidomide.
* Determine the efficacy and tolerability of PLADOTH in patients with initially unresectable noncirrhotic HCC treated with this regimen.
* Determine the rate of complete surgical resection by encouragement of liver transplantation in the treatment strategy as a valid option for tumor removal when partial liver resection or other surgical options remain unfeasible for patients treated with this regimen.
* Determine the long-term remission and decreased relapse rates of patients treated with this regimen based on the postoperative regimen.

Secondary

* Determine the response rate of patients treated with this regimen after treatment with PLADOTH.
* Determine the short-term toxicity and feasibility of PLADOTH in patients treated with this regimen.
* Determine the efficacy and toxicity of the postoperative regimen in terms of maintenance and duration of complete remission (no more evidence of disease and normal alpha-fetoprotein, if initially elevated) in patients treated with this regimen.
* Determine whether response to PLADOTH by the RECIST criteria can be used for better monitoring of response of patients treated with this regimen.
* Determine whether the rate of fall of serum VEGF and bFGF levels during PLADOTH can be used as prognostic factors for short-term and long-term outcome in patients treated with this regimen.
* Determine the feasibility of chemoembolization in patients treated with this regimen who do not respond to PLADOTH.
* Determine which subset of tumors may benefit from an angiostatic treatment approach based on radiological, surgical, and pathological data collected from patients treated with this regimen.
* Identify possible novel factors that might influence treatment choice and disease outcome based on radiological, surgical, and pathological data collected from patients treated with this regimen.
* Determine guidelines for diagnostic, therapeutic, and follow-up management that would improve clinical care for patients treated with this regimen.

OUTLINE: This is a multicenter, nonrandomized, open-label study.

All patients undergo either tumor biopsy or resection. Patients with localized resectable tumors undergo resection. They then proceed directly to the postoperative treatment. Patients with initially unresectable tumors undergo biopsy then proceed to the pre-operative regimen.

* Pre-operative chemotherapy and thalidomide (PLADOTH): Patients receive PLADOTH comprising cisplatin IV continuously over 24 hours on day 1, doxorubicin hydrochloride IV over 1 hour on days 1 and 2 (or IV continuously over 24 hours on days 1 and 3), and oral thalidomide daily on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients whose tumors are deemed resectable proceed to surgery. Patients with responding disease but whose tumors remain unresectable proceed to chemoembolization or receive 2 additional courses of PLADOTH.
* Transarterial hepatic artery chemoembolization (TACE): Patients undergo TACE comprising cisplatin and doxorubicin hydrochloride administered through a catheter placed near the tumor. TACE may be repeated every 3-4 weeks for as long as disease continues to respond or until the tumor becomes resectable. Patients also receive oral thalidomide once daily during TACE. Once the tumor is deemed resectable, patients proceed to surgery.
* Surgery: Patients undergo surgical resection of the tumor. Patients undergo either partial or total hepatectomy followed by a liver transplant and lung surgery, if necessary. Patients then proceed to the postoperative treatment.
* Postoperative treatment: Beginning within 6 weeks after surgery, patients receive oral cyclophosphamide once every other day and oral thalidomide once daily for up to 1 year in the absence of disease progression or unacceptable toxicity.

Patients with metastatic disease who show disease progression at any time during treatment go off study and receive individual advice regarding further treatment based on the decision of the principal investigator.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Combination Chemotherapy and Thalidomide in Treating Younger Patients Undergoing Surgery For Newly Diagnosed Liver Cancer

Hepatocellular Carcinoma Family of Tumours In Children / Adolescents and Young Adults

Children's Cancer and Leukaemia Group

Carcinogenesis

Cell Transformation, Neoplastic

Archived tumor tissue samples are analyzed for hepatoblastoma and other liver tumor biomarkers by microRNA array profiling and exome sequencing. Results are then compared with patients' clinical data.

RNA analysis

gene expression analysis

microarray analysis

nucleic acid sequencing

diagnostic laboratory biomarker analysis

Gail Tomlinson, MD

This research trial is studying biomarkers in tissue samples from young patients with liver cancer. Studying samples of tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and identify biomarkers related to cancer.

PRIMARY OBJECTIVES:

I. To identify biomarker signatures associated with hepatoblastoma subtypes (by microRNA array profiling), and their potential correlation with liver developmental stages as well as outcome.

II. To correlate expression array data with copy number array data.

SECONDARY OBJECTIVES:

I. To carry out a focused sequencing interrogation of amplified or deleted genomic regions as well as genes in key cell pathways involved in embryonic development and/or stem cell signaling pathways for which preliminary data suggests involvement in the pathogenesis of hepatoblastoma.

II. To perform whole exome sequencing in a subset of tumors.

OUTLINE: This is a multicenter study.

Archived tumor tissue samples are analyzed for hepatoblastoma and other liver tumor biomarkers by microRNA array profiling and exome sequencing. Results are then compared with patients' clinical data.

Biomarkers in Tissue Samples From Young Patients With Liver Cancer

Genetics and Biology of Liver Tumorigenesis in Children

National Cancer Institute (NCI)

Children's Oncology Group

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Ear, Nose, and Throat Diseases

Nervous System Diseases

Substance Related Disorders

Wounds and Injuries

Skin and Connective Tissue Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Hearing Loss

Deafness

Sarcoma

Teratoma

Brain Neoplasms

Osteosarcoma

Central Nervous System Neoplasms

Medulloblastoma

Neuroblastoma

Testicular Neoplasms

Nervous System Neoplasms

Ototoxicity

Neoplasms, Germ Cell and Embryonal

Neoplasms, Connective and Soft Tissue

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Glioma

Ear Diseases

Otorhinolaryngologic Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Ovarian Cancer

Ovarian Epithelial Cancer

Soft Tissue Sarcoma

Germ Cells Tumors

Ovarian Germ Cell Tumor

Testicular Germ Cell Tumor

Medulloblastoma, Childhood

Extragonadal Germ Cell Tumor

Neuroepithelioma

Sodium thiosulfate

Antidotes

Protective Agents

Antioxidants

Antitubercular Agents

Chelating Agents

Patients receive sodium thiosulfate IV (dosage 16 g/m2 or 533 mg per kg for patients whose therapeutic protocol administers cisplatin on a per kg basis due to young age or small body) over 15 minutes beginning 6 hours after the completion of each cisplatin infusion. Treatment with sodium thiosulfate continues until the completion of cisplatin therapy.

Patients do not receive sodium thiosulfate.

sodium thiosulfate

Patients undergo audiological assessments periodically

examination

David R. Freyer, DO, MS

RATIONALE: Sodium thiosulfate may reduce or prevent hearing loss in young patients receiving cisplatin for cancer. It is not yet known whether sodium thiosulfate is more effective than no additional treatment in preventing hearing loss.

PURPOSE: This randomized phase III trial is studying sodium thiosulfate to see how well it works in preventing hearing loss in young patients receiving cisplatin for newly diagnosed germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancy.

OBJECTIVES:

Primary

* To compare the efficacy of sodium thiosulfate vs observation in preventing hearing loss in young patients receiving cisplatin for the treatment of newly diagnosed germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancy.

Secondary

* To compare the mean change in hearing thresholds for key frequencies in these patients.
* To compare the incidences of cisplatin-related grade 3 and 4 nephrotoxicity and grade 3 and 4 cytopenia in these patients.
* To compare the event-free survival and overall survival of these patients.
* To evaluate the association of two key gene mutations (TPMT and COMT) with the development of cisplatin-induced hearing loss in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to prior cranial radiation (yes vs no), age (\< 5 years vs ≥ 5 years) and duration of cisplatin infusion (\< 2 hours vs ≥ 2 hours). Patients are randomized to 1 of 2 arms.

* Arm I (sodium thiosulfate): Patients receive sodium thiosulfate IV over 15 minutes beginning 6 hours after the completion of each cisplatin infusion. Treatment with sodium thiosulfate continues until the completion of cisplatin therapy.
* Arm II (observation): Patients do not receive sodium thiosulfate.

Patients undergo audiological assessment at baseline, prior to each course of cisplatin, and then at 4 weeks and 1 year after the last course of cisplatin or other cancer treatment. Some patients may undergo saliva collection for DNA studies.

After completion of study, patients are followed periodically for 10 years.

Sodium Thiosulfate in Preventing Hearing Loss in Young Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy

A Randomized Phase III Study of Sodium Thiosulfate for the Prevention of Cisplatin-Induced Ototoxicity in Children

Hearing loss defined by comparing hearing sensitivity at follow up evaluation relative to baseline measurements using ASHA criteria.

Mean change in hearing threshold (post-pre) at 500 hz.

Mean change in hearing threshold (post-pre) at 1000 hz.

Mean change in hearing threshold (post-pre) at 2000 hz

Mean change in hearing threshold (post-pre) at 4000 hz.

Mean change in hearing threshold (post-pre) at 8000 hz.

Proportion of patients event free at 4 years following enrollment. See EFS outcome measure description.

Proportion of patients alive free at 4 years following enrollment. See OS outcome measure description.

Serious Adverse Events were reported on this study via the NCI AERS reporting system. Per protocol, no expedited reports were submitted for patients on Observation only arm of the study. Thus, no patients enrolled on the Observation arm of the trial were at risk for having a Serious Adverse Event reported.

STS Arm (Sodium Thiosulfate Treatment)

Observation Arm

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Data was and never will be collected for Outcome Measure #9, Hearing Loss Among Patients Carrying/Not-carrying Two Key Gene Mutations (TPMT and COMT).

Results Reporting Coordinator

55 eligible patients enrolled on the observation Arm had complete audiometry data for evaluation; 49 eligible patients enrolled on the STS arm had complete data audiometry for evaluation.

Incidence of Hearing Loss

38 eligible patients in the STS arm had paired audiometry at 500 hz; 45 patients in the observation arm had paired audiometry at 500 hz.

Change in Hearing Thresholds For Key Frequencies at 500 hz

37 eligible patients in the STS arm had paired audiometry at 1000 hz; 47 patients in the observation arm had paired audiometry at 1000 hz.

Change in Hearing Thresholds For Key Frequencies at 1000 hz

38 eligible patients in the STS arm had paired audiometry at 2000 hz; 47 patients in the observation arm had paired audiometry at 2000 hz.

Change in Hearing Thresholds For Key Frequencies at 2000 hz

38 eligible patients in the STS arm had paired audiometry at 4000 hz; 47 patients in the observation arm had paired audiometry at 4000 hz.

Change in Hearing Thresholds For Key Frequencies at 4000 hz

38 eligible patients in the STS arm had paired audiometry at 8000 hz; 42 patients in the observation arm had paired audiometry at 8000 hz.

Change in Hearing Thresholds For Key Frequencies at 8000 hz

61 eligible patients were enrolled on the STS arm; 64 eligible patients were enrolled on the observation arm.

Event-Free Survival (EFS)

Overall Survival (OS)

Patients receive sodium thiosulfate IV (dosage 16 g/m2 or 533 mg per kg for patients whose therapeutic protocol administers cisplatin on a per kg basis due to young age or small body) over 15 minutes beginning 6 hours after the completion of each cisplatin infusion. Treatment with sodium thiosulfate continues until the completion of cisplatin therapy.

sodium thiosulfate: Given IV

examination: Patients undergo audiological assessments periodically

Patients do not receive sodium thiosulfate.

examination: Patients undergo audiological assessments periodically

Observation Arm (No Sodium Thiosulfate Treatment)

Hearing Loss Among Patients Carrying/Not-carrying Two Key Gene Mutations (TPMT and COMT)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy in Treating Children With Liver Cancer	NCT00003912	Liver Cancer	carboplatin cisplatin doxorubicin hyd... conventional su...	- 16 Years	National Cancer Institute (NCI)
Combination Chemotherapy and Thalidomide in Treating Younger Patients Undergoing Surgery For Newly Diagnosed Liver Cancer	NCT00276705	Liver Cancer	cisplatin cyclophosphamid... doxorubicin hyd... thalidomide adjuvant therap... conventional su... neoadjuvant the...	- 29 Years	National Cancer Institute (NCI)
Biomarkers in Tissue Samples From Young Patients With Liver Cancer	NCT01336881	Childhood Hepat... Stage I Childho... Stage II Childh... Stage III Child... Stage IV Childh...	RNA analysis gene expression... microarray anal... nucleic acid se... diagnostic labo...	- 16 Years	Children's Oncology Group
Sodium Thiosulfate in Preventing Hearing Loss in Young Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy	NCT00716976	Brain Tumor Central Nervous... Childhood Germ ... Extragonadal Ge... Liver Cancer Neuroblastoma Ototoxicity Ovarian Cancer Sarcoma	sodium thiosulf... examination	1 Year - 18 Years	Children's Oncology Group
Biomarkers in Tissue Samples From Young Patients With Liver Cancer	NCT01336881	Childhood Hepat... Stage I Childho... Stage II Childh... Stage III Child... Stage IV Childh...	RNA analysis gene expression... microarray anal... nucleic acid se... diagnostic labo...	- 16 Years	Children's Oncology Group

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