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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

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

Conditions
-----------------
Brain Tumor, Central Nervous System Tumor, Childhood Germ Cell Tumor, Extragonadal Germ Cell Tumor, Liver Cancer, Neuroblastoma, Ototoxicity, Ovarian Cancer, Sarcoma

Intervention / Treatment
-----------------
* Drug: sodium thiosulfate
* Procedure: examination


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Newly diagnosed (previously untreated or currently receiving cancer treatment for the diagnosis that made the patient eligible for this study) with germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancy Planning to receive a chemotherapy treatment regimen that includes a cumulative cisplatin dose ≥ 200 mg/m² with individual cisplatin doses to be infused over ≤ 6 hours Enrolled on hearing assessment clinical trial COG-ACCL05C1 Normal auditory results PATIENT CHARACTERISTICS: Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) Lansky PS 50-100% (for patients ≤ 16 years of age) Serum sodium normal Absolute granulocyte count > 1,000/mm³ Platelet count > 100,000/mm³ Creatinine clearance or radioisotope glomerular filtration rate ≥ 70mL/min OR serum creatinine between 0.4 and 1.7 mg/dL, based on age and gender Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age AST or ALT < 2.5 times ULN for age Not pregnant or nursing Negative pregnancy test (if patient has child-bearing capacity) Fertile patients must use effective contraception No known hypersensitivity to sodium thiosulfate or other thiol agents (e.g., amifostine trihydrate, N-acetylcysteine, MESNA, or captopril) PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior platinum-based chemotherapy (cisplatin or carboplatin) Other prior chemotherapy allowed Prior cranial radiotherapy (e.g., for treatment of medulloblastoma) allowed provided normal hearing is documented after completion of radiotherapy and before enrollment and administration of cisplatin chemotherapy At least 6 months since prior hematopoietic stem cell transplantation. No evidence of graft-versus-host disease No concurrent enrollment on another COG clinical trial for treatment of the cancer. Concurrent enrollment on a non-COG clinical trial (e.g., Head start) allowed. Cranial irradiation after the completion of all systemic chemotherapy allowed provided post end-of-treatment audiometry is completed prior to beginning irradiation. Concurrent radiotherapy to extracranial sites allowed.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STS Arm (sodium thiosulfate treatment)<br>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. | Drug: sodium thiosulfate<br>* Given IV<br>* Other names: IND#72877;Procedure: examination<br>* Patients undergo audiological assessments periodically<br>|
| Experimental: Observation Arm (No sodium thiosulfate treatment)<br>Patients do not receive sodium thiosulfate. | Procedure: examination<br>* Patients undergo audiological assessments periodically<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Hearing Loss | Hearing loss defined by comparing hearing sensitivity at follow up evaluation relative to baseline measurements using ASHA criteria. | 4 weeks after last dose of cisplatin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hearing Thresholds For Key Frequencies at 500 hz | Mean change in hearing threshold (post-pre) at 500 hz. | 4 weeks after last dose of cisplatin | 
| Change in Hearing Thresholds For Key Frequencies at 1000 hz | Mean change in hearing threshold (post-pre) at 1000 hz. | 4 weeks after last dose of cisplatin | 
| Change in Hearing Thresholds For Key Frequencies at 2000 hz | Mean change in hearing threshold (post-pre) at 2000 hz | 4 weeks after last dose of cisplatin | 
| Change in Hearing Thresholds For Key Frequencies at 4000 hz | Mean change in hearing threshold (post-pre) at 4000 hz. | 4 weeks after last dose of cisplatin | 
| Change in Hearing Thresholds For Key Frequencies at 8000 hz | Mean change in hearing threshold (post-pre) at 8000 hz. | 4 weeks after last dose of cisplatin | 
| Event-Free Survival (EFS) | Proportion of patients event free at 4 years following enrollment. See EFS outcome measure description. | 4 years after enrollment | 
| Overall Survival (OS) | Proportion of patients alive free at 4 years following enrollment. See OS outcome measure description. | 4 Years after enrollment | 
| Hearing Loss Among Patients Carrying/Not-carrying Two Key Gene Mutations (TPMT and COMT) |  | 4 weeks after the last dose of cisplatin | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ototoxicity, childhood central nervous system germ cell tumor, childhood extracranial germ cell tumor, childhood extragonadal germ cell tumor, childhood malignant testicular germ cell tumor, childhood malignant ovarian germ cell tumor, childhood teratoma, childhood medulloblastoma, disseminated neuroblastoma, regional neuroblastoma, localized resectable neuroblastoma, localized unresectable neuroblastoma, stage 4S neuroblastoma, localized osteosarcoma, metastatic osteosarcoma, childhood hepatoblastoma, stage I childhood liver cancer, stage II childhood liver cancer, stage III childhood liver cancer, stage IV childhood liver cancer