Cisplatin With or Without Sodium Thiosulfate in Treating Young Patients With Stage I, II, or III Childhood Liver Cancer

A Multi-centre Open-label Randomised Phase III Trial of the Efficacy of Sodium Thiosulphate in Reducing Ototoxicity in Patients Receiving Cisplatin Chemotherapy for Standard Risk Hepatoblastoma

RATIONALE: Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as sodium thiosulfate, may protect normal cells from the side effects of chemotherapy. It is not yet known whether giving sodium thiosulfate is effective in reducing hearing damage caused by cisplatin in treating young patients with liver cancer.

PURPOSE: This randomized phase III trial is studying how well sodium thiosulfate works to decrease hearing loss caused by cisplatin in treating young patients with stage I, stage II, or stage III childhood liver cancer.

OBJECTIVES:

Primary

• To assess the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by cisplatin chemotherapy.

Secondary

• To carefully monitor any potential impact of STS on response to cisplatin and survival.
• To assess the short- and long-term tolerability of the combination of STS and cisplatin
• To prospectively evaluate and validate biological, radiological and pathological features of standard-risk hepatoblastoma for future risk adapted management
• To investigate the effect of STS on the formation of cisplatin-DNA adducts.
• To prospectively collect patient DNA specifically for the analysis of possible genetic factors that may contribute to the development of treatment-related ototoxicity and nephrotoxicity

OUTLINE: This is a multicenter study. Patients are stratified according to country, median age (< 15 months vs ≥ 15 months), and PRETEXT tumor classification (I vs II vs III). Patients are randomized to 1 of 2 treatment arms.

• Arm I (Neoadjuvant and adjuvant cisplatin): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 2 weeks for 4 courses. Patients with progressive disease after course 4 are taken off study. Patients without evidence of disease progression proceed to surgery. Beginning within 3 weeks after surgery, patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
• Arm II (Neoadjuvant and adjuvant cisplatin and sodium thiosulphate): Patients receive cisplatin IV over 6 hours and sodium thiosulphate IV over 15 minutes (beginning 6 hours after completion of cisplatin) on day 1. Treatment repeats every 2 weeks for 4 courses. Patients with progressive disease after course 4 are taken off study. Patients without evidence of disease progression proceed to surgery. Beginning within 3 weeks after surgery, patients receive cisplatin IV over 6 hours and sodium thiosulphate IV over 15 minutes (as in neoadjuvant therapy) on day 1. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection and tumor biopsies periodically for biological and pharmacological studies consisting of biomarker analysis, gene expression profiling, IHC, proteomic analysis, and gene rearrangement analysis. Patients undergo auditory evaluations at baseline, and at the completion of study treatment or at an age of at least 3.5 years to measure ototoxicity and hearing impairment.

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

Inclusion Histologically confirmed newly diagnosed hepatoblastoma

• Standard risk hepatoblastoma (Pretext I,II,III)
• Age ≤ 18 years and > 1 month
• Written informed consent and national/local ethics committee and regulatory approval
• Centre/country willing and able to organise audiometry at the minimum required quality standard and to provide the contact details of the Consultant Audiologist or Ear Nose and Throat Surgeon who will take the responsibility for seeing that this is done
• Ability to comply with requirements for submission of material for central review
• For females of child-bearing potential, a negative pregnancy test prior to study treatment is required.
• Any patient who is of reproductive age should agree to use adequate contraception for the duration of the trial.

Exclusion:

High risk hepatoblastoma

• Hepatocellular carcinoma
• Treatment starting more than 15 days from written biopsy report
• Abnormal renal function
• Any previous chemotherapy
• Recurrent disease
• Previous hypersensitivity to STS
• Patient unable to follow the protocol for any reason