USE OF IV N-ACETYLCYSTEINE IN COMBINATION WITH SODIUM THIOSULFATE FOR PREVENTION OF OTOTOXICITY IN PEDIATRIC PATIENTS

Although the childhood cancers medulloblastoma, osteosarcoma, hepatoblastoma, germ cell tumors, and neuroblastoma affect a relatively small number of children, with prevalence under 110,000 in the United States, the impact of these life-threatening illnesses on children and their families is significant. Standard therapy for pediatric cancers typically involves alkylating platinum chemotherapeutics, primarily cisplatin and carboplatin. Platinum chemotherapeutics and other free-radical inducing therapies such as radiotherapy can cause multiple severe systemic and neurological side effects, including permanent ototoxicity. The overall incidence of permanent bilateral hearing loss in children during cisplatin chemotherapy is 60%.(1) Our goal is to decrease the toxic side effects of cisplatin and enhance long-term quality of life by reducing lasting toxicities. Based on our preclinical and clinical studies, we hypothesize that the appropriate timing and dosing of combination chemoprotectants may reduce systemic and neurologic toxicities while maintaining dose intensity, and may even allow for the use of new strategies, such as dose-escalation or chemo-enhancement, for improved cancer control. In particular, our studies have demonstrated that high dose (400 mg/kg) intravenous (IV) N-acetylcysteine (NAC) (Acetadote®) is critical to achieve high plasma concentrations for optimum chemoprotective activity. Recently completed Phase III studies of sodium thiosulfate (STS) otoprotection in children have shown no compromise in efficacy of cisplatin if the tumor is localized (as it is in 50 + % of patients). We have applied for orphan-drug designation of IV NAC in combination with STS for prevention of ototoxicity caused by platinum-based chemotherapeutic agents in children, in addition we are developing a phase I trial of increasing NAC doses in combination with the phase III dose of STS. 1. 1. Brock PR, et al. Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol 30(19), 2408-2417.