Sodium Thiosulfate Receives FDA Approval to Protect Against Cisplatin-Related Hearing Loss

To reduce the risk of cisplatin-associated ototoxicity, or hearing loss, in paediatric patients aged 1 month or older with localised, non-metastatic solid tumours, sodium thiosulfate (Pedmark, Fennec Pharmaceuticals Inc.) received approval from the US Food and Drug Administration (FDA) on 20 September 2022.

Cisplatin is an effective chemotherapy drug widely used for ovarian, testicular, bladder, lung, and head and neck cancers, as well as paediatric cancers such as hepatoblastoma. It exerts antitumour activity by forming cross-links between DNA bases. These links trigger apoptotic, or programmed, and necrotic cell death.

What Is Cisplatin-Associated Ototoxicity, and Why Does It Cause Hearing Loss?

The main reported adverse effects associated with cisplatin are nephrotoxicity, peripheral neurotoxicity and ototoxicity, affecting the kidneys, nervous system and hearing, respectively. Although hydration can improve nephrotoxicity, approved preventive treatments for ototoxicity and neurotoxicity are unfortunately unavailable. Ototoxicity develops more slowly than other adverse effects but is considered the most common dose-limiting adverse effect because it affects a high proportion of patients.

Cisplatin-induced ototoxicity is associated with high doses and accumulation in the cochlea, the hearing organ of the inner ear, where the drug remains for a long time after treatment. Cisplatin primarily damages the outer sensory hair cells, but it can also damage spiral ganglion neurons in the cochlea.

It can also cause some damage to cochlear inner hair cells. Hyperactivity of dorsal cochlear nucleus neurons is thought to cause cisplatin-induced tinnitus.  

Cisplatin-Associated Ototoxicity in Children

Among children receiving cisplatin chemotherapy for cancer, ototoxicity occurs in 22% to 70%. Young children, especially those in early language development or with other impairments such as visual or cognitive dysfunction, are at greater risk of moderate to severe cisplatin-related hearing loss than adults. High-frequency speech sounds are essential for intelligibility, and even mild hearing loss at these frequencies can affect young children’s academic and social-emotional development. This is therefore considered cisplatin’s most common dose-limiting adverse effect.

FDA Approval to Prevent Cisplatin-Related Ototoxicity

Sodium thiosulfate was evaluated in 2 multicentre, open-label, randomised controlled studies of paediatric patients receiving cisplatin-based cancer chemotherapy: SIOPEL 6 and COG ACCL0431.

SIOPEL 6 included 114 patients with standard-risk hepatoblastoma receiving 6 cycles of perioperative cisplatin-based chemotherapy. Patients were randomised to cisplatin-based chemotherapy with or without sodium thiosulfate, given at 10 g/m2, 15 g/m2 or 20 g/m2 according to actual body weight. The primary outcome was the percentage of patients with hearing loss of Brock grade 1 or greater than 1, assessed by pure-tone audiometry after treatment or at a minimum age of 3.5 years, whichever was later. Hearing loss was less frequent with sodium thiosulfate plus cisplatin (39%) than with cisplatin alone (68%).

COG ACCL0341 included 125 paediatric patients with solid tumours receiving chemotherapy regimens with individual cisplatin doses administered over 6 hours or less and a cumulative cisplatin dose of at least 200 mg/m2. Patients were randomised to cisplatin-based chemotherapy with or without sodium thiosulfate. Efficacy was assessed in a subgroup of 77 patients with localised, non-metastatic solid tumours. The primary outcome was hearing loss, assessed using American Speech-Language-Hearing Association (ASHA) criteria at baseline and 4 weeks after the last cisplatin course. Hearing loss was less frequent with sodium thiosulfate plus cisplatin (44%) than with cisplatin alone (58%).

In both studies, the most common adverse effects, occurring in ≥ 25% with a between-group difference of > 5% compared with cisplatin alone, were vomiting, nausea, decreased haemoglobin, and increased blood sodium and potassium.

The recommended sodium thiosulfate dose is based on body surface area according to actual body weight. It is administered as an intravenous infusion over 15 minutes following cisplatin infusions lasting 1 to 6 hours.