Otoprotectant Guards Against Cisplatin-Induced Hearing Loss

Pam Harrison

June 21, 2018

Cisplatin-induced hearing loss can be reduced by the delayed administration of the otoprotectant sodium thiosulfate (Pedmark, Fennec Pharmaceuticals).

The finding comes from a trial conducted in 101 children treated with cisplatin for standard-risk hepatoblastoma. The patients were randomly assigned to receive either cisplatin alone or cisplatin followed 6 hours later by sodium thiosulfate.

The intervention reduced the incidence and the severity of cisplatin-induced hearing loss without affecting either overall or event-free survival.

Hearing loss of grade 1 or higher (which would necessitate the use of a hearing aid) occurred in 33% of children who received sodium thiosulfate after cisplatin, compared to 63% in children treated with cisplatin alone (P = .002).

This translates to a 48% lower risk for hearing loss in children who received the additional otoprotectant, report the authors, led by Penelope Brock, MD, consultant at the Great Ormond Street Hospital in London, the United Kingdom.

Cisplatin is a highly effective treatment for hepatoblastoma, but about two thirds of children who receive the drug experience some hearing loss, the authors note. It occurs because cisplatin, though rapidly eliminated from the body, is retained in the cochlea, the portion of the inner ear responsible for hearing, which is subsequently damaged.

The hearing loss is permanent and "can be utterly debilitating," Brock said in a statement. Even mild hearing loss can severely affect a child's development.

For example, key consonants, such as "s", "h" and "f," are heard at high frequencies; their loss can be particularly difficult for children who have yet to develop speech.

The median age of the children was 12 to 13 years, but the trial also included infants who were just older than 1 year.

"This treatment combination could help ensure that parents aren't faced with an upsetting scenario where successful cancer treatment comes at the cost of their child's hearing," she added.

The study was published online June 20 in the New England Journal of Medicine.

Sodium thiosulfate has already received a breakthrough therapy designation by the US Food and Drug Administration and will be filed under a pediatric use marketing application in the European Union.

Study Details

SIOPEL 6 was a randomized trial designed to evaluate whether delayed administration of sodium thiosulfate after the administration of cisplatin would reduce the incidence and severity of hearing loss caused by cisplatin.

Cisplatin was administered at a dose of 80 mg/m2 in a continuous intravenous 6-hour infusion for four preoperative and two postoperative courses given at 14-day intervals, with or without the administration of sodium thiosulfate.

In the intervention group, sodium thiosulfate 20 g/m2 was administered intravenously over a period of 15 minutes 6 hours after the end of the cisplatin infusion.

The children (median age, 12-13 years) were assessed for hearing loss by means of pure-tone audiometry. Assessments were conducted both before and throughout treatment cycles, when possible. A final hearing test was conducted a median of 3 years after the children had been enrolled in the study.

"The primary end point in this trial was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years," the investigators write.

"The administration of sodium thiosulfate was associated with a trend toward reduced ototoxicity in all the Brock grades," they report.

At a median follow-up of 52 months, overall survival at 3 years was 98% for children who received additional sodium thiosulfate following treatment with cisplatin; it was 92% for those who received cisplatin alone.

Event-free survival rates at 3 years were 82% and 79%, respectively, for the two groups.

These findings provide reassurance that the 6-hour delay in the administration of sodium thiosulfate following completion of cisplatin infusion did not adversely affect disease outcomes, the researchers point out.

Side Effects

The incidence of acute adverse events was as expected, the researchers comment, although an unexpected and serious reaction developed in one child. This child developed metabolic acidosis after the third infusion of the otoprotectant; the infusion was subsequently stopped, and the child recovered rapidly with fluid resuscitation.

The otoprotective dose of sodium thiosulfate was associated with a high sodium load, which is a factor to consider in planning treatment, the researchers comment. However, neither hypertension nor a high serum sodium level resulted in the discontinuation of the intervention.

Sodium thiosulfate was emetogenic despite the use of prophylactic antiemetic agents; nausea and vomiting were common adverse events.

Renal function was acceptable in the children, although it was reduced in four children, for whom the glomerular filtration rate was less than 60 mL/min/1.73 m2 at the end of treatment or follow-up.

"Hearing Is Precious"

"No child should have to suffer a disability as a result of their cancer treatment," Pam Kearns, MD, Cancer Research UK's expert on children's cancers at the University of Birmingham, United Kingdom, said in a statement.

"Hearing is precious, and we're delighted to see that we can safeguard the future development of more children without compromising the chance of curing their cancer," she added.

In the United Kingdom, young children with hearing loss of grade 1 and all children with a hearing loss of grade 2 or 3 are given hearing aids, if acceptable to parents.

Children with grade 4 hearing loss are offered cochlear implants. The researchers note that children with hearing of grade 0 may not have completely normal hearing but can manage life with little or no additional help.

The study was funded by Cancer Research UK. The study drug was supplied by Fennec Pharmaceuticals. Dr Brock has disclosed no relevant financial relationships.

N Engl J Med. Published online June 20, 2018. Abstract

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