USE OF SODIUM THIOSULFATE IN ORDER TO REDUCE CISPLATIN OTOTOXICITY

Sodium thiosulfate reduces cisplatin-induced hearing loss in children with cancer, according to a phase 3 trial.

"The era of merely accepting cisplatin-induced deafness as the inevitable price to pay for cure is over," Dr. David R. Freyer from Children's Hospital Los Angeles told Reuters Health. "Having shown that hearing can be protected, it is now incumbent on researchers interested in this problem to continue the quest for safe, effective methods to preserve hearing in childhood cancer survivors."

Cisplatin is a standard component of chemotherapy regimens for a variety of childhood cancers, Dr. Freyer and colleagues note in The Lancet Oncology, online November 30. Of the more than 2,000 children aged 1-15 years who receive cisplatin annually in the U.S., about 40% develop cisplatin-induced hearing loss, and the incidence approaches 100% in some patient groups, the researchers add.

The team compared the proportional incidence of post-treatment cisplatin-induced hearing loss between children randomly assigned to receive or not receive sodium thiosulfate daily over 15 minutes beginning six hours after the completion of each cisplatin dose.

Hearing loss at four weeks was identified in 28.6% (14 of 49) of children in the sodium thiosulfate group, compared with 56.4% (31 of 55) of children in the control group (p=0.0002).

The difference was more pronounced in children under 5 (21.4% vs. 73.3%). Among older children, 31.4% on those on sodium thiosulfate developed hearing loss versus 50.0% of those not given the drug.

Hearing loss at one year was also significantly less common in the sodium thiosulfate group (28%) than in the control group (54%).

Hematological toxicity did not differ significantly between the treatment groups, but aggregate nephrotoxicity was more common in the sodium thiosulfate group (25% of cycles) than in the control group (13% of cycles). There were, however, no cases of grade 3 increased creatinine or reduced GFR in either group.

There were no significant differences between the groups in event-free survival or overall survival. In the subset of children with disseminated disease, overall survival was significantly lower in the sodium thiosulfate group.

"We don't know whether this is, in fact, evidence of tumor protection or just an appearance due to the variation in randomized patients that can occur in relatively small studies like this," Dr. Freyer said.

"At present, we believe the role of sodium thiosulfate cannot yet be defined confidently on the basis of these results alone," he said. "While the data are clear that sodium thiosulfate can protect hearing, they are not so clear about the question of whether the drug might also protect the tumor from chemotherapeutic effect in certain patients."

"There is another study, SIOPEL-6, that is ongoing and in 2017 should provide more data about both hearing protection and safety," Dr. Freyer said. "There will be more data to inform our recommendations at that time."

Dr. Eric Bouffet from The Hospital for Sick Children in Toronto, Canada, who wrote an accompanying editorial, told Reuters Health by email, "I think this result is quite compelling, and we should now move on and use it for all children receiving cisplatin."

"We should have a strategy to better investigate the possible/questionable impact of this drug on survival in patients with disseminated disease," he said. "We should not leave this stone unturned and consider that patients with advanced disease are not candidate for this drug. More needs to be done."

Dr. Sofia Waissbluth from Pontifical Catholic University of Chile in Santiago, who recently reviewed platinum-induced ototoxicity, also highlighted the uncertainties.

"Further research is necessary in order to make conclusions about the current role of sodium thiosulfate in children," she told Reuters Health by email. "This study included a heterogeneous group of patients presenting with different cancer types, and it is not possible to make any assumptions at this point. It will be of interest to see the long-term follow-up of the children who did receive sodium thiosulfate."

"This study is extremely important," added Dr. Waissbluth. "Regardless of the limitations of the study, which the authors did recognize, it demonstrates a potential treatment for cisplatin-induced ototoxicity, a condition for which no treatment is currently available."

Dr. Elvira van Dalen from Emma Children's Hospital/Academic Medical Center in Amsterdam, who recently reviewed medical interventions for the prevention of platinum-induced hearing loss in children with cancer, said, "As far as I'm aware, this is the first randomized trial on the use of sodium thiosulfate for that purpose."

"Its results are promising, but I agree with the authors that more research is needed to be able to give recommendations for its use in clinical practice. Hopefully the results of SIOPEL-6, the other randomized trial addressing sodium thiosulfate, will become available soon and can provide more insight into this preventive option."

The trial was funded by the U.S. National Cancer Institute.

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