STS (Sodium thiosulfate)

> Long-term complications



Cisplatin and other platinum-based chemotherapies are important therapeutic agents in cancer therapy, but are associated with the frequent and severe complication of ototoxicity, particularly hearing loss. Children receiving curative cisplatin-containing chemotherapy programs for their pediatric cancers have been shown to develop significant and irreversible hearing loss that can compromise cognitive and language development, learning ability and quality of life. Similar platinum-induced hearing loss is also seen in adults, particularly with head and neck cancers. Up to 60% of children and adults receiving cisplatin develop the need for hearing aids. It is estimated that in the U.S. alone, 30,000 adults and 2,000 children are at risk for development of cisplatin-induced hearing loss each year and additional patients receiving other platinum-based chemotherapy, such as carboplatin, are also at risk.


Sodium thiosulfate, or STS, has been shown to protect against cisplatin-induced hearing loss without interfering with the antitumor activity of the cisplatin. 


STS is currently marketed for use in humans as part of a treatment for cyanide poisoning. 


STS: Mechanism of Action

When STS is administered approximately 6 hours after cisplatin, it inactivates the metabolic by-products of cisplatin circulating in the plasma, which appear to be responsible for the hearing loss. Because STS remains only in the plasma and does not distribute into the cells where cisplatin produces its anticancer effects, there appears to be no effect on the anticancer effectiveness of cisplatin. Further, the anticancer activity of cisplatin occurs during the first two hours after administration when the free (unbound) cisplatin distributes into the cancer cells. The cisplatin that remains in the plasma is either excreted or metabolically altered to effectively eliminate its anticancer (but not its toxic) properties. STS inactivates the residual activity of these metabolites in the plasma, neutralizing their ability to cause hearing loss.


STS: Clinical Development

Adherex currently has two Phase III trials ongoing with STS, one in collaboration with the International Childhood Liver Tumour Strategy Group known as SIOPEL, a multi-disciplinary group of specialists under the umbrella of the International Society of Pediatric Oncology, and one in collaboration with the Children’s Oncology Group, or COG, in the United States. 


The SIOPEL study was launched in October 2007 and is expected to enroll approximately 100 evaluable children with hepatoblastoma at participating SIOPEL centers in up to 33 countries. Patients will be randomized to receive either cisplatin alone, a platinum-based drug associated with frequent hearing loss used to treat hepatoblastoma, or cisplatin plus STS. The study, which will be coordinated through the Children’s Cancer and Leukaemia Group in the U.K., will compare the level of hearing loss, or ototoxicity, associated with cisplatin alone versus the combination of cisplatin plus STS, as well as the safety, tolerability and anti-tumor activity in both arms of the study.


The COG trial was launched in March 2008 and the goal of the study is to evaluate whether STS is an effective and safe means of preventing hearing loss in children receiving cisplatin chemotherapy for newly diagnosed germ cell, liver (hepatoblastoma), brain (medulloblastoma), nerve tissue (neuroblastoma) or bone (osteosarcoma) cancers.  Eligible children will be 1 to 18 years of age who are scheduled to receive cisplatin according to their disease-specific regimen and, upon enrollment in this study, will be randomized to receive STS or placebo.  Efficacy of STS will be determined through comparison of hearing sensitivity at follow-up relative to baseline measurements using standard audiometric techniques.  The trial is expected to enroll up to 120 patients over approximately three years in up to 230 COG centers in the United States, Canada, Australia and Europe.


Adherex will be providing drug and drug distribution for both of the above Phase III studies, with the remaining clinical trial and data management costs being covered by the cooperative groups. Adherex will have exclusive access to the data for regulatory submission purposes.


In May 2008, Adherex acquired rights to the use of data from a completed Phase III trial conducted by the Netherlands Cancer Institute. In this trial, the efficacy of STS as a hearing protectant in adult head and neck cancer was confirmed without any apparent effect on disease treatment outcome. [Zuur CL et al. Ototoxicity in a randomized phase III trial of intra-arterial compared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer. J Clin Oncol 2007;25(24):3759–65.]


For additional information about Adherex's ongoing clinical trials of STS, please visit


STS: Market Opportunity

In the United States alone, there are an estimated 30,000 adults and 2,000 children at risk of cisplatin chemotherapy-related hearing loss each year. Currently, there are no commercially available drugs to prevent this type of hearing loss.


A 2007 market report on hearing loss and hearing protective agents found that:

·         approximately one million people in the U.S. and western Europe undergoing cisplatin chemotherapy each year would benefit from a hearing protective agent

·         the potential value of a hearing protectant targeting cisplatin-induced hearing loss is estimated at US$250 million

·         the value of the cancer supportive therapy market is US$8 billion.

[Source: Ototoxicity and otoprotective agents market report. Royal National Institute for Deaf People (RNID) 2007,]


Adherex has received Orphan Drug Designation in the U.S. for the use of STS in the prevention of platinum-induced ototoxicity in pediatric patients. 

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