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A Pilot, Randomized, Self-controlled Study of the Effects of Intratympanic Sodium Thiosulfate on the Degree of Hearing Loss in Patients Receiving Cisplatin Therapy

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Trial Information

A Pilot, Randomized, Self-controlled Study of the Effects of Intratympanic Sodium Thiosulfate on the Degree of Hearing Loss in Patients Receiving Cisplatin Therapy

Platinum-based chemotherapeutic agents are used to treat a number of malignant tumors, both
in children and adults. Examples of such tumors include: osteosarcoma, Wilms' tumor,
rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, primary brain tumors, carcinoma, and
various other solid tumors. Cisplatin is associated with a dose-dependent, high frequency
sensorineural hearing loss. With increasing doses, the hearing loss worsens to include the
speech frequencies. Vestibular function can also be damaged by platinum-based toxicity.
Cisplatin causes ototoxicity through the formation of reactive oxygen species and activation
of the apoptotic pathway in outer hair cells and the stria vascularis.

Rates of ototoxicity are approximately 80% with audiologic findings of hearing loss, and 20%
with symptomatic hearing loss. These numbers are higher for those receiving high dose
cisplatin, children, those with prior irradiation and those with prior hearing loss.

A number of agents have been investigated in animal models as otoprotection against the
toxic effects of cis- and carboplatin. Among these, sodium thiosulfate (STS) has shown
particular promise as an otoprotective agent. STS is approved by the US Food and Drug
Administration (FDA) as an antidote for cyanide and nitroprusside toxicity and for
calciphylaxis. STS has been shown to act as both an antioxidant as well as a chelating
agent in vivo. The chelating properties of the sulfur-thiol functional group are believed
to be responsible for the otoprotective effects of STS, binding to, and inactivating the
platinum. The thiol compound may also act to scavenge reactive oxygen species produced by
the platinum, thus preventing the initiation of the apoptotic pathway.

Several studies have demonstrated the otoprotective effects of intravenous STS in animal
models. Subsequent studies have shown similar benefit when STS is administered
intravenously to humans. A major drawback to this mode of delivery, however, is the fear
that it reduces the anti-tumor activity of the platinum. Sodium thiosulfate is believed to
bind to cisplatin, forming a complex that is then excreted by the kidneys. Though this may
decrease the ototoxicity associated with the platinum, it may also decrease the
anti-neoplastic properties of the agent. There are conflicting reports of reduced
tumoricidal properties of STS in vitro, though there are no in vivo studies suggesting this
adverse effect in vivo.

In view of the potential for systemic STS to reduce the tumoricidal effects of platinum
agents, researchers have sought an alternate mode of delivery. Recent animal studies have
examined the effect of sodium thiosulfate delivered locally to the middle ear space.
Stocks, et al demonstrated an otoprotective effect of STS delivered to the middle ear space
of guinea pigs. Wang, et al showed complete prevention of the ototoxic effects of cisplatin
in guinea pigs treated with round window application of STS. In their study, both the
compound action potential (CAP) and distortion product otoacoustic emissions (DPOAE) were
unchanged, and both outer hair cells (OHC) and inner hair cells (IHC) were preserved. This
effect, however, was not demonstrated in a similar study by Wimmer, et al. The temporal
and spatial separation of the platinum and STS in these animal studies prompted Zuur and
colleagues to state that, "in the future, it may be desirable to examine additional
possibilities for two-route administration schemes for chemotherapy and otoprotective drugs
in humans." There are no studies to date of intratympanic sodium thiosulfate in humans.

Inclusion Criteria:

1. Adults receiving cisplatin therapy in the dose range of 80-120mg/m2

2. Subjects are capable of giving informed consent, or if appropriate, have an
acceptable surrogate capable of giving consent on the subject's behalf.

Exclusion Criteria:

1. Subjects with active middle ear disease (unilateral or bilateral)

2. Subjects with prior treatment with platinum-based chemotherapeutic agent or other
ototoxic agent

3. Subjects with an allergy to sodium thiosulfate

4. Subjects with tumors involving cranial nerve VIII

5. Subjects with preexisting absence of otoacoustic emissions (unilateral or bilateral)

6. Subjects with more than 5 dB interaural difference in puretone threshold on initial
audiometric screening

7. Chronic use of known ototoxic agent (e.g. furosemide, aminoglycosides, etc)

8. Subjects with a history of prior irradiation to the head and neck.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Efficacy of Intratympanic Sodium Thiosulfate (STS)

Outcome Description:

To assess the efficacy of intratympanic sodium thiosulfate (STS) on reducing the degree or incidence of hearing loss in patients receiving systemic cisplatin therapy using puretone and speech audiometry, and distortion product otoacoustic emissions (DPOAE). Pure tone and speech audiometry: hearing will be assessed prior to any initiation of cisplatin therapy, again at three weeks, 6 weeks, 12 weeks, and every 6 months thereafter for up to one year.

Outcome Time Frame:

Through 1 year post-treatment

Safety Issue:


Principal Investigator

David Cognetti, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University


United States: Institutional Review Board

Study ID:




Start Date:

August 2011

Completion Date:

August 2017

Related Keywords:

  • Cancer
  • cisplatin
  • STS
  • sodium thiosulfate
  • Adults
  • dose range of 80-120mg/m2
  • Hearing Loss
  • Deafness



Thomas Jefferson UniversityPhiladelphia, Pennsylvania  19107-6541