The Effect of Sodium Thiosulfate Eardrops on Hearing Loss in Patients Who Receive 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.