Cancer
Conditions
Keywords
cisplatin, STS, sodium thiosulfate, Adults, dose range of 80-120mg/m2
Brief summary
This is a pilot, randomized, self-controlled study of the effects of intratympanic sodium thiosulfate (STS) on the degree of hearing loss in patients receiving cisplatin therapy. Sodium thiosulfate is an inactive ingredient contained in sulfacetamide ophthalmic solution which is used routinely as an otic solution delivered to the middle ear space. The hypothesis of this study is that local administration of sodium thiosulfate (STS) will result in improved hearing compared to ears not receiving the study drug in patients receiving systemic cisplatin therapy.
Detailed description
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.
Interventions
PROCEDUREInsertion of Pressure Equalization (PE) Tubes
If the subject consents to participate in the study, a separate consent for insertion of pressure equalization (PE) tubes will be obtained. The PE tubes will then be inserted into the posterior inferior quadrant of the tympanic membrane in the office under topical anesthesia.
Drops of STS will be added to the experimental ear only prior to initial cisplatin infusion.
OTHERSaline (Placebo)
Drops of balanced saline solution will be added to the placebo comparator ear prior to initial cisplatin infusion.
DRUGCisplatin
Cisplatin chemotherapy infusion in the dose range of 80-120mg/m2
Sponsors
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Intratympanic Sodium Thiosulfate (STS) | Through 1 year post-treatment | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sodium Thiosulfate (STS) Ear & Placebo Ear Subjects enrolled to study will have their ears randomized for treatment with STS. The experimental ear will receive STS treatments, while the comparator ear will receive a placebo.
Insertion of Pressure Equalization (PE) Tubes: If the subject consents to participate in the study, a separate consent for insertion of pressure equalization (PE) tubes will be obtained. The PE tubes will then be inserted into the posterior inferior quadrant of the tympanic membrane in the office under topical anesthesia.
Sodium Thiosulfate (STS): Drops of STS will be added to the experimental ear only prior to initial cisplatin infusion.
Cisplatin: Cisplatin chemotherapy infusion in the dose range of 80-120mg/m2 | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Sodium Thiosulfate (STS) Ear & Placebo Ear |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 69.26 years STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Efficacy of Intratympanic Sodium Thiosulfate (STS)
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.
Time frame: Through 1 year post-treatment