Prevention of Cisplatin-Induced Hearing Loss by Intratympanic Dexamethasone Treatment.
Prevention of Cisplatin-Induced Hearing Loss by Intratympanic Dexamethasone Treatment.
Cisplatin is a widely used chemotherapeutic agent for the treatment of various malignant
neoplasms, including testicular, ovarian, bladder, cervix uteri, head and neck and lung
Dose limiting side effects of Cisplatin include nephrotoxicity, neurotoxicity and
ototoxicity. While nephrotoxicity can be diminished or controlled with hydration therapy
there are no known cure or preventive treatments available for neurotoxicity and ototoxicity
Cisplatin-associated ototoxicity is characterized by bilateral, symmetric progressive and
usually irreversible sensorineural hearing loss. The hearing impairment is dose related,
cumulative and takes place within hours to days from the administration of cisplatin 1-4.
The reported incidence of cisplatin-induced hearing loss is variable. Schweitzer calculated
from a large number of studies an average incidence of 62% with a range from 11 to 97% 5-6.
Damage from cisplatin initially affects the outermost row of outer hair cells located at the
cochlear basal turn, which codes hearing at the high frequency range. Further insult affects
the remaining rows of outer hair cells, inner hair cells, and supporting cells. The pattern
of destruction proceeds from the basal turn towards the more apical regions of the cochlea,
with increasing impact on hearing acuity in lower frequencies 7.
Cisplatin induces cochlear toxicity by the production of reactive oxygen species (ROS) on
one hand and depletion of antioxidant enzymes on the other hand. This leads to lipid,
protein and nucleic acids peroxidation with destruction of various cell organs and apoptosis
Various chemoprotectants have been suggested to ameliorate cisplatin-induced ototoxcity.
These include sodium thiosulfate, amifostine, diethyldithiocarbamate, 4-methylthiobenzoic
acid, D- and L-methionine, N-acetylcysteine, and glutathione ester. The mechanisms of action
include direct antioxidant activity and maintenance of glutathione levels 2,4.
Unfortunately, systemic delivery of many of these agents have been found to inhibit the
tumoricidal effects of cisplatin and/or have toxicities or unknown effects in humans 2,9.
Abundant corticosteroids receptors were demonstrated within the mouse critical inner ear
structures suggesting active role of these compounds in inner ear homeostasis 10.
Dexamethasone has been reported to up-regulate cochlear anti ROS enzymes activity in various
small mammals animal models2,3,11.
Dexamethasone treatment is currently practiced for various pathologies afflicting the inner
ear in which ROS are involved in immediate or delayed ischemia-reperfusion mechanism of
injury. These include sudden sensorineural hearing loss, noise-induced hearing loss,
salicylate and aminoglycoside ototoxicity 2.
The above discussion suggests rationale for the prevention of cisplatin ototoxicity by
Intratympanic (IT) delivery of drugs is a contemporary method based on the diffusion of the
active remedy across the round window into the inner ear where it exerts its therapeutic
effects 12-14. This method allows for high inner ear concentration when compared to oral or
parenteral administration while avoiding the undesirable systemic side-effects 12.
IT administration of steroids is vastly used in the last decades for the treatment of sudden
sensorineural hearing loss and Meniere's disease. 2,3,12 Currently employed techniques for
IT drug delivery include trans-tympanic membrane injection into the middle ear cavity either
directly or through a tympanostomy; placing a wick attached to the round window niche which
is suggested to facilitate better administration of the drug to the target organ;
implantation of a round window microcatheter connected to a micro-pump for continuous drug
delivery. Experimental IT strategies include the application of various hydrogels and
nanoparticles as drug carriers, and direct delivery of medication to the inner ear via
osmotic pumps and reciprocating perfusion systems 12.
Our review of the literature yielded three animal studies which examined the protective
effect of IT dexamethasone in the prevention of cisplatin-induced hearing loss. These
studies demonstrated promising results pointing to the potential for IT dexamethasone in the
prevention of cisplatin ototoxicity in humans. Daldal et al carried a controlled study in
the guinea pig model. The study groups were treated by IT dexamethasone either before or
after intra-peritoneal injections of cisplatin, one control group had cisplatin injections
alone and the second control group was given only IT dexamethasone. IT dexamethasone caused
no cochlear damage as evaluated by distortion product otoacoustic emissions (DPOAEs).
Cisplatin caused significant decrease in DPOAEs amplitudes and SNR values, while both IT
dexamethasone treated groups demonstrated significant protection from cisplatin ototoxicity
11. Hill et al evaluated ABR click and tone burst evoked thresholds in mice receiving
intra-peritoneal cisplatin. In each animal one ear was treated by IT dexamethasone while the
second ear had IT saline injection and served as a control. The results showed significant
protection for the click, 8 and 16 kHz threshold shifts in the IT dexamethasone treated ears
3. Paksoy et al employed similar ABR evaluations to examine the potential otoprotective
effect of IT dexamethasone in cisplatin treated rats. While significant thresholds
elevations were demonstrated in the cisplatin treated rats, IT dexamethasone preserved ABR
We could not find any previously published study that examined the role of IT dexamethasone
in the prevention of cisplatin-induced ototoxicity in humans.
The purpose of this study is to examine possible protective effect of IT dexamethasone on
cisplatin-induced hearing loss, in humans.
Our study hypothesis is that IT dexamethasone treatment would prevent cisplatin-induced
Patients and Methods:
The study design is a prospective cohort controlled research. The participants would be 30
consecutive patients suffering from a neoplastic disease for which the treatment protocol
includes cisplatinum not previously delivered to them. The cumulative cisplatin dose would
be at least 300mg divided to treatment sessions and dosages as dictated by the oncologist.
After receiving an explanation about the study goals and methods, candidates for
participation in the study would sign an informed consent.
Baseline evaluation would include detailed history with emphasis on previous or existing ear
disease, microscopic otoscopy, pure tone, speech and impedance audiometry, and Distortion
Product Otoacoustic Emissions (DPOAEs) testing. This test specifically evaluates the
functioning of the cochlear outer hair cells which are the primary target organ for
cisplatin ototoxicity. It has been previously shown that decreased signal-to-noise ratio
(SNR) of the otoacoustic emissions precedes the appearance of the audiological pure tone
threshold shift and identify sub-clinical hearing loss.15 Exclusion criteria would include
the followings: age < 18 years; existing or previous pathology of the external or middle ear
avoiding IT drug delivery or the performance of DPOAEs testing; retrocochlear hearing loss;
Meniere's disease; Autoimmune Inner Ear Disease; fluctuating hearing loss; history of sudden
sensory neural hearing loss; previous radiation therapy to the head and neck region;
baseline average pure tone audiometry thresholds for 500-3000 Hz and 4000-8000 Hz greater
than 40 dB; average SNR below 6 dB for DPOAEs f2 frequencies 500-3000 Hz and 4000-8000 Hz.
Under topical anesthesia of Emla cream (mixture of lidocaine 2.5% and prilocaine 2.5%),
0.7ml of Dexamethasone Phosphate 10mg/ml would be injected unilaterally to the middle ear
using 25 gauge spinal needle. The injected side would serve as the study ear while the
contralateral side would be the control ear. The ear receiving the treatment would be
randomly chosen using a computerized "randomizer"16. The trans-tympanic membrane injection
would take place at the posterior inferior quadrant of the ear drum facing the round window
niche. The patient would be instructed to lie down for 20 minutes after the injection with
the treated side up and to avoid swallowing or coughing. These measures are taken to allow
maximal contact of the Dexamethasone solution with the round window membrane while
minimizing medication loss via the Eustachian tube. Intratympanic Dexamethasone would be
delivered immediately prior to each cisplatin treatment as maximal level of the medication
in the scala tympani is anticipated 1 hour post injection 10,17,18 while the maximal
perilymph concentration of cisplatinum after intravenous injection in the guinea pig model
is reached after 20 minutes19.
Pure tone, speech and impedance audiometry and DPOAEs would be recorded prior to the first
cisplatinum administration and before each consecutive treatment. The final testing would
take place 7 days after the last treatment session in which the cumulative dose of 300mg was
The following parameters would be compared between the study and control ears for the
baseline and consecutive examinations: Pure tone average thresholds for 500-3000 and
4000-8000 Hz; DPOAEs SNR averages for 500-3000 and 4000-8000 f2 frequencies.
Normal distribution of the results would be examined by the Shapiro-Wilk test. The
comparisons between the study and control ears for the baseline and consecutive evaluations
would be done using the Student's paired two-tailed t-test. Longitudinal changes in pure
tone audiometry thresholds and DPOAEs SNR would be evaluated by repeated measures ANOVA.
Sample size calculation was based on the following parameters: The event rate for
cisplatinum-induced sensorineural hearing loss is 60% 6; each patient serves as his own
control when one ear is treated and the hearing level is compared to that of the untreated
ear; A successful treatment is defined as preventing at least third of the anticipated
hearing loss in the study population; the desired statistical power is 80% with p<0.05.
Taking the above parameters into consideration the calculated required sample size is 30
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
Examine possible protective effect of IT dexamethasone on cisplatin-induced hearing loss. Hearing assessment would include:pure tone, speech and impedance audiometry, and Distortion Product Otoacoustic Emissions (DPOAEs) testing.
Distortion Product Otoacoustic Emissions (DPOAEs) testing is a test that specifically evaluates the functioning of the cochlear outer hair cells which are the primary target organ for cisplatin ototoxicity.
Tal M Marshak, MD
Clalit Health Services
Israel: Clalit Health Services