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Cisplatin Ototoxicity and OAEs
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Report compiled by : Claudia Cavallini MA, Center of Bioacoustics, University of Ferrara,
Italy
Cisplatin is an antineoplastic agent
with known ototoxic effects. It is used in the treatment of testicular,
ovarian and head and neck squamous cell malignancies in adults.
Children receive Cisplatin for the treatment of central nervous
system tumors, neuroblastoma and osteosarcoma. It is usually administered
in a single dose over several hours or in smaller doses over 2 to
5 days. The dose is generally repeated every 3 to 4 weeks. Although
nephrotoxicity has been the main dose-limiting side effect, that
has been effectively managed with concomitant use of diuretic and
intravenous hydration, ototoxicity side effects remain as a un-resolved
clinical problem. The ototoxic effect in adults is characterized
as an irreversible, progressive and bilateral high-frequency sensorineural
hearing loss associated with tinnitus. In adults the hearing loss
is usually moderate with threshold in the 15 to 40 dB.
The symptoms
and audiologic findings in patients with Cisplatin ototoxicity are
most consistent with a cochlear process, which is more pronounced
in the basal turn. Ultrastructural examination of human temporal
bones has shown that the primary site of the Cisplatin ototoxicity
is the outer hair cells (OHCs) of the basal and middle turns of
the cochlea (Sie and Norton, 1997).
There have
been numerous clinical and experimental reports on cisplatin -induced
ototoxicity, and there are many report on the short -term effects
of cisplatin on OAE measured in different rodent species (Sockalingam
et al, 2000). Evoked otoacoustic emissions (EOAEs)
are potentially useful in following ototoxic insults involving OHCs
as a measure of outer hair cell function. For the latter several
animal models have been developed to study the effect of antineoplastic
agents on OHCs (Hatzopoulos et al,
2002) and TEOAEs and DPOAEs have
been utilized as early indicators of cisplatin-induced ototoxicity
in different rodents species. Sie
and Norton (1997) measured distortion- product
otoacoustic emissions (DPOAEs) , in gerbils at 2, 4, 6,
8, 10 and 12 kHz after a single large
dose of Cisplatin ( 10mg/kg subcutaneously). Animals treated with
saline served as controls. The findings were compared to auditory
brainstem evoked response (ABR) threshold, using
tone pips of the same frequencies. The DPOAE and ABR thresholds
were measured before treatment and again 2, 5 and 14 days after
the drug administration. No treatment effect was observed in the
2-day group. Animals treated with Cisplatin demonstrated significant
elevation of DPOAE and ABR thresholds compared with control animals
at 5 and 14 days. There was no significant difference between the
threshold changes in the 5 and 14-day group. However the DPOAE and
TEOAE responses were also normal before cisplatin treatment, but
depressed 3 days after cisplatin administration.
Sockalingam
et al (2000), used
three rodent species (the guinea pig, the albino rat, and the fat
sand rat) to determine which of these is the most susceptible to
cisplatin-induced ototoxicity. Cisplatin (Abiplatin 50mg/50ml,ABIC,Netanya,Israel)was
systemically administered as a single high dose (12mg/kg
intra-peritoneally) and the ototoxic effect were measured before
and 3 days after treatment. Among the three rodent species the guinea
pig showed to be the most sensitive animal model for cisplatin
ototoxicity studies, demonstrating the greatest degree of ABR depression
and OAE signal levels attenuation.
An experiment
by Ekborn et al (2000)
investigated the influence of drug administration (bolus vs slow infusion) on the observed
cisplatin induced hearing-los was investigated . The cisplatin peak concentration was considerably higher, 19.2+/-2.4 microg/ml, in the bolus injection group than in the infusion group, 6.7+/-0.5 microg/ml (mean+/-S.E.M.). The area under the blood ultrafiltrate concentration time curve (AUC) for cisplatin was slightly greater in the infusion group, 442+/-26 microg/ml/min, than in the bolus injection group, 340+/-5 microg/ml/min. A significant ototoxic effect was observed in both groups at 20 and 12.5 kHz, but there was no difference between the groups in the extent of threshold shift. The interindividual variability in susceptibility to ABR threshold shift was far greater than the variability in pharmacokinetics, suggesting that other factors are more important in determining the degree of hearing loss.
Most studies
have focused on the effects of CDDP on the outer hair cells. The
ototoxic effect of cisplatin has been evaluated in a Sprague-Dawley
rat model by recordings of auditory brainstem responses and transiently
evoked otoacoustic emissions, and has been demonstrated that the
use of OAEs can provide not only a verification of the presence
of an ototoxic effect, but evidence regarding the progress of the
ototoxicity as seen from the perspective of the OHCs (Hatzopoulos
et al, 2002).
The ototoxic
insult is not limited to the outer hair cells but has a significant
impact on the stria-vascularis. Meech
et al (1998) provided data on the stria induced
alterations working with Wistar rats. Results from the semiquantitative
analysis employed indicate that cisplatin has a deleterious effect
on the stria vascularis including strial edema; bulging, rupture
and/or compression of the marginal cells and depletion of the cytoplasmic
organelles.
The ototoxic
effects of cisplatin and relative antineoplastic molecules (ie
carboplatin) have fueled research in the direction of
oto-protection. Currently there are numerous reports that D-methionine
protects systemically the inner ear, but in most studies
no emission protocols have been used.
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Useful References (in alphabetical order)
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RP Meech, KC Campbell, LP Hughes, LP Rybak. A
semiquantitative analysis of the effect of cisplatin on the rat
stria vacsularis. Hearing Research 124(1998) 44-59.
A. Ekborn, G.Laurell, A.Andersson, I.Wallin, S.Eksborg,
H.Ehrsson. Cisplatin-induced hearing-loss: influence of
the mode of drug administration in the guinea pig. Hearing Research
140 (2000) 38-44.
S. Hatzopoulos , J.Petrucelli, G.Laurell, P.Avan, M.Finesso,
A.Martini. Ototoxic effects of cisplatin in a Sprague-Dawley
rat animal model as revealed by ABR and transiently evoked otoacoustic
emission measurements. Hearing Research 170(2002)70-82.
Kathleen Y. Sie and Susan J. Norton. Changes in
otoacoustic emissions and auditory brain stem response after cis-platinum
exposure in gerbils. Otolaryngol head Neck Surg 1997; 116; 585-92.
R. Sockalingam, S. Freeman, L. Cherny and H. Sohmer.
Effect of high-dose cisplatin on Auditory Brainstem Responses and
Otoacoustic Emissions in laboratory animals. Am J Otol. 2000 Jul;21(4):521-7.
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