Ototoxicity and OAEs

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 (i.e, 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.


Useful References (in alphabetical order)

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.