Ototoxicity from cisplatin therapy continues to be a common side effect that has been shown to afflict a majority of cancer patients receiving this chemotherapeutic agent. A recent evaluation of intravenous cisplatin ototoxicity in adults showed that 88% of patients had measurable hearing loss with 49% becoming candidates for hearing aids after the therapy24
. A significant impact has also been demonstrated in the younger population. Another recent study investigating patients under 23 years of age showed 61% of patients receiving intravenous cisplatin experienced measurable hearing loss with 25% becoming candidates for hearing aids25
Several studies have explored the possibility of administering an otoprotectant in an effort to reduce the negative impact of cisplatin on hearing. One area of focus has been on administering antioxidant compounds in an attempt to reduce the accumulation of reactive oxygen and nitrogen species before they induce apoptosis in the inner ear. Several thiol antioxidants (e.g., sodium thiosulfate, diethyldithiocarbamate, d- or l-methionine, methylthiobenzoic acid, lipoic acid, N
-acetylcysteine, tiopronin, glutathione ester and amifostine) have been evaluated for protective effect against cisplatin ototoxicity. While thiols appear to have otoprotectant properties against cisplatin, some diminish the anti-neoplastic properties of cisplatin, thus are not suitable for clinical application1
. In addition, promising experimental findings have not translated into clinical success. A recent phase III clinical trial performed involving sodium thiosulfate showed that 36% of patients treated with cisplatin still qualified for hearing aids26
. In another clinical study, amifostine, a broad-spectrum cytoprotectant which reduces cisplatin associated neuro- and nephrotoxicity, did not protect against cisplatin ototoxicity27
In the current study we investigated the otoprotective effect of dexamethasone administered intratympanically in cisplatin-treated mice. Our results show that intratympanic dexamethasone played a protective role against cisplatin-induced ototoxicity by reducing ABR threshold shifts. This finding extends the results of a recently published report from Turkey, where intratympanic dexamethasone at a concentration at 4 mg/mL protected outer hair cell function, as measured by DPOAE's at frequencies up to 6 kHz, in guinea pigs injected with cisplatin28
. Our results evaluate ABR thresholds which estimate auditory function and are believed to reflect functional capacity of cochlear hair cells (both inner and outer), spiral ganglion cells and neurons in the brainstem auditory nuclei. Furthermore, our results provide additional information about ABR thresholds at relatively higher frequencies than the Daldal study. In the guinea pig, 6 kHz represents approximately 50% of the distance from the apex of the cochlea29
. For comparison in the mouse, 32 kHz is approximately at 70% of the distance from the apex, 16 kHz approximately 43% of the distance from the apex and 8 kHz approximately 18% of the distance from the apex of the cochlea30
. We believe higher frequencies, representing areas of the cochlea closer to the base, are very important to investigate, as they have been shown to be affected by cisplatin ototoxicity first. Our study showed good protection at 8 and 16 kHz but none at 32 kHz. Decreased efficacy of any antioxidant may be expected at the highest frequencies, as the basal turn of the cochlea is the most susceptible to cisplatin ototoxicity. In general, destruction of OHCs due to drug toxicity progresses in a base-to-apex gradient. This gradient may be related to a differential vulnerability of basal and apical OHCs demonstrated in guinea pig organotypic cultures arising from lower levels of antioxidant glutathione in the base and thus intrinsic susceptibility to free radicals31
. In our study, the damage in this area may have been too extensive to be prevented by intratympanic steroids. This may reflect some limitations of dexamethasone to protect the highest frequencies, or more likely, this may be a reflection of the relatively large bolus dose of cisplatin given in this study that had a 20% mortality rate. It is possible a more clinically relevant administration of cisplatin (i.e. a more clinical administration with slow transfusion and multiple smaller doses over several days) would result in less extensive damage at the base of the cochlea which in turn could be protected by intratympanic application of dexamethasone.
The current study has significant translational potential since intratympanic steroids are already used in humans as a simple and safe therapy for other inner ear disorders. Intratympanic steroids provide the advantage of potentially fewer systemic side effects while concentrating the drug in the desired location within the inner ear. This is supported by a recent investigation that measured the perilymph levels of methylprednisolone in humans undergoing cochlear implantation after either intratympanic or parenteral injection of the steroid. It was found that intratympanic injection of methylprednisolone produced perilymph concentrations that were 33-fold higher and plasma concentrations that were 136 fold lower than the respective concentrations from parenteral dosing22
. This study also supports the translational potential of animal studies investigating potential uses of intratympanic steroids.
Prior to this study, there were no investigations of cisplatin ototoxicity in mice available. A mouse model of cisplatin ototoxicity offers several advantages. For example, since the majority of cancer patients are older than 50, consideration has to be given to how age and age-related hearing loss interact with cisplatin-induced ototoxicity, and for that matter, whether a successful otoprotectant identified in the young animal model is effective in an animal model with pre-existing deficits. Mouse models of hearing loss, aging and age-related hearing loss are well established32
. In addition, the mouse genome has been well defined and knock out models are increasingly available that facilitate gene targeting as a future strategy in ameliorating ototoxicity.
In the published cisplatin-induced ototoxicity literature two different dosing models have been utilized: a single large dose28,33
vs. multiple small doses 34,35
. We chose the single, large dose model and study design, comparable to that of Drottar et al.33
, because it is more practical to implement and the resulting data are easier to interpret. It is, however, recognized that in the clinical realm standard treatment protocols utilize a multiple dosing regimen. Dexamethasone as a successful otoprotectant can be examined in the multiple dosing regimens in future investigations.
The present study evaluated ototoxicity up to 8 days after cisplatin administration. Whether this amount of time is sufficient for full expression of cisplatin-induced ototoxicity in the mouse remains to be determined. However, other single-dose studies in the rat and guinea pig suggest that hearing loss has stabilized by 5-7 days after cisplatin injection36,37
. The only other study of dexamethasone effect on cisplatin ototoxicity measured DPOAEs only three days after cisplatin administration28
The limitations of this study include the small number of animal subjects, no inner ear sampling of dexamethasone concentration and no histologic correlation. Further studies will include histologic evaluation, lower concentrations of dexamethasone for intratympanic injection, and variations in dosing of cisplatin to more similarly match what is given clinically.