Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat solid organ malignancies. However, serious side effects have been associated with its use, such as bilateral, progressive, irreversible, dose-dependent neurosensory hearing loss. Current evidence indicates that cisplatin triggers the production of reactive oxygen species in target tissues in the inner ear. A variety of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models. However, many of them interfere with the therapeutic effect of cisplatin, and therefore are not suitable for systemic administration in clinical practice. Consequently, local administration strategies, namely intratympanic administration, have been developed to achieve otoprotection, without reducing the antitumoral effect of cisplatin. While a considerable amount of pre-clinical information is available, clinical data on treatments to prevent cisplatin ototoxicity are only just beginning to appear. This review summarizes clinical and experimental studies of cisplatin ototoxicity, and focuses on understanding its toxicity mechanisms, clinical repercussions and prevention strategies.

Hair cell (HC) loss by epithelial extrusion has been described to occur in the rodent vestibular system during chronic 3,3′-iminodipropionitrile (IDPN) ototoxicity. This is preceded by dismantlement of the calyceal junction in the contact between type I HC (HCI) and calyx afferent terminals. Here, we evaluated whether these phenomena have wider significance. First, we studied rats receiving seven different doses of streptomycin, ranging from 100 to 800 mg/kg/day, for 3–8 weeks. Streptomycin caused loss of vestibular function associated with partial loss of HCI and decreased expression of contactin-associated protein (CASPR1), denoting calyceal junction dismantlement, in the calyces encasing the surviving HCI. Additional molecular and ultrastructural data supported the conclusion that HC-calyx detachment precede HCI loss by extrusion. Animals allowed to survive after the treatment showed functional recuperation and rebuilding of the calyceal junction. Second, we evaluated human sensory epithelia obtained during therapeutic labyrinthectomies and trans-labyrinthine tumour excisions. Some samples showed abnormal CASPR1 label strongly suggestive of calyceal junction dismantlement. Therefore, reversible dismantlement of the vestibular calyceal junction may be a common response triggered by chronic stress, including ototoxic stress, before HCI loss. This may partly explain clinical observations of reversion in function loss after aminoglycoside exposure.