Trends in Pharmacological Sciences
ReviewUnderstanding platinum-induced ototoxicity
Section snippets
Ototoxicity, a platinum-associated side effect, receives renewed attention
The US Food and Drug Administration (FDA) approved cisplatin in 1978 and carboplatin in 1989, despite knowledge of their ototoxic and nephrotoxic side effects. Platinum ototoxicity can manifest in both children and adults. Children, however, are more susceptible to platinum-induced hearing loss than adults, resulting in higher incidence rates (Figure 1). Moreover, deafness due to platinum treatment in childhood is particularly challenging with respect to speech and language development,
Mechanisms
Basic mechanisms of platinum-induced cytotoxicity in normal tissues such as the inner ear are presumably not completely different from those in tumor cells. It is well known that the antineoplastic efficiency of this class of drugs results from the interaction with the nuclear DNA of tumor cells. Platinum compounds such as cisplatin initially induce monoadducts at nucleophilic sites (e.g., of guanine or adenine) and can subsequently lead to intrastrand and interstrand crosslinks in the DNA.
Incidence, risk factors, and clinical presentation
Cisplatin, carboplatin, and oxaliplatin are the only FDA-approved platinum compounds. Because they have been used long-term world-wide, most post-marketing surveillance data are available for these drugs. Overall, the data indicate that cisplatin carries a higher risk of hearing impairment than carboplatin. Nevertheless, treatment with carboplatin still carries a significant risk of mild to severe ototoxicity. Young patients and patients receiving high cumulative doses are at greater risk of
Diagnosis
Structural alterations in the outer hair cells and spinal ganglion neurons of the basal cochlear turn represent the earliest event in cisplatin-induced ototoxicity. These structural alterations are accompanied by reduced auditory sensitivity. High-frequency testing (>6 kHz) permits the early detection of platinum-induced ototoxic damage well before impairments become evident in conventional frequency ranges relevant to everyday life of the child. At present, pure tone audiometry (up to 10 kHz),
Non-genetic risk factors
Established non-genetic risk factors that increase the susceptibility to ototoxic side effects and hearing loss associated with platinum compounds are summarized in Box 1 (see also [8]). An important risk factor is the dose. At a population level, higher cumulative doses of cisplatin are associated with higher rates of ototoxic side effects; the incidence of cisplatin-dependent ototoxicity increases by an average of 5–7% per additional 100 mg/m2 cumulative cisplatin (Figure 1A).
Although clinical
Pharmacogenetics
To date, genetic association studies of ototoxicity have been based on the candidate gene approach. Genes were selected on the basis of established or postulated mechanisms of platinum ototoxicity and a restricted number of polymorphisms in these genes that affect the function or the expression of the encoded protein were evaluated (Figure 2).
The first pharmacogenetic association study was performed by Peters et al. more than one decade ago and focused on polymorphisms in genes of the GST
Prevention strategies
The use of lower cumulative cisplatin doses or replacing cisplatin with a second- or third-generation analog with a lower ototoxic potential has not been implemented as a preventative strategy for cisplatin-induced ototoxicity in routine clinical practice, because it is unclear whether these alternative treatments would fully retain the antitumor efficacy and thus survival rates of standard cisplatin regimens. Nevertheless, recommendations for dose adjustments or the replacement of cisplatin
Concluding remarks
Currently available clinical data were used to develop statistical regression models that predict the risk of developing cisplatin ototoxicity by integrating established clinical variables, namely, patient age and cumulative cisplatin dose. Although these models accurately predict the average risk in a cohort of patients at a given age and cumulative cisplatin dose, they do not precisely map the risk in an individual patient [11]. The reason for this is that only a small fraction of the
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