Author(s): Claudia Lanvers-Kaminsky [*] aff1 , Jason A Sprowl aff2 , Ingrid Malath aff1 , Dirk Deuster aff3 , Maria Eveslage aff4 , Eberhard Schlatter aff5 aff6 , Ron HJ Mathijssen aff7 , Joachim Boos aff1 , Heribert Jürgens aff1 , Antionette G am Zehnhoff-Dinnesen aff2 aff6 , Alex Sparreboom aff2 aff7 , Giuliano Ciarimboli aff5 aff6
cisplatin; ototoxicity; polymorphism; SLC22A2 ; SLC31A1
Cisplatin is one of the most potent anticancer drugs and despite dose-limiting nephro- and ototoxicity it is still recommended as first line treatment for pediatric as well as adult cancers. While nephrotoxicity can be reduced by vigorous hydration, ototoxicity is still of concern in adults and especially in children, who are more sensitive to cisplatin-induced ototoxicity and depend on unaffected hearing as basis for language development, school performance, social integration and an age-based quality of life [1-3 ].
Permanent bilateral hearing loss was observed at least in 60% of children treated with cisplatin [1,3,4 ]. In adults, persisting ototoxicity may affect up to 50% of patients [ 5 ]. Reporting of ototoxicity in clinical trials bases on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and the WHO Common Toxicity Criteria [6,7 ]. These criteria were found to underestimate the incidence of cisplatin ototoxicity and new grading systems were developed, which considered clinical differences in cisplatin-induced hearing loss and their consequences. Brock et al . established a grading system, which is based on standard pure-tone audiologic frequencies at which hearing loss equals or exceeds 40 dB hearing level (HL) [8 ]. This grading system was further modified by Chang and Chinosornvantana and by the SIOP Boston Ototoxicity Scale [1,9 ]. Both grading systems considered 20 dB HL besides 40 dB HL as hearing loss in order to detect mild hearing losses. The Muenster classification, which was applied in this study, further considers tinnitus and minimal hearing losses ([greater than]10 to [less than or equal to]20 dB HL) to already catch beginning ototoxicity classified as grade 1 [8,10,11 ]. Compared to existing scales the acquisition of changes as low as [greater than]10 to [less than or equal to]20 dB HL after the second cisplatin dose by the Muenster classification identifies patients at risk for serious hearing impairment with high sensitivity and predictivity [12 ].
High cumulative dosages of cisplatin are the most important risk factors predicting cisplatin-induced ototoxicity [5,13-15 ]. In addition, bolus-injections of cisplatin, pre-existing renal dysfunction, pre-existing sensorineural hearing loss and cranial radiation significantly increase the risk for cisplatin-induced hearing loss. Children [less than]5 years are significantly more sensitive to cisplatin-induced ototoxicity than older children, while in adults a history of noise exposure further increases the risk of cisplatin-induced ototoxicty [5,13-17 ].
Moreover other individual factors exist which allow some patients to tolerate cisplatin exposure without any signs of ototoxicity, while others experience hearing impairment already after the first dose of cisplatin [ 3,4,18 ]. The hypothesis that genetics may contribute to interpatient variation prompted the search for pharmacogenetic markers associated with patients' individual risk to experience cisplatin-induced ototoxicity. In a high-throughput genotyping approach of 220...