Cisplatin ototoxicity and its relationship with polymorphism

Objective: Cisplatin is an antineoplastic agent which is widely used for the treatment of various pediatric malignancies. Some side effects like ototoxicity, neurotoxicity and nephrotoxicity hinders its usage at higher doses. Up to date various risk factors have been accused for cisplatin ototoxicity. The aim of this study is to analyse genetic and non genetic risk factors contrubuting to cisplatin ototoxicity. Material and Method: Seventy two children who received cisplatin chemoterapy in pediatric oncology department of Dokuz Eylul University School of Medicine and Behçet Uz Children's Hospital were included in this study. Audiological evaluation of all children were done before and minimum 3 months after their treatments by pure tone audiometry, distorsiton product otoacoustic emissions and auditory brainstem response test. Ototoxicity was evaluated using Brock and Muenster classifications. Six different single nucleotid polimorphisms including ERCC1, GSTP1 Ala114Val, GSTP1 IIe105Val, Megalin, TPMT, COMT were evaluated by real time PCR method. Non genetic factors such as cranial irradiation, cumulative doses of cisplatin, age, gender, administration of other ototoxic drugs such as furosemide, carboplatin or aminoglycosides, duration of treatment and administration route were also analysed. By using Chi-square test, all of the risk factors were matched with the two ototoxicity classifications. Risk factors which were found to be significant for ototoxicity by univariate analyses were reevaluated using logistic regression modelling. Results: Of 72 patients, ototoxicity was observed in 24 patients according to Brock and in 30 patients according to Muenster classifications. In univariate analyses, male gender, concurrent use of aminoglycosides and GSTP1 IIe105Val mutant genotype were found to be significantly related with cisplatin ototoxicity ( p<0,05). Logistic regression modelling analyses with these 3 risk factors showed that, male gender and concurrent use of aminoglycosides were found to be significantly related with cisplatin ototoxicity. On the other hand, GSTP1 IIe105Val mutant genotype was not found to be significant, but very close to the level of statistical significance. Conclusion: Our findings suggest that, male gender and the concurrent use of aminoglycosides are significant risk factors for cisplatin ototoxicity in pediatric patients. Patients with GSTP1 IIe105Val mutant genotype should be carefully watched for possible occurence of ototoxicity and re-evaluated in larger series.