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Relationship Between Cisplatin Administration and the Development of Ototoxicity

From the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital and Department of Audiology, Academic Medical Center, Amsterdam; and Faculty of Pharmaceutical Sciences, Division of Drug Toxicology, University Utrecht, Utrecht, the Netherlands.

Address reprint requests to Jeany M. Rademaker-Lakhai, MD, the Netherlands Cancer Institute, Department of Medical Oncology/Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; e-mail: jeanyrademaker{at}quicknet.nl

PURPOSE: To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non–small-cell lung carcinoma patients.

PATIENTS AND METHODS: Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity.

RESULTS: A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m² cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m². Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m².

CONCLUSION: Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m². It is more pronounced when cisplatin is given once every 2 weeks.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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