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Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 918-924 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.077 Relationship Between Cisplatin Administration and the Development of OtotoxicityFrom 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.
Cisplatin is an effective cytotoxic agent that is currently used as standard treatment of a variety of human neoplasms. The incorporation of cisplatin into combination regimens has resulted in high cure rates, for example, of advanced testicular cancer. However, clinical application is limited because of serious and sometimes irreversible toxicity, including GI, neurotoxicity, nephrotoxicity, myelosuppression, and ototoxicity. Forced diuresis pre- and postinfusion limits nephrotoxicity, and with current supportive medication GI toxicity is manageable in the majority of patients. However, despite extensive research, no therapeutic intervention of proven benefit has been found to prevent neuro- and ototoxicity. Myelosuppression is generally easily manageable after cisplatin therapy. In this report we focus on the development of ototoxicity after cisplatin administration. Cisplatin is the most ototoxic drug known, and a mean ototoxicity incidence of 33% has been reported when patients received a single dose of 50 mg/m2 of cisplatin.1 Investigations using audiometric techniques revealed a frequency of cisplatin-induced ototoxicity of approximately 20% to 40% after a high cumulative dose of cisplatin of 400 mg/m2.2 However, this percentage was not observed by all investigators. For example, De Jongh et al3 described the toxicity of weekly high-dose cisplatin (70 to 85 mg/m2) in 400 patients with advanced solid tumors. They observed ototoxicity in 2.5% of the patients. Planting et al4 performed a phase II study of weekly high-dose cisplatin (80 mg/m2) for six cycles in 59 patients with locally advanced squamous cell carcinoma of the head and neck. They observed 13 patients with ototoxicity. Ototoxicity probably is caused by damage to the organ of Corti by cisplatin, including the destruction of auditory sensory cells, and is manifested as hearing loss and/or tinnitus in the high frequency range (beyond 4 kHz).5 Platinum (Pt) ototoxicity has been reported to also include otalgia and, in rare cases, vestibular alterations.6-8 Sometimes these problems can be severe, and ototoxicity and vestibular toxicity are usually irreversible. Ototoxicity affects the inner ear, which is essential in both hearing and balance. High-dose carboplatin can also induce auditory dysfunction with a clinical picture that is largely the same as that after cisplatin therapy.9,10 Auditory function must be monitored carefully because the toxicity can become disabling. Other than higher dosage and longer duration of cisplatin therapy, risk factors useful for predicting the risk of ototoxicity and its reversibility remain undetermined. The cumulative dose of cisplatin applied, its infusional rate, the combination with other drugs, the age of the patient, and pre-existing inner ear hearing impairment may enhance the risk for development of ototoxicity.2,6 However, the influence of the schedule of cisplatin administration on the severity of ototoxicity is largely unknown. Continued high-dose cisplatin chemotherapy necessitates the investigation of strategies to decrease the dose-limiting ototoxicity. Lowering the dose-intensity would not be a preferred option because this might reduce the efficacy of cisplatin. Therefore, it is important to describe the ototoxicity after cisplatin infusion in different infusion schedules. The aim of this study was to assess the auditory toxicity associated with dose- and schedule-intensive cisplatin/gemcitabine chemotherapy in non–small-cell lung carcinoma (NSCLC) patients. We only focus on ototoxicity after the cisplatin administration. The data were obtained in a large clinical trial aimed at assessment of the highest, safely achievable dose-intensity of this combination administered once a week and once every 2 weeks.11,12
Patient Eligibility Criteria Patients were eligible if they had histologically and assessable confirmed advanced NSCLC that was not pretreated with chemotherapy and a performance status of 0 to 2 (WHO Eastern Cooperative Oncology Group). Other eligibility criteria were age older than 18 years, adequate hematologic parameters (absolute neutrophil count  2.0 x 109/L, platelets 150 x 109/L), and adequate hepatic and renal functions (bilirubin < 25 µmol/L, AST/ALT < 2x the upper limit of normal and < 5x the upper limit of normal in case of liver metastases; serum creatinine < 125 µmol/L or creatinine clearance > 50 mL/min). Patients were excluded if they had symptomatic brain metastases, carcinomatous leptomeningitis, or ototoxicity National Cancer Institute Common Toxicity Criteria (CTC) grade more than 1 at start. The local ethics committee approved the study and all patients gave written informed consent. Although assessment of the antitumor activity was not a primary objective of this study, patients with measurable disease were evaluated according to the Response Evaluation Criteria in Solid Tumors Group criteria.13 All toxicities were graded according to the National Cancer Institute CTC version 2.0.14
Treatment Plan
After determination of the maximum-tolerated dose and dose-intensity, the study continued and the following cohorts of patients were treated at a reversed schedule. From the first part of the study the schedule was selected with the highest dose-intensity of cisplatin. This was found to be the schedule with dose administered once every 2 weeks. In this schedule, cisplatin was administered before gemcitabine in one day in an attempt to improve feasibility and patient convenience of this combination (Rademaker-Lakhai et al, submitted for publication). This order of drugs was also administered according to an interpatient dose-escalation scheme (Table 1). The patients received four courses without rest (weeks 1, 3, 5, and 7), which also resulted in a treatment period of 7 weeks. At all schedules cisplatin was administered as a 3-hour intravenous infusion with pre- and posthydration; gemcitabine was administered as a 30-minute intravenous infusion. Pre- and posthydration consisted of 2,000 mL NaCl 0.45%/glucose 2.5% during 14 hours before treatment and 3,000 mL NaCl 0.45%/glucose 2.5% during 18 hours after cisplatin infusion. During the posthydration, patients also received 20 mmol KCl, 500 mg magnesium sulfate, and 290 mg calcium gluconate.
Patients and Audiometric Monitoring Audiometric evaluations were conducted within 3 weeks before start of the cisplatin infusion. The audiometric evaluations were repeated at the end of the cisplatin cycles and when a patient went off study before completion of all planned cycles. Audiometric evaluations were conducted with an Orbiter 922 (Madsen Electronics, Minnetonka, MN). The pure-tone audiometric thresholds in decibels hearing level (dB HL) were obtained through air conduction at frequencies 0.125, 0.25, 0.5, 1, 2, 4, 8, and 12.5 kHz.
Statistics and Data Analysis Every patient was measured on both ears with three different frequencies. Analysis was performed using Proc Mixed (SAS System for Windows 8.02; SAS Institute, Cary, NC). The applied schedule, the other factors described, and relevant interactions are included as fixed effects. To take into account that every patient has six measurements, ear and frequency were specified in the repeated-statement from the Proc Mixed procedure. P values of less than .05 were considered significant. A paired-sample t test was performed to test the significance of the two repeated measurements on the same individual (eg, pre- and post-treatment audiogram measurements) for the frequencies 4, 8, and 12.5 kHz. P values of less than .05 were considered significant. The P values are two sided.
Pharmacokinetics The maximum drug concentration (Cmax) of unbound Pt was derived directly from the experimental data. The area under the curve (AUC) of non–protein-bound Pt was calculated by the linear trapezoidal method. The AUC and Cmax were calculated to observe whether there was a quantitative correlation between these two pharmacokinetic parameters and the development of ototoxicity.
Patient Characteristics Ninety-seven patients met all of the inclusion criteria in this study. For the first three low cisplatin dose levels, no audiograms were performed as defined in the protocol (Table 1) and no pretreatment or follow-up audiograms were obtained for 37 patients in this study. Some patients were lost to follow-up for various reasons, such as termination of treatment or patient refusal. Therefore, of 60 patients, we obtained pretreatment audiograms, audiograms during treatment, and post-treatment audiograms. These patients were used to describe the ototoxicity. The 60 patients had a median age of 52 years (range, 27 to 76 years). Of the 60 observed patients, nine patients had modest hearing impairment before chemotherapy (CTC grade 1). A total of 328 audiograms were analyzed. Some patients had four and others had five audiograms. The observed ototoxicity per patient per schedule as a function of dose is presented in Table 2. No ototoxicity was observed at the schedule administered once a week, in which the highest cisplatin dose applied was 60 mg/m2. For the schedule administered every 2 weeks, no ototoxicity was encountered at the 67.5 and 75 mg/m2 dose levels of cisplatin. In total, 10 patients stopped protocol treatment during cycle 1 or 2 due to ototoxicity after cisplatin treatment. This occurred at different dose levels. Most of the patients who developed clinical signs of ototoxicity developed this toxicity after the second cisplatin administration, which was manifested as hearing loss or tinnitus.
Statistical Analysis One of the major interests was to detect whether there was an effect on hearing impairment from the treatment schedules: once a week versus once every 2 weeks, and once every 2 weeks versus once every 2 weeks reversed schedule. Of note, there were far more patients included in the schedule administered once every 2 weeks than in the schedule administered once a week (43 and 17 patients, respectively). The data showed that hearing impairment was more severe on the schedule administered once every 2 weeks than on the schedule administered once a week when the dose levels with the same dose-intensity were compared. A significant decrease of 5.8 dB HL (P = .011) was found between the estimated effects from the two schedules. For the three frequency groups (I, II, and III), the following differences were calculated between the estimated effects from the schedule administered once every 2 weeks versus once a week. For frequency group I, no significant difference was found (P = .97) in the schedule administered once every 2 weeks compared with the schedule administered once a week. For frequency group II the difference was 6.9 dB HL (P = .063), and for frequency group III the difference was 10.5 dB HL (P = .0015; Fig 1; mean and standard deviation for both schedules are shown in the figure). These data indicate that a significantly larger shift of hearing thresholds occurred in the schedule administered once every 2 weeks compared with the schedule administered once a week at the higher frequencies. For frequency II this shift is not clear, but there seems to be a pattern. It was also observed that there was no significant difference between the hearing loss of the schedule administered once every 2 weeks and the reversed schedule administered once every 2 weeks (P = .26; data not shown). Therefore, these data were pooled for subsequent analyses.
By multivariate analysis it was observed that schedule (P = .011), frequency (P < .0001), the interaction between schedule and frequency (P = .0036), cumulative doses (P = .013), baseline audiometric threshold (P = .0003), and age (P = .013) have a significant effect on hearing loss. After cisplatin treatment, no significant difference in hearing impairment was observed between the right and left ear (P = .49). Moreover, given that the hearing thresholds were almost identical at each frequency in both ears, the data were not presented separately, but were averaged.
PTA At the higher frequencies (1, 2, and 4 kHz), which represent speech perception in noise, a more severe threshold shift was recorded than at the lower frequencies, with increasing severity at dose level 90 mg/m2 and higher dose levels when administered every 2 weeks. The most severe threshold shift was 24 dB HL after administration of cisplatin 105 mg/m2. An increase in hearing thresholds of 13 dB was observed at dose level 97.5 mg/m2. At the lower dose levels (45 to 90 mg/m2) a mean threshold shift of 9 dB was recorded. At the frequency combination of 8 and 12.5 kHz, the ultrahigh sounds, additional hearing impairment was observed, with mean threshold shifts of 32 dB at cisplatin dose levels 67.5, 75, 82.5, 90, 97.5, and 105 mg/m2 when administered every 2 weeks; greater threshold shifts were observed at the higher dosages.
Shifts at Individual Thresholds
By paired sample t test, it was observed that the shift was significant at dose levels 60, 82.5, 97.5, and 105 mg/m2 of the schedules administered every 2 weeks measured at 4 kHz (P = .02, P = .01, P = .01, and P = .001, respectively). At 8 kHz, the shift was significant at dose levels 75, 82.5, 90, 97.5, and 105 mg/m2 of the schedules administered every 2 weeks (P = .01, P = .001, P = .002, P = .03, and P = .03, respectively), and for 12.5 kHz, this shift was significant at dose levels 82.5, 97.5, and 105 mg/m2 of the schedules administered every 2 weeks (P = .03, P = .03, and P = .02, respectively). Moreover, these data indicate that the severity of the shift was greater at the higher dose levels and at the higher frequencies tested, and that hearing is affected in the frequency region relevant for the perception of speech during cisplatin treatment. The paired sample t test was not performed for the other frequencies because the threshold shift in dB was negligible.
Pharmacokinetics
For comparison, the AUC of free Pt was calculated and plotted against the dose of cisplatin in milligrams (Fig 5). This indicated a weak correlation. However, the AUC of free Pt increased with the increasing cisplatin dose. Therefore, it was expected that hearing loss would increase when the AUC of free Pt increased. Unfortunately, there was no correlation between these two parameters. These results indicate that there was a wide variability in the relationship between pharmacokinetic parameters (Cmax and AUC of unbound Pt) and ototoxicity.
We observed that hearing loss after cisplatin therapy was dose dependent, schedule dependent, and frequency dependent. Certain groups of patients were at greater risk of sustained hearing impairment. In other studies patients at greatest risk were those with abnormal renal function and/or with a history of concurrently administered ototoxic drugs.16 Pre-existing hearing loss, age, and the individual sensitivity to the drug can also play a major role.17 In our study, pre-existing hearing loss was present, but for most patients was negligible (based on the CTC criteria) and was only observed at the higher frequencies. Of the 60 patients who were studied, nine patients had modest hearing impairment before chemotherapy (CTC grade 1). There were no patients with abnormal renal function or other risk factors. By multivariate analysis it was observed that schedule (P = .011), frequency (P < .0001), the interaction between schedule and frequency (P = .0036), cumulative doses (P = .013), baseline audiometric threshold (P = .0003), and age (P = .013) had a significant effect on hearing loss. Hearing loss was more severe in older patients than in younger patients. No significant difference in hearing impairment was observed between the right and left ear. The data also showed that hearing impairment was more severe for the schedule administered the every 2 weeks versus every week (P = .011), when the dose levels with the same dose-intensity were compared. This might be explained by the higher total dosages per cycle in the schedule delivered every 2 weeks. It was also observed that there was no significant difference in hearing loss between the schedule administered every 2 weeks and reversed schedule administered every 2 weeks (P = .26). The PTAs were calculated to evaluate the meaning of the audiometric thresholds and their shifts in daily life. The average threshold at 0.5, 1, and 2 kHz can be considered a measure for the perception of speech in silence. The PTA at 1, 2, and 4 kHz is an indicator for speech intelligibility in noise, and the thresholds at the ultrahigh frequencies relate, for example, to the appreciation of music or being able to hear certain sounds in nature. Communication abilities can be considered an aspect of quality of life. The PTA revealed a more severe threshold shift at the higher frequencies (1, 2, and 4 kHz) than at the lower frequencies, with increasing severity at dose level 90 mg/m2 and higher and only in the schedule administered every 2 weeks. At 8 and 12.5 kHz, additional threshold shifts were observed. This occurred at cisplatin dosages above 60 mg/m2 and only in the schedule administered every 2 weeks. The most profound hearing loss, when considering individual frequencies rather than frequency combinations, occurred at 4 and 8 kHz and in those patients receiving the higher doses and dose-intensities of cisplatin. Low frequency (0.125, 0.25, 0.5, and 1 kHz) hearing changes were not observed at any dose and dose-intensity. The shift after cisplatin administration was mild at 12.5 kHz. This could be because there already was a substantial hearing impairment before treatment with cisplatin at this frequency. The pharmacokinetic parameters of unbound Pt in plasma (Cmax and AUC) do not predict ototoxicity better than the dose or dose-intensity. Therefore, probably other parameters at the level of the inner ear determine the severity of the ototoxicity induced by cisplatin. It was expected that the AUC and Cmax of unbound Pt would increase in the schedule administered every 2 weeks, given that the total dose per cycle was higher than in the schedule administered every week. However, there were only 17 patients included in the weekly schedule and it was difficult to observe the effect of schedule by calculation of the Cmax and AUC in comparison with the schedule administered every 2 weeks. There also was a significant interpatient variability. Ototoxicity is presented per patient as a function of dose in Table 2. However, the decrease in hearing threshold measured by audiometry and the subjective hearing loss reported by the patient does not always correlate with the observed CTC grades for ototoxicity.13 Some patients had minimal or mild shifts in hearing thresholds. Nevertheless, ototoxicity was classified as CTC grade 1 or 2. Therefore, the relationship between the decrease in decibels and the ototoxicity CTC grades needs to be elucidated further. In our opinion, CTC grades according to ototoxicity should be applied less strictly. Another issue is that patients were excluded if they had ototoxicity CTC grade more than 1. When this exclusion criterion is used, it is difficult to determine the threshold shift during cisplatin treatment. At present, the only way to prevent the cisplatin-induced ototoxicity is a limitation of the total dose per cycle, the cumulative dose, and the dose-intensity. Obviously, this might reduce the efficacy of this cytotoxic agent. Therefore, it is important to describe the ototoxicity after cisplatin infusion in different infusion schedules. Audiometric monitoring may help to provide early evidence of decreased hearing ability, leading to the possible limitation of the severity of ototoxicity. Moreover, for some patients, it is possible that the drug dosage may be modified. Despite these efforts, ototoxicity will still occur after cisplatin administration. The patients in this study were also treated with gemcitabine. It is generally understood that gemcitabine is not ototoxic. Therefore, we only observed the relation between the administration of cisplatin and the development of ototoxicity. Why cisplatin is ototoxic whereas most other antineoplastic drugs are not remains open for speculation. The molecular mechanism of ototoxicity has not yet been established fully, and relationships between the structure of cisplatin and the induction of ototoxicity have not been determined. Potential causes of cisplatin-induced ototoxicity have been described. One of the possible causes of ototoxicity could be the formation of the monohydrated complex (MHC), which is present in the circulation of cisplatin-treated patients.18 MHC is formed by hydrolytic biotransformation of cisplatin and is considered to be one of the important cytotoxic species mediating the reaction with DNA.19 It is possible that the ionic environment of the inner ear affects the hydrolysis reactions between cisplatin and MHC. Another possible cause is the blocking of outer hair cell transduction channels by cisplatin.20 It is also assumed that cisplatin ototoxicity is related to depletion of glutathione and antioxidant enzymes in the cochlea, which is initiated by the production of reactive oxygen species. These enzymes would protect the cochlea against cisplatin damage and prevent hearing loss. The changes were accompanied by a marked elevation of malondialdehyde.21 There is a need for drugs that prevent cisplatin-induced ototoxicity. Nearly all of the candidate agents are sulfur- or sulfhydryl-containing compounds (thio compounds), known as antioxidants and potent heavy metal chelators. The administration of these potential inhibitors could preserve normal glutathione levels and antioxidant enzyme activities during or after cisplatin treatment, which in turn could prevent ototoxicity. However, from a clinical perspective it is important that the preventive inhibitors do not interfere with the antitumor activity. In conclusion, in our study we observed that hearing loss after cisplatin therapy was dose dependent, frequency dependent, and schedule dependent. We found that hearing loss after cisplatin therapy occurred mainly at cisplatin dosages greater than 60 mg/m2 and at high frequencies (4 and 8 kHz). The observed ototoxicity was more pronounced when the schedule was administered every 2 weeks compared with once every week.
The authors indicated no potential conflicts of interest.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kaufman Arenberg I: Dizziness and Balance Disorder: An Interdisciplinary Approval. New York, NY, Kugler, 1993 2. Bokemeyer C, Berger CC, Hartmann JT, et al: Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. Br J Cancer 77:1355-1362, 1998[Medline] 3. De Jongh FE, van Veen RN, Veltman SJ, et al: Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 88:1199-1206, 2003[CrossRef][Medline] 4. Planting AS, de Mulder PH, de Graeff A, et al: Phase II study of weekly high-dose cisplatin for six cycles in patients with locally advanced squamous cell carcinoma of the head and neck. Eur J Cancer 33:61-65, 1997[Medline] 5. Van der Hulst RJ, Dreschler WA, Urbanus NA: High frequency audiometry in prospective clinical research of ototoxicity due to platinum derivatives. Ann Otol Rhinol Laryngol 97:133-137, 1988[Medline] 6. Reddel RR, Kefford RF, Grant JM, et al: Ototoxicity in patients receiving cis-platinum: Importance of dose and method of drug administration. Cancer Treat Rep 66:19-23, 1982[Medline] 7. Schaefer SD, Wright CG, Post JD, et al: Cis-platinum vestibular toxicity. Cancer 47:857-859, 1981[CrossRef][Medline] 8. Strauss M, Towfighi J, Lipton A, et al: Cis-platinum ototoxicity: Clinical experience and temporal bone histopathology. Laryngoscope 93:1554-1559, 1983[CrossRef][Medline] 9. Wake M, Takeno S, Ibrahim D, et al: Carboplatin ototoxicity: An animal model. J Laryngol Otol 107:585-589, 1993[Medline] 10. Van Warmerdam LJ, Rodenhuis S, Van der Wall E, et al: Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support. Br J Cancer 73:979-984, 1996[Medline] 11. Crul M, Schoemaker NE, Pluim D, et al: Randomized phase I clinical and pharmacologic study of weekly versus twice-weekly dose-intensive cisplatin and gemcitabine in patients with advanced non-small cell lung cancer. Clin Cancer Res 9:3526-3533, 2003 12. Rademaker-Lakhai JM, Crul M, Pluim D, et al: Phase I clinical and pharmacologic study of weekly versus twice-weekly administration of cisplatin and gemcitabine in patients with advanced non-small cell lung cancer. Anticancer Drugs 16:1029-1036, 2005[CrossRef][Medline] 13. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment of cancer: National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 14. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, National Cancer Institute, Division of Cancer Treatment, 1988 15. Committee on Hearing and Equilibrium guidelines for the evaluation of results of treatment of conductive hearing loss: American Academy of Otolaryngology-Head and Neck Surgery Foundation Inc. Otolaryngol Head Neck Surg 113:186-187, 1995[CrossRef][Medline] 16. Schaefer SD, Post JD, Close LG, et al: Ototoxicity of low- and moderate-dose cisplatin. Cancer 56:1934-1939, 1985[CrossRef][Medline] 17. Montaguti M, Brandolini C, Ferri GG, et al: Cisplatin and carboplatin induced ototoxicity in children: Clinical aspects and perspectives for prevention. Acta Otorhinolaryngol 22:14-18, 2002 18. Andersson A, Fagerberg J, Lewensohn R, et al: Pharmacokinetics of cisplatin and its monohydrated complex in humans. J Pharm Sci 85:824-827, 1996[CrossRef][Medline] 19. Johnson NP, Hoeschele JD, Rahn RO: Kinetic analysis of the in vitro binding of radioactive cis- and trans-dichloro-diammineplatinum (II) to DNA. Chem Biol Interact 30:151-169, 1980[CrossRef][Medline] 20. McAlpine D, Johnstone BM: The ototoxic mechanisms of cisplatin. Hear Res 47:191-203, 1990[CrossRef][Medline] 21. Huang MY, Schacht J: Drug-induced ototoxicity: Pathogenesis and prevention. Med Toxicol Adverse Drug Exp 4:452-467, 1989[Medline] Submitted October 28, 2004; accepted November 29, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
9 dB was observed. 
) pretreatment; (
) post-treatment decibels hearing level (dB HL).
