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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1190-1195 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9723 Early Changes in Auditory Function As a Result of Platinum Chemotherapy: Use of Extended High-Frequency Audiometry and Evoked Distortion Product Otoacoustic Emissions
From the Department of Pediatric Audiology, Department of Pediatrics, and Office of Program Evaluation and Research, Child Development and Rehabilitation Center; Department of Pharmacy Practice, College of Pharmacy; Department of Medical Informatics and Clinical Epidemiology and Department of Public Health and Preventive Medicine, College of Medicine; Department of Neurology; Department of Neurosurgery, Oregon Health and Science University; and the Veterans Administration Medical Center, Portland, Oregon Address reprint requests to Edward A. Neuwelt, MD, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, L603, Portland, OR 97201; e-mail: neuwelte{at}ohsu.edu
Purpose: The objective is to describe progressive changes in hearing and cochlear function in children and adolescents treated with platinum-based chemotherapy and to begin preliminary evaluation of the feasibility of extended high-frequency audiometry and distortion product otoacoustic emissions for ototoxicity monitoring in children. Patients and Methods: Baseline and serial measurement of conventional pure-tone audiometry (0.5 to 8 kHz) and evoked distortion product otoacoustic emissions (DPOAEs) were conducted for 32 patients age 8 months to 20 years who were treated with cisplatin and/or carboplatin chemotherapy. Seventeen children also had baseline and serial measurement of extended high-frequency (EHF) audiometry (9 to 16 kHz). Audiologic data were analyzed to determine the incidence of ototoxicity using the American Speech-Language-Hearing Association criteria, and the relationships between the different measures of ototoxicity. Results: Of the 32 children, 20 (62.5%) acquired bilateral ototoxicity in the conventional frequency range during chemotherapy treatment, and 26 (81.3%) had bilateral decreases in DPOAE amplitudes and dynamic range. Of the 17 children with EHF audiometry results, 16 (94.1%) had bilateral ototoxicity in the EHF range. Pilot data suggest that EHF thresholds and DPOAEs show ototoxic changes before hearing loss is detected by conventional audiometry. Conclusion: EHF audiometry and DPOAEs have the potential to reveal earlier changes in auditory function than conventional frequency audiometry during platinum chemotherapy in children.
Children treated with platinum chemotherapy are at risk for acquiring permanent sensorineural hearing loss.1,2 Cisplatin is more ototoxic than carboplatin; however, with increased drug intensity or in sensitive populations, carboplatin is also ototoxic.3 Children treated with cisplatin and carboplatin frequently acquire communicatively significant hearing loss.4,5 Platinum ototoxicity is related to the individual and cumulative treatment doses.1,6 Being younger than 5 years at treatment and having kidney dysfunction and concomitant treatment with other ototoxic medications increase a child's risk for ototoxicity.1,4 Even when controlling for these factors, there is significant individual variability in susceptibility to platinum ototoxicity, and hearing loss cannot be predicted based on the platinum dose or plasma concentration.7 Ototoxicity must be monitored for each individual patient. The standard method for ototoxicity monitoring is the baseline and serial measurement of pure-tone hearing thresholds within the conventional frequency range, 0.25 to 8 kHz. Extended high-frequency (EHF) audiometry and evoked otoacoustic emissions (OAEs) are audiologic tests that are more sensitive to initial ototoxic damage.8-11 EHF audiometry10 and OAEs9,12 may detect changes in hearing or auditory function before ototoxicity affects hearing at frequencies important for speech recognition. EHF audiometry is the measurement of pure-tone thresholds at frequencies higher than 8 kHz. Platinum ototoxicity initially affects the sensory cells within the basal region of the cochlea,13 where high-frequency sounds are processed and changes in hearing are usually first detected in the highest audible frequencies. Measurement of OAEs provides an objective evaluation of the cochlear outer hair cell system.14 The outer hair cells are among the first inner ear structures damaged by platinum drugs,15 and early changes in OAEs may reflect subclinical cochlear damage that could progress to hearing loss if ototoxic treatment is continued.16 When middle-ear function is normal, the amplitude of recorded energy (OAE) reflects the functional status of the cochlea.14 Distortion product otoacoustic emissions (DPOAEs) are stable during 4 to 12 weeks in healthy young adults with normal hearing.17-19 Changes in outer hair cell function are seen as decreases in DPOAE amplitudes, decreases in the dynamic range of the response (signal-to-noise ratio), and/or loss of DPOAEs, specific to regions of outer hair cell damage.14 DPOAEs and hearing thresholds are negatively correlated—a decrease in DPOAE level is correlated with an increase in hearing level. Conventional audiometry, EHF audiometry, and DPOAEs have been studied simultaneously in adults treated with cisplatin.11 The purpose of this study was to evaluate the feasibility of EHF audiometry and DPOAEs for ototoxicity monitoring in children and to begin comparisons among audiologic tests to determine if changes in EHF thresholds and/or DPOAEs occur earlier than in conventional audiometry. We hypothesized that earlier changes in EHF and/or DPOAEs may identify children who would subsequently develop hearing loss in the conventional frequencies.
Patients Between February 2001 and July 2005, the Department of Pediatric Oncology at Doernbecher Children's Hospital, Oregon Health and Science University (Portland, OR), referred 79 children and adolescents scheduled to receive platinum chemotherapy to the pediatric audiology clinic for ototoxicity monitoring. The first author reviewed (K.K.) the audiologic and medical records retrospectively. The institutional review board at the university approved this study. Before March 2002, EHF testing was not part of the pediatric monitoring protocol, and DPOAEs were not routinely measured in patients with complete behavioral audiometric results. Children seen before March 2002 were excluded because of a lack of EHF and/or DPOAE data. Thirty-four children had a baseline evaluation and at least two monitoring evaluations, including conventional audiometry and DPOAEs. However, two children did not have a baseline evaluation until after the second cisplatin treatment and, therefore, were excluded from these analyses. Data was evaluated for the remaining 32 patients, with 17 completing EHF audiometry. The children were between the age of 8 months and 20 years at their baseline hearing evaluation. They were treated according to Children's Oncology Group protocols for medulloblastoma (n = 13), neuroblastoma (n = 6), osteosarcoma (n = 4), germ cell tumor (n = 3), hepatoblastoma (n = 2), primitive neuroectodermal tumor of the CNS (n = 1), astrocytoma of the spinal cord (n = 1), adrenocortical carcinoma (n = 1), and Wilms’ tumor (n = 1). Twenty-one children were treated with cisplatin, 10 received cisplatin and carboplatin sequentially, and one was treated with high-dose carboplatin. Ten patients with medulloblastoma had cranial radiation before platinum chemotherapy. The platinum dose and treatment schedule varied according to the child's tumor type and treatment protocol. One child, patient 32, had a history of prior chemotherapy that did not include platinum. Table 1 presents the patient characteristics.
Audiologic Evaluations Baseline evaluations were conducted before the first platinum treatment in 28 children. Four children had baseline evaluation after the first platinum treatment but before the second treatment. These evaluations were normal and were used as the baseline for comparisons to monitoring evaluations. Audiologic evaluations included otoscopy, tympanometry, pure-tone audiometry (0.5, 1, 2, 3, 4, 6, and 8 kHz), and recording DPOAEs. Pure-tone thresholds were measured using visual reinforcement audiometry, conditioned play audiometry, or standard methods, depending on the child's age and development. EHF thresholds (9, 10, 11.2, 12.5, 14, and 16 kHz) were measured in patients who were able to complete the assessment and who had reliable responses. Limited attention, poor cooperation, and poor response reliability precluded successful EHF testing in children younger than 5 years. DPOAEs corresponding to the frequency 2f1-f2 were recorded as DP-grams (11 log-spaced f2 frequencies between 1453 and 8438 at 4 points per octave); f1 = 65 dB sound pressure level (SPL), f2 = 55 dB SPL, f2/f1 = 1.22. Evoked auditory brainstem responses (ABR) were used to estimate baseline hearing thresholds in five children age 8 to 23 months who could not be tested with behavioral audiometry because of illness or noncooperation. ABR thresholds (0.5, 1, 2, and 4 kHz) were determined within 5 dB nHL. Appendix 1 (online only) provides a detailed discussion of the audiologic methods. The children had between 2 and 10 monitoring evaluations (mean 5.9), generally within 24 hours before platinum chemotherapy cycles. Children were monitored until completion of platinum chemotherapy. Test procedures, instrumentation, and parameters for monitoring evaluations were identical to the baseline evaluation, with the exception of the five children that had baseline evaluation by ABR. These five children were monitored with behavioral audiometry and DPOAEs. ABRs were repeated only when a significant threshold shift at 0.5 to 4 kHz was indicated by changes in behavioral response thresholds and/or loss of DPOAEs.
Determination of Ototoxicity There is no universally accepted criterion for ototoxic change in DPOAEs. For the purposes of this study, decreases in DPOAE greater than 8 dB SPL were considered a significant clinical change, based on the work of Beattie et al19 who reported that differences in DPOAE amplitudes must exceed 7 dB SPL at 1 to 4 kHz to be statistically significant at the 0.05 level of confidence. Changes meeting this criterion were categorized as ototoxic only when changes were consistent or showed further decreases on subsequent evaluations.
Determination of Severity of Hearing Loss
Statistical Methods Descriptive statistics summarized baseline characteristics of the patients. The primary analyses considered time as estimated by the number of chemotherapy treatments until an ototoxic change was observed. For each assessment (conventional audiometry, EHF audiometry, and DPOAEs), the time to ototoxic change was determined, and for patients in whom such a change was not observed, the data were censored at the last observation. As the time to ototoxic change is known to exceed the time of the last observation, but the exact time is unknown, the patient contributed ototoxic-free time to the estimated time to ototoxicity only up to the last obervation. Kaplan-Meier estimates of the times to ototoxic change were plotted for each assessment. A log-rank test, often used for censored data, is not relevant for these data as the different assessments on the same patient at the same time are paired and not independent. To compare which assessment detected ototoxic change earlier, each pair of assessments was compared using the Wilcoxon signed rank test (as the times are discrete with relatively few values). Two analyses were performed: the first ignored the censoring, and the second adjusted for times that were tied between the two assessments when there was ototoxic change in one test but not the other. The adjustment added 0.5 to the time that was censored but not to the time to ototoxic change. To adjust for multiple comparisons among three sets of pairwise tests, a Bonferroni-adjusted significance level of 0.0167 was used for each comparison. Cox proportional hazards regression models were also fit to these data to determine if ototoxic changes in DPOAEs or EHF were predictive of later ototoxicity in conventional frequencies. The presence of ototoxic changes in the potential predictor was included in the model as a time-dependent covariate. The value of the potential predictor was initially zero, and if ototoxic change was detected in the predictor, the value of the covariate changed to one. All tests of hypotheses in this report should be viewed as descriptive rather than definitive. For this patient series, there were no a priori hypotheses and no a priori power calculations. Therefore, these results suggest hypotheses for future study.
At baseline, all 32 children had normal hearing sensitivity in the conventional audiologic frequencies, normal middle ear function, and measurable DPOAEs. In the conventional frequencies, bilateral ototoxicity occurred in 20 (62.5%) of 32 patients. Four additional patients had ototoxic threshold shifts in one ear only. The group mean conventional frequency thresholds at baseline and at completion of treatment are shown in Figure 1. Of the patients who acquired conventional frequency hearing loss, 10 were treated with cisplatin, nine received cisplatin and carboplatin, and one had high-dose carboplatin. There were 13 children in this series that were 5 years or younger at the time of treatment, and 10 of these acquired bilateral conventional frequency hearing loss. Ten children had dose reductions of cisplatin during treatment because of ototoxicity. The Brock's hearing loss grades and the CTCAE ototoxicity grades are reported in Table 1.
DPOAEs were decreased bilaterally relative to baseline in 26 (81.2%) of 32 children. Two other children had reduced DPOAEs in one ear only. Figure 2 shows the group mean DPOAEs at baseline and at completion of treatment. DPOAEs were affected in every child who acquired conventional frequency hearing loss. Two patients had decreased DPOAEs in both ears without bilateral hearing loss in the conventional frequencies.
Seventeen patients completed EHF audiometry. In the EHF range, bilateral ototoxicity occurred in 16 (94.12%) of 17 patients. Of the 17 patients who were monitored with all three measures, DPOAEs were decreased bilaterally in 11 (64.71%), and bilateral conventional frequency hearing loss occurred in eight (47.06%). The eight patients with conventional frequency ototoxicity also had ototoxicity in EHF thresholds and DPOAEs. One patient (patient 9) did not have changes in either ear by any of these three measures. Figure 3 shows the group mean EHF thresholds at baseline and at the end of treatment.
The number of courses until ototoxic changes between each pair of assessments (among conventional, EHF, and DPOAE) were compared, and the results are summarized in Table 3. All comparisons were statistically significant using the Bonferroni-adjusted significance level. More patients had ototoxic changes earlier in DPOAEs than conventional audiometry, EHF than conventional audiometry, and EHF than in DPOAEs (Table 3). When adjustments were made for patients in whom there were ototoxic changes in one assessment and no change in the other, both at the same final audiology assessments, there was little change in the conclusion. The P values for the Wilcoxon signed rank test are .0127 for comparing conventional and DPOAE, .0002 for comparing conventional and EHF, and .0034 for comparing DPOAE and EHF.
When ototoxic change in DPOAE or in EHF was included in Cox proportional hazards regression models (separate models for DPOAE and EHF) as time-dependent covariates to predict number of courses to conventional frequency ototoxicity, neither was statistically significant. The estimated hazard ratios were 2.53 for DPOAE (95% CI, 0.90 to 7.10; P = .077) and 3.89 for EHF (95% CI, 0.69 to 21.8; P = .123).
Changes in hearing and auditory function were reviewed in 32 children and adolescents treated with cisplatin and/or carboplatin chemotherapy. DPOAEs and conventional audiometry were measured in 32 children, and EHF audiometry was measured in a subset of 17 patients. The trend is that ototoxic changes occurred first in EHF thresholds, then in DPOAEs, and last in the conventional audiologic thresholds. The small number of patients studied likely affected the lack of significance using time-dependent covariate analysis. Every child who acquired conventional frequency hearing loss also had ototoxic changes in DPOAEs, as well as in EHF thresholds when they were measured. Ten children had cisplatin dose reductions during treatment because of ototoxicity. Had the dose of cisplatin not been reduced after ototoxicity was detected, the severity of hearing loss may have been greater. EHF audiometry provided the earliest indication of ototoxicity in this series, and EHF testing was feasible and reliable in children who were 5 years and older. There were no instances in which conventional frequency thresholds changed before EHF thresholds. Unfortunately, it is difficult to obtain EHF results in very young children, a population for whom hearing loss is a particular concern as they are in the process of speech and language acquisition and are at greatest risk for platinum-induced hearing loss.1 DPOAEs are especially valuable for monitoring ototoxicity in very young children who may not consistently provide reliable, complete, ear-specific pure-tone threshold responses. The measurement of DPOAEs is objective and noninvasive and does not require the child's active participation. Unfortunately, DPOAEs cannot be measured in the presence of middle ear pathology or in a child who is crying, vocalizing, moving, or trying to remove the sound probe from his or her ear. Two children in this series had middle ear pathology during treatment, and DPOAEs could not be validly measured until the middle ear pathology resolved (six monitoring evaluations). DPOAEs could not be measured at 10 of 188 monitoring evaluations because of patient activity level or noncooperation. Criteria for ototoxic change in DPOAEs have not been determined. The DPOAE ototoxicity criteria used for this study were based on studies of DPOAE variability in healthy young adults.17,19 DPOAEs may be more variable in children. Additionally, patients in this study were followed during a longer period of time than in the adult variability studies. We attempted to control for this by categorizing DPOAE changes as ototoxic only when changes were consistent or worse on subsequent evaluations. Future studies would benefit from having DPOAEs from a control group of age-matched children who are tested over a similar schedule and duration. Only 15 children in this series had monitoring evaluations before every platinum cycle. The time to ototoxic change may have been overestimated in patients who received two or more platinum treatments between hearing evaluations since a clinically significant change may have occurred earlier than was detected. In all but three cases analyzed, this would not have qualitatively changed the results, since ototoxic change still preceded a change in the comparative assessment. In each of the three other cases, ototoxic change occurred in conventional audiometry before the DPOAEs. However, DPOAEs were missing from some evaluations, and therefore, the DPOAEs may have changed at the same time as, or earlier than, the conventional frequencies. The comparisons of the DPOAEs and conventional audiometry could, potentially, be more different than reported. The audiologic methods described in this study are standard monitoring protocols used in our clinic. Measurement of EHF thresholds is typically completed within 10 minutes, and DPOAEs are usually recorded within 5 minutes. Conventional audiometry and DPOAEs should be available at most facilities where children receive cancer care. EHF instrumentation may be less widely available. Hearing can be evaluated in children of all ages while they are receiving chemotherapy treatment, without disrupting their cancer care. Audiologic monitoring provides information about the onset of hearing loss, and when dose modifications are allowed, can avoid communicatively significant hearing loss. When treatment cannot be altered, early detection of hearing loss allows for rehabilitative services to be implemented, helping maintain children's quality of life. At this time no clinical measures can identify patients who are more susceptible to ototoxicity from platinum chemotherapy. Future studies evaluating a larger number of patients with complete audiologic evaluations after every platinum cycle could evaluate if early DPOAE or EHF changes identify children who are at greater risk for acquiring ototoxicity in the conventional frequencies, as suggested by these patients. The hazard ratios estimated from this case series were large (2.53 for DPOAE and 3.89 for EHF) but failed to achieve statistical significance. Assuming a 5% significance level, 80% power, and proportional hazards, hazard ratios of 2.0, 2.5, 3.0, and 3.5 would require sample sizes of 126, 74, 52, and 42, respectively (NCSS/PASS, 2000; NCSS Statistical Software, Kaysville, UT). For 90% power, the respective required sample sizes would be 170, 100, 68, and 56. Several agents are being studied for their potential to prevent or reduce ototoxicity.15,22 If EHF audiometry or DPOAEs identify children at greater risk for platinum ototoxicity, it may be possible to adjust treatment or use a protective agent to avoid communicatively significant hearing loss.
The authors indicated no potential conflicts of interest.
Conception and design: Kristin R. Knight, Christiane Winter, Edward A. Neuwelt Provision of study materials or patients: Kristin R. Knight Collection and assembly of data: Kristin R. Knight, Christiane Winter Data analysis and interpretation: Kristin R. Knight, Dale F. Kraemer, Edward A. Neuwelt Manuscript writing: Kristin R. Knight, Dale F. Kraemer, Christiane Winter Final approval of manuscript: Kristin R. Knight, Edward A. Neuwelt
Audiologic evaluations were conducted by licensed, certified audiologists. Assessments were conducted within single-walled, sound-treated audiologic booths (American National Standards Institute S3.1-1999). Clinical equipment calibrated according to the guidelines of the American Speech-Language-Hearing Association, following American National Standards Institute S3.6-2004. Conventional pure-tone thresholds (0.5, 1, 2, 3, 4, 6, and 8 kHz) were measured using an Interacoustics IA AC 40 (Interacoustics, Assens, Denmark) or a Maico MA 41 (Maico Diagnostics, Eden Prairie, MN) clinical audiometer. Standard pure-tone audiometry was used to evaluate hearing in patients older than 6 years. Conditioned play audiometry was used to measure pure-tone thresholds for children whose age and development was between 30 months to 6 years. Visual reinforcement audiometry was performed for children whose age and development was between 8 and 30 months. Pure-tone thresholds were measured within 5 dB HL using the standard modified Hughson-Westlake technique. A team of two audiologists usually evaluated children younger than 4 years of age; one audiologist was located at the audiometer and controlled the visual reinforcement system, and the other clinician was seated in the test room with the child and parent. The second clinician provided assistance in maintaining the child's interest and attention. Insert earphones (EAR 3A, Etymotic Research, Elk Grove, IL) or circumaural headphones (TDH-39; OTOVATION, King of Prussia, PA) were used for testing all patients, except four children younger than 18 months who would not tolerate headphones or earphones and were instead evaluated using a calibrated soundfield speaker system. Bone conduction thresholds (0.5, 1, 2, and 4 kHz) were measured at baseline if a child had pre-existing hearing loss (defined as any threshold greater than 20 dB HL 0.5 to 8 kHz). Bone conduction thresholds were measured at monitoring evaluations whenever there was a significant threshold shift at 0.5, 1, 2, or 4 kHz (n = 16 patients). EHF thresholds (9, 10, 11.2, 12.5, 14, and 16 kHz) were measured using the Interacoustics IA-AC40 clinical audiometer (Interacoustics) and Sennheiser HAD-200 headphones (Sennheiser Electronic Corp, Old Lyme, CT) in 17 children and adolescents who were able to participate in the assessment and who had reliable test-retest responses. In this series, children who were 5 years and older met this criteria. Limited attention, poor cooperation, and poor test-retest reliability precluded valid measurement of EHF audiometry in children younger than 5 years. Of the 15 patients without EHF testing, 13 were younger than 5 years of age. The other two patients did not have EHF testing because of poor cooperation in one 5-year-old patient and because of very limited attention in a 15-year-old patient who had acquired brain injury after surgical resection of his brain tumor. To ensure response reliability, measurement of pure-tone air conduction thresholds at 2 and 8 (and 12.5 kHz in the children tested by EHF audiometry) were repeated in both ears at the baseline evaluation. Responses were considered reliable if retest thresholds did not exceed 5 dB or greater of the previously measured responses. The response reliability check was repeated whenever there was a significant threshold shift. Only tests meeting the response reliability criteria were included in this analysis. DPOAEs were measured using a Bio-Logic Scout AuDX system (Bio-Logic Systems Corp, Mundelein, IL). DPOAEs corresponding to the frequency 2f1-f2 were recorded as DP-grams (11 log-spaced f2 frequencies between 1453 and 8438 at 4 points per octave); f1 = 65 dB SPL, f2 = 55 dB SPL, and f2/f1 = 1.22. Stimuli were calibrated within the ear canal before each measurement, and noise levels within the ear canal were monitored. Individual DPOAE data points were excluded if the noise level exceeded 0 dB SPL and the signal-to-noise ratio was less than 6 dB SPL (n = 6 tests, at the lowest DPOAE test frequency only). DPOAE data could not be collected at 10 monitoring evaluations because of excessive patient noise or activity level. Immittance measurements were obtained using a GSI-33, version 2, middle ear analyzer (Grason-Stadler Inc, Viasys Healthcare, Madison, WI). Tympanograms were measured with a 226-Hz probe frequency at a sweep pressure of –400 to +300 daPa. Normal middle ear pressure was defined as –100 to +100 daPa, and normal middle ear compliance was determined as 0.2 mmho or greater. The results of otoscopy, tympanometry, and bone conduction audiometry were used to evaluate for conductive middle ear pathology. If a child was found to have abnormal middle ear function and/or conductive hearing loss, the corresponding audiologic results were excluded from the analysis (n = 6 monitoring evaluations in two patients). Evoked ABR and DPOAEs were used to evaluate auditory function and estimate baseline hearing thresholds in five children age 8 to 23 months who were not able to participate in behavioral audiometry because of their illness or noncooperation. The Oregon Health and Science University sedation services team provided intravenous pediatric sedation for the ABR studies. ABRs were recoded using a Bio-Logic Navigator Pro, Version 6.1 (Bio-Logic Systems Corp). Silver disc electrodes were placed on the high forehead (noninverting), mastoid or earlobe (inverting), and chest (ground). Air conduction stimuli were presented through EAR 3A insert earphones (Etymotic Research, Elk Grove, IL). Neurodiagnostic ABRs were recorded in response to 70-dB rarefaction and condensation click stimuli at rates of 21.7 cycles per second (c/s). ABR thresholds were measured in response to alternating polarity frequency specific tone burst stimuli (0.5, 1, 2, and 4 kHz) gated using a Blackman window. Stimulus rates were 31.1 c/s for 0.5 kHz stimuli and 39.7 c/s for 1-, 2-, and 4-kHz stimuli. Responses were filtered between 100 and 3000 Hz for clicks and 30 and 1,500 Hz for tone bursts. For the click stimulus, 0 dB nHL was 35 dB peak SPL. For air conduction tone burst stimuli, 0 dB nHL was 35 dB peak SPL at 0.5 kHz, 25 dB peak SPL at 1 kHz, 27 dB peak SPL at 2 kHz, and 27 dB peak SPL at 4 kHz. Thresholds were determined as the lowest intensity level, within 5 dB nHL, at which detectable, repeatable wave V responses were obtained. Monitoring evaluations consisted of behavioral assessment (visual reinforcement audiometry) and measurement of DPOAEs. ABRs were repeated when a significant threshold shift at frequencies 0.5 to 4 kHz was indicated by changes in behavioral response thresholds and/or loss of DPOAE responses. Decreases in hearing were considered significant for ototoxicity only when ASHA ototoxicity criteria was met, the patient had no indication of middle ear pathology, and decreases in thresholds were confirmed by repeat testing.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Li Y, Womer RB, Silber JH: Predicting cisplatin ototoxicity in children: The influence of age and the cumulative dose. Eur J Cancer: 40:2445-2451, 2004[CrossRef][Medline] 2. Montaguti M, Brandolini C, Ferri GG, et al: Cisplatin and carboplatin-induced ototoxicity in children: Clinical aspects and perspectives for prevention. Acta Otorhinolaryngol Ital 22:14-18, 2002[Medline] 3. Macdonald RM, Harrison RV, Wake M, et al: Ototoxicity of carboplatin: Comparing animal and clinical models at the Hospital for Sick Children. J Otolaryngo l23:151-159, 1994 4. Parsons SK, Neault MW, Lehmann LE, et al: Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant 22:669-674, 1998[CrossRef][Medline] 5. Bertolini P, Lassalle M, Guilaine M, et al: Platinum compound-related ototoxicity in children: Long-term follow-up reveals continuous worsening of hearing loss. Pediatr Hematol Oncol 26:649-655, 2004 6. Brock PR, Bellman SC, Yeomans EC, et al: Cisplatin ototoxicity in children: A practical grading system. Med Pediatr Oncol 19:295-300, 1991[Medline] 7. Lanvers-Kaminsky C, Krefeld B, Dinnesen AG, et al: Continuous or repeated prolonged cisplatin infusions in children: A prospective study on ototoxicity, platinum concentrations, and standard serum parameters. Pediatric Blood and Cancer 47:183-193, 2006 8. Campbell K: Ototoxicity: Understanding oxidative mechanisms. J Am Acad Audiol 14:121-123, 2003[Medline] 9. Lonsbury-Martin BL, Martin GK: Evoked otoacoustic emissions as objective screeners for ototoxicity. Seminars in Hearing 22:377-391, 2001 10. Fausti SA, Larson VD, Noffsinger D, et al: High frequency audiometric monitoring strategies for early detection of ototoxicity. Ear Hear 15:232-239, 1994[Medline] 11. Ress BD, Sridhar KS, Balkany TJ, et al: Effects of cis-platinum chemotherapy on otoacoustic emissions: The development of an objective screening protocol. Otolaryngology – Head and Neck Surgery 121:693-701, 1999 12. Littman TA, Magruder A, Strother DR: Monitoring and predicting ototoxic damage using distortion-product otoacoustic emissions: Pediatric case study. J Am Acad Audiol 9:257-262, 1998[Medline] 13. Wright CG, Schaefer SD: Inner ear histopathology in patients treated with cisplatin. Laryngoscope 92:1408-1413, 1982[Medline] 14. Gorga MP, Neely ST, Bergman B, et al: Otoacoustic emissions from normal-hearing and hearing-impaired subjects: Distortion product responses. J Acoust Soc Am 93:2050-2060, 1993[CrossRef][Medline] 15. Rybak LP, Whitworth CA: Ototoxicity: Therapeutic opportunities. Drug Discovery Today 10:1313-1321, 2005[CrossRef][Medline] 16. Leigh-Paffenroth E, Reavis KM, Gordon JS, et al: Objective measures of ototoxicity. ASHA Special Interest Division 6, Hearing and Hearing Disorders: Research and Diagnostics 9:10-16, 2005 17. Franklin DJ, McCoy MJ, Martin GK, et al: Test/retest reliability of distortion product and transiently evoked otoacoustic emissions. Ear Hear 15:232-239, 1992 18. Shehata-Dieler WE, Dieler R, Teichert K, et al: Intra- and intersubject variability of acoustically evoked otoacoustic emissions II. Distortion product otoacoustic emissions. Laryngorhinootologie 78:345-350, 1999[Medline] 19. Beattie RC, Kenworthy OT, Luna CA: Immediate and short-term reliability of distortion-product otoacoustic emissions. International Journal of Audiology 42:348-354, 2003[Medline] 20. American Speech-Language-Hearing Association: Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA 36:11-19, 1994 (suppl 12) 21. National Cancer Institute: Common Terminology Criteria for Adverse Events, version 3.0, 2006. http://ctep.cancer.gov/forms/CTCAEv3.pdf 22. Blakley BW, Cohen JI, Doolittle ND, et al: Strategies for prevention of toxicity caused by platinum-based chemotherapy: Review and summary of the annual meeting of the blood-brain barrier disruption program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope, 112: 1997-2001, 2002[CrossRef][Medline] Submitted June 20, 2006; accepted December 20, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
