Roadmap to a Global Template for Implementation of Ototoxicity Management for Cancer Treatment.

Ototoxicity is among the adverse events related to cancer treatment that can have far-reaching consequences and negative impacts on quality-of-life for cancer patients and survivors of all ages. Ototoxicity management (OtoM) comprises the prevention, diagnosis, monitoring, and treatment, including rehabilitation and therapeutic intervention, of individuals who experience hearing loss, tinnitus, or balance/vestibular difficulties following exposures to ototoxic agents, including platinum chemotherapy (cisplatin, carboplatin) and cranial radiation. Despite the well-established physical, socioeconomic, and psychological consequences of hearing and balance dysfunction, there are no widely adopted standards for clinical management of cancer treatment-related ototoxicity. Consensus recommendations and a roadmap are needed to guide development of effective and feasible OtoM programs, direct research efforts, address the needs of caregivers and patients at all stages of cancer care and survivorship. Here we review current evidence and propose near-term to longer-term goals to advance OtoM in five strategic areas: (1) beneficiary awareness, empowerment, and engagement, (2) workforce enhancement, (3) program development, (4) policy, funding, and sustainability, and (5) research and evaluation. The goal is to identify needs and establish a roadmap to guide worldwide adoption of standardized OtoM for cancer treatment and improved outcomes for patients and survivors.

Descriptive Characterization of High-Frequency Distortion Product Otoacoustic Emission Source Components in Children.

PURPOSE: Distortion product otoacoustic emissions (DPOAEs) provide an objective assessment of cochlear function and are used for serial ototoxicity monitoring in pediatric cancer patients. DPOAEs are modeled as having distortion (near f2) and reflection (near 2f1-f2) component sources, and developmental changes are observed in these components' relative strengths in infants compared with adults. However, little is known about source component strengths in childhood or at extended high frequencies (EHFs; > 8 kHz). Thus, the purpose of this study was to describe the effects of age and stimulus frequency on DPOAE components in children. METHOD: DPOAEs were collected with varied frequency ratios (f2/f1 = 1.1-1.25) for a wide range of frequencies (2-16 kHz) in 39 younger (3-6 years) and 41 older (10-12 years) children with constant levels (L1/L2) of 65/50 dB SPL. A depth-compensated simulator sound pressure level method of calibration was employed. A time waveform representation of the results across various ratios was created to estimate peak pressures and latencies of each DPOAE component. RESULTS: Estimated peak pressures of DPOAE components revealed the greatest differences in DPOAE sources between children occurring at the highest frequencies tested, where the peak pressure of both components was largest for younger compared with older children. Latency differences between the children were only noted at higher frequencies for the distortion component. CONCLUSIONS: These results suggest that DPOAE levels decrease with age and reflection emissions are vulnerable to cochlear change. This work guides optimization of protocols for pediatric ototoxicity monitoring, whereby including EHF otoacoustic emissions is clearly warranted and choosing to isolate DPOAE sources may prove beneficial. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.23669214.

Rethinking the clinical utility of distortion-product otoacoustic emission (DPOAE) signal-to-noise ratio.

OBJECTIVE: Distortion-product otoacoustic emission (DPOAE) levels are repeatable over time in normal-hearing individuals making DPOAE levels an ideal measurement for monitoring cochlear status in clinic and research applications. However, if DPOAE signal-to-noise ratio (SNR) values instead of levels are used for monitoring, the repeatability of this value needs to be established. This retrospective, cross-sectional study sought to determine DPOAE SNR repeatability in younger children, older children, young adults and a patient population with normal hearing. DESIGN: Each participant attended four sessions where DPOAE discrete frequency sweeps were collected at conventional (≤ 8 kHz) and/or extended-high frequencies (> 8 kHz). To examine the extent of variability to be expected for DPOAE SNR, average absolute SNR differences-between-trials were determined and compared to average absolute DPOAE level differences-between-trials. STUDY SAMPLES: One hundred forty-five participants, incorporating four different groups from three different studies. Ages ranged from 3 to 55 years. RESULTS: Average SNR differences-between-trials across all frequencies are greater than differences for average DPOAE levels. Improved calibration methods result in SNR differences-between-trials that are similar across all frequencies. CONCLUSIONS: When monitoring cochlear health over an extended bandwidth, DPOAE levels are less variable across trials than SNR values, thus allowing earlier indicators of cochlear damage.

Is jet fuel exposure associated with central auditory nervous system difficulties: An exploratory study in military personnel.

Central auditory nervous system dysfunction (CANSD) can manifest as hearing difficulty in the absence of audiometric abnormalities. Effects of noise or jet fuel exposure on the CANS are documented in animal models and humans. This study screened military personnel using the modified Amsterdam Inventory for Auditory Disability (mAIAD) to assess whether concurrent jet fuel and noise (JFN) exposures potentiate central auditory difficulties compared to noise only exposures. A total of 48 age- and sex-matched participants were recruited: 24 military bulk fuel specialists (JFN) and 24 military personnel without jet fuel exposure. All participants completed the mAIAD, the Noise Exposure Questionnaire, and basic audiological testing. Results revealed non-significant differences in pure-tone thresholds between groups, but the JFN group had higher noise exposures. Additionally, the JFN group revealed consistently lower mAIAD scores compared to the noise only group. Interestingly, a JFN stratified subgroup reporting more listening difficulty exhibited statistically significant lower mAIAD scores in the speech intelligibility in noise subdomain. These preliminary data suggest that jet fuel exposure may potentiate noise-induced CANSD, such as speech-in-noise difficulties. Such difficulties may be more prominent among specific military personnel with combined exposures. Hearing conservation programs could add CANSD screening by use of the mAIAD.

Long-Term Variability of Distortion-Product Otoacoustic Emissions in Infants and Children and Its Relation to Pediatric Ototoxicity Monitoring.

OBJECTIVE: Distortion-product otoacoustic emissions (DPOAEs) provide a rapid, noninvasive measure of outer hair cell damage associated with chemotherapy and are a key component of pediatric ototoxicity monitoring. Serial monitoring of DPOAE levels in reference to baseline measures is one method for detecting ototoxic damage. Interpreting DPOAE findings in this context requires that test-retest differences be considered in relation to normal variability, data which are lacking in children. This study sought to (1) characterize normal test-retest variability in DPOAE level over the long time periods reflective of pediatric chemotherapy regimens for a variety of childhood ages and f2 primary frequencies using common clinical instrumentation and stimulus parameters; (2) develop level-shift reference intervals; and (3) account for any age-related change in DPOAE level or measurement error that may occur as the auditory system undergoes maturational change early in life. DESIGN: Serial DPOAE measurements were obtained in 38 healthy children (25 females and 13 males) with normal hearing and ranging in age from one month to 10 years at the initial (baseline) visit. On average, children were tested 5.2 times over an observation period of 6.5 months. Data were collected in the form of DP grams, in which DPOAE level was measured for f2 ranging from 1.4 to 10 kHz, using a fixed f2/f1 ratio of 1.22 and stimulus level of 65/55 dB SPL for L1/L2. Age effects on DPOAE level and measurement error were estimated using Bayesian regression of the longitudinal data. The raw and model-based distribution of DPOAE test-retest differences were characterized using means and standard error of the measurement for several ages and f2's. RESULTS: DPOAE test-retest differences for the children in this study are at the high end of those previously observed in adults, as reflected in the associated shift reference intervals. Further, although we observe substantial child-specific variation in DPOAE level, the pattern of age-related changes is highly consistent across children. Across a wide range of f2's, DPOAE level decreases by 3 to 4 dB from 1 to 13 months of age followed by a more gradual decline of <1 dB/year. An f2 of 6 kHz shows the smallest decrease during the early rapid maturation period. DPOAE measurement error is fairly constant with age. It is 3 to 4 dB at most f2's and is greater (indicating poorer reliability) at 1.5, 8, and 10 kHz. CONCLUSIONS: DPOAE level decreases with childhood age, with the greatest changes observed in the first year of life. Maturational effects during infancy and greater measurement error at very low and high f2's affect test-retest variability in children. An f2 of 6 kHz shows minimal maturation and measurement error, suggesting it may be an optimal sentinel frequency for ototoxicity monitoring in pediatric patients. Once validated with locally developed normative data, reference intervals provided herein could be used to determine screen fail criteria for serial monitoring using DPOAEs. Employing state-of-the-art calibration techniques might reduce variability, allowing for more sensitive screen fail criteria.

High-Frequency Distortion-Product Otoacoustic Emission Repeatability in a Patient Population.

OBJECTIVES: Distortion-product otoacoustic emissions (DPOAEs) are repeatable over time at lower frequencies (≤8 kHz) and higher frequencies (>8 kHz) in healthy, normal-hearing subjects. The purpose of this study was to examine the repeatability of DPOAEs measured with high-frequency (HF) stimuli in a patient population. It was hypothesized that HF DPOAEs would be repeatable over four trials. DESIGN: DPOAEs were measured in 40 cystic fibrosis (CF) patients (17 females and 23 males) with measurable behavioral thresholds and present DPOAEs for at least 2 of the high frequencies tested (8 to 16 kHz). A depth-compensated simulator sound pressure level (SPL) method of calibration was utilized. Each patient attended four trials, in which a complete set of data were collected. At each trial, three different DPOAE paradigms were completed. First, a discrete frequency sweep was measured between 8 and 16 kHz with a ratio (f2/f1) of 1.2 and levels of 65/50 dB SPL for L1/L2. Next, ratio and level sweeps were obtained at the two highest frequencies with a present DPOAE determined from the discrete frequency sweep, and the results were used to calculate DPOAE group delay and DPOAE detection thresholds, respectively. Ratio sweeps were collected with f2/f1 varied from 1.1 to 1.3 and stimulus levels of 60/45 dB SPL (L1/L2). Level sweeps were collected with an f2/f1 of 1.22 and L2 = 50 and L1 varied between 20 and 70 dB SPL. Differences and correlations between trials, SE of the measurement, and confidence intervals were calculated, as well as a repeated-measures analysis of variance. RESULTS: DPOAE response and behavioral threshold variability in CF patients were not significantly different across four trials. It can be expected in 95% of CF patients that differences between trials of DPOAE levels, group delay, and detection thresholds and behavioral thresholds are less than 6.26 dB, 0.87 msec, 9.34 dB, and 9.60 dB, respectively. CONCLUSIONS: HF DPOAEs were repeatable across four test trials for all three paradigms measured in a group of CF patients. These results are encouraging for the measurement of HF DPOAEs to be monitored in those exposed to ototoxic agents.

Serial Monitoring of Otoacoustic Emissions in Clinical Trials.

The purpose of this report is to provide guidance on the use of otoacoustic emissions (OAEs) as a clinical trial outcome measure for pharmaceutical interventions developed to prevent acquired hearing loss secondary to cochlear insult. OAEs are a rapid, noninvasive measure that can be used to monitor cochlear outer hair cell function. Serial monitoring of OAEs is most clearly established for use in hearing conservation and ototoxicity monitoring programs in which they exhibit more frequent and earlier changes compared with pure-tone audiometry. They also show promise in recent human trials of otoprotectants. Questions remain, however, concerning the most appropriate OAE protocols to use and what constitutes a "significant" OAE response change. Measurement system capabilities are expanding and test efficacy will vary across locations and patient populations. Yet, standardizing minimal measurement criteria and reporting of results is needed including documentation of test-retest variability so that useful comparisons can be made across trials. It is also clear that protocols must be theoretically sound based on known patterns of damage, generate valid results in most individuals tested, be accurate, repeatable, and involve minimal time. Based on the potential value added, OAEs should be included in clinical trials when measurement conditions and time permit.

Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial.

Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training. Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account. While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc analyses however, further studies seem warranted and are needed to clarify dose response and the factors that may have played a role in the observed results.

Influence of ultrahigh-frequency hearing thresholds on distortion-product otoacoustic emission levels at conventional frequencies.

This study examined the association between ultrahigh-frequency (UHF) hearing sensitivity and distortion-product otoacoustic emission (DPOAE) levels at conventional frequencies. Behavioral thresholds were measured from 2 through 16 kHz, and DPOAE levels were measured at discrete f2 frequencies between 2 through 8 kHz in 553 young normal-hearing adult male participants. A DPOAE frequency sweep was measured with primary stimulus levels of L1/L2 = 65/55 dB SPL and an f2/f1 of 1.2. Significant negative correlations, although weak, were found between UHF behavioral thresholds and DPOAE levels. As UHF behavioral thresholds worsened, DPOAE levels decreased at all frequencies. When the data were categorized into two groups, "better" and "worse" UHF behavioral thresholds, significant differences were apparent between the two groups for DPOAEs. Additionally, those with better UHF thresholds had better conventional thresholds compared to those in the worse UHF threshold group. The results of this age-restricted, large-sample-size study confirm and augment findings from earlier studies demonstrating that UHF hearing sensitivity has some influence on DPOAE measures at frequencies from 2 through 8 kHz with moderate stimulus levels. However, because those with better UHF thresholds also had better conventional thresholds and the significant correlations found were weak, this work supports the importance of UHF hearing testing in conjunction with otoacoustic emission measures to identify basal cochlear insults not evident from behavioral testing at conventional frequencies.

Racial and gender effects on pure-tone thresholds and distortion-product otoacoustic emissions (DPOAEs) in normal-hearing young adults.

This study examined racial and gender effects on behavioral thresholds and distortion-product otoacoustic emissions (DPOAEs) in the same subjects. Pure-tone behavioral thresholds and DPOAEs were measured in 60 young normal-hearing adult subjects (20 Caucasian, 20 Asian, 20 African-American, with ten females and ten males in each group). Behavioral thresholds were measured from 1000 through 16,000 Hz using Békèsy tracking. A DPOAE frequency sweep was measured with primary stimulus levels of L(1)/L(2)=60/45 dB SPL, and an f(2)/f(1) of 1.2 at discrete f(2) frequencies between 2000 through 12,000 Hz for each subject. Significant racial and gender differences in behavioral thresholds were found at 14,000 and 16,000 Hz, with the African Americans and females having the best hearing sensitivity. Based on the current results, similar findings for DPOAE frequency sweeps can be expected amongst different racial groups given that no significant differences were identified between the groups. To further define the effects of race and gender on auditory measures, future studies should include larger numbers of subjects, measurement of body size and middle ear reflectance, and examine emission generators.

Risk factors for distortion product otoacoustic emissions in young men with normal hearing.

The purpose of this study was to evaluate the possible effects of risk factors on distortion product otoacoustic emissions (DPOAEs) in young adult men with normal hearing. Four hundred thirty-six United States Marine recruit men (mean age = 19.2 years +/- 1.8 years; age range = 17-29 years) participated in this study. Questionnaires were given to each recruit to obtain demographic data and history of noise exposure, solvent exposure, smoking history, and hearing-related histories. Otoscopy, tympanometry, pure-tone air-conduction audiometry (2.0-8.0 kHz) and DPOAEs (2.3-8.0 kHz) were measured. DPOAE levels were lower in Not Hispanic or Latino recruits, in heavy smokers, in recruits who reported loud live music exposure and ringing in their ears after noise exposure. These differences were not statistically significant at all frequencies. Recruits with multiple risk factors had the lowest DPOAEs as compared to recruits with fewer, or no, risk factors; these differences were not statistically significant. Obtaining risk factor data as part of an audiometric evaluation is important even though the individual may have normal hearing.

Repeatability of high-frequency distortion-product otoacoustic emissions in normal-hearing adults.

OBJECTIVES: Distortion-product otoacoustic emissions (DPOAEs) are repeatable over time at lower frequencies (8 kHz) for DPOAE level measurements. The average DPOAE level differences-between-trials for the higher and lower frequencies for the four different stimulus level conditions was 5.15 (SD = 4.40 dB) and 2.80 (SD = 2.70 dB) dB, respectively. Individual subject analysis revealed that high-frequency DPOAE levels varied no more than 10 dB for 87.5 and 83.1% of young adult subjects for the 70/55 and 60/50 dB SPL stimulus level conditions, respectively. For low frequencies, repeated DPOAE level variations were within +/-10 dB for 98.4 and 96% of young adult subjects for the 70/55 and 60/50 dB SPL stimulus level conditions, respectively. For DPOAE group delay, greater variability was noted at lower frequencies (

Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music.

Antioxidants have been reported to be effective in reducing acoustic trauma in animal models but have not been studied in humans. In this study, the antioxidant N-acetylcysteine (NAC) was evaluated to determine if it would reduce temporary changes in auditory function as a result of exposure to loud music in humans. Pure-tone thresholds and distortion product otoacoustic emissions (DPOAEs) were collected in 31 normal-hearing participants, using a randomized, double-blind, placebo-controlled design, before and after two hours of live music in a nightclub. Using repeated measures analysis of variance, no statistically significant differences were found between participants who received NAC versus a placebo for any of the outcome measures. Across all subjects, the largest pure-tone threshold shift occurred at 4 kHz. DPOAE measures were characterized by reductions in amplitude and a trend for shorter group delay values. When the 3 and 4 kHz data were examined by imposing specific criteria of greater than 2 dB DPOAE amplitude reductions and 10 dB or greater pure-tone threshold shifts, DPOAE reductions occurred more often at 3 kHz, and pure-tone shifts occurred more often at 4 kHz.

Perception of spectral contrast by hearing-impaired listeners.

The ability to discriminate the spectral shapes of complex sounds is critical to accurate speech perception. Part of the difficulty experienced by listeners with hearing loss in understanding speech sounds in noise may be related to a smearing of the internal representation of the spectral peaks and valleys because of the loss of sensitivity and an accompanying reduction in frequency resolution. This study examined the discrimination by hearing-impaired listeners of highly similar harmonic complexes with a single spectral peak located in 1 of 3 frequency regions. The minimum level difference between peak and background harmonics required to discriminate a small change in the spectral center of the peak was measured for peaks located near 2, 3, or 4 kHz. Component phases were selected according to an algorithm thought to produce either highly modulated (positive Schroeder) or very flat (negative Schroeder) internal waveform envelopes in the cochlea. The mean amplitude difference between a spectral peak and the background components required for discrimination of pairs of harmonic complexes (spectral contrast threshold) was from 4 to 19 dB greater for listeners with hearing impairment than for a control group of listeners with normal hearing. In normal-hearing listeners, improvements in threshold were seen with increasing stimulus level, and there was a strong effect of stimulus phase, as the positive Schroeder stimuli always produced lower thresholds than the negative Schroeder stimuli. The listeners with hearing loss showed no consistent spectral contrast effects due to stimulus phase and also showed little improvement with increasing stimulus level, once their sensitivity loss was overcome. The lack of phase and level effects may be a result of the more linear processing occurring in impaired ears, producing poorer-than-normal frequency resolution, a loss of gain for low amplitudes, and an altered cochlear phase characteristic in regions of damage.

Level dependence of distortion-product otoacoustic emissions measured at high frequencies in humans.

Given that high-frequency hearing is most vulnerable to cochlear pathology, it is important to characterize distortion-product otoacoustic emissions (DPOAEs) measured with higher-frequency stimuli in order to utilize these measures in clinical applications. The purpose of this study was to explore the dependence of DPOAE amplitude on the levels of the evoking stimuli at frequencies greater than 8 kHz, and make comparisons with those data that have been extensively measured with lower-frequency stimuli. To accomplish this, DPOAE amplitudes were measured at six different f2 frequencies (2, 5, 10, 12, 14, and 16 kHz), with a frequency ratio (f2/f1) of 1.2, at five fixed levels (30 to 70 dB SPL) of one primary (either f1 or f2), while the other primary was varied in level (30 to 70 dB SPL). Generally, the level separation between the two primary tones (L1 > L2) generating the largest DPOAE amplitude (referred to as the "optimal level separation") decreased as the level of the fixed primary increased. Additionally, the optimal level separation was frequency dependent, especially at the lower fixed primary tone levels ( < or = 50 dB SPL). In agreement with previous studies, the DPOAE level exhibited greater dependence on L1 than on L2.

Acoustic reflexes to Schroeder-phase harmonic complexes in normal-hearing and hearing-impaired individuals.

Harmonic complexes generated with positive or negative Schroeder-phases may result in differences in cochlear excitation, even though their long-term spectra and amplitudes are equal. As a measure of possible differences in cochlear excitation resulting from these harmonic complexes, thresholds and growth of the acoustic reflex were assessed in normal-hearing and hearing-impaired subjects. Harmonic complexes with fundamental frequencies of 50, 100, and 200 Hz were constructed with positive and negative-Schroeder phases. In normal-hearing subjects, acoustic reflex thresholds for the 50- and 100-Hz fundamental waveforms were typically lower for negative Schroeder-phase complexes than for positive Schroeder phase stimuli. At the highest fundamental frequency of 200 Hz, there were no significant threshold differences due to phase. Hearing-impaired subjects showed a similar pattern for thresholds between the two phase selections, but with smaller differences than those observed in normal-hearing subjects. At levels above reflex threshold, the magnitude of the acoustic reflex was greater for the negative-phase than the positive-phase stimuli for the lowest fundamental frequency, but no significant differences were observed at fundamental frequencies of 100 and 200 Hz. These results are consistent with generally greater cochlear excitation in response to negative than to positive Schroeder-phase stimuli when the fundamental frequency is sufficiently low. Increased excitation may reflect a synchronization of response across a wide band of frequencies in the cochlea when the rate of frequency sweep within periods of these harmonic complexes is appropriately matched to timing characteristics of the traveling wave.