Ototoxicity prognostic models in adult and pediatric cancer patients: a rapid review.

PURPOSE: A cornerstone of treatment for many cancers is the administration of platinum-based chemotherapies and/or ionizing radiation, which can be ototoxic. An accurate ototoxicity risk assessment would be useful for counseling, treatment planning, and survivorship follow-up in patients with cancer. METHODS: This systematic review evaluated the literature on predictive models for estimating a patient's risk for chemotherapy-related auditory injury to accelerate development of computational approaches for the clinical management of ototoxicity in cancer patients. Of the 1195 articles identified in a PubMed search from 2010 forward, 15 studies met inclusion for the review. CONCLUSIONS: All but 1 study used an abstraction of the audiogram as a modeled outcome; however, specific outcome measures varied. Consistently used predictors were age, baseline hearing, cumulative cisplatin dose, and radiation dose to the cochlea. Just 5 studies were judged to have an overall low risk of bias. Future studies should attempt to minimize bias by following statistical best practices including not selecting multivariate predictors based on univariate analysis, validation in independent cohorts, and clearly reporting the management of missing and censored data. Future modeling efforts should adopt a transdisciplinary approach to define a unified set of clinical, treatment, and/or genetic risk factors. Creating a flexible model that uses a common set of predictors to forecast the full post-treatment audiogram may accelerate work in this area. Such a model could be adapted for use in counseling, treatment planning, and follow-up by audiologists and oncologists and could be incorporated into ototoxicity genetic association studies as well as clinical trials investigating otoprotective agents. IMPLICATIONS FOR CANCER SURVIVORS: Improvements in the ability to model post-treatment hearing loss can help to improve patient quality of life following cancer care. The improvements advocated for in this review should allow for the acceleration of advancements in modeling the auditory impact of these treatments to support treatment planning and patient counseling during and after care.

Sources of distortion product otoacoustic emissions revealed by suppression experiments and inverse fast Fourier transforms in normal ears.

Primary and secondary sources combine to produce the 2f1-f2 distortion product otoacoustic emission (DPOAE) measured in the ear canals of humans. DPOAEs were obtained in nine normal-hearing subjects using a fixed-f2 paradigm in which f1 was varied. The f2 was 2 or 4 kHz, and absolute and relative primary levels were varied. Data were obtained with and without a third tone (f3) placed 15.6 Hz below 2f1-f2. The level of f3 was varied in order to suppress the stimulus frequency otoacoustic emission (SFOAE) coming from the 2f1-f2 place. These data were converted from the complex frequency domain into an equivalent time representation using an inverse fast Fourier transform (IFFT). IFFTs of unsuppressed DPOAE data were characterized by two or more peaks. Relative amplitudes of these peaks depended on overall primary level and on primary-level differences. The suppressor eliminated later peaks, but early peaks remained relatively unaltered. Results are interpreted to mean that the DPOAE measured in humans includes components from the f2 place (intermodulation distortion) and DP place (in the form of a SFOAE). These findings build on previous work by providing evidence that multiple peaks in the IFFT are due to a secondary source at the DP place.

Effects of PMCA2 mutation on DPOAE amplitudes and latencies in deafwaddler mice.

The deafwaddler (dfw) mouse mutant is caused by a spontaneous mutation in the gene that encodes a plasma membrane Ca(2+) ATPase (type 2), PMCA2 (Street et al., 1998. Nat. Genet. 19, 390-394), which is expressed in cochlear and vestibular hair cells. Distortion product otoacoustic emission (DPOAE) amplitudes and latencies were examined in control mice, deafwaddler mutants, and controls treated with the drug furosemide. Furosemide causes a transient reduction of DPOAEs (Mills et al., 1993. J. Acoust. Soc. Am. 94, 2108-2122). We wanted to determine whether DPOAEs obtained in furosemide-treated mice were similar or different from results obtained in +/dfw mice. DPOAE amplitude and phase were measured as a function of f(2)/f(1) ratio. These data were converted into waveforms using inverse fast Fourier transform, and their average latency was used to estimate DPOAE group delay. Homozygous deafwaddlers did not produce DPOAEs. Heterozygous deafwaddlers (+/dfw) had increased DPOAE thresholds and reduced amplitudes at high frequencies, compared to controls. To the extent that DPOAEs depend on functional outer hair cells (OHCs), abnormal DPOAEs in +/dfw mice suggest that PMCA2 is important for OHC function at high frequencies. Similar to the effects of furosemide, the mutation reduced DPOAEs for low-level stimuli; in contrast to furosemide, the mutation altered DPOAEs elicited by high levels.

Distortion product otoacoustic emission input/output functions in normal-hearing and hearing-impaired human ears.

DPOAE input/output (I/O) functions were measured at 7f2 frequencies (1 to 8 kHz; f2/f1 = 1.22) over a range of levels (-5 to 95 dB SPL) in normal-hearing and hearing-impaired human ears. L1-L2 was level dependent in order to produce the largest 2f1-f2 responses in normal ears. System distortion was determined by collecting DP data in six different acoustic cavities. These data were used to derive a multiple linear regression model to predict system distortion levels. The model was tested on cochlear-implant users and used to estimate system distortion in all other ears. At most but not all f2's, measurements in cochlear implant ears were consistent with model predictions. At all f2 frequencies, the ears with normal auditory thresholds produced I/O functions characterized by compressive nonlinear regions at moderate levels, with more rapid growth at low and high stimulus levels. As auditory threshold increased, DPOAE threshold increased, accompanied by DPOAE amplitude reductions, notably over the range of levels where normal ears showed compression. The slope of the I/O function was steeper in impaired ears. The data from normal-hearing ears resembled direct measurements of basilar membrane displacement in lower animals. Data from ears with hearing loss showed that the compressive region was affected by cochlear damage; however, responses at high levels of stimulation resembled those observed in normal ears.

Development of single- and two-tone responses of anteroventral cochlear nucleus neurons in gerbil.

Responses of anteroventral cochlear nucleus (AVCN) neurons in developing gerbils were obtained to single-tone stimuli, and two-tone stimuli elicited by best frequency probes presented over a range of intensities. Neurons displayed Type I, Type I/III, and Type III receptive field patterns. Best frequencies ranged from 1.5 to 10.0 kHz. Two-tone suppression (2TS) was first observed in 5 of 16 neurons examined at 14 dab. and in all neurons examined in gerbils aged 15 to 60 dab. Suppression areas grew larger, and discharge rate reductions became greater with age. Features of the two-tone responses that were highly correlated with single-tone responses across age groups include maximum rate reductions and suppression area thresholds. The intensity level of the CF probe-tone also influenced these features of 2TS. Maximum rate reductions to below spontaneous rate levels of activity were common across age groups. Results suggest that the cochlear amplifier is present and fundamentally adult-like by 15 dab for the regions of the cochlea coding the mid frequencies in gerbil. Over the subsequent week, contributions to the developing two-tone responses by the cochlear amplifier increase slightly. Two-tone responses are influenced by central inhibitory mechanisms as early as 14 dab.