Comprehensive Audiologic Analyses After Cisplatin-Based Chemotherapy

Victoria A Sanchez; Paul C Dinh, Jr; Patrick O Monahan; Sandra Althouse; Jennessa Rooker; Howard D Sesso; M Eileen Dolan; Mandy Weinzerl; Darren R Feldman; Chunkit Fung; Lawrence H Einhorn; Robert D Frisina; Lois B Travis

doi:10.1001/jamaoncol.2024.1233

. 2024 Jun 6;10(7):912–922. doi: 10.1001/jamaoncol.2024.1233

Comprehensive Audiologic Analyses After Cisplatin-Based Chemotherapy

Victoria A Sanchez ^1,^✉, Paul C Dinh Jr ², Patrick O Monahan ³, Sandra Althouse ³, Jennessa Rooker ⁴, Howard D Sesso ⁵, M Eileen Dolan ⁶, Mandy Weinzerl ⁷, Darren R Feldman ⁸, Chunkit Fung ⁹, Lawrence H Einhorn ², Robert D Frisina ¹⁰, Lois B Travis ²

¹Department of Otolaryngology–Head and Neck Surgery, University of South Florida, Tampa

²Department of Medical Oncology, Indiana University, Indianapolis

³Department of Biostatistics and Health Data Science, Indiana University, Indianapolis

⁴College of Nursing, University of South Florida, Tampa

⁵Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

⁶Department of Medicine, University of Chicago, Chicago, Illinois

⁷Rehabilitation Services, Indiana University Health, Indianapolis

⁸Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York

⁹Department of Medical Oncology, J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York

¹⁰Department of Medical Engineering, University of South Florida, Tampa

Accepted for Publication: December 22, 2023.

Published Online: June 6, 2024. doi:10.1001/jamaoncol.2024.1233

^✉

Corresponding Author: Victoria A. Sanchez, AuD, PhD, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 73, Tampa, FL 33612 (vasanchez@usf.edu).

Author Contributions: Drs Dinh and Travis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sanchez, Dinh Jr, Rooker, Sesso, Einhorn, Frisina, Travis.

Acquisition, analysis, or interpretation of data: Sanchez, Dinh Jr, Monahan, Althouse, Dolan, Weinzierl, Feldman, Fung, Frisina, Travis.

Drafting of the manuscript: Sanchez, Dinh Jr, Monahan, Rooker, Einhorn, Travis.

Critical review of the manuscript for important intellectual content: Sanchez, Dinh Jr, Monahan, Althouse, Sesso, Dolan, Weinzierl, Feldman, Fung, Frisina, Travis.

Statistical analysis: Sanchez, Dinh Jr, Monahan, Althouse, Sesso.

Obtained funding: Frisina, Travis.

Administrative, technical, or material support: Sanchez, Dolan, Feldman, Travis.

Supervision: Sanchez, Einhorn, Frisina, Travis.

Conflict of Interest Disclosures: Dr Monahan reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Weinzierl reported receiving grants from Indiana University Health Audiology during the conduct of the study. Dr Feldman reported receiving grants from Decibel, Astellas, and Telix; research funding from Astellas, BioNTech, and PER; and personal fees from Astellas, PER, Renibus Therapeutics, Nova Research, Cigna, and Telix outside the submitted work; in addition, Dr Feldman had a patent for UpToDate; and. Dr Einhorn reported receiving nonfinancial support from AMGEN outside the submitted work. Dr Frisina reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.

Funding/Support: Drs Frisina, Dolan, Sesso, Feldman, Monahan, and Travis were supported by 2 R01 CA157823 funded by the National Cancer Institute (NCI). Dr Sanchez was supported by R01DC019408-01 funded by the National Institute of Deafness and Other Communication Disorders. Dr Feldman was supported by the NIH/NCI Cancer Center Support (grant No. P30 CA008748).

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC11157440 PMID: 38842797

This cohort study evaluates cisplatin-related hearing loss with comprehensive audiologic assessments, assesses the longitudinal progression of cisplatin-related hearing loss, and identifies factors associated with risk.

Key Points

Question

What factors are associated with (1) the progression of cisplatin-related hearing loss (CRHL) in survivors of adult-onset cancer and (2) performance on the Words-in-Noise test (WIN)?

Findings

In this cohort study of 100 cancer survivors, poorer WIN performance was significantly associated with hypercholesterolemia, lower education, and CRHL severity; CRHL progression was significantly associated with hypercholesterolemia and age. Importantly, a significant time-cisplatin dose interaction occurred: patients given 300 mg/m² or less experienced significantly less progression vs those given more than 300 mg/m².

Meaning

These findings suggest follow-up of survivors of cisplatin-treated cancer should include hypercholesterolemia control and audiological assessments and that patients receiving higher doses have greater risk of CRHL with future hearing remaining worse than peers.

Abstract

Importance

Cisplatin is highly ototoxic but widely used. Evidence is lacking regarding cisplatin-related hearing loss (CRHL) in adult-onset cancer survivors with comprehensive audiologic assessments (eg, Words-in-Noise [WIN] tests, full-spectrum audiometry, and additional otologic measures), as well as the progression of CRHL considering comorbidities, modifiable factors associated with risk, and cumulative cisplatin dose.

Objective

To assess CRHL with comprehensive audiologic assessments, including the WIN, evaluate the longitudinal progression of CRHL, and identify factors associated with risk.

Design, Setting, and Participants

The Platinum Study is a longitudinal study of cisplatin-treated testicular cancer survivors (TCS) enrolled from 2012 to 2018 with follow-up ongoing. Longitudinal comprehensive audiologic assessments at Indiana University and Memorial Sloan Kettering Cancer Center included 100 participants without audiometrically defined profound hearing loss (HL) at baseline and at least 3.5 years from their first audiologic assessment. Data were analyzed from December 2013 to December 2022.

Exposures

Factors associated with risk included cumulative cisplatin dose, hypertension, hypercholesterolemia, diabetes, tobacco use, physical inactivity, body mass index, family history of HL, cognitive dysfunction, psychosocial symptoms, and tinnitus.

Main Outcomes and Measures

Main outcomes were audiometrically measured HL defined as combined-ears high-frequency pure-tone average (4-12 kHz) and speech-recognition in noise performance measured with WIN. Multivariable analyses evaluated factors associated with risk for WIN scores and progression of audiometrically defined HL.

Results

Median (range) age of 100 participants at evaluation was 48 (25-67) years; median (range) time since chemotherapy: 14 (4-31) years. At follow-up, 78 (78%) TCS had audiometrically defined HL; those self-reporting HL had 2-fold worse hearing than TCS without self-reported HL (48 vs 24 dB HL; P < .001). A total of 54 (54%) patients with self-reported HL showed clinically significant functional impairment on WIN testing. Poorer WIN performance was associated with hypercholesterolemia (β = 0.88; 95% CI, 0.08 to 1.69; P = .03), lower-education (F₁ = 5.95; P = .004), and severity of audiometrically defined HL (β̂ = 0.07; 95% CI, 0.06 to 0.09; P < .001). CRHL progression was associated with hypercholesterolemia (β̂ = −4.38; 95% CI, −7.42 to −1.34; P = .01) and increasing age (β̂ = 0.33; 95% CI, 0.15 to 0.50; P < .001). Importantly, relative to age-matched male normative data, audiometrically defined CRHL progression significantly interacted with cumulative cisplatin dose (F₁ = 5.98; P = .02); patients given 300 mg/m² or less experienced significantly less progression, whereas greater temporal progression followed doses greater than 300 mg/m².

Conclusions and Relevance

Follow-up of cisplatin-treated cancer survivors should include strict hypercholesterolemia control and regular audiological assessments. Risk stratification through validated instruments should include querying hearing concerns. CRHL progression relative to age-matched norms is likely associated with cumulative cisplatin dose; investigation over longer follow-up is warranted.

Introduction

Cisplatin causes bilateral, permanent sensorineural hearing loss (HL) in up to 80% of patients with cancer,^1,2,3 with many developing tinnitus.^4,5 It is one of the most ototoxic oncologic drugs, causing acute and permanent HL⁶ in approximately 500 000 new patients each year,⁷ without preventive or protective measures available. Worldwide, an estimated 10.5 million individuals are diagnosed annually with cancers where first-line therapy can potentially include platinating agents.^7,8,9 Many of these cancers affect older adults, except testicular cancer (TC), the most common malignant neoplasm among men aged 20 to 34 years.¹⁰ Studies of cisplatin-related HL (CRHL) are important, since cisplatin can result in clinically significant functional impairment in 1 in 3 patients.¹¹ Although several studies have characterized CRHL in adult-onset cancer survivors with pure-tone audiometry,^{1,12,13,14,15,16,17} very few investigations have measured functional hearing ability.¹² Speech-in-noise testing cannot be predicted by pure-tone sensitivity,¹⁸ and is considered the most valid measure of the functional capacity to hear and perform in daily life.^19,20

Understanding how CRHL is associated with the normal trajectory of age-related hearing loss is also important, since cisplatin remains in the cochlea indefinitely.²¹ As patients age, other auditory insults (eg, noise and aminoglycosides)^22,23 can impair hearing, as can smoking,^24,25 hypertension,^1,26 hypercholesterolemia,²⁵ diabetes,²⁶ family history of HL,²⁷ body mass index (BMI),²⁸ and physical inactivity.²⁶ However, we know of no investigation of the temporal progression of CRHL in adult-onset cancer survivors^{13,14,29,30,31,32,33} that takes all of these factors into account (eTable 1 in Supplement 1). Prior studies were also limited by confounding cranial radiotherapy,^30,31,32 small numbers,^13,14,31,32 short follow-up times (<3 months),^14,31 and restricted ranges of audiometric frequencies.^13,29,30,33

Understanding which factors associated with risk (genetic or modifiable) may be associated with CRHL temporal progression is critical to risk stratify survivors for follow-up and available otologic interventions. This is especially important for TCS, given their young age and decades of years in survivorship where age-related HL develops. Although rigorous longitudinal evidence regarding CRHL is lacking, any HL has long-lasting untoward effects, including clinically relevant decreases in communication and health-related quality of life,³⁴ reduced social engagement and depression,^35,36,37 and increased risks of accelerated cognitive decline and dementia.^38,39

The aim of our present work was to address these important gaps; therefore, we conducted comprehensive follow-up audiologic assessments and administered validated patient-reported outcome measures to a subset of TCS in a large multicenter investigation (The Platinum Study; TPS).^1,40,41

Methods

Patients, Sociodemographics, Clinical Features, Health Behaviors, and Adverse Health Outcomes (AHOs)

Cisplatin-treated TCS were enrolled at 8 institutions into TPS-1 (2012-2018),^1,40,41,42 completing surveys, physical examinations, and extensive audiological testing. Under institutional review board approvals at both Indiana University and Memorial Sloan Kettering Cancer Center, subsequent assessments were completed (ie, TPS-2). This report includes 100 TCS that underwent informed consent with completed assessments through December 31, 2022. TPS-1 and TPS-2 denote initial and follow-up assessments, respectively. This cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Demographic and clinical data, including medical history, lifestyle, AHOs, and comorbidities were collected using standardized and validated instruments (see eAppendix and eMethods in Supplement 1 for details, questions, scoring, and variable definitions).⁴³ These included established risk factors for HL (eg, age,^1,41 cumulative cisplatin dose,¹ hypertension,^1,26 hypercholesterolemia,^25,26 diabetes,²⁶ tobacco use,^24,25 physical inactivity,²⁶ BMI,²⁸ and family history of HL²⁷), as well as cognitive dysfunction,³⁹ psychosocial symptoms,⁴⁴ and tinnitus.²⁶ Self-reported race was collected as a demographic variable because there are known associations between race and the study variables.

Comprehensive Audiologic Assessments

Comprehensive audiological evaluations, conducted by audiologists, quantified HL type and magnitude. Pure-tone air conduction thresholds were measured at octaves (250 to 8000 Hz), including interoctaves (1500, 3000, and 6000 Hz), and high frequencies (10 000 and 12 000 Hz). Concentrating on hearing most sensitive to acquired HL (eg, ototoxicity and aging), we calculated combined-ears high-frequency pure-tone average (PTA 4, 6, 8, 10, and 12 k Hz), categorizing it with American Speech-Language and Hearing (ASHA) criteria⁴⁵ (eAppendix in Supplement 1). Speech recognition threshold (SRT) was measured with recorded spondaic words. Word recognition in quiet testing was administered using recorded speech and scored as percentage correct. Speech recognition in noise performance was assessed using the Words in Noise Test (WIN).^46,47 WIN consists of 5 female-spoken word series, mixed with multitalker speech babble increasing in 4-dB increments, for a signal to noise ratio (SNR) range of 24 dB to 0 dB. Total correctly recognized words were summed to determine recognition performance across all SNRs, and to determine the 50% correct threshold (SNR-50%).⁴⁸ Standard clinical SNR-50% groups categorized patients into normal, mild, moderate, severe, and profound difficulty hearing in background noise.⁴⁷ Mild or greater ratings are clinically actionable, with patients referred for audiological interventions.⁴⁷

Statistical Analyses

Descriptive statistics are provided as frequencies (proportions) or medians (range) for categorical and continuous variables, respectively. We defined patients as with or without self-reported HL based upon hearing aid use, difficulty hearing in crowds, and responses to EORTC-Chemotherapy-Induced Peripheral Neuropathy-20⁴⁹ and SCIN⁵⁰ scales (eAppendix in Supplement 1). Bivariate comparisons between patients with and without self-reported HL were conducted using χ² 2-sided Fisher exact tests, or 2-sided Wilcoxon rank sum tests (continuous variables). To evaluate variables associated with WIN performance, we first performed univariable linear regression assessments for a priori–identified variables of interest. Due to the number of significant univariable results, we built a multivariable linear regression model using backward selection, including all variables significant in univariable models. Backward selection continued until all model variables had a P value of less than .05. The model with the smallest Schwarz criterion (SBC) was selected, also having the smallest Mallow Cp, and bayesian information criterion (BIC). Pearson correlations evaluated associations between self-reported hearing handicap (Hearing Handicap Inventory for Adults, HHIA^51,52) and measured hearing (audiometry; WIN).

HL progression was evaluated with univariable and multivariable linear regression analyses. Change from baseline hearing was modeled individually for established HL factors associated with risk, adjusting for baseline hearing. Factors associated with risk with a conservative univariable P < .25 were included as additional multivariable model covariates. Given normal changes in hearing with aging, audiometry results were compared with a large unscreened reference population⁵³ of 51 975 individuals used previously.¹ This population⁵³ provides quartiles of hearing thresholds (0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz) for many age ranges (eg, 20-29, 30-39, 40-49, 50-59, and 60-69 years). For this comparison, averaged hearing at frequencies 4, 6, and 8 kHz for each TCS at each time point were compared with age- and sex-matched normative quartile cut-points for assignment to norm-expected quartiles. We then evaluated percentage TCS in assigned ordinal quartile categories (dependent variable) with independent variables of time (TPS-2 vs TPS-1) and cumulative cisplatin dose (≤300 mg/m² vs >300 mg/m²) through a cumulative logit ordered multinomial model and tested the interaction between time and dose. All analyses were completed in SAS version 9.4 (SAS Institute), and data were analyzed from December 2013 to December 2022.

Results

Table 1 presents sociodemographic, clinical features, health behaviors, and AHOs for all 100 TCS and subgroups with and without self-reported HL (54 and 46 patients, respectively). Overall, median (range) TPS-2 age was 48 (25-67) years, and median (range) time since chemotherapy was 14 (4-31) years. Participants reporting HL significantly differed from those without self-reported HL in terms of less college education (26 patients [48%] vs 9 patients [20%]; χ²₂ = 9.99; P = .01) and higher cumulative cisplatin doses (345 mg/m² vs 317 mg/m²; P = .03), with 21 patients (39%) and 8 patients (17%) receiving 400 or more mg/m², respectively. Significantly larger percentages of TCS with HL had hypertension (20 patients [37%]; χ²₁ = 4.76; P = .03), hypercholesterolemia (25 patients [46%]; χ²₁ = 6.58; P = .01), and tinnitus (43 patients [80%]; χ²₁ = 22.55; P < .001).

Table 1. Sociodemographic Characteristics, Clinical Features, Health Behaviors, and Adverse Health Outcomes for Survivors of Cisplatin-Treated Germ Cell Tumors^a.

Characteristic	Patients, No. (%)			P value^b
Characteristic	Total population (N = 100)	Hearing loss (n = 54)^a	No hearing loss (n = 46)	P value^b
Age at initial TPS-1 assessment, median (range), y	41 (20-61)	43 (20-61)	40 (21-61)	.19
Age at TPS-2 assessment, median (range), y	48 (25-67)	50 (25-67)	46 (27-67)	.23
Time between TPS-1 and TPS-2, median (range), mo	80 (44-99)	83 (50-99)	79 (44-99)	.69
Race
White	94 (94)	51 (94)	43 (94)	>.99
Other/unknown^c	6 (6)	3 (6)	3 (7)	>.99
Marital status
Not married	26 (26)	16 (30)	10 (22)	.37
Married/living as married	74 (74)	38 (70)	36 (78)	.37
Education^d
Not college graduate	35 (35)	26 (48)	9 (20)	.01
College/university graduate	37 (37)	18 (33)	19 (41)
Postgraduate level	28 (28)	10 (19)	18 (39)
Insurance
Employer-based	67 (67)	35 (65)	32 (70)	.29
Spouse/parent	16 (16)	7 (13)	9 (20)
Military/Medicare/Medicaid/public program	7 (7)	6 (11)	1 (2)
Self-purchased/none/other/unknown	10 (10)	6 (11)	4 (9)
Employment
Employed	93 (93)	50 (93)	43 (94)	.29
On disability	1 (1)	1 (2)	0
Retired	4 (4)	3 (6)	1 (2)
Unemployed/student	2 (2)	0	2 (4)
Job category^d
ISCO levels 1-2	22 (31)	12 (31)	10 (30)	.97
ISCO levels 3-4	50 (69)	27 (69)	23 (70)	.97
Clinical features, health behaviors, adverse health outcomes
Age at first GCT diagnosis, median (IQR), y	30.9 (16- 53)	31.6 (16- 53)	30.3 (18-46)	.73
Time since end of chemotherapy, median (IQR), y	14.0 (4-31)	14.6 (4-31)	13.7 (5-30)	.49
Chemotherapy
Cumulative cisplatin dose, mean (range), mg/m²^e	332 (200-600)	345 (260-600)	317 (200-402)	.03
Cisplatin dose group, mg/m²
<300	11 (11)	5 (9)	6 (13)	.12
300	54 (54)	25 (46)	29 (63)
301-400	6 (6)	3 (6)	3 (7)
≥400	29 (29)	21 (39)	8 (17)
Chemotherapy regimen^d
BEPx3	61 (61)	29 (54)	32 (70)	.49
BEPx4	12 (12)	8 (15)	4 (9)
EPx4	3 (3)	2 (4)	1 (2)
Other	24 (24)	15 (28)	9 (20)
Family history of hearing loss^d	15 (18)	10 (22)	5 (13)	.31
Noise exposure^d	39 (48)	23 (51)	16 (43)	.48
Tobacco use
Former/current smoker	27 (27)	17 (32)	10 (22)	.27
Never smoked/not specified	73 (73)	37 (69)	36 (78)	.27
Body mass index^f	28 (19-46)	27 (19-43)	28 (20-46)	0.52
Physical activity: moderate (<6 METs)	95 (95)	51 (94)	44 (96)	>.99
Physical activity: vigorous (6+ METs)	57 (57)	28 (52)	29 (63)	.26
Sedentary h per wk^d	39.3 (6-107)	35.0 (6-107)	42.0 (8-92)	.62
Diabetes	1 (1)	1 (2)	0	>.99
Hypertension	28 (28)	20 (37)	8 (17)	.03
Hypercholesterolemia	35 (35)	25 (46)	10 (22)	.01
Psychosocial symptoms^d	34 (34)	15 (28)	19 (41)	.16
Cognitive dysfunction	9 (11)	7 (15)	2 (5)	.17
Tinnitus^d	58 (58)	43 (80)	15 (33)	<.001
Tinnitus handicap (Tinnitus Primary Function Questionnaire TPFQ)^g
Total score, median (range) (maximum: 100)	17.9 (0-92)	24.9 (0-92)	4.7 (0-33)	.01
Degree of handicap
No handicap (0%-16%)	22 (45)	13 (36)	9 (69)	.05
Mild to moderate handicap (17%-42%)	17 (35)	13 (36)	4 (31)
Severe handicap (>42%)	10 (20)	10 (28)	0

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Abbreviations: BEP, bleomycin, etoposide, and cisplatin; EP, etoposide and cisplatin; GCT, germ cell tumor; ISCO, International Standard Classification of Occupations; METs, metabolic equivalents; TPFQ, Tinnitus Primary Function Questionnaire; TPS-1, The Platinum Study-1; TPS-2, The Platinum Study-2.

^{^a}

Data are from TPS-2 assessments unless otherwise specified.

^{^b}

P values are unadjusted.

^{^c}

Other race includes Black or African American; Asian; American Indiana or Alaskan Native; Native Hawaiian or Other Pacific Islander; other, please specify; or in any combination with or without White.

^{^d}

Definitions and data availability for self-reported hearing loss, education, ISCO job category, chemotherapy regimens, family history of hearing loss, noise exposure, psychosocial symptoms, tinnitus, and others can be found in the eAppendix and eMethods in Supplement 1.

^{^e}

A total of 22 patients received 400 mg/m² and 7 patients received more than 400 mg/m² with a range of 402 to 600 mg/m².

^{^f}

Body mass index is calculated as weight in kilograms divided by height in meters squared.

^{^g}

Only patients who self-reported tinnitus were asked to complete the TPFQ, with data unavailable for 3 of these patients.

The total population is shown in the second column, followed by those with self-reported hearing loss (third column) and those without self-reported hearing loss (fourth column).

Table 2 reports audiologic-related results by self-reported HL. Most TCS had bilateral, symmetrical high-frequency HL (median [range], 38 [4-94] dB HL) that was worse for TCS with vs without self-reported HL (48 vs 24 dB HL; P < .001). Most (43 patients [79%]) TCS reporting HL had mild to profound ASHA-categorized HL, while 24 (52%) without HL were categorized as normal or slight (P = .002, Fisher exact test). Most (32 patients [69%]) patients without self-reported HL had normal, slight, or mild clinical severity of audiometrically defined HL, whereas the majority (32 patients [59%]) of patients self-reporting HL had ratings of profound, severe, moderately severe, or moderate. Of TCS with self-reported HL, 39 (73.9%) reported problems hearing in crowds, and 17 (38%) had clinically actionable HHIA-quantified hearing handicap. HHIA-quantified hearing handicap was moderately correlated (eFigure 1 in Supplement 1) with audiometrically defined HL (r = 0.42; P = .003) and WIN functional performance (r = 0.48; P = .001).

Table 2. Audiologic Features Stratified by Presence or Absence of Self-Reported Hearing Loss for 100 Survivors of Cisplatin-Treated Germ Cell Tumors^a.

Audiologic feature	Participants, No. (%)			Unadjusted P value
Audiologic feature	Total population (N = 100)	Hearing loss (n = 54)^b	No hearing loss (n = 46)	Unadjusted P value
Audiometrically measured hearing, median (range), dB HL
High-frequency PTA at TPS-2 (assessment 2)^c	38.0 (4 to 94)	47.5 (4 to 94)	24.0 (4 to 67)	<.001
Progression of hearing loss: change since TPS-1 (assessment 1)	7.5 (−21 to 30)	8.3 (−21 to 30)	6.8 (−6 to 19)	.09
ASHA: Clinical Severity of Hearing Loss^d
Normal	22 (22)	8 (15)	14 (30)	.002
Slight	13 (13)	3 (6)	10 (22)
Mild	19 (19)	11 (20)	8 (17)
Moderate	25 (25)	13 (24)	12 (26)
Moderately severe	14 (14)	12 (22)	2 (4)
Severe	5 (5)	5 (9)	0
Profound	2 (2)	2 (4)	0
Speech perception, median (range)
Speech recognition threshold, dB HL^e	10.0 (0 to 38)	12.5 (0 to 38)	10.0 (0 to 25)	.02
Change since TPS-1 (assessment 1)	0.0 (−13 to 25)	1.3 (−13 to 25)	0.0 (−10 to 15)	.72
Word recognition in quiet (%)^e	98 (55 to 100)	96 (55 to 100)	98 (92 to 100)	.01
Change since TPS-1 (assessment 1)	0.0 (−41 to 18)	0.0 (−41 to −18)	0.0 (−8 to −4)	.91
Speech-in-noise performance, WIN, dB SNR^e
Total correctly recognized words	25.5 (12 to 30)	24.5 (12 to 28)	26.0 (21 to 30)	<.001
SNR-50, dB SNR	5.6 (2 to 17)	6.4 (4 to 17)	5.2 (2 to 10)	<.001
Clinical scaling: WIN performance (dB SNR)^e
Normal ability (2.0 to 6.0)	65 (65)	25 (46)	40 (87)	<.001
Mild difficulty (6.8 to 10)	27 (27)	21 (39)	6 (13)
Moderate difficulty (10.8 to 14.8)	5 (5)	5 (9)	0
Severe difficulty (15.6 to 19.6)	3 (3)	3 (6)	0
Problems hearing in crowds	39 (39)	39 (74)	0	<.001
Communication partners report patient HL	30 (36)	26 (57)	4 (11)	<.001
Use of hearing aids	3 (4)	3 (7)	0	.35
Hearing Handicap Inventory–Adults^f
Total Score, median (range) (maximum 100)	10.0 (0 to 92)	10.0 (0 to 92)	NA	NA
Degree of handicap
No handicap (0-16)	28 (62)	28 (62)	NA	NA
Mild-moderate handicap (17-42)	7 (16)	7 (16)	NA	NA
Severe handicap (>42)	10 (22)	10 (22)	NA	NA

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Abbreviations: dB HL, decibel reference to hearing level; dB SNR, decibel signal-to-noise ratio; HHIA, Hearing Handicap Inventory Adult; NA, not applicable; PTA, Pure-Tone Average; TPFQ, Tinnitus Primary Frequency Questionnaire; TPS-1, The Platinum Study-1; TPS-2, The Platinum Study-2; WIN, words in noise test.

^{^a}

Data are from TPS-2 measurements unless otherwise specified. Differences between features from initial assessment (TPS-1) and updated assessment (TPS-2) are displayed as ‘change’ in that feature.

^{^b}

Patients were classified with self-reported hearing loss as defined in the eAppendix in Supplement 1.

^{^c}

PTA across both ears: 4000, 6000, 8000, 10 000, and 12 000.

^{^d}

Defined by High-frequency pure-tone average and clinical criteria set forth by the American Speech-Language-Hearing Association (ASHA) (see the eMethods and eAppendix in Supplement 1).

^{^e}

Measurements and definitions for speech recognition threshold, speech recognition threshold change since TPS-1, word recognition in quiet, word recognition in quiet change since TPS-1, speech-in-noise performance, words-in-noise test, and WIN test normative rating and clinical scaling are explained in the eMethods and eAppendix in Supplement 1.

^{^f}

Per clinical standards, the HHIA was only administered to patients with self-reported hearing loss (ie, 54 patients). Of these 54 patients, 45 answered the HHIA.

The total population is shown in the second column, followed by those with self-reported hearing loss (third column) and those without self-reported hearing loss (fourth column). Significant differences using an unadjusted univariable analysis between those with or without hearing loss are in the far right column.

Overall, median (range) SRT was 10 (0-38) dB HL, and median (range) word-recognition performance in quiet was 98% (55%-100%). TCS with HL performed more poorly on both tests vs TCS without HL (13 db HL vs 10 dbHL; 96% vs 98%; P = .02 and .01, respectively). These sensitivity measurements are not reflective of functional ability, unlike WIN testing, where median performance in noise (SNR-50%) was significantly worse for those with self-reported HL (6.4 vs 5.2 dB SNR; P < .001) vs those without self-reported HL. Clinically significant functional impairment in speech-in-noise recognition occurred in 54 (54%) patients with self-reported HL. Figure 1 displays psychometric performance for both groups. TCS with self-reported HL (blue line) are right-shifted, indicating a need for more advantageous or easier listening levels to recognize words in varying background noise levels. Importantly, among TCS with self-reported HL, 21 patients (38.9%), 5 patients (9.3%), and 3 patients (5.6%) had mild, moderate, or severe WIN-quantified functional impairment vs only 6 patients (13%), 0, and 0 TCS without self-reported HL (Fisher exact test; P < .001). Poorer WIN performance correlated with more severe HL (eFigure 1 in Supplement 1) (r = 0.68; P < .001).

Figure 1. — Blue designates patients with self-reported HL, while orange denotes those with no self-reported HL (see the eAppendix in Supplement 1 for detail). Mean performance (percentage correct) for each signal-to-noise ratio (24 to 0 dB SNR) is shown. The performance difference evaluated at the 50% threshold was statistically significant (P < .001) with those self-reporting HL having poorer speech-in-noise perception.

eTable 2 in Supplement 1 shows adjusted bivariate analyses evaluating factors influencing WIN performance, with multiple variables significant. In multivariable modeling (Table 3), hypercholesterolemia (β = 0.88; 95% CI, 0.08-1.69; P = .03), educational-level (overall P = .004; F₂ = 5.95), and greater audiometrically measured HL (β̂ = 0.07; 95% CI, 0.06-0.09; P < .001) were each independently and significantly associated with poorer speech-in-noise performance.

Table 3. Multivariable Regression Models of Factors Associated With Speech-in-Noise Performance Measured With the Words-in-Noise (WIN) Test, and With Progression of Audiometrically Defined Hearing Loss.

Factor	β (95% CI)	P value
Speech-in-noise performance (WIN)
Hypercholesterolemia	0.88 (0.08 to 1.69)	.03
Education
Not college graduate	1 [Reference]	NA
College graduate	−1.43 (−2.29 to −0.56)	.002
Postgraduate	−1.22 (−2.18 to −0.26)	.01
Audiometrically measured hearing^a	0.07 (0.06 to 0.09)	<.001
Temporal progression of audiometrically measured hearing^a
Hypercholesterolemia	−4.38 (−7.42 to −1.34)	.01
Age at TPS-1 (Assessment 1)	0.33 (0.15 to 0.50)	<.001
Time since baseline (TPS-1, Assessment 1)	0.12 (0.02 to 0.23)	.02
Hypertension	1.96 (−1.15 to 5.07)	.22

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Abbreviations: HL, hearing loss; NA, not applicable; TPS-1, The Platinum Study, initial baseline assessment; TPS-2, The Platinum Study, follow-up assessment.

^{^a}

Hearing variable defined as the average of both ears across the higher frequencies measured (ie, pure-tone average of 4, 6, 8, 10, and 12 kHz).

Progression of Audiometrically Measured Hearing, Speech Recognition Threshold, and Word Recognition in Quiet

HL progression was evaluated descriptively with audiometrically measured hearing and speech perception changes since TPS-1. For all TCS, audiometrically measured hearing and word-recognition-in-quiet performance were significantly worse at TPS-2 vs TPS-1 (P < .001; t₉₉ = 9.90; P = .02; t₉₉ = 2.37). Progression stratified by self-reported HL (Table 2, change since TPS-1) showed no statistically significant difference in speech perception scores, but audiometry-measured hearing was marginally significant (8.3 dB HL vs 6.8 dB HL; P = .09) with the self-reported HL subgroup having poorer hearing and more progression. Figure 2A shows each patient’s audiometrically measured hearing at TPS-1 and TPS-2, with nearly all having upward trajectories and some progressing over 15 to 20 dB. Changes in hearing (TPS-1 vs TPS-2) were modeled individually for established HL risk factors (eTable 3 in Supplement 1). Since hypertension, hypercholesterolemia, TPS-1 age, and time each showed P < .25, they were included in the multivariable model, with hypercholesterolemia (β = −4.38; 95% CI, −7.42 to −1.34; P = .01), time since baseline (β = 0.12; 95% CI, 0.02 to 0.23; P = .018, and TPS-1 age (β = 0.33; 95% CI, 0.15 to 0.50; P < .001) remaining significant (Table 3).

Comparison With Normative Population

HL progression from TPS-1 to TPS-2 was compared with age-matched results in normative males (0.25-8kHz).⁵³ Figure 2B overlays age-matched normative audiograms onto median hearing at TPS-1 and TPS-2; this figure is stratified by self-reported HL. At both TPS-1 and TPS-2, participants with self-reported HL demonstrated worse hearing than age-matched norms. eFigure 2 in Supplement 1 shows cumulative cisplatin dose groups and proportion of participants in that dose group within each normative hearing quartile at TPS-1 and TPS-2 (54 patients [54%] received cumulative cisplatin doses of exactly 300 mg/m² and 22 patients [22%] received 400 mg/m²). Importantly, a significant interaction exists between cumulative cisplatin dose and audiometrically measured HL progression relative to age-matched norms (F₁ = 5.98; P = .02); this is visually apparent in eFigure 2 in Supplement 1 where participants’ quartile distributions differentially shift with respect to cumulative dose and time. For 300 mg/m² or less cisplatin, participants at TPS-2 had 4.5 times greater odds of being in better hearing quartiles than at TPS-1 (95% CI, 1.5-13.3; P = .01); thus, participants’ hearing approached norms over time, as the normative population’s HL catches up to acute cisplatin-related hearing insults. In contrast, for participants exposed to more than 300 mg/m² cisplatin, audiometrically measured HL did not significantly differ at TPS-2 vs TPS-1; in fact, a nonsignificant detrimental trend appeared with 1.37 times greater odds of being in worse quartiles at TPS-2 vs TPS-1 (95% CI, 0.52-3.61; P = .51). For example, using absolute percentages, high-dose participants showed a large cisplatin-related hearing insult at TPS-1, with 12 patients (34.3%) in the worst age-matched quartile, and they remained worse relative to norms at TPS-2 (11 patients in worst quartile [31.4%]); likewise, fewer than expected were in the best hearing category at TPS-1 (6 patients [17.1%]), with percentages remaining lower than 25% expectation at TPS-2 (5 patients [14.3%]).

Discussion

To our knowledge, this is the first longitudinal, covariate-adjusted investigation including comprehensive audiologic analyses in cisplatin-treated adult-onset cancer survivors. Clinically significant functional impairment in speech-in-noise recognition occurred in 54% of patients with self-reported HL; with hypercholesterolemia, lower educational levels, and greater audiometrically defined HL, each independently and significantly associated with poorer speech perception performance. Audiometrically defined HL progressed with time, and patients had worse hearing vs an age-matched normative population. Cumulative cisplatin dose was significantly associated with self-reported hearing perception, degree of audiometrically measured HL, and progression with age. Hypercholesterolemia and increasing age were significantly associated with audiometrically measured HL progression.

TCS were able to self-identify hearing concerns that could be objectively verified through comprehensive audiological evaluations. TCS with self-reported HL had a median 20-dB greater HL than those without self-reported HL (ie, 48-dB vs 24-dB HL, P < .001). Most (69%) patients without self-reported HL had normal, slight, or mild clinical severity of audiometrically defined HL, whereas the majority (59%) of patients self-reporting HL had ratings of profound, severe, moderately severe, or moderate. Although cisplatin-related ototoxicity is common, we found that patients can self-identify HL to enable clinicians to better recognize patients needing further audiological-intervention services. This is important since untreated HL loss is associated with many negative health outcomes, such as reduced social engagement,⁵⁴ health-related quality of life,⁵⁵ and physical functioning.⁵⁶

Our patients had clinically measured difficulties hearing in noise, a common everyday listening challenge.²⁰ Over half (54%) of participants self-reporting HL had a degree of difficulty recognizing speech in noise that would warrant an audiological intervention. Speech-in-noise testing reflects everyday communication disability,^57,58 and WIN performance strongly correlated with HHIA-quantified hearing handicap. Clinicians are encouraged to administer the HHIA to help risk-stratify patients requiring additional audiological intervention services, or query about hearing problems such as our dichotomous grouping. Identifying patients with speech-in-noise difficulty is critical beyond communication concerns.⁵⁹ In the general population,⁵⁹ speech-in-noise performance and cognitive function are linked. In a large population-based analysis of the UK Biobank, speech-in-noise impairment was independently associated with a significantly increased 61% risk of incident dementia.⁵⁹ Our findings of a significant relationship between educational level and impaired WIN performance may further reflect the growing evidence linking HL and cognitive decline.³⁹ Moreover, untreated HL has been identified as the single largest potentially modifiable risk factor for dementia.³⁹

Continued audiometrically measured HL progression occurred among TCS given modern cisplatin-based chemotherapy, showing significant interactions with cumulative cisplatin dose. Minimal HL progression vs normative expectations occurred after 300 mg/m² or less cisplatin. However, after more than 300 mg/m² cisplatin, HL was worse than norms at both time points, and deteriorating progression with time vs norms existed. In other words, patients administered 300 mg/m² or less cisplatin experienced comparable HL relative to age-matched counterparts at a median follow-up of 14 years after treatment, whereas those given more than 300 mg/m² cisplatin continued to remain worse than age-matched peers. Specifically, 54% of our patients received cumulative cisplatin doses of exactly 300 mg/m² as administered in 3 cycles of cisplatin-based chemotherapy, and 22% received 400 mg/m², corresponding to 4 cycles.

Very few investigations describe the temporal progression of CRHL in adult-onset cancer survivors (eTable 1 in Supplement 1).^{13,14,29,30,31,32,33} Importantly, most studies did not control for important confounding variables, as done here. Thus, our findings considerably advance clinical knowledge, based on a large homogeneously treated patient population and using comprehensive, quantitative, audiologic assessments designed by hearing scientists. We found progression of CRHL which differs from some reports of adult-onset cancer survivors,²⁹ but is consistent with pediatric studies.^60,61 The extent to which CRHL continues to adversely impact the cochlea and central auditory processing is unknown, and measurements such as speech-in-noise testing better detect real-world deficiencies than pure-tone assessments. We have not yet measured speech-in-noise longitudinally, but this is important for future investigations. We did quantify other speech assessments longitudinally and found no significant CRHL progression in either SRT or word recognition in quiet performance, which is unsurprising as these are not sensitive measures of hearing changes after ototoxic exposures.^62,63 Thus, clinicians should be careful to not overinterpret stable speech-in-quiet tests as they do not reflect real-world functional impairment.¹⁹ Although not measured longitudinally, other investigators¹² measured speech-in-noise performance among patients treated with cisplatin using the Hearing-in-Noise Test (HINT).⁶⁴ They concluded that HINT scores were not significantly associated with cisplatin-based chemotherapy or HL at 4, 6, or 8 kHz,¹² but HINT has less sensitivity and specificity to accurately identify patients with difficulty hearing-in-noise⁶⁵ than WIN (used here). It is important that optimal speech-in-noise assessments be used, since test difficulty and other factors can influence performance and impede interpretation.⁶⁶

Hypercholesterolemia was associated with both progression of audiometrically defined CRHL and impaired WIN performance, and is clinically actionable. Metabolic disorders (eg, diabetes, hypertension, and hyperlipidemia) are known risk factors for HL in general.²⁶ Of note, in a retrospective analysis of 277 patients with head and neck cancer, 50 patients taking atorvastatin during cisplatin-based chemotherapy were 53% less likely to develop HL than 164 nonstatin users (odds ratio, 0.47; 95% CI, 0.30-0.78), and had less severe HL.¹⁶ Hyperlipidemia has been linked with both noise-induced and sudden sensorineural HL,⁶⁷ with posited mechanisms involving vascular ischemia of inner ear arteries. Hyperlipidemia increases plasma viscosity⁶⁸ which can trigger cochlear artery stenosis, resulting in ischemia and subsequent sensorineural HL, thus vascular compromise may play a vital role.⁶⁹

Mechanisms of CRHL are multifaceted,^70,71,72 thus, evaluations should include audiological measures for cisplatin insult(s) at all auditory system levels (ear to brain). Importantly, other studies have shown that patients who report HL but have normal audiometric thresholds may still have functional deficits in speech-in-noise tests such as WIN.⁷³ Normal hearing sensitivity in the presence of abnormal speech perception can indicate cochlear synaptopathy.^73,74 Importantly, the full extent of cisplatin-related auditory damage remains unknown, and whether this differs in children with developing central auditory systems, or adults with fully developed systems, has not been studied. Tests such as WIN and other neurophysiological measures (eg, auditory evoked potentials)⁷⁵ should be included in future investigations of CRHL and its progression. Our findings highlight the need for additional longitudinal assessments in research protocols as well as in standard of care.

Strengths and Limitations

Study strengths include the use of homogenous cisplatin-based chemotherapy at standard doses, using modern TC chemotherapy regimens; collection of detailed treatment-data; statistical comparisons with a large, normative population; and comprehensive audiologic assessments designed by hearing-scientists. Analyses considered numerous confounding factors, including modifiable risk-factors for HL, and patients were treated at high-volume TC centers. Using the large normative population used previously¹ (97% White, such as our participants), we found expected associations between higher cisplatin dose and assignment to worse age-matched hearing quartiles. However, as before,¹ we were not able to fully adjust for potentially differing distributions of hypertension, smoking, and other potential confounders, although any differences are unlikely to affect our overall conclusions. Since hearing tests are not done before cisplatin therapy for TC, baseline measures could not be included.

Conclusions

Based on our results, follow-up of cisplatin-treated cancer survivors should include strict hypercholesterolemia control and regular audiological assessments. Risk stratification through validated instruments should include querying hearing concerns. It is unlikely that CRHL in TCS administered 300 mg/m² or less cisplatin, which now appears comparable with age-matched norms, will begin to accelerate. However, for TCS given more than 300 mg/m² cisplatin, longer follow-up will be needed to understand its longitudinal severity and progression relative to age-matched norms. Survivorship health care is paramount considering that 10-year TC survival rates exceed 95% (largely attributed to the effectiveness of cisplatin-based treatments), and the high benefit-vs-risk ratio using cisplatin for TC. Our study provides increasing support for prechemotherapy otologic baseline measurements with routine follow-up, clinical intervention for CRHL, and survivorship education and support related to future years lived with hearing disability.

Supplement 1.

eAppendix 1. Variable Definitions for Adverse Health Outcomes (AHOs), Audiologic Variables, Clinical Features, Health Behaviors, and Demographics

eTable 1. Summary of Studies With Longitudinal Audiometric Assessments of Adult-Onset Cancer Survivors Given Cisplatin-Based Chemotherapy With or Without Cranial Radiotherapy

eTable 2. Univariable Analysis of Variables and Modifiable Risk Factors Associated With Functional WIN Performance Among Survivors of Cisplatin-Treated Germ Cell Tumors

eTable 3. Bivariate-Adjusted Analysis of Factors Associated With Progression of Audiometrically Defined Hearing Loss Among 100 Survivors of Cisplatin-Treated Germ Cell Tumors

eFigure 1. Correlations Between Audiometrically Defined Hearing and WIN Performance; WIN Performance and Hearing Handicap Inventory - Adult (HHIA); and Audiometrically Defined Hearing With HHIA

eFigure 2. Percentage Testicular Cancer Survivors (TCS) in Each Normative Quartile, Displayed by Time and Dose

eMethods.

jamaoncol-e241233-s001.pdf^{(541.2KB, pdf)}

Supplement 2.

Data Sharing Statement

jamaoncol-e241233-s002.pdf^{(13.9KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eAppendix 1. Variable Definitions for Adverse Health Outcomes (AHOs), Audiologic Variables, Clinical Features, Health Behaviors, and Demographics

eTable 1. Summary of Studies With Longitudinal Audiometric Assessments of Adult-Onset Cancer Survivors Given Cisplatin-Based Chemotherapy With or Without Cranial Radiotherapy

eTable 2. Univariable Analysis of Variables and Modifiable Risk Factors Associated With Functional WIN Performance Among Survivors of Cisplatin-Treated Germ Cell Tumors

eTable 3. Bivariate-Adjusted Analysis of Factors Associated With Progression of Audiometrically Defined Hearing Loss Among 100 Survivors of Cisplatin-Treated Germ Cell Tumors

eFigure 1. Correlations Between Audiometrically Defined Hearing and WIN Performance; WIN Performance and Hearing Handicap Inventory - Adult (HHIA); and Audiometrically Defined Hearing With HHIA

eFigure 2. Percentage Testicular Cancer Survivors (TCS) in Each Normative Quartile, Displayed by Time and Dose

eMethods.

jamaoncol-e241233-s001.pdf^{(541.2KB, pdf)}

Supplement 2.

Data Sharing Statement

jamaoncol-e241233-s002.pdf^{(13.9KB, pdf)}

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PERMALINK

Comprehensive Audiologic Analyses After Cisplatin-Based Chemotherapy

Victoria A Sanchez, AuD, PhD

Paul C Dinh Jr, PhD

Patrick O Monahan, PhD

Sandra Althouse, MS

Jennessa Rooker, BSN

Howard D Sesso, ScD

M Eileen Dolan, PhD

Mandy Weinzerl, AuD

Darren R Feldman, MD

Chunkit Fung, MD

Lawrence H Einhorn, MD

Robert D Frisina, PhD

Lois B Travis, MD, ScD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Patients, Sociodemographics, Clinical Features, Health Behaviors, and Adverse Health Outcomes (AHOs)

Comprehensive Audiologic Assessments

Statistical Analyses

Results

Table 1. Sociodemographic Characteristics, Clinical Features, Health Behaviors, and Adverse Health Outcomes for Survivors of Cisplatin-Treated Germ Cell Tumorsa.

Table 2. Audiologic Features Stratified by Presence or Absence of Self-Reported Hearing Loss for 100 Survivors of Cisplatin-Treated Germ Cell Tumorsa.

Figure 1. Speech-in-Noise Perception Measured With the Words in Noise Test (WIN) and Displayed by Self-Reported Hearing Loss (HL).

Table 3. Multivariable Regression Models of Factors Associated With Speech-in-Noise Performance Measured With the Words-in-Noise (WIN) Test, and With Progression of Audiometrically Defined Hearing Loss.

Progression of Audiometrically Measured Hearing, Speech Recognition Threshold, and Word Recognition in Quiet

Figure 2. Audiologic Performance Stratified by Self-Reported Hearing Loss (HL).

Comparison With Normative Population

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 1. Sociodemographic Characteristics, Clinical Features, Health Behaviors, and Adverse Health Outcomes for Survivors of Cisplatin-Treated Germ Cell Tumors^a.

Table 2. Audiologic Features Stratified by Presence or Absence of Self-Reported Hearing Loss for 100 Survivors of Cisplatin-Treated Germ Cell Tumors^a.