Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer

Abstract

Purpose: Cisplatin is widely used but highly ototoxic. Effects of cumulative cisplatin dose on hearing loss have not been comprehensively evaluated in survivors of adult-onset cancer.

Patients and methods: Comprehensive audiological measures were conducted on 488 North American male germ cell tumor (GCT) survivors in relation to cumulative cisplatin dose, including audiograms (0.25 to 12 kHz), tests of middle ear function, and tinnitus. American Speech-Language-Hearing Association criteria defined hearing loss severity. The geometric mean of hearing thresholds (0.25 to 12 kHz) summarized overall hearing status consistent with audiometric guidelines. Patients were sorted into quartiles of hearing thresholds of age- and sex-matched controls.

Results: Increasing cumulative cisplatin dose (median, 400 mg/m(2); range, 200 to 800 mg/m(2)) was significantly related to hearing loss at 4, 6, 8, 10, and 12 kHz (P trends, .021 to < .001): every 100 mg/m(2) increase resulted in a 3.2-dB impairment in age-adjusted overall hearing threshold (4 to 12 kHz; P < .001). Cumulative cisplatin doses > 300 mg/m(2) were associated with greater American Speech-Language-Hearing Association-defined hearing loss severity (odds ratio, 1.59; P = .0066) and worse normative-matched quartiles (odds ratio, 1.33; P = .093) compared with smaller doses. Almost one in five (18%) patients had severe to profound hearing loss. Tinnitus (40% patients) was significantly correlated with reduced hearing at each frequency (P < .001). Noise-induced damage (10% patients) was unaffected by cisplatin dose (P = .59). Hypertension was significantly related (P = .0066) to overall hearing threshold (4 to 12 kHz) in age- and cisplatin dose-adjusted analyses. Middle ear deficits occurred in 22.3% of patients but, as expected, were not related to cytotoxic drug dosage.

Conclusion: Follow-up of adult-onset cancer survivors given cisplatin should include routine inquiry for hearing status and tinnitus, referral to audiologists as clinically indicated, and hypertension control. Patients should be urged to avoid noise exposure, ototoxic drugs, and other factors that further damage hearing.

Fig 1.

Representative left- and right-ear audiograms with varying levels of severity defined by American Speech-Language-Hearing Association criteria in the Platinum Study cohort. Results shown here are derived from patients age 28 to 35 years. The median (blue line) is derived from the normative cohort of men in each patient's respective age group (20 to 29 or 30 to 39 years; Table 4 in Engdahl et al 2005). Hearing loss classification: (A) normal hearing, (B) sensorineural, (C) mixed (sensorineural and conductive), (D) sensorineural, (E) sensorineural, (F) sensorineural.

Fig 2.

Distribution of hearing threshold levels (decibels of hearing loss) at each audiometric frequency (Hz; N = 488 patients). The threshold level for each patient represents the mean of left- and right-ear audiogram thresholds. Boxes define the interquartile range (IQR), and the gold horizontal line represents the median. The upper whisker extends from the third quartile to the highest value that is within 1.5 × IQR. The lower whisker extends from the first quartile to the lowest value within 1.5 × IQR. Outliers beyond 1.5 × IQR are plotted as individual data points.

Fig 3.

Severity of American Speech-Language-Hearing Association–defined hearing loss according to cumulative cisplatin dose group (mg/m²).

Fig 4.

(A) Comparison of overall hearing threshold (4 to 8 kHz) among study subjects with quartiles of age-specific normative data. Quartiles 1-4 represent the following normative percentile ranges, respectively: 10% to 24.9%, 25% to 49.9%, 50% to 74.9%, and 75% to 90%. (B) Comparison of the two cumulative cisplatin dose groups with quartiles of age-specific normative data.

Fig 5.

(A) Comparison of overall hearing threshold (4 to 12 kHz) to cumulative cisplatin dose. The P value is for the dose term in the following linear regression model: dB = dose + age at audiometry. (B) Comparison of overall hearing threshold (4 to 12 kHz) to the Scale for Chemotherapy-Induced Long-Term Neurotoxicity items for ringing in ears and reduced hearing. The P value is for the response term in the following linear regression model: dB = response + age at audiometry. (C) Comparison of speech recognition threshold to the Scale for Chemotherapy-Induced Long-term Neurotoxicity items for ringing in ears and reduced hearing. The P value is for the response term in the following linear regression model: dB = response + age at audiometry.

Fig A1.

Comparison of hearing thresholds at each audiometric frequency to cumulative dose of cisplatin (mg/m²). The P value represents the dose term in the following linear regression model: hearing threshold = dose + age at audiometry. The dose term effect size (β) and 95% CIs for each frequency are shown at lower right.