EClinicalMedicine · 2026
Impact of cisplatin dose, renal function, and other factors on audiometrically-assessed ototoxicity in more than 1400 adult-onset cancer survivors from The Platinum Study: a multicentre cohort study.
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Sanchez Victoria A, Dinh Paul C, Monahan Patrick O, Fung Chunkit, Althouse Sandra, Stump Tim, Rooker Jennessa, Dolan M Eileen, Feldman Darren R, Hamilton Robert J, Pierorazio Phillip M, Martin Neil E, Huddart Robert, Kollmannsberger Christian, Root James, Sesso Howard D, Weinzierl Mandy, Einhorn Lawrence H, Frisina Robert D, Travis Lois B
Аннотация
BACKGROUND: Cisplatin is broadly used, but it is nephrotoxic and ototoxic. No large-scale investigation has analysed cisplatin-related ototoxicity while considering quantified renal function, cumulative dose, comorbidities, and modifiable risk factors. Our aim was to fill this knowledge gap.
METHODS: The Platinum Study is a well-characterised multicentre cohort study of cisplatin-treated testicular cancer survivors enrolled 2012-18 in eight academic cancer centres in the USA, Canada, and the UK, with follow-up ongoing. Measures include audiometrically assessed hearing (0.25-12 kHz), real-world speech-in-noise perception, and hearing loss progression. Multivariable analyses evaluated associations of audiometrically-assessed hearing with estimated glomerular filtration rate (eGFR), comorbidities, health-behaviours, and cisplatin dose. Mediation analyses tested direct and indirect eGFR contributions to ototoxicity and eGFR-dose interactions.
FINDINGS: Among 1422 survivors (median age 38 years, IQR 31-47), ototoxicity affected 1061 (75%), and audiometrically-assessed hearing was significantly associated with cumulative cisplatin dose (β = 8.72 per 100 mg/m2, p = 0.0004), reduced eGFR (β = 3.90 per 20 mL/min/1.73 m2, p = 0.043), hypertension (β = 4.06, p = 0.0005), non-White race (β = 3.26, p = 0.014), physical inactivity (β = -0.24 per 1000 kCal/week, p = 0.034), and age (β = 5.21 per 5 years, p < 0.0001). Cisplatin dose significantly interacted with eGFR (p = 0.017); 7.2% (95% CI 0.9-18.8; p < 0.05) of cisplatin's ototoxicity was mediated through reduced eGFR and 5.6% (0.4-16.1; p < 0.05) through interaction effects. Poorer speech-in-noise perception was associated with cognitive dysfunction (β = 1.01, p = 0.026), hypercholesterolaemia without statin use (β = 0.71, p = 0.029), lower education (β = 0.91, p = 0.0098), and hearing loss severity (β = 0.08, p < 0.0001). Hearing loss progression was associated with age (β = 0.30, p < 0.0001), while statin use for hypercholesterolaemia was protective (β = -4.09, p = 0.0048).
INTERPRETATION: Cisplatin's dose-dependent ototoxicity is amplified by its nephrotoxicity, with the dose-response becoming stronger as eGFR worsens. Given age-related declines in both eGFR and hearing, follow-up of cisplatin-treated survivors should monitor both, and include strict control of cardiovascular risk factors. Statin use for hypercholesterolaemia appeared protective against hearing loss progression, suggesting a potential therapeutic intervention for reducing long-term auditory complications in this population.
FUNDING: The National Cancer Institute.
METHODS: The Platinum Study is a well-characterised multicentre cohort study of cisplatin-treated testicular cancer survivors enrolled 2012-18 in eight academic cancer centres in the USA, Canada, and the UK, with follow-up ongoing. Measures include audiometrically assessed hearing (0.25-12 kHz), real-world speech-in-noise perception, and hearing loss progression. Multivariable analyses evaluated associations of audiometrically-assessed hearing with estimated glomerular filtration rate (eGFR), comorbidities, health-behaviours, and cisplatin dose. Mediation analyses tested direct and indirect eGFR contributions to ototoxicity and eGFR-dose interactions.
FINDINGS: Among 1422 survivors (median age 38 years, IQR 31-47), ototoxicity affected 1061 (75%), and audiometrically-assessed hearing was significantly associated with cumulative cisplatin dose (β = 8.72 per 100 mg/m2, p = 0.0004), reduced eGFR (β = 3.90 per 20 mL/min/1.73 m2, p = 0.043), hypertension (β = 4.06, p = 0.0005), non-White race (β = 3.26, p = 0.014), physical inactivity (β = -0.24 per 1000 kCal/week, p = 0.034), and age (β = 5.21 per 5 years, p < 0.0001). Cisplatin dose significantly interacted with eGFR (p = 0.017); 7.2% (95% CI 0.9-18.8; p < 0.05) of cisplatin's ototoxicity was mediated through reduced eGFR and 5.6% (0.4-16.1; p < 0.05) through interaction effects. Poorer speech-in-noise perception was associated with cognitive dysfunction (β = 1.01, p = 0.026), hypercholesterolaemia without statin use (β = 0.71, p = 0.029), lower education (β = 0.91, p = 0.0098), and hearing loss severity (β = 0.08, p < 0.0001). Hearing loss progression was associated with age (β = 0.30, p < 0.0001), while statin use for hypercholesterolaemia was protective (β = -4.09, p = 0.0048).
INTERPRETATION: Cisplatin's dose-dependent ototoxicity is amplified by its nephrotoxicity, with the dose-response becoming stronger as eGFR worsens. Given age-related declines in both eGFR and hearing, follow-up of cisplatin-treated survivors should monitor both, and include strict control of cardiovascular risk factors. Statin use for hypercholesterolaemia appeared protective against hearing loss progression, suggesting a potential therapeutic intervention for reducing long-term auditory complications in this population.
FUNDING: The National Cancer Institute.