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.

Abstract

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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).<h4>Interpretation</h4>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.<h4>Funding</h4>The National Cancer Institute.