COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

Simon J Crabb,Ian Ratcliffe,Louise Stanton,Ben Lineton,Ronald Moody,Mary Ellis,Chris Nutting,Tom Maishman,Karen Martin,Mike Bayne,Angeliki Galanopoulou,Christian Ottensmeier,Thomas Geldart,Robert Huddart,Sanjay Popat,Carolynn Lamb,Roger Thornton,Julia Abab,John D Chester ,J M Davies ,A Hartley ,Johnathan Joffe ,Gareth J Thomas ,Emma V King

doi:10.1016/j.ejca.2017.09.033

Abstract

BackgroundCisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. MethodsA total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. ResultsAlthough aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. ConclusionsAspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.

Highlights

Cisplatin is a commonly used cytotoxic chemotherapeutic agent to treat a wide variety of cancer types, including head and neck, bladder, lung and germ-cell malignancies
Baseline hearing tests were recorded before receiving the first cisplatin dose and included pure tone audiometry (PTA) and otoacoustic emissions (OAEs)
The primary outcome was combined hearing loss in decibels, assessed as total post-treatment hearing after chemotherapy, adjusted for baseline total hearing. This was assessed in the intention-to-treat (ITT) cohort using an analysis of covariance (ANCOVA) model adjusted for treatment arm and the stratification factor cisplatin dose

Summary

Introduction

Cisplatin is a commonly used cytotoxic chemotherapeutic agent to treat a wide variety of cancer types, including head and neck, bladder, lung and germ-cell malignancies. In each of these diseases, cisplatin is used in curative as well as palliative treatment settings. Adverse effects of treatment which are irreversible will potentially impact on patients for prolonged periods of time, thereby reducing health-related qualityof-life. Cisplatin has well-documented side-effects, including one of the highest rates of ototoxicity of all chemotherapy agents [1,2]. Cisplatin-related ototoxicity includes high-frequency bilateral and symmetrical hearing loss, which may be permanent and irreversible and is often associated with tinnitus [2,3].

Methods

Results

Conclusion