COAST (Cisplatin Ototoxicity Attenuated by Aspirin Trial): A phase II double blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing loss


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Emma King1,Simon Crabb1,Karen Martin1,Julia Abab1,Ian Ratcliffe1,Roger Thornton1,Ben Lineton1,Mary Ellis1,Ron Moody2,Louise Stanton1,Tom Geldart3,Mike Bayne4,Joe Davies5,Carolynn Lamb6,Sanjay Popat7,Christopher Nutting7,John Chester8,Andrew Hartley9,Gareth Thomas1,Christian Ottensmeier1,Robert Huddart10,Keith Pugh11
1University of Southampton,2Patient representative,3Royal Bournemouth Hospital Trust,4Poole Hospital NHS Foundation Trust,5Poole Hospital NHS Foundation Tru,6University of Glasgow,7Royal Marsden Hospital,8University of Cardiff,9University of Birmingham,10Royal marsden hospital,11Southampton Clinical Trials Unit

Abstract

Background

Cisplatin has the highest ototoxic potential of platinum containing drugs leaving 50% of patients with a permanent and irreversible hearing-loss, and associated reduction in quality of life. There are no preventative treatment strategies to minimise this common side-effect. Both 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 tested the hypothesis that aspirin could reduce ototoxicity from cisplatin based chemotherapy.

Method

94 patients were recruited into a phase II, double blind, placebo controlled, 2-arm trial, and randomised 1:1 from multiple tumour-sites (head and neck, thoracic, bladder, germ cell) in the U.K. Patients underwent pure tone audiometry (PTA) before, and following their final cisplatin dose at 7 and 90 days. Patients received aspirin 975mg tid and omeprazole 20 mg od, or placebos; from the day before, to 2 days after their cisplatin dose, for each cisplatin cycle. The primary endpoint was total hearing difference, comparing pre- and post-cisplatin PTA at 6 and 8kHz in both ears.

Results

Although aspirin was well-tolerated, it did not protect protect hearing in patients receiving cisplatin [mean difference 9.38 60% CI (-1.45, 20.22) one sided p-value of 0.233 in favour of placebo 71% (56/79) patients demonstrated hearing loss following cisplatin administration (median loss of 35db IQR 0-90 range -85 to 180, mean 42.4 SD 56.3). The extent of hearing-loss was not associated with cisplatin dose, age or hearing loss at presentation. Patients undergoing treatment for head and neck malignancy experienced the biggest hearing loss.

Conclusion

Aspirin was well-tolerated but did not protect hearing suggesting that cisplatin and gentamicin may have distinct ototoxic mechanisms or that cisplatin is more ototoxic, requiring larger protective doses. Cisplatin induced ototoxicity results in significant morbidity and further research is required to prevent it.