12th Yahya Cohen Memorial Lecture – The Cellular and Molecular Basis of Radiation-induced Sensori-neural Hearing Loss

Abstract

Introduction: Sensori-neural hearing loss (SNHL) is a frequent complication of conventional radiotherapy for head and neck tumours, especially nasopharyngeal carcinoma. To manage radiation-induced ototoxicity appropriately, an understanding of the cellular and molecular basis of this complication is necessary. Materials and Methods: A medline search of relevant literature was done, focusing on the radiation-induced cellular and molecular processes that lead to hair cell death in the cochlea. Results:Radiation-induced SNHL occurs in the cochlea, with the retro-cochlear pathways remaining functionally intact. By simulating radiotherapy regimes used clinically, radiation-induced cochlear cell degeneration in the absence of damage to the supporting structures and blood vessels has been demonstrated in animals. This could be due to apoptotic cochlear cell death, which has been shown to be associated with p53 upregulation and intra-cellular reactive oxygen species (ROS) generation. Oxidative stress may initiate the upstream processes that lead to apoptosis and other cell death mechanisms. Conclusions: A model of radiation-induced SNHL based on a dose and ROS-dependant cochlear cell apoptosis, is proposed. This model supports the feasibility of cochlear implantation, should one be clinically indicated. It can explain clinical observations such as radiation-induced SNHL being dose-dependent and affects the high frequencies more than the lower frequencies. It also opens up the possibility of preventive strategies targeted at different stages of the apoptotic process. Antioxidants look promising as effective agents to prevent radiation-induced ototoxicity; they target upstream processes leading to different cell death mechanisms that may co-exist in the population of damaged cells. Radiation-induced sensori-neural hearing loss (SNHL) has long been recognised as a complication of radiotherapy (RT) for head and neck tumours, if the auditory pathways had been included in the radiation fields. In Singapore, nasopharyngeal carcinoma (NPC) is common and the prevalence of SNHL after radiotherapy for NPC has been reported to be as high as 24%. Radiation-induced ototoxicity is therefore an important clinical problem in Singapore. To be able to manage radiation-induced ototoxicity appropriately, a good understanding of the cellular and molecular basis of this complication is necessary. Key words: Apoptosis, Deafness, Hair cell, Ototoxicity, Radiotherapy