Physiological, Behavioral and Predictive Correlates of Ototoxicity in Humans

点击翻译按钮获取中文摘要

Ototoxicity is a well-established toxicity of the platinum-based chemotherapies that are in frequent use for the treatment of solid tumors of the head and neck, lung, ovary, testicle, and bladder in adults. Early indicators of ototoxicity, which could prompt intervention to potentially prevent the health-related and psychosocial impacts for these patients, are not apparent in the absence of direct auditory measurement. National audiology guidelines, have stipulated that prospective monitoring for ototoxicity (OM) be conducted for all patients at high risk for this harmful side effect to allow for early detection, aural rehabilitation, and potential modification of the drug treatment before the effects become disabling. Specifically, for patients receiving cisplatin, monitoring prior to each treatment is recommended practice (ASHA 1994; AAA 2009). Based on our current research, OM must target those patients who will receive the most benefit to be feasible for large-scale implementation in VA. The goal of this study is to address the critical need in hearing healthcare for improved OM, diagnoses and clinical interventions in patients receiving treatment with cisplatin, carboplatin, and oxaliplatin chemotherapeutics by providing new knowledge of the mechanisms of ototoxicity, its functional manifestation, and new insights on the patient and provider perspective. Our overall approach is to investigate relationships among the specific behavioral deficits, sites of lesion, and hearing healthcare priorities of chemotherapy patients to learn which patients will develop ototoxicity, how much damage they can expect, and whether it will impact their everyday life. This knowledge is needed to shift current OM practice patterns toward a more effective and clinically feasible approach so that Veterans at elevated risk for ototoxicity could have their auditory concerns addressed through patient-centered OM, rehabilitation and/or drug therapy interventions. Clinical impacts include estimates of ototoxicity incidence for Veterans receiving platinum-based chemotherapeutic treatments; and tools to generate an individual ototoxicity risk profile that when combined with the patient-provider team priorities, will inform OM resource allocation, pre-treatment counseling, and decision making for ototoxic drug treatment. Knowledge gains include increased understanding of tinnitus generation and speech understanding deficits and the implications of these symptoms regarding the underlying ototoxic injury. To understand more about the mechanisms underlying ototoxicity-caused tinnitus and hearing problems [Aim 1], we will refine and expand our previously published dose-ototoxicity model and determine its utility for predicting changes in auditory deficits for individual patients. One refinement will be to include pre-treatment ABR and DPOAE measures in the model because we expect post-treatment tinnitus and hearing status to be a function of the combination of any new (ototoxicity-induced) damage with pre-exposure (age and/or noise- related) damage. Sensory and neural damage will be indirectly estimated using a novel approach that combines ABRs and DPOAEs (e.g. Bramhall et al. 2017). Neurodegeneration will also be estimated using wideband acoustic reflex testing, which elicits the reflex to lower stimulus levels than traditional tests, and can be administered at bedside unlike ABR (Feeney et al. 2017). To determine the clinical impacts of ototoxicity [Aim 2] we will assess the extent to which speech understanding in background noise is compromised following chemotherapy treatment, using a task that manipulates the temporal cues used for localization (Gallun et al. 2013). Tinnitus and hearing handicap questionnaires will provide knowledge of perceived auditory dysfunction. Combined information about the clinical impacts and ototoxicity mechanisms will create ototoxicity risk profiles for individual patients based on their age, planned chemotherapy, and pre-exposure inner ear function. A national survey of oncologists will be used to review oncology- and OM-related practice patterns in the US. These results are expected to change current audiological best practice recommendations and are crucial to advance widespread implementation of OM both within and outside VA.