Physiological, Behavioral and Predictive Correlates of Ototoxicity in Humans

人类耳毒性的生理、行为和预测相关性

• 批准号: 10350588
• 负责人: DAWN L KONRAD-MARTIN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350588
• 关键词: Address; Adult; Adverse effects; Aftercare; Age; Aging; Animal Model; Audiology; Auditory; Auditory Brainstem Responses; Behavioral; Bladder; Cancer Center; Cancer Survivor; Carboplatin; Caring; Cisplatin; Clinic; Clinical; Cochlea; Cognitive; Communication; Communication impairment; Comprehensive Cancer Center; Counseling; Cueing for speech; Cues; Decision Making; Diagnosis; Dose; Early Diagnosis; Functional disorder; Generations; Goals; Guidelines; Head and Neck Neoplasms; Health; Healthcare; Hearing; Hearing Tests; Hearing problem; Human; Hyperacusis; Incidence; Individual; Injury; Intervention; Knowledge; Labyrinth; Learning; Lesion; Letters; Life; Lung; Measurement; Measures; Methods; Modeling; Monitor; Morbidity - disease rate; National Cancer Institute; Nerve Degeneration; Neuronal Plasticity; Noise; Oncologist; Oncology; Outcome; Outer Hair Cells; Ovary; Patient Self-Report; Patient risk; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Platinum; Policies; Predisposition; Provider; Publishing; Quality of life; Questionnaires; Recommendation; Reflex action; Rehabilitation therapy; Research; Resource Allocation; Risk; Risk Assessment; Sampling; Sensory; Site; Solid Neoplasm; Speech; Speech Perception; Stimulus; Surveys; Symptoms; System; Testing; Testis; Therapeutic Intervention; Time; Tinnitus; Toxic effect; Universities; Veterans; Visit; Washington; Work; acoustic reflex; auditory pathway; aural rehabilitation; base; chemobrain; chemotherapy; cisplatin induced hearing loss; cost effective; diagnostic tool; drug modification; early awareness; experience; follow-up; hearing impairment; high risk; improved; individual patient; injury burden; insight; medical schools; neoplasm registry; novel diagnostics; novel strategies; otoacoustic emission; ototoxicity; oxaliplatin; patient oriented; predictive modeling; prevent; processing speed; prospective; psychosocial; relating to nervous system; side effect; sound; speech in noise; standard of care; survivorship; tool

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.

耳毒性是以铂为基础的化疗药物的一种公认的毒性，这些化疗药物经常用于 治疗成人头颈部、肺、卵巢、睾丸、膀胱等实体肿瘤。早期指标 耳毒性，这可能促使进行干预，以潜在地预防与健康有关的和心理社会影响 对于这些患者，在没有直接听觉测量的情况下并不明显。民族听力学 指南规定，对所有处于高水平的患者进行前瞻性耳毒性(OM)监测 这种有害副作用的风险，以便及早发现、听力康复和潜在的修改 在药效失效之前进行药物治疗。具体地说，对于接受顺铂的患者，监测之前 每种治疗都有推荐做法(Asha，1994；AAA，2009)。根据我们目前的研究，OM必须 以那些将获得最大利益的患者为目标，以便在退伍军人管理局大规模实施。 这项研究的目标是解决听力保健中改善OM、诊断和治疗的关键需求 接受顺铂、卡铂和奥沙利铂化疗的患者的临床干预 通过提供关于耳毒性机制的新知识，其功能表现，以及对 从患者和提供者的角度来看。我们的总体方法是调查特定的 了解化疗患者的行为缺陷、病变部位和听力保健优先事项 患者会出现耳毒性，他们可能会受到多大的损害，以及这是否会影响他们的日常生活 生活。需要这种知识来将当前的OM实践模式转变为更有效和临床可行的模式 方法，以便耳毒性风险较高的退伍军人可以通过 以患者为中心的OM、康复和/或药物治疗干预。临床影响包括估计 接受基于铂的化疗治疗的退伍军人的耳毒性发生率；以及产生 个人耳毒性风险概况，当与患者-提供者团队的优先事项相结合时，将告知OM 耳毒性药物治疗的资源分配、治疗前咨询和决策。知识收益 包括对耳鸣的产生和言语理解缺陷及其影响的更多了解 关于潜在的耳毒性损伤的这些症状。 进一步了解耳毒性引起的耳鸣和听力问题的机制 [目标1]，我们将改进和扩展我们之前发表的剂量-耳毒性模型，并确定其在 为个别患者预测听力缺陷的变化。一项改进将包括预处理 ABR和DPOAE在模型中进行测量，因为我们预计治疗后耳鸣和听力状态是 任何新的(耳毒性引起的)损害与暴露前(年龄和/或噪声- 相关)损坏。感觉和神经损伤将使用一种新的方法间接评估，该方法结合了 ABR和DPOAE(例如，BramHall等人2017年)。神经退行性变也将使用宽带进行估计 声反射测试，它可以引起比传统测试更低的刺激水平的反射，并且可以 与ABR不同，在床边给药(Feeney等人)。2017年)。确定耳毒性的临床影响 2]我们将评估在背景噪声中的语音理解受到损害的程度 化疗，使用操纵用于定位的时间线索的任务(Gallun等人)。 2013年)。耳鸣和听力障碍问卷将提供感知到的听力障碍的知识。 有关临床影响和耳毒性机制的综合信息将创建耳毒性风险概况 针对个别患者，根据他们的年龄、化疗计划和暴露前的内耳功能。一名国民 对肿瘤学家的调查将用于审查美国肿瘤学和OM相关的实践模式。 这些结果预计将改变目前的听力学最佳实践建议，并对 推动退伍军人事务部内部和外部广泛实施OM。