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.

耳毒性是基于铂的化学疗法的公认毒性，所述基于铂的化学疗法经常用于治疗耳毒性。 治疗成人头颈部、肺、卵巢、睾丸和膀胱的实体瘤。的早期指标 耳毒性，这可能会促使采取干预措施，以潜在地预防与健康相关的影响和心理社会影响 对于这些患者，在没有直接听觉测量的情况下并不明显。国家听力学 指南规定，对所有高血糖患者进行耳毒性（OM）前瞻性监测， 这种有害的副作用的风险，以允许早期发现，听力康复，和潜在的修改， 药物治疗的效果之前，成为禁用。具体而言，对于接受顺铂的患者， 每种治疗方法都是推荐的实践（阿莎1994; AAA 2009）。根据我们目前的研究， 目标是那些将获得最大受益的患者，以便在VA中大规模实施。 本研究的目的是解决听力保健中对改善OM、诊断和 接受顺铂、卡铂和奥沙利铂化疗药物治疗的患者的临床干预 通过提供耳毒性机制的新知识，其功能表现，以及对 患者和供应商的观点。我们的总体方法是调查特定的 行为缺陷，病变部位，以及化疗患者的听力保健优先级，以了解 患者是否会出现耳毒性，他们可能会受到多大的损害，以及它是否会影响他们的日常生活 生活需要这些知识来将当前的OM实践模式转向更有效和临床可行的 方法，以便耳毒性风险升高的退伍军人可以通过以下方式解决他们的听觉问题 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 接受铂类化疗的退伍军人的耳毒性发生率;以及生成 当与患者-提供者团队优先级相结合时，将告知OM的个体耳毒性风险概况 资源分配、治疗前咨询和耳毒性药物治疗决策。知识增益 包括增加对耳鸣产生和言语理解缺陷的理解， 这些症状与潜在的耳毒性损伤有关。 了解更多关于耳毒性引起耳鸣和听力问题的机制 [Aim 1]，我们将完善和扩大我们以前发表的剂量耳毒性模型，并确定其效用， 预测个体患者听觉缺陷的变化。一个改进将包括预处理 ABR和DPOAE测量模型中，因为我们预计治疗后耳鸣和听力状态是一个 任何新的（耳毒性诱导的）损伤与预先暴露（年龄和/或噪声）的组合的功能， 相关）损害。感官和神经损伤将间接估计使用一种新的方法，结合 ABR和DPOAE（例如Bramhall等人，2017）。还将使用宽带估计神经变性。 声反射测试，它比传统测试更能激发对较低刺激水平的反射， 与ABR不同，在床边给药（Feeney et al. 2017）。确定耳毒性的临床影响[目的 2]我们将评估在背景噪声中语音理解受到损害的程度， 化疗治疗，使用操纵用于定位的时间线索的任务（加伦et al. 2013年）。耳鸣和听力障碍问卷将提供感知听觉功能障碍的知识。 关于临床影响和耳毒性机制的综合信息将创建耳毒性风险特征 根据患者的年龄、计划的化疗和暴露前内耳功能，国家 对肿瘤学家的调查将用于审查美国的肿瘤学和OM相关实践模式。 这些结果有望改变目前的听力学最佳实践建议， 推动在VA内外广泛实施OM。