Individualized Objective Techniques for Early Detection of Ototoxicity

早期检测耳毒性的个体化客观技术

• 批准号: 8894387
• 负责人: Marilyn F. Dille
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894387
• 关键词: Address; Affect; Audiology; Audiometry; Auditory; Auditory Brainstem Responses; Behavioral; Cell physiology; Characteristics; Chemotherapy-Oncologic Procedure; Cisplatin; Clinic; Clinical; Clinical Trials; Communication impairment; Counseling; Data; Decision Theory; Diagnosis; Diagnostic; Disabled Persons; Dose; Ear; Early Diagnosis; Exposure to; Frequencies; Funding; Future; Gold; Healthcare; Hearing; Hearing Tests; Individual; Intervention; Investigation; Lead; Left; Measurement; Measures; Medical; Medical center; Methodology; Methods; Modeling; Monitor; Noise; Outcome; Outer Hair Cells; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Predisposition; Procedures; Receiver Operating Characteristics; Rehabilitation therapy; Research; Resolution; Resource Allocation; Risk; Risk Assessment; Sampling; Stimulus; Structure; Survival Analysis; Techniques; Testing; Time; Travel; Treatment Protocols; Validation; Veterans; Visit; Weight; Withholding Treatment; base; behavior test; cancer type; chemotherapy; clinical application; design; detector; dosage; evidence base; experience; handicapping condition; hearing impairment; improved; otoacoustic emission; ototoxicity; ototoxin; performance tests; prevent; programs; treatment planning

DESCRIPTION (provided by applicant): Project Summary: Chemotherapeutic treatment with cisplatin is highly effective against many types of cancer. Unfortunately, cisplatin can produce cochlear damage resulting in irreversible hearing loss if treatment continues. Preventing or minimizing cochlear damage is critical, especially in a population of Veterans where pre-existing hearing losses are often present prior to drug treatment. At least 30% of Veterans become unable to provide reliable behavioral data during the course of their treatment. A rapid, sensitive and reliable non-behavioral method that does not require an alert and attentive patient would be indispensable for an ototoxicity monitoring program. During the current support period, we developed a multivariate ototoxicity risk assessment (ORA) model combining the pre-exposure (to medication) audiogram and cumulative cisplatin dose with fine resolution distortion-product otoacoustic emission (DPOAE) level changes observed at each chemotherapeutic visit. The ORA is a quick, sensitive and reliable detector of ototoxicity that can provide hearing information for those Veterans who are unable to take a hearing test. Before it can be used in the clinic, however, the ORA must be validated. Objectives: The first objective is to validate the ORA on a new and independent group of subjects. The second objective is to evaluate if the ORA can be improved even further by using multiple DPOAE frequencies (2f1-f2 and 2f2-f1) or, alternatively, by using stimulus-frequency otoacoustic emissions (SFOAEs). The third objective is to determine if OAEs can predict an individual's susceptibility for hearing change during future treatment with cisplatin. Objectives 2 and 3 can be accomplished using the validation procedures with only a small increase in testing time for the SFOAEs. Methods: Two hundred and forty-six subjects receiving cisplatin and 30 control subjects receiving non-ototoxic chemotherapy medications will be screened at the Portland VA Medical Center (PVAMC) during the study period. Behavioral audiometric thresholds at conventional and extended high frequencies and fine structure OAE level measures (DPOAEs and SFOAEs) with 1/48th-octave precision will be obtained bilaterally on each subject within 24hrs of starting their chemotherapy regimen, at each subsequent treatment and at one-month after cessation of treatment. Testing will be done on the chemotherapy unit at PVAMC Analysis: The ORA will be used to diagnose hearing change for each subject at each monitoring visit. Receiver Operating Characteristic curve analysis will be used to evaluate the accuracy of the ORA on this new sample to address aim #1. Aim #2 will be addressed using leave-one-out cross-validation analysis of candidate ORAs using SFOAE and multiple DPOAE measures and compared to the original ORA using non-parametric statistical tests. Aim #3 will be evaluated using discrete-time survival analysis to predict the risk of hearing change over the course of treatment as a function of baseline OAE measurements along with other patient factors. This proposal has three major strengths over previous attempts to use OAE testing for the early detection of ototoxicity. First, it is unique in its utilization of Clinical Decision Theory methodology for evaluating test performance and developing criteria for determining that a significant change in the OAE has occurred. Second, we use a multivariate approach by combining OAEs obtained over a range of frequencies with pre-cisplatin exposure hearing data and the cisplatin cumulative dose, in order to obtain the ototoxicity risk assessment. Finally, individual components of the ORA are weighted such that the linear combination of these components best distinguishes ears of cisplatin-treated subjects with ototoxic hearing change from those without. The final ORA diagnostic model will be selected from a set of competing models using cross validation procedures.

描述（由申请人提供）： 项目摘要：顺铂化疗对多种癌症非常有效。不幸的是，如果继续治疗，顺铂会造成耳蜗损伤，导致不可逆转的听力损失。预防或最大程度地减少耳蜗损伤至关重要，特别是对于退伍军人群体来说，在药物治疗之前通常就已经存在听力损失。至少 30% 的退伍军人在治疗过程中无法提供可靠的行为数据。一种快速、灵敏和可靠的非行为方法，不需要患者警惕和专心，对于耳毒性监测计划是必不可少的。在当前的支持期内，我们开发了一种多变量耳毒性风险评估 (ORA) 模型，将暴露前（药物）听力图和累积顺铂剂量与每次化疗就诊时观察到的精细分辨率畸变产物耳声发射 (DPOAE) 水平变化相结合。 ORA 是一种快速、灵敏且可靠的耳毒性检测仪，可为无法进行听力测试的退伍军人提供听力信息。然而，在临床使用之前，ORA 必须经过验证。目标：第一个目标是在一组新的独立受试者上验证 ORA。第二个目标是评估是否可以通过使用多个 DPOAE 频率（2f1-f2 和 2f2-f1）或使用刺激频率耳声发射 (SFOAE) 进一步改善 ORA。第三个目标是确定 OAE 是否可以预测个体在未来顺铂治疗期间对听力变化的易感性。目标 2 和 3 可以使用验证程序来实现，只需少量增加 SFOAE 的测试时间。方法：在研究期间，将在波特兰退伍军人管理局医疗中心 (PVAMC) 对 246 名接受顺铂的受试者和 30 名接受非耳毒性化疗药物的对照受试者进行筛查。将在开始化疗方案后 24 小时内、每次后续治疗以及停止治疗后一个月内，获得每位受试者双侧常规和扩展高频的行为听力阈值以及精度为 1/48 倍频程的精细结构 OAE 水平测量（DPOAE 和 SFOAE）。测试将在 PVAMC 的化疗装置上进行 分析：ORA 将用于在每次监测访视时诊断每个受试者的听力变化。接收者操作特征曲线分析将用于评估此新样本的 ORA 准确性，以实现目标 1。目标 #2 将通过使用 SFOAE 和多个 DPOAE 测量对候选 ORA 进行留一交叉验证分析来解决，并使用非参数统计测试与原始 ORA 进行比较。将使用离散时间生存分析来评估目标#3，以预测治疗过程中听力变化的风险，作为基线 OAE 测量值以及其他患者因素的函数。与之前使用 OAE 测试早期检测耳毒性的尝试相比，该提案具有三个主要优点。首先，它的独特之处在于利用临床决策理论方法来评估测试性能并制定确定 OAE 是否发生重大变化的标准。其次，我们采用多变量方法，将一系列频率下获得的 OAE 与顺铂暴露前听力数据和顺铂累积剂量相结合，以获得耳毒性风险评估。最后，对 ORA 的各个分量进行加权，以便这些分量的线性组合能够最好地区分顺铂治疗的具有耳毒性听力变化的受试者的耳朵与没有耳毒性听力变化的受试者的耳朵。最终的 ORA 诊断模型将使用交叉验证程序从一组竞争模型中选出。