Individualized Objective Techniques for Early Detection of Ototoxicity

描述(由申请人提供)： 项目简介：顺铂化疗对多种癌症都有很好的疗效。不幸的是，如果继续治疗，顺铂可能会产生耳蜗损伤，导致不可逆转的听力损失。预防或最大限度地减少耳蜗损伤是至关重要的，特别是在退伍军人群体中，先前存在的听力损失通常出现在药物治疗之前。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，不需要警觉和专心的患者，将是耳毒性监测计划不可或缺的。在目前的支持期间，我们开发了一个多变量耳毒性风险评估(ORA)模型，将暴露前(药物)听力图和顺铂累积剂量与每次化疗访问时观察到的精细分辨率失真产物耳声发射(DPOAE)水平变化相结合。ORA是一种快速、灵敏和可靠的耳毒性检测器，可以为那些无法进行听力测试的退伍军人提供听力信息。然而，在它可以在临床上使用之前，ORA必须经过验证。目标：第一个目标是在一组新的和独立的受试者身上验证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)或通过使用刺激频率耳声发射(SFOAE)来进一步改善ORA。第三个目标是确定耳声发射是否能预测个体在未来接受顺铂治疗期间听力变化的易感性。目标2和目标3可以使用验证程序来实现，而SFOAE的测试时间只会略有增加。方法：在研究期间，波特兰退伍军人医学中心将对246名接受顺铂治疗的受试者和30名接受非耳毒性化疗药物的对照组受试者进行筛查。每个受试者将在化疗开始后24小时内，在每次后续治疗和停止治疗后一个月内，获得常规和扩展高频下的行为听力学阈值和精确到1/48倍频程的精细结构OAE水平测量(DPOAEs和SFOAEs)。测试将在PVAMC分析公司的化疗单元上进行：ORA将在每次监测访问时用于诊断每个受试者的听力变化。将使用接收器操作特征曲线分析来评估针对目标1的新样本的ORA的准确性。将使用SFOAE和多个DPOAE测量对候选ORA进行留一交叉验证分析，并使用非参数统计检验将其与原始ORA进行比较。目的#3将使用离散时间生存分析进行评估，以预测治疗过程中听力变化的风险，作为基线耳声发射测量和其他患者因素的函数。与以前使用耳声发射测试早期检测耳毒性的尝试相比，这一提议有三个主要优势。首先，它的独特之处在于它使用临床决策理论方法来评估测试性能，并制定确定耳声发射是否发生重大变化的标准。其次，我们使用多变量方法，将在一定频率范围内获得的耳声发射与顺铂暴露前的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的单个组件进行加权，以便这些组件的线性组合最好地区分有耳毒性听力变化的顺铂治疗受试者的耳朵和没有改变的受试者的耳朵。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择。 公共卫生相关性： 项目简介：使用个性化行为和客观技术的全面耳毒性监测计划将显著减少需要昂贵康复费用的永久性致残听力损失退伍军人的数量。在目前的支持期间，我们开发了一个多变量耳毒性风险评估(ORA)模型，将暴露前(药物)听力图和顺铂累积剂量与每次化疗访问时观察到的精细分辨率失真产物耳声发射(DPOAE)水平变化相结合。这种多变量ORA模型在无法直接测量耳毒性听力变化时具有很高的精确度。然而，在它可以用于临床之前，ORA模型必须得到验证。进一步的改进，例如可以通过联合使用2f1-f2和2f2-f1 DPOAE或刺激频率耳声发射来实现，对于听力损失更大的患者也是可取的。

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. PUBLIC HEALTH RELEVANCE: Project Narrative: A comprehensive ototoxicity monitoring program using individualized behavioral and objective techniques will significantly reduce the number of Veterans who suffer permanent disabling hearing loss requiring costly rehabilitation. 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. This multivariate ORA model is highly accurate at detecting ototoxic hearing changes when they cannot be directly measured. Before it can be used in the clinic, however, the ORA model must be validated. Further improvements, such as may be accomplished through the combined use of 2f1-f2 and 2f2-f1 DPOAEs or stimulus- frequency otoacoustic emissions, are also desirable for testing patients with greater hearing loss.