Individualized Objective Techniques for Early Detection of Ototoxicity

描述（由申请人提供）： 项目概述：顺铂的化疗对许多类型的癌症都非常有效。不幸的是，顺铂可以产生耳蜗损伤，导致不可逆的听力损失，如果继续治疗。预防或最大限度地减少耳蜗损伤至关重要，特别是在退伍军人人群中，在药物治疗之前，预先存在的听力损失往往存在。至少有30%的退伍军人在治疗过程中无法提供可靠的行为数据。一个快速，灵敏和可靠的非行为方法，不需要警觉和细心的病人将是必不可少的耳毒性监测计划。在当前的支持期间，我们开发了一个多变量耳毒性风险评估（ORA）模型，该模型结合了暴露前（药物治疗）听力图和累积顺铂剂量以及每次化疗访视时观察到的精细分辨率畸变产物耳声发射（DPOAE）水平变化。ORA是一种快速，灵敏和可靠的耳毒性检测仪，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，在临床使用之前，ORA必须经过验证。目的：第一个目的是在一组新的独立受试者中验证ORA。第二个目标是评估ORA是否可以通过使用多个DPOAE频率（2f 1-f2和2f 2-f1）或替代地通过使用刺激频率耳声发射（SFOAE）来进一步改善。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完成，SFOAE的测试时间仅略有增加。研究方法：研究期间，将在波特兰VA医学中心（PVAMC）对246例接受顺铂的受试者和30例接受非耳毒性化疗药物的对照受试者进行筛选。将在开始化疗方案后24小时内、每次后续治疗时和停止治疗后1个月，对每例受试者进行双侧常规和扩展高频行为测听阈值和精细结构OAE水平测量（DPOAE和SFOAE），精确度为1/48倍频程。将在PVAMC分析的化疗单元上进行测试：ORA将用于诊断每例受试者在每次监查访视时的听力变化。接受者工作特征曲线分析将用于评价ORA对该新样本的准确度，以解决目标1。目标2将通过使用SFOAE和多个DPOAE指标对候选奥拉斯进行留一法交叉验证分析来解决，并使用非参数统计检验与原始ORA进行比较。将使用离散时间生存分析评价目标3，以预测治疗过程中听力变化的风险，作为基线OAE测量值沿着其他患者因素的函数。该建议有三个主要优势，在以前的尝试，使用OAE测试早期检测耳毒性。首先，它是独特的，在其利用临床决策理论方法来评估测试性能和开发标准，以确定一个显着的变化，在OAE发生。其次，我们使用多变量方法，将在一系列频率范围内获得的OAE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的各个分量进行加权，使得这些分量的线性组合最好地区分具有耳毒性听力变化的顺铂治疗受试者的耳朵与没有耳毒性听力变化的耳朵。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。

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.