## 1 Introduction
### Serial Monitoring for Ototoxic Therapies  
Serial monitoring of auditory function provides opportunities for identification of cochlear dysfunction at the earliest indications of ototoxicity. Ideally, this includes a baseline evaluation prior to exposure to potentially ototoxic therapies followed by regular monitoring evaluations at an interval dictated by the treatment regimen (typically, from weeks to months) to compare to the baseline evaluation (refer to [3; 4; 5]). Current clinical evaluations are focused to a limited frequency range (up to 8 kHz); however, this approach does not permit the earliest detection of ototoxicity, most likely to be observed at the highest frequencies (up to 20 kHz). Of note, higher frequency audiometry allows for earlier detection of damage from ototoxic agents than conventional audiometry [6]. However, pure-tone behavioral thresholds are subjective and can be dependent on aspects of the patient other than their auditory function. Patient populations receiving chemotherapeutic treatments may be difficult to test with pure-tone audiometry, exhibiting \"poor cooperation and easy distractibility\" due to their health status and levels of fatigue, causing unreliable results [7]. In a Veteran population, a substantial number (approximately 33%) of patients became unable or unwilling to participate in behavioral hearing testing [8]. This makes DPOAEs, an objective test not requiring patient participation, an ideal measure for monitoring.  
Many therapeutic agents used to treat cancer are often ototoxic, among these are platinum derivatives, such as cisplatin, oxaliplatin, and carboplatin, frequently impacting OHCs at the base of the cochlea first [3; 5; 9]. The damage caused by cisplatin is generally focused on the OHCs within the cochlea, starting with the OHCs in the cochlear base, and spreading more apically as the dose increases [10]. Damage spreads beyond OHCs to surrounding structures, including the stria vascularis, with increased exposure (see review by [3; 9]). Oxaliplatin has been shown in animal models to have comparable effects on the OHCs in the basal end of the cochlea [11]. The damage associated with carboplatin has been thought to impact inner hair cells (IHCs) more than OHCs in animal models [12; 13]; however, carboplatin has been shown to cause OHC loss in chinchillas [14], especially at higher doses [12; 15], and in humans [16]. In conjunction with these lifesaving treatment options, monitoring hearing is important to make adjustments to treatment dosage/protocol (if possible) and/or to provide intervention if their hearing declines [3]. Close monitoring of the auditory system while on an ototoxic drug regimen permits care teams the opportunity to manage treatment side effects, intervene when appropriate during the course of treatment as well as provide the patient with intervention methods (i.e., hearing aids, communication strategies, and aural rehabilitation) in a timely manner to optimize quality of life outcomes. DPOAEs are particularly important for ototoxic monitoring because they are correlated with OHC damage in animals (e.g., [17]), the portion of the auditory system predominately impacted by ototoxic therapies [10; 11]. Monitoring OHC function directly can allow for the earliest actions to be taken in either preventing further damage or providing audiologic intervention. Due to the ability of DPOAE measures to assess the status of OHCs, they are distinctively qualified to give information about the health of OHCs and give insight into potential damage from ototoxic therapies.