Concurrent chemoradiotherapy with three 100 mg/m2 cisplatin cycles administered every 3 weeks is the standard treatment regimen for head and neck squamous cell carcinoma in both adjuvant and definitive therapy settings. Cumulative cisplatin doses frequently induce severe acute toxicities, including hearing loss, affecting up to 80% of adult patients (Frisina et al., 2016). The substantial inter-individual variability in the development and severity of hearing loss suggests a genetic predisposition to cisplatin-induced ototoxicity. Hearing outcomes have been associated with several genetic polymorphisms using pure-tone audiometry (PTA) as the gold-standard assessment method (Brown et al., 2015; Clemens et al., 2020; Drögemöller et al., 2017; Meijer et al., 2021; Spracklen et al., 2017; Xu et al., 2015). Such genes are expressed in the cochlear tissues and are functionally involved in the cellular antioxidant detoxification system, such as GSTT1, GSTM1, GSTP1, NFE2L2, and SOD2, or potentially related to cisplatin transporters, such as LRP2, SLC22A2, and SLC16A5. However, the genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear because of the small effect size of each variant.

In the early stages of ototoxicity, cisplatin uptake into the cochlea increases the production of reactive oxygen species (ROS), which promote outer hair cell (OHC) degeneration, causing progressive hearing loss (Rybak et al., 2007). Distortion product otoacoustic emissions (DPOAEs) are considered the ideal method for detecting early ototoxicity, as they provide an objective measure of active cochlear responses that primarily involve OHC electromotility (Ashmore, 2008). Reavis et al. established frequency- and time-specific reference limits for the retest variability of DPOAE levels and considered level shifts larger than the corresponding reference limit to be clinically significant (Reavis et al., 2015). Thus, early DPOAE level changes after initial cisplatin administration can be a sensitive marker for cochlear cisplatin vulnerability before PTA threshold changes become apparent (Konrad-Martin et al., 2016).

In this study, we measured DPOAE levels 21 days after the initial cisplatin cycle in patients with head and neck cancer undergoing chemoradiotherapy with high-dose cisplatin cycles. Based on whether DPOAE changes exceeded the corresponding reference limit, the patients were grouped into the “early ototoxicity present” and “early ototoxicity absent” groups, and the development and severity of cisplatin-induced hearing loss were compared between the groups. Furthermore, we investigated the relationship between early ototoxicity and the genetic polymorphisms associated with cisplatin-induced ototoxicity. This study aimed to gain insight into the genotype-phenotype relationship in cisplatin-induced ototoxicity, allowing for early intervention in sensitive patients for better long-term functional outcomes.