Subjects were initially assigned to either the nonstatin user group or the statin user group based on their use of any statin medication at the start of cisplatin treatment. Based on the prevalence of each statin type within the statin user group (Table 2), we also examined atorvastatin and simvastatin in isolation. Both ears were used in the data analyses because of possible influences of asymmetric hearing losses either at baseline (observed in 12% of all subjects, defined as a ≥15 dB difference in the PTA of 0.5, 1, 2, and 4 kHz) and/or a result of differential radiation doses to the 2 cochleas because high doses of radiation (≥45 Gy) have been reported to be ototoxic (43). Including both ears from each subject introduces correlation among observations that can incorrectly reduce the standard error of certain estimates. We corrected for this bias by including subject-specific random intercepts in the statistical model (56). This method allowed us to make use of all of the data from each ear while accounting for the fact that the 2 ears of each individual will be correlated.

A 2-way ANOVA using Dunnett’s post hoc multiple-comparison test (GraphPad Prism 8) was conducted to compare the threshold shifts as a function of frequency (0.25–12.5 kHz) between nonstatin users and subjects taking any statin, atorvastatin, or simvastatin. However, although the comparison between atorvastatin and nonstatin users remained sufficiently powered (>0.8), our study was underpowered for the comparison of simvastatin users versus nonstatin users.

Our primary outcome measure was based on changes in hearing as defined by CTCAE v5.0 scale criteria (Supplemental Table 3) and were analyzed using categorical incidence (per ear) data. The incidence and severity distribution of a clinically meaningful hearing change, per ear, relative to statin use was analyzed using χ2 analyses (SAS PROC FREQ procedure). The rate difference, with a 95% CI, of a CTCAE-defined hearing loss between atorvastatin and nonstatin users was estimated by fitting the Poisson model using PROC NLMIXEDA for the total population as well as for subgroups (sex, cumulative cisplatin dose, individual cisplatin dose, baseline hearing status, and radiation). A logistic regression analysis (SAS PROC LOGISTIC procedure) with calculation of ORs and 95% CIs was performed to identify associations between CTCAE-defined changes in hearing and statin use after adjustment for significant covariates.

Our secondary outcome measure utilized high-frequency audiometric threshold data. A mixed-effect model analysis (SAS PROC GLIMMIX procedure) was applied to average high-frequency threshold shift data (PTA of 6–12.5 kHz) to determine the influence of other model effects on cisplatin-induced threshold shift within this high-frequency region. Fixed effects included statin use, sex, age, cumulative cisplatin dose, radiation exposure, and baseline hearing. Subject ID was defined as a random effect to account for the inclusion of 2 ears in the analysis. Statin use, sex, and radiation exposure were included as dichotomous variables, whereas age, cumulative dose, and baseline hearing based on the PTA of 1, 2, and 4 kHz were treated as continuous variables. A Pearson R correlation analysis was used to assess the association of atorvastatin drug dose and high-frequency threshold shift within Prism 8 (GraphPad Software).

Overall survival and disease-free survival were calculated as Kaplan-Meier curves using GraphPad Prism 8 software on all available data from URMC at up to 3 years after treatment (N = 175). Survival curves were compared using the log-rank (Mantel-Cox) test. Cochlear radiation dose data presented in the supplemental materials (Supplemental Figure 2) were analyzed using Pearson R and Spearman R correlation analysis within GraphPad Prism 8.

All statistical analyses were performed in SAS version 9.4 (SAS Institute Inc.) or GraphPad Prism 8. P values of less than 0.05 were considered significant

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