Atorvastatin is associated with reduced cisplatin-induced hearing loss

Abstract

BACKGROUNDCisplatin is widely used to treat adult and pediatric cancers. It is the most ototoxic drug in clinical use, resulting in permanent hearing loss in approximately 50% of treated patients. There is a major need for therapies that prevent cisplatin-induced hearing loss. Studies in mice suggest that concurrent use of statins reduces cisplatin-induced hearing loss.METHODSWe examined hearing thresholds from 277 adults treated with cisplatin for head and neck cancer. Pretreatment and posttreatment audiograms were collected within 90 days of initiation and completion of cisplatin therapy. The primary outcome measure was a change in hearing as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).RESULTSAmong patients on concurrent atorvastatin, 9.7% experienced a CTCAE grade 2 or higher cisplatin-induced hearing loss compared with 29.4% in nonstatin users (P < 0.0001). A mixed-effect model analysis showed that atorvastatin use was significantly associated with reduced cisplatin-induced hearing loss (P ≤ 0.01). An adjusted odds ratio (OR) analysis indicated that an atorvastatin user is 53% less likely to acquire a cisplatin-induced hearing loss than a nonstatin user (OR = 0.47; 95% CI, 0.30-0.78). Three-year survival rates were not different between atorvastatin users and nonstatin users (P > 0.05).CONCLUSIONSOur data indicate that atorvastatin use is associated with reduced incidence and severity of cisplatin-induced hearing loss in adults being treated for head and neck cancer.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT03225157.FUNDINGFunding was provided by the Division of Intramural Research at the National Institute on Deafness and Other Communication Disorders (1 ZIA DC000079, ZIA DC000090).

Keywords: Head and neck cancer; Neurological disorders; Oncology; Otology.

Conflict of interest statement

Conflict of interest: LLC, NCS, and KAF hold a provisional patent for the use of statins to prevent drug-induced hearing loss (“Use of Statins to Treat or Prevent Drug Induced Hearing Loss,” patent 62/966,794).

Figures

Figure 1. Flow diagram of study design and participants.

Retrospective and prospective data were combined for analyses. Two institutions, Walter Reed National Military Medical Center and the University of Rochester Medical Center, contributed retrospective audiometric data pertaining to subjects meeting study eligibility criteria. Additional data were collected prospectively through an observational clinical study conducted by the NIH in partnership with Johns Hopkins University. Eligibility criteria were the same in both the retrospective and prospective segments. A total of 277 subjects were included in the analyses.

Figure 2. Atorvastatin use is associated with reduced cisplatin-induced hearing loss.

Baseline audiometric thresholds were compared with thresholds obtained after cisplatin treatment to determine threshold shifts. (A) In subjects not taking a statin (N = 324 ears), cisplatin treatment resulted in threshold shifts that were more severe at higher frequencies. Subjects taking any statin (N = 219 ears) had significantly less cisplatin-induced hearing loss than subjects who were not taking a statin. Atorvastatin users (N = 97 ears) had significantly less cisplatin-induced hearing loss than nonstatin users. In contrast, cisplatin-induced threshold shifts among simvastatin users (N = 70 ears) were not significantly different from those of nonstatin users. Data represent mean ± SEM, 2-way ANOVA, Dunnett’s multiple-comparison test. (B) Atorvastatin dose was not correlated with high-frequency (6–12.5 kHz) hearing loss. Each dot represents 1 ear. Nonstatin users (N = 324 ears) had 15.9 ± 20.3 dB shifts in high-frequency pure tone average (HF PTA). Atorvastatin users (N = 97 ears) had shifts of 7.8 ± 11.8 dB. There was no correlation between atorvastatin dose and threshold shift. Pearson R correlation. (C) The incidence of cisplatin-induced hearing loss among nonstatin users was 48% per CTCAE criteria. Subjects taking any statin had significantly lower incidence of hearing loss than nonstatin users. The incidence of hearing loss was further reduced among atorvastatin users. Data are percentage of ears per group. Statistical analysis consisted of the χ2 test. (D) Statin use, atorvastatin in particular, was associated with reduced severity of hearing loss. CTCAE criteria were used to categorize the severity of hearing loss. χ2 Analysis showed a significant difference in the distribution of CTCAE hearing loss grades, where the incidence of a grade 2 or higher hearing loss was reduced in statin users compared with nonstatin users. This difference was even greater for atorvastatin users. Data are percentage of ears per group. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 3. Atorvastatin use significantly reduces the odds of a clinically meaningful cisplatin-induced hearing loss.

An analysis of the incidence of a CTCAE-defined hearing loss due to cisplatin therapy in the full cohort and key subgroups is shown. For the full cohort and the subject subgroups, the difference in the incidence (% of ears) and 95% CI were estimated using a nonlinear mixed-effect analysis, fitting the Poisson model. Significant differences (red diamonds) in the calculated incidence of a CTCAE grade 1 or higher hearing loss were observed for the full cohort as well as for the male subgroup and for those receiving higher (>200 mg/m2) cumulative cisplatin dose, those receiving radiation, and those with mild hearing loss at baseline. CNT, could not test because of insufficient sample size in atorvastatin + cisplatin therapy comparison group.

Figure 4. Three-year overall survival and disease-free survival are not different among statin users, atorvastatin users, and those not taking a statin.

Kaplan-Meier estimates of overall (A) and disease-free (B) survival are shown. A log-rank (Mantel-Cox) test indicated no significant differences in either overall or disease-free survival among groups (P > 0.05). No statin group, n = 107; any statin group, n = 68; atorvastatin group, n = 33.