N-acetylcysteine for the Prevention of Cisplatin-Induced Hearing Loss: A Systematic Review and Meta-analysis

Abstract

Objective.

Cisplatin is an effective antineoplastic drug used worldwide in the treatment of various malignancies. However, it is associated with side effects, including cisplatin-induced hearing loss (CIHL). N-acetylcysteine (NAC) has been suggested as a promising drug to prevent or reduce cisplatin-derived ototoxicity. To evaluate the evidence supporting the efficacy of NAC in preventing CIHL, we conducted a systematic review and meta-analysis of the literature.

Data Sources.

A systematic search was conducted on PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane Library.

Review Methods.

Articles reporting the administration of systemic or transtympanic injection of NAC for CIHL prevention were considered. The outcomes of interest included the presence of hearing loss events and changes in hearing thresholds at 0.5 through 12 kHz following cisplatin treatment.

Results.

A total of 7 studies involving 217 patients met inclusion criteria. Of these patients, 175 received systemic administration of NAC, and the remaining received transtympanic injection of NAC. No significant differences were found in CIHL prevention between the use of either systemic or transtympanic NAC administration compared to placebo (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.54–1.19; P = .28, and RR 0.89; 95% CI 0.51–1.54; P = .67, respectively). No significant differences were found at 0.5 to 8 kHz between groups. Qualitative analyses suggested a tendency to otoprotection in ultra-high frequencies (10 and 12 kHz).

Conclusion.

Our findings suggest that, regardless of administration route, current published evidence does not show that NAC is effective in preventing CIHL in the standard clinical audiogram range. Further studies with larger samples are needed to confirm our findings.

Level of Evidence.

I.

Cisplatin is a widely used chemotherapy agent to treat solid malignancies.^1,2 However, it carries severe side effects including nephrotoxicity, peripheral neuropathy, myelosuppression, and ototoxicity,³ which can result in significant permanent comorbidities. Cisplatin exposure can lead to permanent, bilateral, high‐frequency sensorineural hearing loss with tinnitus,^4,5 affecting up to 80% of adults, and at least 50% of pediatric patients following treatment.^5‐10 The mechanisms underlying cisplatin‐induced hearing loss (CIHL) have been hypothesized to be complex and multifactorial, including the generation of reactive oxygen species, leading to oxidative damage of the cochlea sensory cells.¹¹ Additionally, there have been studies demonstrating long‐term retention of cisplatin in the inner ear, which could contribute to its ototoxicity effects.^12,13

While there have been advancements in protective interventions for nephrotoxicity, options to mitigate the ototoxic effects of cisplatin remain lacking.^14‐16 To date, sodium thiosulfate administered systemically is the only approved treatment by the Food and Drug Administration (FDA) to reduce the risk of CIHL in children and adolescents,¹⁷ although there is no current recommendation for the prevention of CIHL in the adult population.¹⁸ However, there is a concern that thiol compounds such as sodium thiosulfate, as well as other antioxidants, can reduce the oncologic effectiveness of cisplatin when delivered systemically.^19‐21 Therefore, there are active research efforts to identify alternative drugs and delivery methods for otoprotection against CIHL.

Among other antioxidants, N‐acetylcysteine (NAC) is another thiol medication that has been explored as a potential treatment for cisplatin‐induced toxicities through systemic and local delivery methods. In addition to its well‐established safety profile and clinical use as a mucolytic agent,^22,23 antidote for acetaminophen overdose,^22,24,25 and protective agent against contrast‐induced nephropathy,²⁶ NAC has shown promise in mitigating cisplatin‐induced toxicities without compromising the antitumor efficacy of platinum.²⁷ However, its effectiveness for preventing CIHL remains controversial.^18,28

The present study sought to investigate the efficacy of NAC in preventing CIHL through a systematic review and meta‐analysis of the available literature.

Methodology

This systematic review and meta‐analysis followed the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) Statement guidelines,^29,30 and was registered in PROSPERO (CRD42024496731).

Eligibility Criteria

Studies were included based on the following eligibility criteria: (1) randomized clinical trials (RCTs) or observational cohorts; (2) comparing the use of NAC to placebo or no treatment for the prevention of CIHL; (3) using objective hearing evaluation tests, including behavioral audiogram (250‐8000+ Hz), otoacoustic emissions (OAE), and/or auditory brainstem response (ABR) waveforms; (4) studies published in English, Portuguese, or Spanish; and (6) studies reporting any of the outcomes of interest. There was no restriction on age or follow‐up for inclusion.

Search Strategy, Data Extraction, and Outcomes

The search was performed in Pubmed, Embase, Web of Science, Cochrane Library, and Clinicaltrials.gov from inception to January 10, 2024, with the following terms and their synonyms: “Cisplatin,” “Platinum,” “Chemotherapy,” “Hearing Loss,” “Inner ear injury,” “N‐acetylcysteine,” and “Otoprotection.” Detailed search strategy is available in Table S1. The references from all the included studies, previous systematic reviews, and meta‐analyses were also searched manually for any additional studies. Two authors (J.P. and T.C.) independently screened the articles for eligibility using Covidence Software (Veritas Health Innovation)³⁸ and extracted the data that were subsequently cross‐checked by the third author (R.M.K). The Webplotdigitizer Software (Version 4.8) was utilized to extract data directly from the graphs.^39,40 The outcomes of interest included (1) hearing loss events, defined as the development of hearing loss during cisplatin treatment as identified by each study, and (2) hearing threshold shifts along each frequency (500‐8000+ Hz) during cisplatin treatment.

Quality Assessment

Two independent authors (J.P. and J.C.) completed the risk of bias assessment. RCTs were assessed using the revised Cochrane Risk of Bias Assessment Tool (RoB 2),⁴¹ which assigns categories of low, “some, ” and “high” risk of bias. Non‐randomized studies were assessed using the Risk of Bias in Non‐randomized Studies of Interventions Tool (ROBINS‐I),⁴² which assigns categories of “low,” “moderate,” “serious,” and “critical” risk of bias.

Disagreements were resolved through a consensus after discussing reasons for discrepancy. In cases where consensus could not be reached, the third author (R.M.K.) was consulted to provide guidance. Publication bias was investigated by funnel plot analysis of point estimates concerning study weight.

Statistical Analysis

Statistical analyses were conducted using Review Manager Web (Version 8.7.0, Cochrane Center, The Cochrane Collaboration).⁴³ To assess the intervention effect, categorical endpoints were assessed using a risk ratio (RR) with 95% confidence intervals (CI), and continuous outcomes were compared using mean difference (MD) in endpoints reported in the same unit. Heterogeneity was assessed using I² statistics and Cochran Q test; P < 10 and I² > 25% were considered significant heterogeneity. To address heterogeneity, the DerSimonian and Laird random‐effects model was applied. Additionally, sensitivity analyses were performed by removing each study from the outcome assessment, and using adjusted odds estimates from non‐randomized studies when available.

Results

Study Selection and Baseline Characteristics

The initial search identified 921 results. After removing duplicates and illegible studies by title/abstract, 13 underwent full‐text review. Seven studies were included, involving 217 patients from 6 RCTs^31,33‐37 and 1 prospective cohort study.³² NAC was administered systemically in 4 studies,^31‐34 while the remaining studies utilized a transtympanic approach.^35‐37 The study selection process is demonstrated in Figure 1.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram.

Study characteristics are reported in Table 1. A total of 86 (39.63%) patients received systemic administration of NAC, 89 (41.10%) received placebo or no treatment, and 42 (19.35%) patients received a transtympanic injection of NAC in 1 ear while the contra‐lateral one remained untreated as control, leading to a total of 84 ears assessed. Among the studies with systemic administration, one used an intravenous route,³² while the others administered NAC orally.^31,33,34 One study included patients younger than the age of 18 years.³²

Table 1.

Baseline Characteristics of Included Studies

Study	Muñoz et al (2021)31	Orgel et al (2023)32	Visacri et al (2019)33	Yildirim (2010)34	Riga et al (2013)35	Yoo (2014)36	Cavelier (2019) (NCT04226456)37
Design	RCT	Non-RCT	RCT	RCT	RCT	RCT	RCT
Country	Chile	USA	Brazil	Turkey	Greece	Canada	Belgium
Patients NAC/Co	22/21	18/21	28/29	18/18	20e/20e	11e/11e	10/9
Male, % NAC/Co	100/90.9	58/68	89.3/93.1	61.1/55.6	75	100	78.9
Agea (y), NAC/Co	62/60	0–5 y: 9/12 6–10 y: 7/4 >11 y: 8/12b	56/57	34/36	58	54	57.2
Delivery method	Sys (PO)	Sys (IV)	Sys (PO)	Sys (PO)	TT	TT	TT
NAC dose	1200 mg/d for 1 wk, followed by 600 mg/d	225–450 mg/kg	600 mg/d	600 mg/d	10% (0.4–0.8 mL)	2% (2–3 mL)	10% (0.4–1 mL)
Time of NAC administration	Initiated 1 wk before cisplatin treatment and continued throughout the duration of the treatment	4 h after cisplatin infusion infusion	7 consecutive days (2 days before cisplatin, on the day of cisplatin, and 4 days after cisplatin (in each cycle of cisplatin)	NI	During the hydration procedure preceding cisplatin infusion	30–60 min before cisplatin infusion	40–60 min before cisplatin infusion
Cisplatin dose, CD or no. of cycles	CD: 240 mg/m2	CD: 460.85/399.25 mg/m2c	CD: 240–300 mg/m2	NI	CD: 405 mg/m2	No. of cycles: 3.1	CD: 286.2 mg/m2
Radiotherapy	Yes (concomitant)	Yes (prior)	Yes (concomitant)	NI	No	Yes (concomitant)	NI
Type of hearing evaluations and frequency range	Audiometry (0.125–16 kHz)	Audiometry (0.5–12.5 kHz), DPOAE, ABR (0.5–6 kHz)	NI	Audiometry (10–12 kHz) ABR (clicks)	Audiometry (0.25–8 kHz)	Audiometry (0.25–20 kHz)	NI
Type of primary tumor, %, NAC/Co	OPhX: 52,17%, HPhx: 13.94%, Lx: 34.78%/OPhx: 50,00%, HPhx: 18.18%, Lx: 31.81%	Hepatic 21%, CNS 38%, Osteosarcoma 42%, Other 0%/Hepatic 21%, CNS 36%, Osteosarcoma 18%, Other 32%c	OPhx 53.6%, HPhx 7.1%, Lx 32.2%, OC 7.1%, OPhx+ OC 0.0%/OPhx 51.8%, Lx 27.6%, OC 13.8%, HPhx 3.4%, OPhx + OC 3.4%	NI	H&N 25%, Gastric 20%, Ovarian 15%, Bladder 10%, Testis 10%, Other 20%	Tonsil 54.6%, BOT 27.3%, NPhx 9.1% (1), Unknown 9.1%	RPHx 15.79%, OPhx 21.05%, HPHx 15.79%, Lx 5.26%, OC 10.53%, Bladder 10.53%, Lung 15.79%, Parotid gland 5.26%
Metastatic/advanced, %, NAC/Co	30.4/27.3	0/79c	85.7/96.6	NI	95	72.7	57.89
CIHL criteria	ASHA	SIOP	CTCAE v4	NA	ASHA	ASHAd	CTCAE v5
Follow-up teste, mo	3–6	12	1	1.27–1.4f	1	1–2	6
Audiometric evaluation during follow-up	Baseline, during (half of treatment), posttreatment	Baseline, during (before every cisplatin cycle), posttreatment	Baseline, posttreatment	Baseline, posttreatment	Baseline, during (every 2–3 cisplatin cycles), posttreatment	Baseline, posttreatment	Baseline, posttreatment

Abbreviations: ABR, auditory brainstem response; admin, administration; BOT, base of tongue; CD, cumulative dose; DPOAE, distortion-product otoacoustic emissions; e, ears; eval, evaluations; H&N, head and neck; HPhx, hypopharynx; IV, intravenously; Lx, larynx; NA, not applicable; NI, no information reported; non-RCT, non-randomized cohort; NPhx, nasopharynx; OC, oral cavity; PO, per os; RCT, randomized controlled trial; RPHx, rhinopharynx; Sys, systemic; TT, transtympanic; v, version.

^aMean or median.

^bNumber of patients in each age interval.

^cStatistical difference between N-acetylcysteine (NAC) and Control (Co) groups.

^dASHA ototoxicity criteria was applied to the reported data.

^eAfter completion of cisplatin treatment.

^fMonths after the first round of cisplatin.

All studies conducted a baseline hearing assessment before the initiation of cisplatin therapy.^31‐37 We found significant inter‐study variability regarding criteria to define an ototoxic hearing loss event. Two studies^31,35 used the American Speech Language‐Hearing Association criteria (ASHA; ie, >20 dB decline in hearing at any single test frequency or >10 dB decline at two adjacent frequencies),⁴⁴ 1 study³² employed the International Society of Pediatric Oncology Ototoxicity Scale (SIOP; ie, a threshold shift of >20 dB at 4 kHz or higher),⁴⁵ and 2 other studies^33,37 applied the Common Terminology Criteria for Adverse Events (CTCAE; ie, threshold shift of 15‐25 dB averaged at 2 contiguous test frequencies in at least 1 ear).⁴⁶ Since Yoo et al³⁶ reported hearing threshold shifts from baseline across 250 Hz to 20 kHz for each patient rather than using a formal ototoxicity grading scale to determine if an ototoxic effect occurred, we applied the ASHA ototoxicity grading scale to their data to determine ototoxic hearing loss events as previously described,²⁸ enabling us to include their study in the pooled analysis of hearing loss events after cisplatin treatment. Yildirim et al³⁴ reported mean threshold shifts in ultra‐high frequencies rather than occurrence of CIHL. Additionally, there was noteworthy variability in hearing outcome measures (behavioral audiogram, ABRs, and OAE) and tested frequency range, timing of NAC administration in relation to cisplatin, drug regimen and concentration for both systemic and transtympanic studies, as well as disease staging and follow-up duration (Table 1).

Pooled Analyses of All Studies

While there is a trend toward decreased hearing loss associated with cisplatin treatment in the intervention group, no significant differences were found in the number of hearing loss events after the administration of either systemic or transtympanic NAC compared to the control group (60.29% vs 73.24%; RR 0.80; 95% CI 0.54, 1.19; P = .28; I² = 59%, and 41.66% vs 54.05%; RR 0.89; 95% CI 0.51, 1.54; P = .67; I² = 32%, respectively; depicted in Figures 2 and 3). Two studies^35,36 on transtympanic administration reporting individual frequency thresholds were combined to assess threshold shifts along each frequency, and no significant difference was found from 0.5 through 8 kHz (illustrated in Figure 4A‐E). A similar analysis for studies on systemic administration was not possible due to insufficient data.

Figure 2.

Overall prevention of hearing loss events with systemic administration of NAC.

Figure 3.

Overall prevention of hearing loss events with transtympanic administration of NAC.

Figure 4.

Severity of hearing loss represented in hearing threshold shifts from 0.5 to 8 kHz on studies with transtympanic administration of NAC. (A) 0.5 kHz. (B) 1 kHz. (C) 2 kHz. (D) 4 kHz. (E) 8 kHz.

Analysis of Ultra-high Frequencies

A total of 3 studies reported high‐frequency audiometry (>8000 Hz) in addition to the standard clinical audiogram (250‐8000 Hz), of which 2 performed systemic administration^31,34 of NAC and 1 used a transtympanic approach.³⁶ Yildirim et al³⁴ and Muñoz et al³¹ both found a statistically significant otoprotective effect in ultra‐high frequencies. Yildirim et al³⁴ reported an MD in the intervention group of −9.95 dB and −12.75 dB at 10 and 12 kHz, respectively, compared to the control, while Muñoz et al³¹ found an MD of −10 dB at both frequencies. Similarly, Yoo et al³⁶ observed a trend toward otoprotection in the intervention group, with an MD of −6.85 dB and −5.90 dB at 10 and 12 kHz, respectively. However, this difference was not statistically significant. Due to insufficient reported data, we were unable to perform a quantitative pooled analysis for these outcomes.

Subgroup Analysis by Age Group

Since there was 1 study on systemic administration of NAC in patients under 18 years of age,³² a pooled analysis was performed of the other 2 studies^31,33 enrolling adult patients only (n = 100). No difference was found in reduction of hearing loss events in adults receiving systemic administration of NAC compared to controls (66% vs 80%; RR 0.80; 95% CI 0.45, 1.42; P = .44; I² = 79%; Figure S1).

Subgroup Analysis by NAC Concentration in Transtympanic Injection

Among the 3 studies on transtympanic administration of NAC, 1 study³⁶ injected a 2% NAC solution into the middle ear space, whereas the remaining studies infiltrated a 10% NAC solution.^35,37 In pooled results of the latter, there was no statistically significant difference in hearing loss events between the ears injected with NAC compared to controls (20.00% vs 38.46%; RR 0.63; 95% CI 0.14, 2.86; P = .55; I² = 65%; Figure S2).

Subgroup Analysis by Criteria to Define Ototoxic Effects

The ASHA system was used to define ototoxicity effects in 2 out of the 3 studies assessing transtympanic administration of NAC.^35,36 There was no statistically significant difference in the number of hearing loss events following transtympanic administration of NAC compared to controls, based on the same ototoxicity criteria (38.70% vs 54.83%; RR 0.57; 95% CI 0.07, 4.62; P = .60; I² = 88%; Figure 3). A similar analysis using other ototoxicity grading systems was not feasible due to the differing criteria employed in the remaining studies.

Subgroup Analysis by Follow-Up Duration

Given the variability in follow‐up duration (1‐12 months), studies were divided into 2 categories for further analysis: (1) “early follow‐up,” including studies with follow‐up shorter than 2 months, and (2) “late follow‐up,” including studies with follow‐up longer than 2 months. No difference was found in the number of hearing loss events in the pooled results of studies on transtympanic administration of NAC reporting shorter follow‐up durations (early follow‐up: 38.70% vs 54.83%; RR 0.57; 95% CI 0.07, 4.62; P = .60; I² = 88%; Figure S4).^35,36 However, the pooled results of studies on systemic administration of NAC reporting longer follow‐up durations showed a statistically significant reduction in the number of hearing loss events (47.50% vs 71.43%; RR 0.64; 95% CI 0.44, 0.93; P = .02; I² = 0%; illustrated in Figure 5).^31,32 Late follow‐up subgroup analysis of the transtympanic studies and early follow‐up subgroup analysis of the systemic studies could not be conducted due to an insufficient number of studies.

Figure 5.

Subgroup analysis of hearing loss events by follow-up duration on studies with systemic administration of NAC.

Sensitivity Analysis

After removing the observational study on systemic NAC administration,³² the results remained statistically nonsignificant for the reduction of hearing loss events (Figure S5). Furthermore, an influence analysis was conducted by leaving out each included study one at a time (Figures S6 and S7). The pooled risk ratios remained within the 95% CI of the initial overall analysis in both routes of administration. However, when excluding Visacri et al,³³ the systemic administration of NAC significantly favored the intervention over the control group, while also substantially reducing the heterogeneity (RR 0.64; 95% CI 0.44, 0.93; P = .02; I² = 0%; Figure S6). Additional sensitivity analysis including the adjusted odds estimates from the observational study³² did not result in a significant reduction of hearing loss events (odds ratio [OR] 0.32; 95% CI 0.08, 1.39; P = 0.13; I² = 64%; Figure S8).

Quality Assessment

Two studies were considered to have a high risk of bias. Muñoz et al,³¹ a single‐blinded study in which only participants were blinded to the intervention, was evaluated as high risk in the randomization process domain due to potential bias. Similarly, Yoo et al,³⁶ an open‐label study, was also classified as high risk of bias in this domain, given the absence of blinding procedures. Another study, Orgel et al,³² was assessed as having a moderate risk of bias, primarily due to its intrinsic limitations as an observational study, particularly in the confounding domain. Additionally, potential bias was present in the outcome measurement domain, as the assessors were aware of the intervention received by participants. Detailed data on the risk of bias are illustrated in Figures 6A,B and 7A,B. Funnel plot analysis demonstrated a symmetric distribution concordant with an absence of publication bias (Figures S9‐S15).

Figure 6.

Risk of bias. (A) Randomized control trials (RCTs): Risk of Bias 2 (RoB 2). (B) Observational studies (non-RCTs): ROBINS-I.

Figure 7.

Percentage of risk of bias. (A) Randomized control trials (RCTs): Risk of Bias 2 (RoB 2). (B) Observational studies (non-RCTs): ROBINS-I.

Discussion

This is among the first reviews examining the efficacy of NAC in reducing cisplatin‐induced cochleotoxicity, specifically CIHL. In this systematic review and meta‐analysis, we included a total of 7 studies, comprising 217 patients, the majority of whom were adults. The pooled results indicated that NAC delivered by either systemic or transtympanic approach does not prevent or mitigate CIHL in the standard clinical audiogram range. However, there seems to be a tendency to reduced severity of CIHL for both routes of administration, especially at ultra‐high frequencies.

Ototoxicity is a common and debilitating side effect of cisplatin treatment, regardless of the treatment dose.^5,47,48 Ototoxicity associated with cisplatin treatment not only occurs during therapy but has also been shown to lead to worsening hearing after treatment has concluded.⁴⁹ The negative impact of hearing impairment on communication, cognitive development, and quality of life is well‐documented in the literature.^8,50‐52 Therefore, the high prevalence of cisplatin ototoxicity, along with its associated significant morbidity, highlights the urgent need for effective monitoring, management, and, most importantly, preventive strategies. Moreover, cisplatin‐induced ototoxicity may present with other symptoms of cochlear dysfunction beyond hearing loss, including tinnitus, hyperacusis, and vestibular issues such as vertigo, dizziness, or imbalance.⁵³ Unfortunately, the studies included in this review provided limited information on other potential ototoxic symptoms. Although Yoo et al³⁶ and Cavelier³⁷ intended to document tinnitus as part of their methodology, no detailed data were provided in their results, except for Yoo et al,³⁶ who briefly reported that NAC had no significant effect on tinnitus. Additionally, none of the studies included in this review specifically documented vestibular symptoms, nor did they include any form of vestibular testing.

A variety of strategies to mitigate or reverse the ototoxic effects of cisplatin have been explored in preclinical and clinical studies. Prior in vitro and in vivo experiments have shown promising results on the use of thiol compounds such as sodium thiosulfate, amifostine, D‐methionine, and NAC for preventing cisplatin‐induced ototoxicity,^{19,20,54‐57} although clinical studies have reported variable outcomes.⁵⁸ Apart from sodium thiosulfate, which is the only currently FDA‐approved drug for reduction of CIHL in children,¹⁷ none of the other thiol compounds have shown the required efficacy to meet regulatory approval standards, although many of them remain in the investigational stage. Among the few meta‐analyses looking into the efficacy of thiol drugs for CIHL prevention,^58,59 only sodium thiosulfate has shown significant risk reduction of ototoxic effects,⁵⁹ while amifostine appeared to have a trend toward decreased ototoxicity.⁵⁸ NAC is another drug with promising otoprotective efficacy that, like other thiol compounds, can bind cisplatin and free radicals, thereby reducing oxidative damage caused by cisplatin.^60,61 Additionally, NAC has the unique capacity of promoting cochlear production of endogenous antioxidants and enhancing the intrinsic antioxidant capacity of cochlear cells, offering protection against hair cell and neuronal damage induced by cisplatin, as demonstrated in both in vitro and in vivo studies.^57,62‐65 Nevertheless, our study failed to demonstrate a significant effect of NAC to reduce the number of hearing loss events in individuals receiving cisplatin chemotherapy.

The American Academy of Audiology and ASHA have proposed guidelines for monitoring ototoxicity in patients receiving potentially ototoxic treatments, such as cisplatin.^44,66 Their recommendations include various audiological tests, such as OAE, tympanometry, behavioral pure‐tone audiometry across the standard range (250‐8000 Hz), ultra‐high‐frequency audiometry (9000‐20,000 Hz), and hearing questionnaires.^44,66 Despite these guidelines, these tests appear to be underutilized, and the monitoring methods applied and frequencies tested vary widely across studies. This inconsistency was also evident in our study, limiting our ability to objectively compare hearing changes across groups. Specifically, among the 5 studies included in our review that detailed their monitoring methods, some used a single modality, while others employed a combination of audiological tests, including behavioral audiogram,^{31,32,34‐36} ABRs^32,34 and OAE.³² Moreover, recent studies have suggested that extended high‐frequency hearing loss may be within the spectrum of “hidden hearing loss,”^67,68 which may result in difficulty understanding speech in background noise in spite of normal hearing as measured by a standard frequency range audiogram.^69‐72 While it is well‐established in the literature that high frequencies are typically the first to be affected during CIHL,⁷³ only 3 out of the 7 studies included in this review reported ultra‐high‐frequency audiometry.^31,34,36 Unfortunately, we were unable to perform further analyses due to insufficient data reported. Nevertheless, there appeared to be a trend toward better thresholds in ultra‐high frequencies among patients who received NAC.

Ototoxicity grading scales to define ototoxicity are also not uniform in clinical practice and across studies. Various grading scales are available, and prior studies have demonstrated that the scale used can significantly impact prevalence estimates and sensitivity in detecting ototoxicity.^74‐76 This may result in under or overestimation of ototoxic hearing loss events during cisplatin chemotherapy.⁷⁷ Among the studies included in this review, the more commonly used grading scales were ASHA and CTCAE.^31,33,35,37 Theunissen et al have shown that grading systems incorporating high‐frequency testing, such as ASHA, are more sensitive in identifying ototoxicity.⁷⁸ However, their comparison of false positive rates indicated that CTCAE v4 is more prone to generating false positives than ASHA when applied too soon after completing the cisplatin treatment.⁷⁸ While a detailed discussion of the ideal method for defining ototoxicity is beyond the scope of this review, these findings highlight the need for a standardized classification system to consistently monitor ototoxicity. Variable grading scale systems and consequently inadequate report of hearing outcomes could explain part of the variability in the subgroup and sensitivity analysis results favoring otoprotection with the use of NAC.

Different methods to deliver otoprotective drugs to the inner ear have been explored in the literature. While systemic administration may seem a straightforward option, there is a higher chance of side effects. In addition, there are challenges with drug clearance and permeability through the blood‐labyrinth barrier that may negatively impact drug bioavailability.^79,80 Moreover, there is a concern that the use of thiol compounds, such as NAC, could decrease the oncological effectiveness of cisplatin when delivered systemically.^19,81‐84 To overcome these concerns, local delivery methods such as transtympanic injection have been explored in pre‐clinical and clinical studies, without reduction of antitumor efficiency.^79,80 However, this route of administration also carries challenges related to the drug diffusion through the round window membrane, drug distribution within the inner ear, and eustachian tube clearance.^85,86 Middle ear abnormalities such as middle ear effusion, which can occur in patients with head and neck cancer receiving radiotherapy, can further limit the effectiveness of this approach.⁸⁷ While our pooled results for both routes of NAC administration failed to significantly reduce ototoxic hearing loss events, there seems to be a trend toward otoprotection for both approaches.

This study has several limitations. First, the limited number of studies for each route of administration, along with their relatively small sample sizes, could have resulted in insufficient statistical power to effectively determine the efficacy of NAC in preventing CIHL. Second, while a review limited to RCTs would be ideal, the inclusion of an observational study introduces potential confounding factors and heterogeneity that could impact the validity and reliability of the pooled analyses. We therefore performed an analysis including the adjusted OR from the observational study, and the pooled result remained statistically nonsignificant. Third, there was considerable variability across studies in ototoxicity grading scales and hearing evaluation methods, which could lead to inaccurate estimates of the ototoxic hearing loss events. Additionally, timing of administration, drug regimens and concentration were not uniform across studies. Fourth, most studies included patients that either underwent radiation prior or concurrent to the cisplatin treatment, which can increase the risk of ototoxicity.^88,89 Also, with the exception of Orgel et al³² and Yoo et al,³⁶ the studies lacked information on whether the cisplatin dose was adjusted to the baseline renal function or nephrotoxicity during treatment, which could impact cisplatin concentration and thereby influence the observed outcomes. All of these factors may have influenced the results observed in the sensitivity analysis after removing one study.³³ with systemic administration of NAC. Fifth, studies included in this review provided limited information on other ototoxic symptoms, preventing us from drawing any conclusions regarding the potential role of NAC in preventing cisplatin‐induced ototoxicity. Sixth, one of the included studies on systemic administration of NAC included pediatric patients, whereas the remaining studies were in adults. However, our subgroup analysis by age remained without statistical significance for the reduction of hearing loss events in adults receiving systemic NAC. Lastly, we were unable to assess additional outcomes such as side effects and survival given insufficient data and short follow‐up durations.

Conclusion

In this systematic review and meta‐analysis, we reviewed 7 studies administrating NAC through a systemic and local method of delivery for the prevention of hearing loss in patients undergoing cisplatin chemotherapy. Our findings suggest that, regardless of the administration route, NAC is not effective in preventing or mitigating CIHL in frequencies comprising the clinical audiogram. However, NAC may play a role in reducing the severity of hearing loss in ultra‐high frequencies. Further studies with larger samples are needed to confirm our findings.

Supplementary Material

Additional supporting information is available in the online version of the article.