Assessment and Management of Chemotherapy-Induced Ototoxicity in Children

Heonjeong Oh; Moo Kyun Park

doi:10.7874/jao.2025.00073

J Audiol Otol > Volume 29(2); 2025 > Article

Oh and Park: Assessment and Management of Chemotherapy-Induced Ototoxicity in Children

Review

Journal of Audiology and Otology 2025;29(2):79-85.

Published online: April 18, 2025

DOI: https://doi.org/10.7874/jao.2025.00073

Assessment and Management of Chemotherapy-Induced Ototoxicity in Children

Heonjeong Oh^1,^2,³

, Moo Kyun Park^1,^2,³

¹Department of Medicine, Seoul National University College of Medicine, Seoul, Korea

²Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea

³Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea

Address for correspondence Moo Kyun Park, MD, PhD Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul 03080, Korea Tel +82-2-2072-2447 Fax +82-2-745-2387 E-mail entpmk@gmail.com

Received February 6, 2025 Revised April 5, 2025 Accepted April 9, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Chemotherapy-induced ototoxicity is a significant concern in pediatric patients with cancer, particularly those treated with platinum-based agents, such as cisplatin and carboplatin. This study reviewed its prevalence, risk factors, early diagnosis, and management strategies. A literature review was conducted to assess the effects of ototoxic chemotherapy, screening methods, and treatment approaches. Various grading scales and rehabilitation strategies were analyzed. Platinum-based chemotherapy causes ototoxic hearing loss in approximately 100% of cases, including high-frequency and delayed-onset losses. Younger age, higher cumulative dose, and cranial irradiation increased the risk. Screening adherence remains suboptimal, despite guidelines recommending early detection through high-frequency audiometry. Sodium thiosulfate may reduce ototoxicity in nonmetastatic cases. If appropriate, hearing aids and cochlear implants can support communication and language development. Ototoxic hearing loss is a prevalent, yet underdiagnosed, complication of pediatric cancer treatment. Standardized screening, otoprotective strategies, and early rehabilitation are essential to minimize their impact on language and quality of life. Greater awareness and national guidelines are required to improve the care of pediatric cancer survivors.

Keywords: Ototoxicity · Hearing loss · Cisplatin · Neoplasms · Child.

Introduction

Chemotherapy remains a leading cause of ototoxic hearing loss. As advancements in cancer treatment have increased the 5-year survival rate of children and adolescents to over 80% [1], greater attention has focused on ototoxic hearing loss and its impact on pediatric cancer survivors’ quality of life. Platinum-based chemotherapy induces ototoxic hearing loss in 60% of cases [2], with cisplatin specifically linked to rates of 75%–100% [3]. Ototoxic hearing loss typically affects high frequencies and is frequently accompanied by tinnitus. Platinum-based agents (e.g., cisplatin, carboplatin) are particularly effective against pediatric cancers such as osteosarcoma, neuroblastoma, hepatoblastoma, brain tumors, and malignant germ cell tumors [4]. Radiotherapy is another critical treatment for head and neck tumors; however, exposure of the temporal bone or brainstem to doses exceeding 30 Gy can cause ototoxic hearing loss. Pediatric patients are known to be more vulnerable to these effects than adults [5].

In children, ototoxic hearing loss affects not only auditory function but also language development, social skills, emotional well-being, and academic performance [6-8]. Sensorineural hearing loss from platinum-based agents often leads to irreversible quality-of-life declines. Cisplatin-induced damage typically begins with high-frequency hearing loss and may progress to involve all frequencies. Since high-frequency sounds are critical for speech clarity, even mild impairment can disrupt language acquisition and academic achievement, potentially contributing to long-term social and psychological challenges [9]. Despite these risks, only 43% of high-risk patients undergo regular audiological evaluations [10]. In South Korea, awareness of this issue is even lower, with insufficient long-term follow-up and auditory rehabilitation for delayed-onset hearing loss.

This review outlines current trends and guidelines for the early diagnosis, treatment, and auditory rehabilitation of ototoxic hearing loss in pediatric cancer survivors.

Prevalence of Ototoxic Hearing Loss Following Cancer Treatment

While ototoxicity is widely recognized, its reported prevalence varies due to inconsistent diagnostic criteria and grading systems. Cisplatin causes hearing loss in over 60% of cases, carboplatin in 20%, and combination therapy with both agents in 90% [2,11,12]. Radiotherapy targeting the head and neck region results in hearing loss in 10%–14% of cases, whereas combined radiotherapy and cisplatin elevate this rate to 80%. Studies suggest cisplatin may cause ototoxic hearing loss in 100% of cases when high-frequency and delayed-onset losses are included. Carboplatin appears less ototoxic than cisplatin, while oxaliplatin rarely causes hearing loss.

Research on tinnitus prevalence in platinum-based chemotherapy remains limited, with existing studies likely underestimating its occurrence. A recent investigation of long-term ototoxicity in pediatric patients treated with platinum-based chemotherapy and/or radiotherapy found that 66.7% experienced tinnitus despite normal hearing thresholds [13]. Ototoxic drugs can also affect vestibular function. Vestibular dysfunction is also underreported, as compensatory mechanisms often mask symptoms such as dizziness or imbalance [14,15].

Mechanisms and Risk Factors of Ototoxic Hearing Loss

Cisplatin, a representative ototoxic anticancer drug, induces hearing loss and kidney dysfunction through mechanisms including gastrointestinal disturbances, bone marrow suppression, peripheral neuropathy, and reactive oxygen species (ROS) generation [16]. It directly damages cochlear hair cells, supporting cells, and spiral ganglion cells, entering the cochlea via the stria vascularis and penetrating hair cells through the endolymph [17]. By promoting proinflammatory cytokines and activating NADPH/xanthine oxidases, cisplatin depletes antioxidant defenses, leading to ROS-induced inflammation and cell death (Fig. 1) [18,19]. Cisplatin generates iron-induced free radicals in the proximal tubules of the kidney and impacts hair cells in the cochlea, leading to hearing loss. Additionally, it damages vestibular hair cells, causing a reduction in vestibular function. However, due to differences in vestibular function thresholds, clinical symptoms are not commonly observed [14].

As a potent inhibitor of tumor proliferation, cisplatin is widely used for ovarian and head/neck squamous cell carcinomas. However, high doses cause nephrotoxicity, neuropathy, hypomagnesemia, nausea, vomiting, and ototoxicity. The occurrence and severity of ototoxicity vary across clinical studies but are generally bilateral and symmetrical. Ototoxicity is dose-dependent, typically resulting in permanent high-frequency hearing loss and tinnitus, with tinnitus often appearing first. Hearing loss usually occurs at high frequencies (4–8 kHz) and is thought to result from damage primarily at the basal turn of the cochlea.

A study conducted in Korea investigated ototoxicity in 37 pediatric patients who underwent chemotherapy, including cisplatin. Hearing tests performed after chemotherapy completion revealed that 20 patients were classified as Brock’s grade 0, nine as grade 1, and eight as grade 2. Overall, 17 patients (46%) exhibited hearing impairment of grade 1 or higher. The risk factors for cisplatin-induced ototoxicity included being younger than 12 years at the time of solid tumor diagnosis and receiving a cumulative cisplatin dose of ≥500 mg/m². These factors were associated with an increased incidence of ototoxicity, which persisted even after treatment concluded (Table 1). However, factors such as the patient’s sex and individual cisplatin dosage did not significantly correlate with the occurrence of ototoxicity [20].

Early Diagnosis of Ototoxic Hearing Loss

Clinical practice guidelines for the early diagnosis of ototoxic hearing loss have been established for pediatric and adolescent cancer survivors. However, recommendations vary by country, and no domestic guidelines currently exist in Korea. The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) and the European Unionfunded PanCare Consortium have proposed screening programs for ototoxic hearing loss in cancer survivors through expert panels [5].

Screening for ototoxic hearing loss is considered essential for patients treated with cisplatin or those receiving radiation therapy exceeding 30 Gy to the head and neck region. Experts also highlight an increased risk of hearing loss in cases involving high-dose carboplatin (>1,500 mg/m²) or cerebrospinal fluid shunts.

The Common Terminology Criteria for Adverse Events (CTCAE) categorizes hearing loss into four grades (Tables 2 and 3) [21,22]. However, discrepancies exist between CTCAE grades and clinical management strategies. For example, the severity of hearing loss requiring cochlear implants in Grade 4 ototoxicity may not align with CTCAE-defined criteria. For Grade 2 and 3 hearing loss, reducing or modifying chemotherapy dosage may be considered, though this could compromise treatment efficacy and impact survival rates [23].

Therefore, it is critical to develop appropriate screening and management protocols that minimize the impact on patient survival while effectively preventing hearing loss [23].

The American Speech-Language-Hearing Association (ASHA) recommends evaluations 1 month and 3 months after completing chemotherapy. Experts suggest annual hearing tests for children until 6 years old, biennial tests for those aged 6–12, and tests every five years after age 12 (Fig. 2). Despite these guidelines, routine screening for ototoxic hearing loss is often not implemented in practice [24].

The ASHA defines ototoxic hearing loss as a change of 20 dB or more at a single frequency, 10 dB or more at two consecutive frequencies, or loss of response at three consecutive frequencies [25]. The Chang [26] and TUNE [27] classification system further refines these criteria by incorporating changes in high-frequency hearing loss, dividing them into a grade system (Table 4).

There is ongoing debate about the degree of hearing change that should warrant modifications to chemotherapy. Generally, a worsening of 20 dB or more at 4 kHz—a frequency critical for speech discrimination—is considered clinically significant and potentially impactful for speech recognition [22].

For screening ototoxic hearing loss, pure-tone audiometry capable of measuring up to 8 kHz is essential. High-frequency audiometry and otoacoustic emissions testing can provide additional diagnostic support [5].

Automated and portable hearing assessment tools could significantly improve the early detection of ototoxic hearing loss following chemotherapy.

In pediatric patients undergoing chemotherapy, conducting hearing tests in a soundproof booth may not always be feasible due to the patient’s condition. In such cases, automated and portable audiometric devices can be used to diagnose hearing loss. These tools are particularly useful during weekends or nighttime, when standard audiometric testing may not be available. For younger children who may struggle to cooperate, game-based hearing tests offer an effective alternative.

For example, the EasyTone audiometer (MAICO Diagnostics), originally developed for school hearing screenings, can be used by simply connecting earphones to a smartpad. It is capable of assessing high-frequency hearing up to 8 kHz (Fig. 3).

Pharmacological Prevention of Ototoxic Hearing Loss

Sodium thiosulfate is recommended for preventing ototoxic hearing loss in children but should only be used in cases of non-metastatic cancer. As a thiol-containing reducing agent and free radical scavenger, sodium thiosulfate has shown promise in reducing hearing loss. In a clinical trial by the International Childhood Liver Tumor Strategy Group (SIOPEL 6), its use significantly lowered the incidence of hearing loss to 33% (18/55) compared to 63% (29/46) in the control group, while also improving survival rates [28]. However, a study by the Children’s Oncology Group (ACCL0431) on metastatic can-cers found that sodium thiosulfate was associated with decreased survival rates [29]. Amifostine and sodium diethyldithiocarbamate are not recommended for preventing ototoxic hearing loss [30]. Additionally, altering the dosing interval of cisplatin does not appear to provide significant benefits [30]. The effectiveness of intratympanic steroid injections for preventing ototoxicity remains insufficiently supported by evidence (Table 5) [5,30].

Auditory Rehabilitation for Ototoxic Hearing Loss

The primary goal of auditory rehabilitation in children with hearing loss is to restore communication skills and promote normal language development through appropriate interventions. For mild to moderate hearing loss, hearing aids are typically the first option. These devices amplify external sounds and are widely used for hearing loss caused by various factors, including ototoxicity. They are simple and convenient, even for children. For preschool-aged children, who generally live in quiet home environments, amplification alone is often sufficient to support communication and language development. However, school-aged children frequently encounter noisy environments, such as kindergartens or schools, where background noise can make it difficult to distinguish specific voices. Recent advancements in hearing aids have improved noise reduction features, enabling selective amplification of sounds within the speech range. This allows children with hearing loss to communicate effectively in everyday noisy settings. If children continue to struggle in academic environments—such as difficulty understanding teachers despite using hearing aids with noise reduction features—frequency modulation (FM) systems can be added to improve auditory rehabilitation and academic performance. For moderate-to-severe hearing loss, hearing aids are also initially recommended. However, in cases of profound or severe hearing loss, amplified sound via hearing aids may still result in poor speech recognition, hindering effective communication. If speech discrimination and language development remain inadequate after 3–6 months of auditory rehabilitation with hearing aids, cochlear implantation may be considered (Fig. 4).

Ototoxic hearing loss is often caused by damage to hair cells, resulting in sensorineural hearing loss [31]. Since the auditory nerve typically remains intact, cochlear implantation can be highly effective for patients with ototoxic hearing loss [32]. For patients with significant high-frequency hearing loss but preserved low-frequency residual hearing, an electroacoustic stimulation approach can be employed during cochlear implantation. This involves using a short electrode to stimulate highfrequency regions while preserving residual low-frequency hearing for amplification with a hearing aid. This method improves speech recognition, directional hearing, and language processing in noisy environments [33,34]. In summary, auditory rehabilitation for children with ototoxic hearing loss primarily involves hearing aids and cochlear implantation, with the choice depending on the degree of hearing loss. Hearing aids are generally the first option for all levels of hearing loss, while cochlear implantation is considered if hearing aids prove insufficient. Brock’s classification from 1991 categorizes ototoxic hearing loss into grades 0 to 4 based on frequency-specific thresholds, reflecting the characteristic high-frequency hearing loss in ototoxicity [22]. However, this classification, which differs from the commonly used ANSI standards, is not an absolute determinant for rehabilitation methods. Ultimately, the choice of rehabilitation should be tailored to the individual child’s circumstances and developmental needs.

Conclusions

The incidence of ototoxic hearing loss following pediatric cancer treatment is expected to exceed 60%, and this figure may rise as cancer treatment success rates improve. Given that childhood is a critical period for auditory development, hearing loss can significantly impact language development, emotional well-being, social skills, and overall quality of life. Consequently, the early diagnosis and rehabilitation of hearing loss—without compromising cancer treatment outcomes— demand the attention and collaboration of otolaryngologists, pediatricians, and radiation oncologists.

To facilitate early diagnosis, hearing tests, including highfrequency measurements above 8 kHz, should be conducted before and during each cycle of chemotherapy. If significant hearing changes are observed at frequencies above 8 kHz, more frequent follow-up assessments or the administration of thiosulfate during subsequent chemotherapy cycles should be considered. Conversely, if significant hearing changes are detected at frequencies below 4 kHz, which are critical for speech discrimination, adjustments to the chemotherapy regimen should be carefully evaluated.

For children undergoing chemotherapy, conventional hearing tests conducted in soundproof booths may not always be feasible. Therefore, there is a need to develop alternative methods for assessing hearing. Additionally, since delayed-onset hearing loss can occur, it is important to continue regular hearing assessments even after the completion of cancer treatment.

Providing educational resources for patients and caregivers on preventing hearing loss could be beneficial. Additionally, the use of hearing aids for proactive auditory rehabilitation is recommended when hearing loss occurs. Finally, developing guidelines tailored to local circumstances for the early diagnosis and rehabilitation of hearing loss is essential.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Author Contributions

Conceptualization: Moo Kyun Park. Funding acquisition: Moo Kyun Park. Visualization: Heonjeong Oh. Writing—original draft: Heonjeong Oh. Writing—review & editing: Moo Kyun Park. Approval of final manuscript: Heonjeong Oh, Moo Kyun Park.

Funding Statement

This research was supported and funded by SNUH Kun-hee Lee Child Cancer & Rare Disease Project, Republic of Korea (grant number: FP-2022-00004).

Acknowledgments

None

Fig. 1.

Proposed mechanism of cisplatin-induced ototoxicity. ROS, reactive oxygen species. Adapted from Gentilin, et al. Trends Mol Med 2019;25:1123-32 [18], with permission from Elsevier.

Fig. 2.

Suggested flowchart for hearing screening of patients at risk for ototoxicity. Pt, platinum; CTx, chemotherapy; RT, radiotherapy. Based on Children's Oncology Group (www.survivorshipguidelines.org) [24].

Fig. 3.

Hearing tests for children. The images show a portable audiometer and a child-friendly hearing test using a racecar game. A clinician can test a child with a portable device, while the screen displays a colorful racing game to keep the child engaged. This gamified approach makes the hearing test fun and less intimidating. Images from MAICO Diagnostics (https://www.maico-diagnostics.com/).

Fig. 4.

Hearing rehabilitation when ototoxic hearing loss occurs.

Table 1.

Risk factors for cisplatin-induced hearing loss [16-19]

Risk factors
Dose, duration, and mode of administration
Age extremes
Previous or concurrent cranial irradiation
Previous history of hearing loss
Renal disease
Concomitant use of other ototoxic agents
Volume status
Genetic predisposition (GSTM1, GSTT1, ERCC, megalin, mitochondrial mutations)

Table 2.

National Cancer Institute Common Terminology Criteria for Adverse Events v5.0: hearing impairment in children

Grade	Description
Grade 1	Pediatric (1, 2, 3, 4, 6, and 8 kHz audiogram): threshold shift ＞20 dB hearing loss (i.e., 25 dB hearing loss or greater); sensorineural hearing loss above 4 kHz (i.e., 6 or 8 kHz) in at least one ear
Grade 2	Pediatric (1, 2, 3, 4, 6, and 8 kHz audiogram): threshold shift ＞20 dB at 4 kHz in at least one ear
Grade 3	Pediatric (1, 2, 3, 4, 6, and 8 kHz audiogram): hearing loss sufficient to indicate therapeutic intervention, including hearing aids; threshold shift ＞20 dB at 2 to ＜4 kHz in at least one ear
Grade 4	Pediatric: audiologic indications for cochlear implant; ＞40 dB hearing loss (i.e., 45 dB hearing loss or more); sensorineural hearing loss at 2 kHz and above

Adapted from Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [21].

Table 3.

Brock’s Grading System Compared with CTCAE

Grade	Brock’s Grading System [22]	CTCAE v5.0 (Pediatric) [21]
0	≤40 dB at all frequencies at both ears at both ears	-
1	＞40 dB at 8 kHz at both ears	Threshold shift ＞20 dB above 4 kHz in at least one ear
2	＞40 dB at 4-8 kHz at both ears	Threshold shift ＞20 dB at 4 kHz in at least one ear
3	＞40 dB at 2-8 kHz at both ears	Threshold shift ＞20 dB at 2 kHz to ＜4 kHz in at least one ear
4	＞40 dB at 1-8 kHz at both ears	＞40 dB HL at 2 kHz and above

CTCAE, Common Terminology Criteria for Adverse Events; HL, hearing level

Table 4.

Ototoxicity criteria

Grade	Chang grading system [26]	TUNE grading system [27]	ASHA^* [25]
0	≤20 dB at 1, 2, and 4 kHz	No hearing loss	≥20 dB decrease in pure tone thresholds at any test frequency
1a	≥40 dB at any frequency from 6 to 12 kHz	Threshold shift ≥10 dB at 8, 10, and 12.5 kHz
1b	＞20 and ＜40 dB at 4 kHz	Threshold shift ≥10 dB at 1, 2, and 4 kHz
2a	≥40 dB at 4 kHz and above	Threshold shift ≥20 dB at 8, 10, and 12.5 kHz	OR ≥10 dB decrease at two adjacent frequencies
2b	＞20 and ＜40 dB at any frequency below 4 kHz	Threshold shift ≥20 dB at 1,2, and 4 kHz	OR loss of response at three consecutive test frequencies where responses were previously obtained
3	≥40 dB at 2 or 3 kHz and above	≥35 dB HL at 1, 2, and 4 kHz
4	≥40 dB at 1 kHz and above	≥70 dB HL at 1, 2, and 4 kHz

^* no grading system is applied.

ASHA, American Speech-Language-Hearing Association, HL, hearing level

Table 5.

Suggested otoprotective agents

Agent	Mechanism	Clinical effectiveness	Limitations
Sodium thiosulfate	Free radical scavenger; reduces ROS-mediated cochlear damage [28,29]	Reduced ototoxicity in non-metastatic cancers [28]	May reduce survival in metastatic disease [29]
Amifostine	Cytoprotective agent; reduces cisplatin-induced oxidative stress [35,36]	Not significantly reduced ototoxicity [35,36]	Side effects including hypocalcemia, nausea, hypotension [35,37]
Intratympanic dexamethasone	Local anti-inflammatory effect [38]	Preliminary studies show modest protective effects; not yet validated in large trials [39,40]	Limited data; invasive procedure; may not be feasible in children
Intratympanic N-acetylcysteine	Free radical scavenger [41]	Preliminary studies show modest protective effects; not yet validated in large trials [42]	Limited data; invasive procedure; may not be feasible in children

ROS, reactive oxygen species

REFERENCES

1. Public Health Agency of Canada. Release notice – Cancer in young people in Canada: a report from the enhanced childhood cancer surveillance system. Health Promot Chronic Dis Prev Can 2017;37:393

2. Langer T, am Zehnhoff-Dinnesen A, Radtke S, Meitert J, Zolk O. Understanding platinum-induced ototoxicity. Trends Pharmacol Sci 2013;34:458–69.

3. McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Saf 1995;13:228–44.

4. Ruggiero A, Trombatore G, Triarico S, Arena R, Ferrara P, Scalzone M, et al. Platinum compounds in children with cancer: toxicity and clinical management. Anticancer Drugs 2013;24:1007–19.

5. Clemens E, van den Heuvel-Eibrink MM, Mulder RL, Kremer LCM, Hudson MM, Skinner R, et al. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium. Lancet Oncol 2019;20:e29–41.

6. Einarsson EJ, Petersen H, Wiebe T, Fransson PA, Grenner J, Magnusson M, et al. Long term hearing degeneration after platinum-based chemotherapy in childhood. Int J Audiol 2010;49:765–71.

7. Schreiber JE, Gurney JG, Palmer SL, Bass JK, Wang M, Chen S, et al. Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro Oncol 2014;16:1129–36.

8. Brinkman TM, Bass JK, Li Z, Ness KK, Gajjar A, Pappo AS, et al. Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: results from the St. Jude Lifetime Cohort Study. Cancer 2015;121:4053–61.

9. Olivier TW, Bass JK, Ashford JM, Beaulieu R, Scott SM, Schreiber JE, et al. Cognitive implications of ototoxicity in pediatric patients with embryonal brain tumors. J Clin Oncol 2019;37:1566–75.

10. Weiss A, Kuonen R, Brockmeier H, Grotzer M, Candreia C, Maire R, et al. Audiological monitoring in Swiss childhood cancer patients. Pediatr Blood Cancer 2018;65:e26877.

11. Qaddoumi I, Bass JK, Wu J, Billups CA, Wozniak AW, Merchant TE, et al. Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol 2012;30:1034–41.

12. Bass JK, Hua CH, Huang J, Onar-Thomas A, Ness KK, Jones S, et al. Hearing loss in patients who received cranial radiation therapy for childhood cancer. J Clin Oncol 2016;34:1248–55.

13. Waissbluth S, Chuang A, Del Valle Á, Cordova M. Long term platinum-induced ototoxicity in pediatric patients. Int J Pediatr Otorhinolaryngol 2018;107:75–9.

14. Prayuenyong P, Taylor JA, Pearson SE, Gomez R, Patel PM, Hall DA, et al. Vestibulotoxicity associated with platinum-based chemotherapy in survivors of cancer: a scoping review. Front Oncol 2018;8:363

15. Maru D, Malky GA. Current practice of ototoxicity management across the United Kingdom (UK). Int J Audiol 2018;57(sup4):S29–41.

16. Steyger PS. Mechanisms of aminoglycoside- and cisplatin-induced ototoxicity. Am J Audiol 2021;30(3S):887–900.

17. Kros CJ, Steyger PS. Aminoglycoside- and cisplatin-induced ototoxicity: mechanisms and otoprotective strategies. Cold Spring Harb Perspect Med 2019;9:a033548

18. Gentilin E, Simoni E, Candito M, Cazzador D, Astolfi L. Cisplatin-induced ototoxicity: updates on molecular targets. Trends Mol Med 2019;25:1123–32.

19. Jung DJ. [Cisplatin-induced ototoxicity: updates on potential molecular mechanism]. Korean J Otorhinolaryngol-Head Neck Surg 2022;65:569–79. Korean.

20. Jang HJ, Cho HR, Lee JH, Bae KY, Seo JJ, Moon HN, et al. [Ototoxicity in children receiving cisplatin chemotherapy]. Korean J Pediatr 2010;53:210–4. Korean.

21. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Internet]. Rockville: National Cancer Institute;025 [cited 2025 Apr 1] Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.

22. Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 1991;19:295–300.

23. Fligor BJ. Pediatric ototoxicity: current trends and management. Semin Hear 2019;40:154–61.

24. Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Version 6.0 [Internet]. Monrovia, CA: Children’s Oncology Group;2023 [cited 2025 Apr 1] Available from: www.survivorshipguidelines.org.

25. Chang KW, Chinosornvatana N. Practical grading system for evaluating cisplatin ototoxicity in children. J Clin Oncol 2010;28:1788–95.

26. Theunissen EA, Dreschler WA, Latenstein MN, Rasch CR, van der Baan S, de Boer JP, et al. A new grading system for ototoxicity in adults. Ann Otol Rhinol Laryngol 2014;123:711–8.

27. Konrad-Martin D, Helt WJ, Reavis KM, Gordon JS, Coleman LL, Bratt GW, et al. Ototoxicity: early detection and monitoring. ASHA Lead 2005;10:1–14.

28. Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med 2018;378:2376–85.

29. Freyer DR, Chen L, Krailo MD, Knight K, Villaluna D, Bliss B, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017;18:63–74.

30. Freyer DR, Brock PR, Chang KW, Dupuis LL, Epelman S, Knight K, et al. Prevention of cisplatin-induced ototoxicity in children and adolescents with cancer: a clinical practice guideline. Lancet Child Adolesc Health 2020;4:141–50.

31. Katzenstein HM, Chang KW, Krailo M, Chen Z, Finegold MJ, Rowland J, et al. Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma: a report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children’s Oncology Group. Cancer 2009;115:5828–35.

32. Gallegos-Castorena S, Martínez-Avalos A, Mohar-Betancourt A, Guerrero-Avendaño G, Zapata-Tarrés M, Medina-Sansón A. Toxicity prevention with amifostine in pediatric osteosarcoma patients treated with cisplatin and doxorubicin. Pediatr Hematol Oncol 2007;24:403–8.

33. Kemp G, Rose P, Lurain J, Berman M, Manetta A, Roullet B, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14:2101–12.

34. Nagura M, Iwasaki S, Wu R, Mizuta K, Umemura K, Hoshino T. Effects of corticosteroid, contrast medium and ATP on focal microcirculatory disorders of the cochlea. Eur J Pharmacol 1999;366:47–53.

35. Nasr WF, Abdelhady M, Abd Elbary MES, Nada E. Treatment of cisplatin-induced ototoxicity by intra-tympanic corticosteroid injection. Indian J Otol 2018;24:33–7.

36. Marshak T, Steiner M, Kaminer M, Levy L, Shupak A. Prevention of cisplatin-induced hearing loss by intratympanic dexamethasone: a randomized controlled study. Otolaryngol Head Neck Surg 2014;150:983–90.

37. Thomas Dickey D, Muldoon LL, Kraemer DF, Neuwelt EA. Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hear Res 2004;193:25–30.

38. Riga MG, Chelis L, Kakolyris S, Papadopoulos S, Stathakidou S, Chamalidou E, et al. Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy. Am J Clin Oncol 2013;36:1–6.

39. Cardinaal RM, de Groot JC, Huizing EH, Veldman JE, Smoorenburg GF. Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea. Hear Res 2000;144:135–46.

40. Sharma SD, Cushing SL, Papsin BC, Gordon KA. Hearing and speech benefits of cochlear implantation in children: a review of the literature. Int J Pediatr Otorhinolaryngol 2020;133:109984

41. Gfeller KE, Olszewski C, Turner C, Gantz B, Oleson J. Music perception with cochlear implants and residual hearing. Audiol Neurootol 2006;11(Suppl 1):12–5.

42. Sato M, Baumhoff P, Tillein J, Kral A. Physiological mechanisms in combined electric-acoustic stimulation. Otol Neurotol 2017;38:e215–23.