Cancer therapy‐induced ototoxicity: Current challenges and emerging management strategies

Abstract

Cochleovestibular impairment is a debilitating sequela of oncological intervention, resulting from multifaceted organic damage to the inner ear. Clinically manifesting as sensorineural hearing loss and vestibular dysfunction, ototoxicity significantly compromises cognitive health and long‐term quality of life. Despite its prevalence, early detection and prophylactic intervention remain clinically suboptimal. This review provides a comprehensive analysis of the molecular pathogenesis and risk factors—including age, specific genetic polymorphisms, and cumulative dosage—associated with various cancer modalities such as platinum‐based chemotherapy, radiotherapy, and emerging immunotherapies. We specifically evaluate the cellular mechanisms of cisplatin‐induced irreversible damage to the stria vascularis and hair cells. Furthermore, this article critiques current clinical monitoring protocols, advocating for the integration of baseline audiological screening and high‐frequency auditory assessments as mandatory standards of care. Finally, we synthesize the current therapeutic landscape, ranging from established otoprotective agents and cochlear implants to novel candidate drugs in the preclinical pipeline. By bridging mechanistic research with translational evidence, this review emphasizes a precision‐medicine approach to balance therapeutic efficacy with the preservation of auditory integrity for cancer survivors.

This review comprehensively examines the key risk factors for cancer therapy‐induced ototoxicity, including cumulative drug dose, genetic susceptibility, and combined treatment regimens. It highlights current challenges in ototoxicity monitoring, such as insufficient timeliness and limited clinical adoption, and advocates for standardized auditory assessments throughout oncology care. Furthermore, the review summarizes emerging otoprotective strategies and highlights the importance of personalized interventions and early prevention to protect auditory health in cancer patients.

1. INTRODUCTION

Ototoxicity in oncology refers to therapy‐related structural damage and functional impairment of the auditory and vestibular systems, most commonly induced by iatrogenic exposure to anticancer agents. ¹ Clinically, it is characterized by sensorineural hearing loss, tinnitus, and vestibular dysfunction, all of which can substantially compromise communication, daily functioning, and long‐term quality of life in cancer survivors. As the global burden of cancer continues to rise, with approximately 20 million new cases and nearly 10 million deaths reported in 2022, treatment‐related complications are becoming an increasingly important component of survivorship care. ² Nevertheless, despite the profound clinical consequences of auditory and vestibular injury, the long‐term effects of cancer therapy on non‐target sensory organs, particularly the cochlea, remain insufficiently emphasized in routine oncology practice. Given projections that global cancer incidence may nearly double by 2070 compared with 2020 levels, the development of effective strategies to prevent or mitigate treatment‐related sensory dysfunction has become an urgent clinical priority. ³

Current anticancer treatment modalities, including cytotoxic chemotherapy, radiotherapy, and immunotherapy, are all associated with a risk of irreversible cochlear injury. Among them, platinum‐based agents, especially cisplatin, are the most extensively recognized ototoxic drugs, with hearing loss reported in up to 40% of treated population. ⁴ , ⁵ Radiotherapy involving the head and neck region can further exacerbate auditory dysfunction through injury to both the cochlea and central auditory pathways. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ In addition, emerging immune checkpoint inhibitors, such as pembrolizumab and nivolumab, introduce a new dimension of risk, with cochlear injury potentially mediated by immune dysregulation and autoimmune mechanisms. ¹¹ , ¹² , ¹³ As these treatment strategies are increasingly adopted across a broad range of malignancies, greater attention to their auditory adverse effects is warranted. Although their survival benefits are unquestionable, the associated impairment in auditory function is frequently underrecognized in clinical management, despite its direct impact on communication ability, social participation, daily activities, and overall well‐being. ¹⁴ , ¹⁵ , ¹⁶ With the growing population of long‐term cancer survivors, the persistent auditory consequences of cancer therapy demand greater clinical awareness and more effective management strategies.

This review synthesizes current knowledge on cancer therapy‐induced ototoxicity, with a particular focus on pathogenic mechanisms, risk factors, and management strategies (Scheme 1). Major determinants of ototoxic risk, including age, genetic susceptibility, cumulative drug exposure, and treatment modality, are discussed to support more individualized approaches to auditory monitoring and preservation. Important gaps in current clinical practice are also highlighted, particularly the lack of standardized ototoxicity surveillance, underscoring the need to integrate routine audiological assessment into oncology care pathways. In addition, emerging otoprotective strategies, personalized treatment frameworks, and innovative therapeutic approaches, including biomaterial‐based interventions with translational potential, are summarized. Collectively, this review aims to reframe ototoxicity not as an inevitable adverse effect of cancer therapy, but as a potentially preventable and clinically manageable complication that warrants proactive attention throughout the continuum of cancer care.

SCHEME 1.

Schematic overview of cancer therapy‐induced ototoxicity. This figure illustrates the major anticancer treatment modalities, including chemotherapy, radiotherapy, and immunotherapy, that may induce cochlear and vestibular injury. Multiple risk factors, such as age, sex, cumulative drug exposure, and combination treatment regimens, may influence individual susceptibility to ototoxicity. Monitoring strategies include patient self‐reporting and serial audiological assessments performed throughout treatment and during long‐term follow‐up. Current interventions for hearing rehabilitation include pharmacologic agents, hearing aids, cochlear implants, and emerging therapeutic candidates that are still under preclinical investigation. Created with BioRender.com.

2. CONCEPTS OF OTOTOXICITY

2.1. Anatomy and physiology of the ear

The ear is the primary sensory organ for hearing and balance and is anatomically divided into the outer ear, middle ear, and inner ear. The outer ear, consisting of the auricle and external auditory canal, collects sound waves and directs them toward the tympanic membrane. In the middle ear, vibrations of the tympanic membrane are transmitted through the ossicular chain (malleus, incus, and stapes) to the oval window of the inner ear. The inner ear comprises the cochlea, vestibule, and semicircular canals. Within the cochlea, vibrations of the basilar membrane generate traveling waves that deflect stereocilia of hair cells, thereby converting mechanical stimuli into electrical impulse signals that are transmitted via the auditory nerve to the auditory cortex for sound perception. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ Simultaneously, the vestibular apparatus detects head movement and spatial orientation, thereby maintaining postural balance and equilibrium.

Due to its highly specialized architecture and vascular properties, the ear is particularly vulnerable to systemic therapeutic insults. The inner ear is protected by the blood‐labyrinth barrier (BLB), a specialized endothelial barrier functionally homologous to the blood–brain barrier (BBB), which plays a critical role in maintaining ionic and metabolic homeostasis. ²¹ , ²² , ²³ Although the BLB limits the entry of most circulating agents, certain ototoxic drugs, including platinum‐based chemotherapeutics and aminoglycosides, are capable of crossing this barrier and accumulating within cochlear fluids. For example, cisplatin may enter the perilymph through fenestrated capillaries or transcytosis across the BLB and subsequently diffuse into the endolymph to reach cochlear hair cells. ²⁴ , ²⁵ These agents may also cross the basilar membrane to access the organ of Corti, where they progressively accumulate in sensory hair cells because of inefficient clearance. The resulting cytotoxicity leads to progressive cochlear damage, ultimately manifesting as irreversible hearing loss and auditory dysfunction.

2.2. Ototoxic manifestations: Hearing loss, tinnitus, and vestibular dysfunction

Ototoxicity refers to structural and functional injury to the auditory and/or vestibular systems induced by pharmacological agents, environmental toxins, or other exposures. Clinically, it may manifest as hearing loss, dizziness, tinnitus, balance impairment, or, in severe cases, ear pain or profound deafness. Prolonged exposure to ototoxic agents frequently results in irreversible auditory deficits.

Among the various symptoms, hearing loss is the most prevalent and clinically significant. It typically affects high frequencies and most often presents as irreversible sensorineural hearing loss (SNHL). According to the World Report on Hearing (WHO, 2021), a pure tone audiometry (PTA) average exceeding 20 dB in the better‐hearing ear is indicative of impairment. ²⁶ Platinum‐based chemotherapies, particularly cisplatin and carboplatin, are strongly associated with ototoxic hearing loss, with incidence rates up to 43.17%, affecting an estimated 500 000 individuals annually worldwide. ⁴ Tinnitus, defined as the phantom perception of sound, such as ringing or buzzing, in the absence of external acoustic stimulation, constitutes another frequent ototoxic sequela. It significantly diminishes quality of life, contributing to sleep disturbances, impaired concentration, and psychological distress. ²⁷ Its prevalence among cancer survivors ranges from 3% to 60%, which is higher than the 5%–43% reported in the general population. ²⁸ For instance, up to 40% of testicular cancer survivors report tinnitus, with 15.8% experiencing severe symptoms. ²⁹ Vestibular dysfunction, arising from injury to the balance structure of the inner ear, is also a common consequence of ototoxic injury. It may present as dizziness, postural instability, and spatial disorientation. Published studies have reported post‐chemotherapy vestibular impairment in 0%–50% of patients. ²⁸ Approximately 30% of cancer survivors experience falls, and vestibular impairment accounts for over 50% of falls among those receiving neurotoxic treatments, posing a substantial threat to patient safety. ³⁰

Beyond physical impairments, ototoxicity exerts profound psychosocial and cognitive consequences. Hearing loss and tinnitus can precipitate social withdrawal, depression, reduced occupational performance, and accelerated cognitive decline. Social isolation itself is a recognized risk factor for mental disorders, dementia, and increased mortality. ⁶ , ⁷ Despite these impacts, ototoxicity remains underrecognized in oncology. Therapeutic decision‐making is often dominated by tumor control and survival, with limited emphasis on auditory outcomes. Many patients are unaware that their auditory symptoms are treatment‐related until irreversible deficits have already developed. Misconceptions persist, with some assuming that hearing changes are transient. Clinical monitoring remains inadequate: a UK‐based survey reported that only 28% of institutions had ototoxicity surveillance protocols, and 95% of patients in one cohort did not undergo baseline audiometry before chemotherapy. ³¹ , ³² This lack of awareness and standardized screening delays diagnosis, worsens long‐term outcomes, and compounds the burden of survivorship.

3. CANCER THERAPIES ASSOCIATED WITH OTOTOXICITY

3.1. Platinum‐induced ototoxicity

3.1.1. Potential mechanisms

Platinum‐based chemotherapeutic agents, particularly cisplatin, induce ototoxicity through a series of complex pharmacokinetic and molecular mechanisms. Following systemic administration, these compounds bind to serum proteins and are distributed to tissues via the bloodstream. Their entry into the inner ear is primarily mediated by organic cation transporters (OCTs), which facilitate transport across the BLB into cochlear fluids. ³³ , ³⁴ In the stria vascularis, copper transporter 1 (CTR1), which is expressed in marginal, basal, and intermediate cells, drives continued uptake into the endolymph through the stria vascularis‐to‐endolymph route. ²⁵ , ³⁵ Platinum agents can also diffuse into the perilymph through strial capillaries and enter the endolymph via transcytosis across epithelial cells. Once in cochlear fluids, platinum compounds gain access to sensory hair cells through multiple pathways, including cation transporters and mechanical–electrical transduction (MET) channels (Figure 1A). The endocochlear potential produced by the stria vascularis activates the MET channels in cochlear hair cells, facilitating the intracellular accumulation of platinum compounds. ⁴⁰ Beyond transporter‐mediated uptake, cisplatin also disrupts cochlear vascular integrity. It increases hypoxia‐inducible factor‐1α (HIF‐1α) and its downstream target vascular endothelial growth factor (VEGF), leading to strial capillary leakage and barrier disruption (Figure 1B). ³⁶ Cisplatin additionally triggers extracellular signal‐regulated kinase 1/2 (ERK1/2), cytoplasmic phospholipase A2 (cPLA2), and cyclooxygenase‐2 (COX‐2) signaling pathways, therefore enhancing the production of inflammatory mediators, including prostaglandin E2 (PGE2) and VEGF, which further exacerbate cochlear damage. ³⁵ , ⁴¹

FIGURE 1.

Mechanisms of platinum‐induced ototoxicity. (A) Schematic illustration of cisplatin transport pathways into cochlear hair cells. Created with BioRender.com. (B) Fluorescein isothiocyanate (FITC)‐dextran (MW: 76 KDa) extravasation reveals vascular leakage within the stria vascularis; the affected area is indicated by the white box. Scale bar: 50 μm. ³⁶ (C) Laser ablation inductively coupled plasma mass spectrometry (ICP‐MS) mapping of a human cochlea obtained 25 days after the final cisplatin infusion. Green arrowhead: Stria vascularis; yellow arrowheads: Cochlear nerve fibers; white arrowheads: Boundary between cochlear nerve and cochlear modiolus bone; white arrows: Endosteum of the cochlear canal; asterisks: Surrounding cochlear bone; white box: Organ of Corti. Scale bar: 500 μm. Platinum intensities are shown in arbitrary units. ³⁷ (D) Quantification of outer hair cells (OHC) and inner hair cells (IHC) numbers. Solid traces represent OHC numbers (blue, purple, red, green); dotted lines represent IHC numbers. Values are mean ± SEM, n = 6 cochleae (3 females and 3 males) per group, total n = 24. Significance assessed by two‐way analysis of variance (ANOVA) followed by Tukey's multiple‐comparison test. ³⁸ (E) Immunostaining of cochlear turns with Myosin 7a (cyan) showing OHC and IHC distribution. Scale bar: 20 μm. ³⁸ (F) qPCR quantification of apoptosis‐related transcripts (Bax, caspase‐3, caspase‐8, caspase‐9, and Fadd) in House Ear Institute‐Immortomouse^TM cochlear cell line (HEI‐OC1) cells. Data were normalized to β‐Actin and are reported as mean ± SD; ***p < 0.001, ****p < 0.0001 versus control (blue) and cisplatin (black). One‐way ANOVA with Bonferroni correction; n = 3 per condition. ³⁹

Platinum compounds persist in the cochlea long after administration and accumulate within the stria vascularis, spiral ganglion neurons, and organ of Corti (Figure 1C). ³⁷ Inside hair cells, they trigger oxidative stress, impair mitochondrial function, provoke inflammatory cascades, and ultimately initiate apoptotic or necrotic cell death (Figure 1D,E). ³⁸ The cellular stress also injures marginal cells and further amplifies inflammatory responses, resulting in irreversible impairment of cochlear architecture. ³⁵ Neurotoxic effects on spiral ganglion neurons, mediated through interactions with intracellular DNA and proteins, contribute to both auditory and vestibular dysfunction. Recent studies have identified Toll‐like receptor 4 (TLR4) as a critical mediator of this process: cisplatin‐induced activation of TLR4 provokes oxidative damage, inflammatory cascades, and hair cell apoptosis across in vitro and in vivo systems (Figure 1F). ³⁹ , ⁴²

3.1.2. Risk factors

The incidence and severity of platinum‐induced ototoxicity are influenced by multiple factors, including patient characteristics, tumor type and location, treatment regimen, and renal function (Figure 2A). ⁵

FIGURE 2.

Risk factors associated with platinum‐induced ototoxicity. (A) Overview of clinical and treatment‐related risk factors. Created with BioRender.com. (B) Pure‐tone audiometry after chemotherapy demonstrates more pronounced threshold shifts in patients younger than 5 years at the start of treatment, with significant differences at 3, 4, 6, and 8 kHz (*). ⁴³ (C) Prevalence of moderate‐to‐severe cisplatin‐related hearing loss by tumor type; inter‐group comparison by χ ² test, p < 0.001. Hearing loss graded using the international Society of Pediatric Oncology Ototoxicity Grade (SIOP) ototoxicity scale (0–4). ⁴⁴ (D) Baseline and follow‐up mean hearing thresholds in patients receiving cisplatin‐based chemoradiation on weekly versus 3‐week schedules. ⁴⁵ (E) Mean post‐treatment threshold shifts (dB), grouped by cisplatin dosing regimen and evaluation time; values averaged for left and right ears. ⁴⁶ (F) Incidence of tinnitus by cumulative cisplatin dose (<300, 300, 400, and >400 mg/m²). Logistic regression demonstrated a dose‐dependent association (OR [odds ratio] = 1.38, 95% confidence interval [CI]: 1.1–1.7, p = 0.007), with post hoc χ ² confirming a significant increase in patients receiving >400 mg/m² (p < 0.0001). Sample sizes per group are indicated on the x‐axis. ²⁹ (G) Heatmap of p‐values from univariate regression analyses linking treatment‐induced toxicities at 3, 6, and 12 months with clinical outcomes. ⁴⁷

Age is a major determinant of susceptibility. Both pediatric and elderly populations are at a particularly high risk. Elderly patients (>65 years old) and young children (<5 years old) show the highest susceptibility to platinum‐induced hearing loss. ⁴³ In children, the auditory system is still developing, making it particularly vulnerable to the cytotoxicity of agents such as cisplatin and carboplatin. Reported incidence rates of ototoxicity in pediatric cancer patients range from 22% to 70%. ⁴⁸ Studies have shown that subjects younger than 18 years have a higher risk of ototoxicity (risk factor 0.95) relative to adults (risk factor 0.83), ⁴⁹ with children under 5 years old demonstrating significantly poorer auditory outcomes following chemotherapy (Figure 2B). ⁴⁴ Infants younger than 6 months are especially susceptible to cisplatin because their inner‐ear structures are still immature. In elderly patients, age‐related degeneration of the auditory system, compounded by platinum exposure, further elevates the risk. Cisplatin‐induced ototoxicity may exacerbate preexisting presbycusis, tinnitus, and peripheral neuropathy, particularly in individuals over 45 years old. ⁵⁰

Gender also appears to influence susceptibility, with male patients generally more prone to hearing loss. For example, male pediatric patients with solid tumors exhibit higher hearing loss rates (16.7%) than females (9.5%). ⁵¹ , ⁵²

Tumor type and anatomical location further modulate ototoxic risk. Cancers near auditory structures (e.g., head and neck) increase local otologic damage, whereas CNS tumors such as medulloblastomas and optic nerve gliomas are linked to higher ototoxicity. In contrast, germ cell tumors or osteosarcomas are associated with lower risk (Figure 2C). ⁴⁴ Testicular cancer survivors frequently report ototoxicity: tinnitus (68%), hearing loss (59%), or both (52%). ⁵³ Renal function is critical, as cisplatin is primarily eliminated via renal excretion. Impaired kidney function reduces clearance, leading to systemic accumulation and increased ototoxic risk. Dose adjustment and monitoring are essential in these patients.

Treatment regimens, including drug type, cumulative dose, and frequency, has a substantial impact on the development of ototoxicity. Cisplatin and carboplatin are more ototoxic than oxaliplatin. ⁵⁴ Concomitant administration with other ototoxic agents, such as aminoglycosides or NSAIDs, further elevates risk. ⁵⁵ For example, cisplatin can synergistically exacerbate aminoglycoside toxicity; in animal models, combined cisplatin and gentamicin produced profound hair cell loss and 40–50 dB increases in compound action potential thresholds. ⁵⁶ Prolonged treatment and multiple cycles increase cumulative damage: patients receiving high‐dose cisplatin every 3 weeks have a 56% incidence of severe hearing loss versus 13% in low‐dose weekly regimens (Figure 2D,E). ⁴⁵ , ⁴⁶ Audiometric thresholds worsen linearly with cumulative exposure; each additional 100 mg/m² of cisplatin produces an average 2.92 dB increase in hearing threshold shift. ⁵⁷ Tinnitus risk is similarly dose‐dependent; exposure >400 mg/m² increases risk by 2.61‐fold compared with exposure of ≤400 mg/m² (Figure 2F). ²⁹ Importantly, cisplatin‐induced ototoxicity often has a delayed onset, emerging around 6 months post‐treatment and potentially progressing long after therapy ends (Figure 2G). ⁴⁷

The development of ototoxicity is multifactorial, influenced by patient‐specific characteristics, tumor biology, and therapeutic regimens. These variables interact to affect the severity and trajectory of auditory damage. Therefore, proactive identification of high‐risk populations and the implementation of individualized treatment strategies are crucial for minimizing long‐term auditory morbidity.

3.2. Other medications

Chemotherapy‐related ototoxicity is not limited to platinum‐based agents; several other commonly used chemotherapeutic drugs also carry substantial risks of auditory injury. Cyclophosphamide, a widely used immunosuppressive and antineoplastic agent, induces apoptosis through the formation of DNA alkyl adducts. ⁵⁸ The sensorineural hearing loss resulting from cyclophosphamide is dose‐dependent. Although cyclophosphamide‐induced ototoxicity is often reversible at an early stage, the risk of irreversible damage increases with cumulative exposure. ⁵⁹ Therefore, patients receiving prolonged or high‐dose cyclophosphamide treatment require careful auditory monitoring. As microtubule‐stabilizing agents, paclitaxel and its derivative cabazitaxel can directly damage cochlear hair cells, auditory nerve fibers, and spiral ganglion neurons, thereby causing dose‐dependent sensorineural hearing loss. ⁶⁰ Clinical studies have shown that breast cancer patients may develop significant hearing impairment after as few as 1–8 treatment cycles. ⁶¹ In addition, cabazitaxel has demonstrated marked cochlear toxicity in animal models, with dose‐dependent injury observed in the stria vascularis, spiral limbus, and organ of Corti. ⁶² Methotrexate serves as a key therapeutic agent for acute lymphoblastic leukemia and is administered alongside cisplatin in osteosarcoma treatment. Notably, a study of childhood and adolescent cancer survivors aged 2–24 years found that approximately 37.5% of patients treated with methotrexate alone, without cisplatin or radiation therapy, developed mild to severe hearing loss. By comparison, around 83.3% of those treated concurrently with cisplatin manifested delayed auditory impairment. ⁶³ Although the incidence and severity of ototoxicity associated with these non‐platinum agents are generally lower than those observed with platinum‐based drugs, their risks are supported by both well‐defined pathological mechanisms and clinical evidence. Therefore, systematic auditory monitoring and timely intervention during treatment remain essential to reduce the likelihood of permanent hearing damage.

3.3. Radiation therapy

Radiotherapy remains a cornerstone of oncology, with over 50% of patients receiving it during treatment. Although highly effective for tumor control, radiotherapy inevitably exposes adjacent healthy tissues to irradiation, leading to adverse effects. Reported rates of severe radiation‐related toxicity range from 59.0% to 73.7%. ⁶⁴ Radiation induces cellular damage through both direct DNA breaks and indirect mechanisms involving oxidative stress and inflammatory response, ultimately triggering apoptosis, autophagy, or necrosis. ⁶⁵

Ototoxicity is a well‐documented complication of radiotherapy, particularly for head, neck, or central nervous system tumors. The cochlea, owing to its anatomical proximity to the irradiation field and delicate cellular architecture, is highly vulnerable to radiation‐induced oxidative injury affecting hair cells, spiral ganglion neurons, vascular endothelial cells, and supporting cells. In addition, central nervous system irradiation can damage the brainstem or auditory pathways, resulting in irreversible SNHL. The likelihood of auditory toxicity is influenced by baseline hearing status, total radiation dose, fractionation regimen, patient age, and concurrent chemotherapy. ⁶⁴

Radiation dose is the principal determinant of ototoxicity risk. When 50% of the cochlea is exposed to 45 Gy, or 40% of the internal auditory canal receives 50 Gy, auditory injury risk rises markedly. Similarly, a minimum canal dose >44 Gy or coverage of >45% of its volume by a 60 Gy isodose line significantly increases the likelihood of severe hearing loss (Figure 3A). ⁶⁶ Dose–response analyses have demonstrated a progressive increase in risk: 30–40 Gy results in a 27% chance of profound hearing loss; 40–50 Gy, 28%; and 50–60 Gy, 35%. ⁴⁹

FIGURE 3.

Ototoxicity caused by radiation therapy. (A) Dose–response effects of volume 45 Gy of the inner ear (IEV45) and volume 50 Gy of the internal ear canal (IACV50) on the risk of hearing impairment, and minimum dose of internal ear canal (IACmin) and volume 60 Gy of the internal ear canal (IACV60) on the risk of severe hearing impairment. ⁶⁶ (B) Hair cell counts obtained at different times after 15 Gy irradiation. *Mark examples of the sites of lost outer hair cells (OHCs). Scale bar = 10 μm. (C) Time‐to‐event (survival) analysis showing the cumulative percentage of patients with hearing loss ≥2b (Muenster classification) over time following the start of treatment. ⁶⁷ (D) Proportion of ototoxicity categories and number of patients' reported outcomes. ⁵⁰

Anatomical exposure site and treatment sequence further influence ototoxic outcomes. Head‐targeted irradiation is associated with higher auditory thresholds than irradiation elsewhere. In an animal model, auditory brainstem response (ABR) thresholds increased after 10–20 Gy exposure, with greater deterioration observed 21 days after 20 Gy than at earlier time points, indicating progressive cochlear injury. ⁶⁸ Another study found that mice experienced significant loss of outer hair cells 4–8 weeks after 15 Gy irradiation, which subsequently resulted in hearing dysfunction (Figure 3B). ⁶⁹ Clinical longitudinal data also reveal sequence‐dependent effects: patients receiving platinum chemotherapy before radiation developed hearing loss after a median of 1.2 years, compared to 4.4 years when chemotherapy followed radiation (Figure 3C). ⁶⁷

Although radiotherapy is indispensable, its auditory consequences remain underappreciated. Ototoxicity has been reported in 52.9% of symptomatic patients, making it the most prevalent radiation‐related toxicity, followed by ocular damage, xerostomia, skin fibrosis, and swallowing dysfunction. Most patients (81.2%) present with ≤2 symptoms, but 71.7% experience at least one otologic manifestation (Figure 3D). ⁵⁰ Therefore, mitigating strategies, including dose adjustment, precise field targeting, and judicious sequencing with chemotherapy, are essential to reduce auditory complications and improve long‐term quality of life.

3.4. Immune checkpoint inhibitor‐induced ototoxicity

Immune checkpoint inhibitors (ICIs) elicit antineoplastic activity by interrupting checkpoint–ligand binding, thereby reversing T‐cell tolerance to tumor antigens. However, ICIs affect not only tumor cells but may also affect normal organs and tissues, leading to a range of immune‐related adverse events, including rheumatologic autoimmune reactions, thyroid dysfunction, hypophysitis, myocarditis, pneumonia, and autoimmune diabetes. ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ Although ICI‐associated ototoxicity is relatively rare, its incidence may increase in patients receiving long‐term or combination immunotherapy. ICIs function by blocking immune regulatory checkpoint receptors such as CTLA‐4, PD‐1, and their ligand PD‐L1, thereby restoring T cell activation and antitumor immunity. ⁷⁵ The associated toxicity primarily affects barrier‐rich organs and is driven by immune overactivation and inflammatory responses. Specifically, CTLA‐4 and PD‐1 normally suppress T cell signaling, reduce early T cell activation, and modulate B cell activity. ⁷⁶ Therefore, blockade of these pathways may trigger dysregulated immune responses and multi‐organ inflammation. CTLA‐4, in particular, promotes TNF‐α production by CD4⁺ T cells, further contributing to systemic toxicity. ⁷⁷ Once activated, T cells may misrecognize and attack self‐antigens, or proliferate excessively, resulting in autoimmune inner ear inflammation and tissue damage (Figure 4A).

FIGURE 4.

Ototoxicity associated with surgical intervention and immune checkpoint inhibitor (ICI) therapy. (A) Schematic representation of the mechanism by which immune checkpoint inhibitors induce immune‐related adverse events through T cell overactivation. Created with BioRender.com. (B) Post‐treatment audiograms from three patients with metastatic melanoma showing immune checkpoint inhibitors (ICIs)‐related hearing loss. ⁷⁸

ICI‐associated ototoxicity commonly presents with SNHL, tinnitus, and balance disturbances, and may result in severe auditory dysfunction. This form of ototoxicity is generally immune‐mediated and inflammatory in nature. Numerous cases of ICI‐induced auditory damage have been reported. For instance, some melanoma patients developed moderate SNHL and tinnitus during ICI therapy. Notably, in several cases, hearing partially recovered following discontinuation of ICIs and initiation of hearing rehabilitation therapies (Figure 4B). ⁷⁸ , ⁷⁹ A prospective hearing assessment of 35 patients receiving ICIs showed that 76.3% received concurrent immunosuppressive therapy. Of these, 68.6% (24 patients) exhibited bilateral SNHL, whereas 14.3% (5 patients) developed unilateral SNHL. At least one of the 24 patients with SNHL had additional immune‐related adverse events, such as uveitis, vitiligo, or hypophysitis. ⁸⁰ These findings highlight the importance of recognizing ICI‐associated ototoxicity and underscore the need for proactive monitoring in clinical settings.

Bevacizumab, an anti‐VEGF monoclonal antibody occasionally used in combination with ICIs, may also contribute to ototoxicity. Data indicate that although 0.5% of patients in standard chemotherapy reported vertigo, the rate increased to 2% in the bevacizumab‐treated group, with symptoms ranging from mild to moderate. ⁸¹ ICIs are most commonly associated with hearing abnormalities within the first 4 months of treatment initiation. Furthermore, age appears to be a significant risk factor. All reported cases of ICI‐related ototoxicity have occurred in patients over 40 years old, with a predominance among the elderly. ⁸⁰

4. MONITORING HEARING DURING CANCER THERAPIES

Routine audiological monitoring is a critical component of managing cancer‐related ototoxicity. Early detection of auditory impairment enables timely clinical intervention, such as dose adjustment, treatment modification, or the initiation of otoprotective strategies, thereby helping to mitigate permanent hearing loss. Structured auditory monitoring during and after chemotherapy helps preserve hearing and improve long‐term quality of life and treatment outcomes. Moreover, systematic hearing assessments contribute to more comprehensive, patient‐centered care by addressing sensory side effects that are often underrecognized in oncology practice.

4.1. Detection frequency

Ototoxicity is a significant concern during cancer treatment, and well‐designed monitoring protocols are essential for early detection and prevention of long‐term sequelae. The frequency and duration of monitoring should be tailored to the type of therapy, specific agents, treatment duration, and individual patient risk factors. Monitoring is generally divided into three stages: pre‐treatment evaluation, intra‐treatment monitoring, and post‐treatment surveillance. A thorough pre‐treatment audiological evaluation is essential before ototoxic therapy is started. This evaluation should include high‐frequency audiometry, tympanometry, and otoacoustic emissions to establish a detailed auditory profile. Baseline data serve as a reference point for identifying hearing threshold shifts and for recognizing patients at higher risk for ototoxicity. ⁸² , ⁸³ In such cases, more frequent assessments are warranted.

Intra‐treatment monitoring is essential, as ototoxic effects can occur early and progress with cumulative exposure. For instance, patients receiving cisplatin frequently develop tinnitus or high‐frequency hearing loss within 1–2 weeks of treatment, with severity correlating with cumulative dose. Accordingly, audiological evaluations are recommended at the start of each chemotherapy cycle. ⁸⁴ , ⁸⁵ Beyond chemotherapy, immunotherapy has also been associated with bilateral vestibular and cochlear toxicity after only 1–3 cycles, highlighting the need for early and regular testing. Patients should be encouraged to report early symptoms such as tinnitus, dizziness, or hearing fluctuation.

Post‐treatment surveillance is equally important because ototoxic effects may emerge or progress after therapy has ended. Cisplatin, for example, can persist in cochlear tissues, leading to delayed hair cell, strial, and spiral ganglion neuron injuries. ³⁷ The ASHA and AAA ototoxicity monitoring guidelines recommend assessments at baseline, throughout treatment, and for at least 12 months post‐treatment. ⁸⁶ However, longer‐term follow‐up may be necessary. In children treated with carboplatin for retinoblastoma, ototoxic symptoms emerged 2–75 months post‐treatment (median: 18.5 months). ⁸⁷ Another study found that ototoxicity prevalence rose from 39.5% at the end of chemotherapy to 52.5% at 5 years. ⁸⁸ For radiotherapy recipients, long‐term monitoring is also essential. SNHL can emerge several years post‐exposure, with a median onset of 3.6 years and persistent bilateral hearing loss reported in 65.5% of cases (Figure 5A). ⁸⁹ Recommended follow‐up includes audiologic testing every 6 months for 5 years, then annually for an additional 5–10 years, depending on risk profile and cumulative radiation dose.

FIGURE 5.

Physician and patient concerns regarding cancer therapy‐induced ototoxicity. (A) Count of patients exhibiting sensorineural hearing loss (SNHL) (Chang grade >0) versus normal hearing, stratified by age at radiotherapy initiation (N = 235). ⁸⁹ (B) Distribution of speech recognition threholds (SRT)‐based hearing disability by self‐reported health category. ⁹⁰ (C) Rates of audiological monitoring among patients undergoing cisplatin‐based chemotherapy, showing ototoxicity surveillance coverage during treatment. ⁹¹ (D) Proportion of oncologists (N = 35) who implement baseline auditory evaluation versus symptom‐triggered monitoring for ototoxicity. ⁹²

4.2. Patient and physician monitoring preferences

Despite its importance, ototoxicity monitoring is often underutilized in oncology care, reflecting gaps in both patient participation and physician practice. Oncologic care often prioritizes tumor control and survival outcomes, relegating sensory toxicities, such as hearing loss or tinnitus to secondary concern, particularly during chemotherapy. As a result, ototoxic symptoms are frequently overlooked or misattributed to unrelated causes, leading to delayed diagnosis and intervention. In its early stages, ototoxicity typically presents with subtle manifestations, such as mild high‐frequency hearing loss or transient tinnitus, which patients may not notice or report. This issue is particularly pronounced among older adults, who may attribute new auditory changes to age‐related decline rather than treatment‐induced toxicity. Moreover, studies indicate that patient participation in ototoxicity surveillance remains limited: only 32.1% of patients undergo hearing assessments within 6 months of cisplatin administration, with follow‐up rates declining as treatment continues. Patients in rural or resource‐limited settings face additional barriers to consistent audiological evaluation, thereby exacerbating disparities in detection and care (Figure 5B,C). ⁹³ , ⁹⁴

From the physician's perspective, awareness of ototoxicity risk is generally high, yet adherence to monitoring protocols remains inconsistent. A recent survey revealed that although 97% of oncologists inform patients about the ototoxic risks of cisplatin, only 18% perform baseline audiological assessments, and 69% initiate testing only after symptom onset. Notably, 35% of physicians report not performing regular monitoring at all during therapy (Figure 5D). ⁹² This disconnect between knowledge and practice likely reflects competing clinical priorities, limited access to audiological services, and the absence of standardized institutional guidelines. Both limited patient engagement and provider‐level implementation gaps contribute to the underdiagnosis and undertreatment of cancer therapy‐induced ototoxicity. To mitigate the risk of irreversible auditory damage, it is essential to strengthen education, interdisciplinary communication, and the integration of structured ototoxicity surveillance into cancer care workflows. Early identification, baseline assessment, and continuous follow‐up facilitate timely intervention and improve long‐term quality of life in cancer survivors.

4.3. Detection methods

Effective detection of ototoxicity is essential for minimizing auditory damage during cancer treatment, particularly in patients receiving cisplatin. A variety of monitoring strategies are available, including subjective symptom reporting, audiological testing, genetic screening, and standardized ototoxicity grading systems. These approaches facilitate early diagnosis and timely intervention, contributing to better preservation of hearing and overall quality of life.

Subjective assessment remains a practical and widely used method in clinical settings. Patients may self‐report symptoms such as tinnitus, hearing loss, or vertigo, often via structured questionnaires or clinician‐led interviews. Although this method depends on patient perception and may lack sensitivity, it is useful for preliminary screening and for tracking symptom progression over time. Several validated instruments assist with symptom quantification. For tinnitus, tools such as the Tinnitus Handicap Inventory (THI), Tinnitus Functional Index (TFI), Tinnitus and Hearing Survey (THS), Beck Depression Inventory (BDI), and Skarzynski Tinnitus Scale (STS) have been employed to assess severity and impact. ⁹¹ , ⁹⁵ , ⁹⁶ For subjective hearing function, the Active‐Empathic Listening Scale (AELS) evaluates perception, processing, and response dimensions, offering insight into functional hearing in daily life. ⁹⁷ These tools enhance communication between patients and clinicians and promote early symptom recognition.

Audiological tests provide objective measures and are central to ototoxicity monitoring. The most commonly used tests include the following: (1) PTA assesses hearing thresholds across frequencies and remains the gold standard for evaluating the degree of hearing loss. Changes in PTA thresholds have been strongly associated with ototoxicity. A study reported that each unit increase in the logarithm of baseline PTA was associated with a 254% higher risk of developing ototoxicity. ⁹⁸ (2) Otoacoustic emission (OAE) measures cochlear outer hair cell function, offering high sensitivity for early detection of cochlear damage before threshold shifts are detectable by PTA. ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² (3) High‐frequency audiometry evaluates hearing beyond 8 kHz, often identifying ototoxic damage at an earlier stage, as high‐frequency regions are affected first. ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ (4) Brainstem auditory evoked potentials (BAEPs) and speech recognition testing evaluate auditory nerve conduction and functional hearing ability, especially useful in non‐cooperative or pediatric patients. Using a combination of these tools enables the early identification of subclinical changes and supports personalized intervention planning. Emerging genetic screening protocols aim to detect individuals at increased risk for drug‐related auditory injury. Genome‐wide studies identified that the genes such as SLC16A5 and OTOS are significantly associated with cisplatin‐induced ototoxicity. ²⁹ , ¹⁰⁷ Overexpression of the OTOS gene has been shown to have a protective effect against cisplatin cytotoxicity in cochlear cell lines and to reduce patients' susceptibility to tinnitus. To facilitate early risk identification, detection methods targeting these relevant genes may be developed to enable the rapid identification of susceptible individuals before treatment. This approach can guide dose optimization and strategies for preventing ototoxicity.

Ototoxicity grading scales help quantify severity and standardize reporting. The Common Terminology Criteria for Adverse Events classify ototoxicity from Grade 1 (mild) to Grade 4 (profound loss or deafness). ¹⁰⁸ These scales are often used alongside audiometric data to guide clinical decisions (Table 1). The American Speech‐Language‐Hearing Association (ASHA) guidelines also define significant auditory changes, such as a ≥20 dB loss at a single frequency or ≥10 dB loss at two adjacent frequencies, as criteria that should prompt clinical intervention. In pediatric oncology, additional age‐appropriate grading systems have been developed to quantify hearing impact and direct rehabilitative planning. ²⁵ , ⁸⁹ A multimodal approach integrating subjective reports, objective audiological assessments, genetic susceptibility screening, and standardized scoring frameworks provides a comprehensive strategy for detecting ototoxicity during and after cancer therapy. Such protocols enable early diagnosis, individualized intervention, and long‐term hearing preservation for cancer patients at risk.

TABLE 1.

Commonly used ototoxicity scales.

Classification	Grade	Frequency	Hearing threshold shift (dB)
Chang Scale	0	1, 2, 4 kHz	≤20
	1a	6–12 kHz	≥40
	1b	4 kHz	>20 and <40
	2a	>4 kHz	≥40
	2b	<4 kHz	>20 and < 40
	3	>2 kHz	≥40
	4	>1 kHz	≥40
AHSA Scale	A	At least 1	≥20
	B	2 adjacent tests	≥10
	C	3 previously detectable contiguous frequencies	Absence of measurable thresholds
Boston SIOP Scale	0	All	≤20
	1	>4 kHz	>20
	2	≥4 kHz	>20
	3	>2 kHz	>20
	4	>2 kHz	>40
Brock Scale	0	All	<40
	1	8 kHz	≥40
	2	>4 kHz	≥40
	3	>2 kHz	≥40
	4	>1 kHz	≥40
POG Scale	0	All	No change
	1	>4 kHz	20–40
	2	4 kHz	>40
	3	>2 kHz	>40
	4	<2 kHz	40
Muenster Scale	0	All	≤10
	1	At least 1	>10–20
	2	≥4 kHz	2a: 20–40
			2b: 40–60
			2c: >60
	3	<4 kHz	3a: 20–40
			3b: 40–60
			3c: >60
	4	<4 kHz	>80

Abbreviation: SIOP, Society of Pediatric Oncology Ototoxicity Grade. AHSA, American Speech‐Language‐Hearing Association. POG, Pediatric Oncology Group's objective criteria.

5. TREATMENT AND PREVENTION OF OTOTOXICITY

5.1. Otoprotective agents for clinical use

Although early intervention can mitigate the severity of cancer therapy‐induced ototoxicity, no current available pharmacological treatment can fully reverse established SNHL. Mild deficits can show partial recovery with intervention, whereas profound loss usually remains permanent and requires lifelong auditory rehabilitation, such as hearing aids or cochlear implantation. Consequently, clinical focus has shifted toward prevention strategies, particularly the prophylactic use of otoprotective agents during administration of ototoxic drugs. Several pharmacologic classes have been investigated for their otoprotective potential, including antioxidants, neurotrophic factors, anti‐inflammatory agents, and vasodilators. These agents aim to mitigate cochlear damage by reducing oxidative stress, suppressing inflammatory responses, and enhancing cochlear microcirculation, thereby preserving hair cell integrity during exposure to ototoxic agents. Among clinically validated options, sodium thiosulfate has shown the most promising results. Its primary mechanism is the direct inactivation of cisplatin, thereby attenuating cochlear and auditory nerve toxicity. In September 2022, the FDA approved sodium thiosulfate for children aged ≥1 month with localized non‐metastatic solid tumors to mitigate cisplatin‐induced ototoxicity. ¹⁰⁹

Regulatory review is underway in the European Union for comparable pediatric indications (1 month to 18 years of age). Clinical trials have confirmed the efficacy of sodium thiosulfate in reducing cisplatin‐related ototoxicity. In one randomized trial involving 114 pediatric patients, hearing loss occurred in 39% of those receiving sodium thiosulfate versus 68% in the control group. ¹¹⁰ Another study of 125 patients reported hearing loss in 44% of patients treated with sodium thiosulfate compared to 58% in those receiving cisplatin alone. ¹¹¹ These findings underscore the potential of sodium thiosulfate as a protective adjunct in cisplatin‐based chemotherapy. Although irreversible damage cannot be reversed, early prophylactic administration of agents such as sodium thiosulfate provides a feasible approach to reduce ototoxic risk and preserve auditory function during cancer therapy.

5.2. Preclinical otoprotection strategies based on animal models

Preclinical studies utilizing animal models have provided a solid theoretical and experimental basis for the in‐depth investigation of ototoxicity mechanisms and the development of corresponding prevention and therapeutic strategies. Rodent and zebrafish models are indispensable in ototoxicity research, serving as essential platforms for validating specific molecular pathways, systematically evaluating protective interventions, optimizing drug delivery approaches, and exploring potential synergistic therapies.

In cisplatin‐induced ototoxicity models, studies POG, Pediatric Oncology Group's objective criteria.n mice have highlighted the pivotal role of macrophages in regulating drug accumulation within the cochlea. Notably, depletion of cochlear tissue‐resident macrophages using the colony‐stimulating factor 1 receptor inhibitor PLX3397 led to a significant reduction in cochlear cisplatin levels, resulting in improved auditory function and enhanced survival of outer hair cells. ³⁸ In addition, CORM‐2, a carbon monoxide‐releasing molecule, has shown protective effects by restoring the integrity of the stria vascularis barrier and reducing cisplatin accumulation in the cochlea. ¹¹² In the context of radiation‐induced ototoxicity, radiation‐exposed mouse models provide a valuable tool for further elucidating its pathogenesis. Studies have demonstrated that the injectable RADA 32‐HRN‐dexamethasone (RHD) hydrogel loaded with dexamethasone can effectively alleviate radiation‐induced cochlear inflammatory and oxidative damage, promote the recovery of auditory function, and offer a novel strategy for the intervention of radiation‐induced injury. ¹¹³

Oxidative stress is a central mechanism underlying cisplatin‐induced ototoxicity, and various intervention strategies targeting this pathway have been rigorously validated in animal models. For instance, intratympanic administration of astaxanthin markedly attenuates cisplatin‐induced oxidative damage and cochlear hair cell apoptosis. This protective effect is mediated through the activation of the NRF2 signaling pathway, ultimately reducing hearing impairment. ³⁹ Animal models also serve as a critical platform for evaluating the feasibility of localized drug delivery systems for the inner ear. Through intratympanic injections or hydrogel‐based delivery systems, precise control over drug distribution and retention within the cochlea can be achieved. Moreover, high‐resolution real‐time imaging in zebrafish models enables dynamic monitoring of macrophage behavior during hair cell apoptosis, as well as the identification of cisplatin‐induced pro‐inflammatory macrophage subsets. ¹¹⁴ These findings not only deepen the understanding of the pathophysiological mechanisms underlying ototoxicity but also provide novel insights into the development of targeted therapeutic strategies.

5.3. Hearing aids

Hearing aids remain a cornerstone of rehabilitative management for managing SNHL, particularly in cases where pharmacological reversal is not feasible. Roughly 30–55 million people in the United States live with hearing loss, yet only about one‐third adopt hearing aids. ¹¹⁵ Similarly, a large‐scale study in Australia reported that although one‐third of participants suffered from severe hearing loss, only 11% used hearing aids. ¹¹⁶ Low adoption rates are linked to multiple sociodemographic and economic factors, including race and ethnicity, geographic location, income level, and marital status. ¹¹⁷ Evidence indicates that financial subsidies for hearing aids significantly increase adoption rates and consequently improve quality of life. ¹¹⁸ Overall, the uptake of hearing assistive devices is influenced by various factors, and policy interventions, such as increasing subsidies, could significantly enhance the quality of life for individuals with hearing impairments.

A variety of hearing aid types are available to accommodate different severities of hearing loss, anatomical needs, and aesthetic preferences. These include behind‐the‐ear (BTE), in‐the‐ear (ITE), in‐the‐canal (ITC), completely‐in‐the‐canal (CIC), invisible‐in‐the‐canal (IIC), and bone conduction hearing aids. ¹¹⁹ , ¹²⁰ BTE devices are typically recommended for moderate to severe hearing loss due to their greater amplification capabilities, although they are more visible. In contrast, smaller devices such as ITE, ITC, CIC, and IIC offer greater discretion and are generally preferred by individuals with mild to moderate hearing loss, albeit with reduced amplification. Technological advancements have significantly improved hearing aid performance. Modern devices now incorporate features such as active noise cancellation, directional microphones, speech enhancement algorithms, and adaptive environmental adjustments, which collectively enhance speech perception and listening comfort across diverse auditory environments. ¹²¹ , ¹²² , ¹²³ , ¹²⁴

A comprehensive audiological assessment is essential before device selection, followed by fitting and customization guided by an audiologist. ¹²⁵ Some patients, particularly older adults and pediatric populations, may benefit from hearing rehabilitation or auditory training programs to facilitate adaptation and improve user satisfaction. ¹²⁶ Routine maintenance (e.g., cleaning, battery changes) is critical for device performance, and caregiver involvement may be necessary for certain populations. ¹²⁷ In addition to technical performance, hearing aids carry social and psychological implications. A national survey in France revealed that only 15% of hearing aid users reported never feeling socially excluded due to their hearing aids, whereas 72% of individuals with untreated hearing loss reported frequent social exclusion. ¹¹⁵ These findings highlight the dual challenge of addressing auditory dysfunction and stigma, underscoring the need for broader public education and support to improve social integration among hearing aid users.

Hearing‐aid uptake has risen markedly over the past 25 years. By 2022, the number of users had doubled, and more than 75% of hearing aid owners attributed their success to professional support from audiologists. ¹²⁸ Additionally, the proportion of users receiving financial assistance for hearing aids rose from 27% in 1991 to 54% in 2022. ¹²⁸ These patterns indicate that broader professional access and financial assistance are key drivers for scaling hearing‐aid adoption and enhancing outcomes for people with hearing loss.

5.4. Cochlear implants

Despite their well‐established efficacy, cochlear implants (CIs) remain markedly underutilized (Figure 6). In the United States, nearly 80% of adults with hearing loss have never discussed CIs with a healthcare provider. ¹²⁹ This underutilization appears to be particularly pronounced among cancer survivors. In a study of 376 individuals with severe sensorineural hearing loss, 218 participants were considered eligible for cochlear implants; however, 91 of these individuals (41.7%) were not using hearing aids. ¹³⁰ Furthermore, available data indicate that, as of 2015, approximately 170 000 cochlear implant procedures had been performed in the United States. ¹³¹ In Japan, statistics from 2017 showed that fewer than 1.6% of potential adult candidates ultimately underwent cochlear implantation. ¹³² Cochlear implants are surgically implanted neuroprosthetic devices that bypass damaged hair cells and deliver electrical pulses directly to the auditory nerve. First approved by the FDA in 1985, they are considered among the most successful neural prosthetic technologies. ¹³³ The system consists of an external microphone and processor, which capture and convert sound into electrical signals, and an internal receiver implanted under the skin. The signals travel to an electrode array threaded into the cochlea; the contacts activate auditory‐nerve fibers directly, enabling sound perception. ¹³⁴ Unlike hearing aids that merely amplify sound, CIs replace cochlear function by transmitting auditory signals directly to the brain.

FIGURE 6.

Clinical treatment methods for cancer‐related ototoxicity. Created with BioRender.com.

Despite their efficacy, implantation entails surgical and rehabilitative risks, including complications related to anesthesia, infection, and, in rare cases, further hearing deterioration. ¹³⁵ Rehabilitation may be prolonged, and total costs (surgery, device, training) can be substantial. Additionally, CI performance also depends on age at surgery, length of deafness, remaining hearing, cognitive function, and the underlying cause of hearing loss. ¹³⁶ A patient's willingness to undergo cochlear implantation is influenced by multiple factors. A survey of 113 adults eligible for cochlear implantation showed that, although all participants met the criteria for surgery, only 66.3% ultimately elected to proceed with the procedure, whereas 33.6% chose to postpone it. The most commonly cited reason for postponement was concern about the potential loss of residual hearing, followed by issues related to overall medical condition and concerns about the cost of the implant as well as its long‐term financial burden. ¹³⁷ Nonetheless, strong evidence supports CIs in improving speech perception, auditory communication, and quality of life, particularly in patients with ototoxic or radiation‐induced hearing loss. ¹³⁸ , ¹³⁹ Patient‐reported outcomes consistently indicate high satisfaction rates with cochlear implant use. Improvements in speech comprehension in both quiet and noisy environments, as well as enhanced social participation, have been widely documented. As technological advancements continue to improve CI hardware and signal processing algorithms, the clinical indications for implantation are expanding. Furthermore, increased patient and provider education may help close the current awareness gap and facilitate broader access to this transformative intervention.

6. OPPORTUNITIES AND CHALLENGES

6.1. Detection and prevention of ototoxicity

Progress in oncologic treatment has markedly prolonged survival. As a result, increasing attention has been directed toward the long‐term quality of life of cancer survivors. Among the treatment‐related adverse effects, ototoxicity remains underrecognized, despite its potential to cause irreversible auditory and vestibular dysfunction, thereby impairing communication, psychosocial well‐being, and daily functioning. As summarized in Table 2, a range of common cancer therapies that may induce ototoxicity, therefore, early detection and prevention, are essential to mitigate its long‐term impact.

TABLE 2.

Cancer therapies associated with ototoxicity.

Therapeutic category	Drug	Populations	Type of ototoxicity	Reported incidence	References	Mechanism
Platinum	Platinum compounds	n = 609, ≥18‐year‐old	SNHL	34.3%	Miaskowski et al. 140	Oxidative stress, mitochondrial dysfunction, DNA damage, inflammatory signaling, apoptotic process
			Tinnitus	31.1%
	Cisplatin	n = 198, 18–65‐year‐old, locoregionally advanced nasopharyngeal carcinoma	Hearing‐related problems	21%	Tang et al. 141
		n = 1280, ≤18‐year‐old	SNHL	39.2%	Moke et al. 44
	Carboplatin	n = 71, childhood retinoblastoma	SNHL	33.8%	Soliman et al. 87
	Nedaplatin	n = 200, 18–65‐year‐old, locoregionally advanced nasopharyngeal carcinoma	Hearing‐related problems	9.5%	Tang et al. 141
	Orixaplatin	48‐year‐old, female, pancreatic cancer	Tinnitus, dizziness, fullness, and hearing impairment of left ear	–	Kim et al. 142
		70‐year‐old, female, rectal cancer	Single dose of SNHL	–	Malhotra et al. 143
Other traditional chemotherapy drugs	Cyclophosphamide	n = 18, 25–59‐year‐old	SNHL	–	Oliveira et al. 144	Not fully elucidate
	Methotrexate	n = 8, 2–22‐year‐old, 2–19 years after treatment	SNHL	37.5%	Moore et al. 63
	Paclitaxel	n = 121, children of mothers treated with taxane‐based chemotherapy	SNHL or auditory processing impairment	3.3%	van Assche et al. 145
	Docetaxel	n = 2, female, breast cancer	SNHL, inner ear microcirculation obstruction, peripheral neuritis	–	Xuan et al. 61
Targeted therapy	Osimertinib	72‐year‐old, male, non‐small cell lung cancer and brain metastasis	SNHL	–	Lim et al. 146	Not fully elucidate
	Regorafenib	48‐year‐old, female, colon cancer	Bilateral SNHL	–	Cheng et al. 147
Immune checkpoint inhibitors	Nivolumab	67‐year‐old, male, stage IV malignant melanoma	Vertigo, bilateral SNHL	–	Tampio et al. 148	Immune‐mediated injury
	Immune checkpoint inhibitors	n = 6, 40–62‐year‐old, melanoma	Bilateral high‐frequency hearing loss, tinnitus	–	Rosner et al. 78
Radiotherapy	Intensity modulated radiation therapy	n = 588, ≤30‐year‐old, non‐metastatic nasopharyngeal carcinoma	SNHL	39.5% have SNHL, of which 29.7% have severe SNHL	Chen et al. 66	DNA breaks, oxidative stress, inflammatory response, ultimately triggering apoptosis, autophagy, or necrosis
	Radiation therapy	n = 171, ≤ 18‐year‐old, CNS and head‐and‐neck tumors	SNHL	–	Keilty et al. 149
	Intensity modulated radiation therapy	n = 112, 19–74‐year‐old, nasopharyngeal carcinoma	Chronic suppurative otitis media	7.8%	Hsin et al. 150
			Otitis media with effusion	29.4%
Combination therapy	Radiation + cisplatin/cetuximab	n = 407, 29–73‐year‐old, locally advanced squamous cell carcinoma of the head and neck	Ear and labyrinth disorders	7.4%	Hitt et al. 151	–
	Radiation + cisplatin	n = 193, 33–83‐year‐old, Human Papillomavirus + oropharyngeal cancer	SNHL	32%	Runge et al. 152

Abbreviations: CNS, central nervous system; SNHL, sensorineural hearing loss.

One of the foremost challenges is the limited awareness among healthcare professionals and patients. Educational programs for clinicians can encourage routine audiological monitoring, promote early detection, and support timely interventions. Similarly, patient education—delivered through informed discussions with oncology providers—can increase vigilance regarding subtle symptoms, such as tinnitus, high‐frequency hearing loss, or dizziness, which may precede overt ototoxic injury. These early symptoms are frequently nonspecific, making self‐reporting by patients a critical component of early recognition.

Systematic early screening and post‐treatment surveillance should be integrated into standard oncology care to enhance prevention. Conventional auditory assessments—pure‐tone audiometry, speech testing, OAE, and ABR—allow early detection of subclinical hearing changes. Because ototoxicity may manifest months or even years post‐treatment, long‐term monitoring is essential, especially for patients treated with cisplatin or other high‐risk agents.

A comprehensive, individualized hearing follow‐up program is critical. Surveillance schedules should be tailored based on cancer type, treatment modality, and patient‐specific risk factors. The selection of appropriate testing intervals and tools is critical for early diagnosis. For patients who develop signs of ototoxicity, prompt clinical action—such as adjusting drug regimens, initiating otoprotective agents, or, when appropriate, modifying or discontinuing ototoxic therapies—may prevent progression and preserve residual hearing.

6.2. Treatment of ototoxicity

Ototoxicity is a debilitating side effect of many cancer therapies, primarily mediated by ROS that overwhelm endogenous antioxidant defenses and damage cochlear tissues. Although early‐stage or mild damage may respond to pharmacologic or biological interventions, established hearing loss remains challenging to treat. Current strategies include antioxidants, neurotrophic factors, anti‐inflammatory agents, and vasodilators, though their clinical effectiveness is limited by poor cochlear drug delivery, particularly across the BLB. Recent developments in nanotechnology‐based drug delivery systems aim to overcome these barriers by increasing BLB permeability, improving drug stability, and enabling targeted delivery. ¹⁵³

Antioxidants remain a cornerstone of pharmacologic treatment. Traditional agents such as vitamin C, vitamin E, coenzyme Q10, and α‐tocopherol have shown protective effects in models of cisplatin‐induced damage. ¹⁵⁴ Emerging compounds, including epigallocatechin‐3‐gallate (EGCG) and curcumin, exhibit enhanced ROS‐scavenging capabilities and promote endogenous antioxidant enzyme activity. ¹⁵⁵ , ¹⁵⁶ , ¹⁵⁷ , ¹⁵⁸ Mitochondria‐targeted antioxidants, like MitoQ, enhanced efficacy by localizing activity to the source of oxidative stress. Combination therapies, such as N‐acetylcysteine (NAC) with NFAT inhibitors, show synergistic effects in reducing both oxidative damage and inflammation. ¹⁵⁹ , ¹⁶⁰ Neurotrophins such as nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), and fibroblast growth factor (FGF) enhance cochlear cell survival and promote regeneration. NGF is effective against gentamicin‐induced ototoxicity, whereas BDNF supports synaptic integrity and auditory neuron survival in cisplatin models. ¹⁶¹ , ¹⁶² , ¹⁶³ , ¹⁶⁴ , ¹⁶⁵ FGF shows promise for hair cell regeneration but raises concerns regarding pro‐tumorigenic potential, warranting cautious clinical development. ¹⁶⁶ , ¹⁶⁷ , ¹⁶⁸ , ¹⁶⁹

Cell‐based therapies represent a promising frontier. These include stem cell transplantation for structural repair and gene editing technologies that stimulate endogenous hair cell regeneration programs—both of which are in preclinical stages, but hold transformative potential. Inflammation also contributes significantly to ototoxicity. Anti‐inflammatory agents such as ebselen (SPI‐1005) and glucocorticoids (e.g., dexamethasone) have shown efficacy in reducing inflammation‐mediated cochlear injury. ¹⁷⁰ , ¹⁷¹ Systemic glucocorticoids, however, exhibit poor cochlear penetration, limiting efficacy. ¹⁷² , ¹⁷³ , ¹⁷⁴ , ¹⁷⁵ To overcome this limitation, localized delivery systems such as RADA32‐HRN‐dexamethasone hydrogels have been developed, enabling sustained cochlear drug release. ¹¹³

Vasodilators, including caffeine, nimodipine, and sildenafil, have been explored for tinnitus and vertigo management. Nimodipine, in particular, shows protective effects against cisplatin‐induced damage. ¹⁷⁶ However, some vasodilators may worsen ototoxicity, underscoring the need for individualized treatment plans. ¹⁷⁷ For patients with irreversible hearing loss, hearing aids and ICs remain the primary rehabilitative options. Advances in miniaturization, 3D printing, and artificial intelligence (AI) have enhanced device customization, comfort, and functionality. AI‐enabled hearing aids can now automatically adapt to environmental noise and optimize speech perception, significantly improving patient experience (Figure 7).

FIGURE 7.

Challenges and prospects for cancer‐related ototoxicity. Created with BioRender.com.

Effective management of ototoxic injury relies on an integrated effort spanning pharmacology, nanomedicine, neurobiology and biomedical engineering. Emerging innovations in targeted drug delivery, regenerative medicine, and auditory prosthetics offer new opportunities to preserve hearing and enhance quality of life in patients affected by treatment‐induced hearing loss.

AUTHOR CONTRIBUTIONS

Yuqi Huang: Writing – original draft; writing – review and editing. Baoying Xu: Writing – review and editing. Xinru Chen: Writing – review and editing. Yu Chen: Conceptualization; supervision; writing – review and editing. Dehong Yu: Conceptualization; supervision; writing – review and editing.

FUNDING INFORMATION

This work was supported by the National Natural Science Foundation of China (81970874), National Key Research and Development Program of China (2023YFC2306500), Shanghai Shuguang Program (21SG39), and Shanghai Science and Technology Program (24520712900).

CONFLICT OF INTEREST STATEMENT

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ETHICS STATEMENT

This article does not contain any studies with human or animal participants.