Hearing Loss in Cancer Patients
Alongside advancements in otoprotective drug delivery and radiation techniques, it is imperative to recognize the extreme impact of hearing loss on the overall well-being of oncologic patients.
Samuel H. Smith, MD, David S. Lee, MD, and Celine Richard, MD, PhD, for the Hearing Committee
Alongside advancements in otoprotective drug delivery and radiation techniques, it is imperative to recognize the extreme impact of hearing loss on the overall well-being of oncologic patients. Early intervention and rehabilitation measures should be prioritized to address this issue effectively. Moreover, fostering awareness among healthcare providers and patients about the importance of monitoring and managing hearing health throughout the oncologic journey is paramount for optimizing patient outcomes and quality of life.
Addressing Hearing-Related Issues in Cancer Patients
As innovative cancer therapies continue to evolve, there has been a discernible increase in the survival rates of individuals afflicted with cancer, with an anticipated rise of nearly 25% in the population of cancer survivors within the coming decade.1 This progress has prompted a shift toward addressing both immediate and long-term complications and quality of life issues particularly around cancer treatments. Particularly relevant to the otolaryngologist is the onset of hearing impairment, which, while not immediately life-threatening, can profoundly impact quality of life across all age groups.
In children, even subtle high-frequency hearing loss can lead to delays in speech and language acquisition2 and pose challenges that accrue over time, resulting in academic underachievement and diminished quality of life compared to peers with normal hearing.3 In adults, hearing loss may precipitate social isolation and depression, particularly within a patient population already at high risk of psychosocial distress.4,5 The ototoxic effects of cancer treatment have enduring implications, adversely affecting communication, work capacity, mental well-being, and various other factors that influence quality of life during survivorship.
Hearing impairment related to cancer treatment can arise from multiple modalities, including surgical or radiation treatment to the head and neck or systemic chemotherapy. In combination, these treatments may lead to synergistic auditory dysfunction. Given the escalating concern surrounding treatment-related ototoxicity, understanding and addressing hearing-related issues in cancer patients is imperative for delivering holistic care throughout the continuum of survivorship. In this article, we discuss hearing loss resulting from platinum-based chemoradiation therapy and recent advancements in ototoxicity treatment and prevention, laying the groundwork for future research.
Chemotherapy-Induced Hearing Loss
Sensorineural hearing loss (SNHL) secondary to chemotherapy has been well established with multiple individual drug and drug combinations, the most potent being the platinum based agents.6 Platinum compounds cisplatin, carboplatin, and oxaliplatin are used to treat both solid and hematologic malignancies where they act to interrupt DNA transcription, leading to cell death. Cisplatin, a frequent agent in chemotherapy protocols and most often administered as a multidose, multicycle protocol,7 exhibits enhanced antineoplastic properties owing to its unique stereochemical structure. But the drug also displays heightened ototoxicity, leading to SNHL. Different mechanisms, which include DNA crosslinking, cell cycle disruption,8 defective mitochondrial function,9,10 generation of STve nitrogen or oxygen compounds,11,12 and stimulation of proinflammatory cytokines pathways related to involving ERK and NF-kb,13,14 are involved in cisplatin-induced ototoxicity. When entering cells, cisplatin undergoes physicochemical changes due to the lower intracellular chloride concentration, preventing its exit from the cytoplasm.15–19 This accumulation leads to subsequent damage to inner ear structures, particularly to the outer hair cells, spiral ganglion cells, and stria vascularis (Figure 1),20,21 in a dose-dependent manner.22 This accumulation disrupts the function of the stria vascularis, causing an imbalance in endolymphatic fluid and compromising the function and survival of hair cells.23,24 The cochlear ototoxicity induced by cisplatin displays an apicobasal gradient, with the outer hair cells at the basal turn being most vulnerable.22,23,25
Clinically, cisplatin-induced hearing loss typically presents as an irreversible,26–28 bilateral high-frequency SNHL, often accompanied by tinnitus. Onset occurs within hours to days following administration, with progression over several years.23,29,30 Patient and treatment factors, such as age (<5 years),31,32 higher dose,33 treatment duration, nutritional status, administration method, number of cycles, renal insufficiency, and concurrent radiation therapy,34–37 contribute to increased prevalence of ototoxicity. Sensitivity to platinum-based drugs also differs among individuals38,39 with genetic variations in metabolic enzymes such as thiopurine methyltransferase and catechol O-methyltransferase.40,41 Thus, recommendations for pre-treatment pharmacogenetic testing have been developed to identify individuals at high risk for ototoxicity.42 Notably, any agent that disrupts cochlear blood flow (e.g., loop diuretics43–46) or enhances cisplatin influx to the cochlea (e.g., ethacrynic acid),47 or influences endolymphatic homeostasis or neural conduction, may intensify cisplatin-induced ototoxicity.
Prevention and Therapeutic Options to Counterbalance Chemotherapy Effects
Although the precise mechanisms underlying ototoxicity are incompletely understood, multiple mitigating agents are under evaluation. Four agents are of primary interest in preventing cisplatin-induced SNHL: sodium thiosulfate (STS),48,49 N-acetyl cysteine (NAC),50,51 alpha lipoic acid (ALA),52,53 and D-methionine.48,54 Administration of these agents has been trialed in systemic and direct application.55 STS and NAC act as neuroprotectants by preventing cisplatin binding to cellular components. However, STS can also bind cisplatin, thus decreasing therapeutic effect. Carefully scheduled drug administration in select patients may reduce ototoxicity in children where the effect in adults is less certain.56 Transtympanic NAC has been proposed to preserve hearing at the 8 kHz frequency,16 while the preventive effect of transtympanic STS gel application remains under consideration.57 ALA serves as a vital mitochondrial cofactor for antioxidant enzyme functions,58,59 exhibiting a protective effect against cisplatin-induced cochlear hair cell damage, albeit altering stereocilia shape. Its mechanism involves downregulating various proinflammatory pathways.25 In vitro and murine models have demonstrated that ALA protects mitochondrial function by preventing reactive oxygen species accumulation, prompting the need for clinical trials.60
Several more commonly used medications have also been investigated as mitigating agents. Widely available dexamethasone, known for its anti-inflammatory, antioxidant, and apoptotic effects, has demonstrated positive outcomes in clinical trials without compromising the efficacy of cisplatin.61 Statins have also gained attention as promising candidates. Lovastatin, in particular, has shown efficacy in mitigating cisplatin-induced hearing loss among adults receiving cisplatin therapy for head and neck cancer.55,62
Radiation-Induced Hearing Loss
Although chemotherapy-induced hearing loss is primarily sensorineural, ototoxicity from head and neck radiation may manifest as sensorineural, conductive, or mixed hearing loss. Radiation therapy (RT) plays an integral role in the management of head and neck cancer and neuro-oncological tumors, but it often involves the temporal bone and brainstem within the treatment area. This can lead to significant radiation exposure and can affect hearing at any level of the auditory pathway. While radiation-related hearing loss is widely acknowledged, comprehensive characterization remains limited.63 This is particularly true in regard to the interplay between radiation and its treatment counterparts, platinum-based chemotherapy agents.
Radiation-related SNHL is characterized as a late, progressive, generally permanent side effect of treatment. Although radiation can affect different levels of the auditory pathway, damage to the middle and inner ear prevails.
Radiation can affect the skin of the external ear and ear canal leading to erythema and desquamation (Figure 1), potentially resulting in pain and otorrhea and increasing the risk of local infections. In the early stages, the middle ear is similarly affected by disturbances in vascular flow, ciliary dysfunction, and mucinous gland loss, which heighten susceptibility to otitis media and conductive hearing loss.64,65 In later stages, fibrosis of the middle ear mucosa and eustachian tube musculature can lead to middle ear dysfunction lasting years after treatment.66 Further late complications include occasional structural damage, such as tympanic membrane perforation, and the risk of ossicular necrosis and temporal bone necrosis in adults (Figure 1).67
Recent findings indicate that children are more vulnerable to hearing impairment compared with adults, with a clear correlation between cochlear radiation dose and the risk of hearing impairment.68 Elevated cochlear radiation doses heighten the likelihood of such complications. However, data regarding pediatric support for the 30 to 35 Gy cochlear limit69,70 and the interplay between RT and cisplatin in hearing loss are scarce. There is ongoing uncertainty about which RT dose measurement—such as mean, median, minimum, or maximum—best predicts hearing loss, especially in non-tumor areas like the cochlea, where RT doses can vary widely.
Several mechanisms have been proposed based on the observed characteristics of radiation-induced SNHL. Ionizing radiation exerts an effect by causing damage to the DNA through direct and indirect mechanisms following the creation of free radicals from water molecules, disrupting normal intracellular homeostasis.71 Multiple subsites, including the cochlear duct, basilar membrane, spiral ligament, and stria vascularis, show cell loss in histopathologic evaluations, possibly via p53-independent pathways involving vascular endothelial damage.72
Advances in imaging, pre-treatment planning, and radiation modalities have led to improved outcomes for hearing in adults and children. In the effort to improve precision in targeting radiation to tumors while sparing healthy surrounding tissues, indication for and availability of proton radiotherapy (PRT) have significantly expanded, particularly in childhood cancer treatment. Its effectiveness in managing pediatric brain tumors, head and neck cancers, and adult skull base malignancies has been a driving force behind this growth. PRT has shown promising results with acceptable levels of toxicity, thanks to its ability to deliver lower doses to normal tissues, potentially minimizing both short-term and long-term treatment-related side effects.73–75 Improvements to existing radiation delivery mechanisms have also been developed. Intensity-modulated radiation therapy and volumetric-modulated arc therapy plans, for instance, can produce highly precise dose distributions that lead to decreased toxicity, and decreased treatment durations.76,77 These advancements in radiation technology have paved the way for the emergence of intensity-modulated PRT for patients with head and neck cancers. Early findings indicate promising outcomes in terms of reducing treatment-related toxicity and potentially increasing dose levels while adhering to tissue dose constraints.78
Hearing Rehabilitation
Hearing loss can create additional challenges for patients during their cancer journey, regardless of age. In children, it affects their communication abilities and social engagements, impacting neurocognitive development, educational progress, and overall well-being.79 For adults and seniors, it can lead to psychological distress,80 social isolation, diminished quality of life81 and accelerated cognitive decline,82 raising the risk of dementia.83 Evidence suggests that hearing rehabilitation can mitigate most of these challenges and reduce cognitive decline in high-risk individuals.84
The treatment of the primary tumor should not delay the provision of hearing aids. Close monitoring of hearing is necessary for any oncologic patients exposed to potentially ototoxic therapies. A multidisciplinary approach involving oncologists, radiation therapists, audiologists, and otolaryngologists will facilitate early rehabilitation with tailored solutions for each patient. This could include various options such as conventional hearing aids, CROS, bi-CROS, bone-conduction devices, including osseointegrated solutions, or non-surgical alternatives like soft bands, metal headbands, eyeglasses, or adhesives when suitable. For individuals experiencing severe to profound hearing loss and seeing minimal improvement with traditional hearing aids, recent reports indicate the benefits of cochlear implantation in the oncology patient population, with emerging indications for electric-acoustic stimulation.85
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