Increasing Awareness of Audiovestibular Adverse Events From Immune Checkpoint Inhibitors

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Immune checkpoint inhibitors are widely used for treatment of patients and have significantly improved treatment outcomes for many types of cancer. Immune-related adverse events are toxicities that result from treatment with immune checkpoint inhibitors. The most common adverse events—skin, endocrine, pulmonary, and gastrointestinal—are commonly well recognized, and their management was standardized by the National Comprehensive Cancer Network. Rare immune-related adverse events such as renal, neurologic, and ophthalmologic events are poorly recognized due to lack of information. There are no national guidelines regarding management of rare immune-related adverse events.

Audiovestibular immune-related adverse events is one of the rare complications of immunotherapy, and very often it is unrecognized or misrecognized due to lack of awareness. The audiovestibular toxicity that is described in literature is mostly case studies. Patients undergoing treatment may complain of dizziness, vertigo, and ear pressure. There are different reasons that can cause these symptoms such as otitis media, dehydration, electrolyte imbalance, etc. But it can also be a rare complication of immunotherapy.

It is imperative for nurses to recognize symptoms in a timely manner and take appropriate actions. The most common symptoms are aural fulness or pressure, dizziness/vertigo, bilateral tinnitus, and imbalance. Patients may also complain of unilateral or bilateral hearing loss, which can be progressive or sudden. Patients may have concurrent immune-related adverse events. Patients may seek care from the primary care provider, as they may not realize that these symptoms are related to treatment.

Early recognition of symptoms and prompt referral to otology can significantly reduce the negative impact of toxicities. Onset of audiovestibular immune-related adverse events is usually within the first 4 months of treatment, and patients experience a wide range of the severity of audiovestibular toxicity. It is more common among patients with intracranial metastasis and undergoing concurrent radiation treatment within proximity to the inner ear.

Work-up includes a review of current medication to identify use of ototoxic agents and a physical exam to rule out infectious ideology. Patients without a previous history of intracranial involvement need imaging to rule out involvement of the central nervous system. Urgent referral to otology for hearing evaluation is imperative. Audiometric evaluation helps to identify the type of hearing loss and usually reveals sensorineural hearing loss, reduced word recognition ability, and reduced speech recognition threshold.

The pathophysiology of audiovestibular toxicity is not well understood. Literature suggests that the pathophysiological process is similar to the process that occurs with adoptive cell therapy. Treatment with immune checkpoint inhibitors activates T cells with high anti-melanocyte activity. Melanocytes are presents in different organs of the body: skin, inner ear, lung, and heart. Stria vascularis is an epithelium layer of the cochlea and contains melanocytes also known as intermediate cells. The disruption in the activity of the intermediate cells leads to hearing changes. It is not clear if there is a correlation between audiovestibular toxicity and effectiveness of treatment. Literature provides information which is controversial. There is no clear data about the incidence of audiovestibular immune-related adverse events. Treatment interventions are directed to suppress the immune system using corticosteroids. Oral methylprednisolone or intratympanic dexamethasone injections can be used for the management of audiovestibular immune-related adverse events. It is imperative to initiate steroids within 2 weeks of hearing loss. Both oral and intratympanic steroids are equally effective. Not every patient is a candidate for treatment with oral steroids, and the following factors may exclude patients from use of oral steroids: diabetes, gastritis, osteoporosis, and psychiatric disorders. The oral dose is prescribed for at least 1 week followed by at least 1 week taper.

Intratympanic injections are performed by physicians, and the use of an otomicroscope is recommended. Injection has low risk of complications; only about 1% of patients will experience tympanic membrane perforation. Dexamethasone is administered through a myringotomy in the middle ear cleft. The amount of dexamethasone administered is about 0.6 ml, which is equal to the volume of the middle ear. The goal is to administer the maximum amount possible, which will allow medication to pass to the cochlea. Patients are instructed to avoid swallowing and remain in laying position for 20 to 30 minutes. Swallowing allows steroid solution to drain to the back of the throat which should be avoided. Intratympanic treatment is administered 3 to 4 times, and it is recommended to repeat the audiogram before each treatment.

Literature shows that patients will have their hearing returned to pre-treatment level or partial recovery. Current guidelines do not recommend baseline audiogram testing before initiating immunotherapy. Patients with previous noise exposure or age-related decreased hearing acuity have permanent sensorineural hearing loss of high frequency. These patients do not respond to intratympanic injections and will require the use of hearing aids.

Some patients will experience permanent hearing loss and have negative impact on quality of life, which may lead to social isolation. Depending on the level of hearing loss, patients need hearing aids or a cochlear implant. Tinnitus and vertigo are symptoms that appear concurrent with the onset of hearing changes. Tinnitus resolves with the return of hearing. Persistent tinnitus is managed with sound therapy alone or in combination with hearing aids, cognitive therapy, relaxation therapy, cognitive behavioral therapy, antidepressants, electrical stimulation, microvascular decompression, acupuncture, or hyperbaric oxygen. Vertigo and dizziness management includes pharmacological therapy and physical therapy to improve balance and restore functionality.

Audiovestibular immune-related adverse events is a rare complication of treatment with immune checkpoint inhibitors. It is often missed due to lack of recognition. It can have a negative impact on a patient’s life and early recognition of symptoms is imperative. Prompt interventions are imperative. There are no current guidelines on how to identify and manage this immune-related adverse events.

References

1. Barron CC, Stefanova I, Cha Y, et al. Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review. J Immunother Cancer. 2023;11(8):e006500. doi:10.1136/jitc-2022-006500
2. Dalrymple SN, Lewis SH, Philman S. Tinnitus: Diagnosis and Management. Am Fam Physician. 2021;103(11):663-671.
3. Page JC, Gidley PW, Nader ME. Audiovestibular Toxicity Secondary to Immunotherapy: Case Series and Literature Review. J Immunother Precis Oncol. 2022;5(1):2-6. Published 2022 Feb 3. doi:10.36401/JIPO-21-17
4. Rosner S, Agrawal Y, Sun DQ, et al. Immune-mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma. J Immunother Cancer. 2020;8(2):e001675. doi:10.1136/jitc-2020-001675
5. Zibelman M, Pollak N, Olszanski AJ. Autoimmune inner ear disease in a melanoma patient treated with pembrolizumab. J Immunother Cancer. 2016;4:8. Published 2016 Feb 16. doi:10.1186/s40425-016-0114-4