Chemotherapy-Induced Hearing Loss and Health Inequality

This project will inform and guide future care for cancer patients by investigating how cancer patients are affected by chemotherapy-induced hearing loss. Platinum-based chemotherapy drugs are known to cause damage to the ear. One of the most toxic chemotherapy drugs is cisplatin, which is used to treat testicular, ovarian, lung, bladder, head \& neck, oesophageal, cervical, and stomach cancers. Platinum-based chemotherapy agents cause oxidative stress and cell death in cochlear cells in the ear, which leads to permanent damage to the hearing system.

This damage presents as hearing loss, and hearing loss is not routinely screened for or detected in cancer patients. Furthermore, individuals from more deprived backgrounds (based on Indices of Multiple Deprivation (IMD) quintiles, which represent levels of socioeconomic deprivation across the UK) are more likely to experience hearing loss due to multiple factors related to health inequity. These include barriers to accessing health services and education; lifestyle factors, such as working in manual jobs where noise exposure is high; and experiencing poor cardiovascular health. Individuals with lower socioeconomic status are also likely to recover less well from the acute effects of chemotherapy due to reduced overall health and physiological resilience. Therefore, cancer patients living in Quintile 1 (Q1; the most socioeconomically deprived 20% of areas in the UK according to the IMD) may be particularly vulnerable to experiencing chemotherapy-induced hearing loss and therefore a reduced quality of life, after receiving platinum-based chemotherapy. No research has explored whether cancer patients from more deprived quintiles may be disproportionately affected by chemotherapy-induced hearing loss. Furthering understanding of the association between hearing health and socioeconomic deprivation will help to guide future hearing screening and intervention following platinum-based chemotherapy.

Individuals with hearing loss may be at greater risk of experiencing cognitive decline and dementia. Previous research indicates that long-term hearing loss is associated with structural changes in auditory brain areas, including brain atrophy. Such changes may reduce the quality of neural input to other regions involved in auditory processing and language comprehension, such as the temporal lobe. Consequently, individuals with hearing loss may not only struggle to perceive sounds clearly but may also experience difficulties understanding speech and engaging in social situations.

Additionally, individuals with hearing loss may rely more on cognitive resources to understand speech in noisy environments. If capacity-limited cognitive resources are redirected to support listening, there may be reduced cognitive resources available for other daily tasks. This is important in the context of cancer, as chemotherapy is already known to cause cognitive dysfunction, so-called 'chemo brain', which is also a risk factor for cognitive decline. This means that cancer patients receiving platinum-based chemotherapy drugs relative to non-platinum chemotherapy drugs have a potentially greater risk of cognitive decline: 1) from the risk of neural dysfunction associated with chemo brain, and 2) from the risk of ototoxicity associated with hearing loss. Further, hearing loss is associated with social withdrawal due to difficulties listening in noisy environments, which has been linked with increased feelings of loneliness and reduced mental well-being.

This research is particularly relevant to the North West of England, where approximately 32% of the population lives in the most deprived areas in England. This is reflected in cancer diagnosis rates, with the North West population being 25% more likely to be diagnosed with cancer than those in the rest of England. Health inequalities in this region may also contribute to a higher prevalence of hearing loss compared to those from the South of England. Among 61-70-year-olds, 21.8% in the North West experience hearing loss, compared to 14.6% in the South East. For those aged 71-80, the prevalence is even greater, with 43% in the North West affected compared to 35.7% in the South East. Furthermore, the proportion of deaths due to dementia and Alzheimer's disease in the North West was 12.6% in 2019 (n = 9060), which was the fourth highest in England and Wales.

This study will recruit cancer patients from across the North West of England who are due to receive platinum-based chemotherapy treatment. The primary aim is to determine how platinum-based chemotherapy treatment affects hearing function in cancer patients. As a secondary aim, the study will examine changes in cognitive function and whether these changes are associated with changes in hearing following treatment. Specifically, the study will test whether the difference between pre- and post-treatment speech-in-noise performance predicts post-treatment cognitive performance. The study will also explore whether socioeconomic background influences these relationships.

Participants will be asked to complete a series of online tests to measure auditory and cognitive function at baseline (pre-chemotherapy), within seven days post-chemotherapy treatment completion, and 6-months post-chemotherapy treatment completion.

Hearing test:

Participants will complete an antiphasic Digit Triplet Test (DTT), an automated speech-in-noise test designed to screen an individual's hearing ability. The test takes five minutes to complete, and participants will identify three digits in background noise, where the volume of the digits decreases with each correct answer. The test determines the signal-to-noise ratio (SNR) at which 50% of the speech can be understood. In the antiphasic configuration, masking noise will be presented diotically (identical and in phase in both ears), while the speech signal will be presented with an interaural phase inversion (180-degree phase shift between ears). Specifically, the digit triplets will be delivered identically to the left and right channels, except that the waveform in the right channel will be inverted relative to the left, producing antiphasic speech presentation. The antiphasic configuration exploits the binaural masking level difference, whereby interaural phase disparities allow the auditory system to segregate the speech signal from the masking noise, improving speech detection in noise. The test is a fast and efficient tool that approximates how a person hears in a typical environment. If a participant's score is above a given screening threshold (a threshold of -6 dB SNR will be used in this study), then it may indicate poorer hearing compared to typical listeners. These participants will be contacted and advised that the result may indicate potential hearing difficulty, and they will be advised to seek further guidance from their GP/Oncologist or an audiologist if they have concerns about their hearing.

Cognitive tests:

Participants will complete the Flanker Test, which is a computerised cognitive task used to assess executive function. The test takes approximately five minutes to complete, during which participants will identify the direction of a central target arrow, flanked by distractor arrows on either side. The arrows may be congruent (pointing in the same direction) or incongruent (pointing in opposite directions). The test measures how well participants can focus on the target stimulus while ignoring irrelevant distractions. The Flanker Test provides insight into an individual's ability to manage interference and selective attention, offering a quick and efficient evaluation of executive function in a controlled environment.

Participants will complete the Forward Digit Span Test, a cognitive assessment used to evaluate short-term memory. The test takes approximately five minutes to complete, during which participants will be shown a sequence of digits on a screen and required to recall them in the same order. The length of the digit sequence increases with each correct response. This test measures short-term memory, providing insight into an individual's ability to temporarily store and recall information in everyday settings.

Participants will also complete the Backwards Digit Span Test, a cognitive assessment designed to measure working memory. The test takes approximately five minutes to complete, during which participants will be shown a sequence of digits on a screen and must recall them in reverse order. The test becomes progressively more challenging as the digit sequences increase in length. This test evaluates an individual's working memory.

Primary aims: The project aims to further understanding of how platinum-based chemotherapy treatment affects hearing function in cancer patients in the North West from a variety of backgrounds of deprivation.

Secondary aims: The project aims to examine whether chemotherapy-induced changes in hearing are associated with cognitive outcomes following platinum-based chemotherapy treatment.

Primary Outcome: Change in hearing function (measured by the Digit Triplet Test) from baseline to end of chemotherapy and 6 months after completing chemotherapy.

Secondary Outcomes: Change in global cognitive function (measured via the Flanker Test, Forwards, and Backwards Digit Span tests) from baseline to the end of chemotherapy, and 6 months after chemotherapy.

Linear mixed effects models will be used to examine predictors of hearing change following platinum-based chemotherapy treatment. For the primary analyses, the change in the Digit Triplet Test speech reception threshold between baseline and post-chemotherapy will be modelled as the outcome variable. Predictors will include socioeconomic quintile group, cumulative chemotherapy dosage, age, baseline hearing, and baseline cognitive performance. A second linear mixed effects model will be used to address the secondary aim by examining whether a change in Digit Triplet Test performance predicts post-treatment cognitive performance, while also exploring the influence of socioeconomic deprivation, cumulative chemotherapy dosage, and treatment duration.