Audiological ototoxicity monitoring guidelines: a review of current evidence and appraisal of quality using the AGREE II tool

Abstract

Objective

The effectiveness of audiological monitoring for detecting early hearing changes in patients receiving ototoxic medication could be limited by the lack of adequate audiological ototoxicity monitoring (OtoM) guidelines. This study aimed to evaluate existing OtoM guidelines using the AGREE II tool for guideline evaluation.

Design

Guideline Review.

Study Sample

Three audiological OtoM guidelines.

Results

An online search identified three audiological OtoM guidelines published by the American Speech-Language and Hearing Association (ASHA), the American Academy of Audiology (AAA) and the Health Professionals Council of South Africa (HPCSA). Evaluation using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool found the HPCSA audiological OtoM guideline scored higher than the ASHA and AAA guidelines in five of the six tool domains. All guidelines received average domain ratings of less than 50% with each reviewer recommending all three guidelines for use following modification.

Conclusion

The findings of this study could partly explain the poor uptake of audiological OtoM practices internationally, further investigation is needed to identify the specific factors limiting the implementation of audiological OtoM in clinical practice.

Keywords:

• Ototoxicity
• ototoxicity monitoring
• audiological monitoring
• hearing loss
• hearing loss prevention
• guideline evaluation
• AGREE II tool

Ototoxicity is one of the leading causes of preventable hearing loss that occurs over the lifespan (WHO 2021). It is often characterised by cellular degeneration of cochlear and/or vestibular tissue due to the adverse effects of certain therapeutic agents (Ganesan et al. 2018). Global prevalence rates of ototoxic hearing loss are as high as 63% for aminoglycoside antibiotics (WHO 2021), 43% for cisplatin and/or carboplatin chemotherapy (Dillard et al. 2022), and 6–7% for Furosemide (a loop diuretic) (WHO 2021). These hearing losses can be prevented or minimised through early detection of hearing changes that can guide patient and doctor decisions regarding modifying treatment, the use of otoprotectants, early patient education and counselling, and audiological management including hearing devices.

The degree and type of hearing loss caused by ototoxic medications depends, among other things, on drug type and dose (Garinis et al. 2017). Most of these ototoxic effects target the cochlea where ototoxic agents are thought to arrive having first entered the body through systemic or topical pathways and then passing through the blood-labyrinth-barrier (the barrier between the vasculature and the inner ear fluids, either endolymph or perilymph) to enter the cochlea (Fu et al. 2021). Once in the cochlea, examples of different ototoxic effects include damaging outer hair cells and spiral ganglion cells (Guo et al. 2021); stimulating the production of free radicals that damage mitochondria and lead to hair cell death (Kovacic and Somanathan 2008; Pickles 1982); damaging the stria vascularis (Pickles 1982; Rybak and Ramkumar 2007); reducing cochlear blood flow and damaging outer hair cells (Cazals 2000; Jung et al. 1993); inducing vasoconstriction and decreasing cochlear blood flow (Jung et al. 1993); increasing permeability of the blood-labyrinth barrier and loss of endolymphatic potential (EP) (Steyger 2011); and causing cellular apoptosis (Kros and Steyger 2019).

For the individual, the effects of ototoxic hearing loss are most felt in the areas of communication and social and emotional wellbeing. A recent review describing oncology patient experiences found that patients reported ototoxicity to have a significant negative impact on quality of life (Pearson et al. 2022). Other effects included exhaustion and frustration from continuous tinnitus, decreased social interaction and an inability to communicate effectively with others (Pearson et al. 2022). Whilst not specific to ototoxicity, sensorineural hearing loss (SNHL) has also been associated with a decline in speech comprehension (Pichora-Fuller and Singh 2006), attention (Shinn-Cunningham and Best 2008) and cognitive processing (Castiglione et al. 2016). Hearing loss has been identified as the single largest modifiable risk factor for dementia among nine health and lifestyle factors (Livingston et al. 2017).

Similarly, SNHL has been linked to increased rates of depression, anxiety and social dissatisfaction (Jayakody et al. 2018; Heine and Browning 2004) as well as accelerated cognitive decline (Loughrey et al. 2018; Wahl et al. 2013). Compared to adults with no hearing loss, individuals with hearing loss had an increased risk of experiencing moderate to severe psychological distress and those with a moderate hearing loss were more likely to seek mental health care (Bigelow et al. 2020).

Ototoxic hearing loss also carries significant costs on a larger, societal level. In 2017, the WHO estimated the effect of a moderate or worse hearing loss on social isolation, communication difficulties and stigma cost the global economy an estimated USD573 billion per year as the monetary value attached to avoidance of a year lived with disability and the disability adjusted life years (DALY) attributed to hearing loss. Of this, the cost to the health sector alone was estimated to be USD67-107 billion (WHO 2017). The majority of the societal costs associated with SNHL relate to lost productivity resulting from absenteeism, unemployment and/or early retirement (WHO 2017). Other costs related to the provision of services needed to support persons with hearing loss including health (e.g. ENT and general practice), allied health (e.g. audiology, speech pathology, psychology, etc.), education, and employment. Crude estimates drawn from meta-analyses conducted by Dillard et al. (2022) suggest approximately half a million new cases of ototoxicity occur every year following the use of cisplatin and carboplatin chemotherapies alone. Given the prevalence of ototoxicity and high burden of disease, audiological ototoxicity monitoring (OtoM) and preventative strategies should be prioritised.

To address and negate the effects of ototoxicity on individuals and society, health professionals have developed protocols to monitor hearing during ototoxic treatment (Ganesan et al. 2018). Audiological OtoM is the monitoring of hearing thresholds in the range in which ototoxic hearing loss is most likely to occur. The monitoring is typically completed by an audiologist and often consists of a thorough case history and baseline hearing assessment followed by repeat assessments, and patient education/counselling throughout the period of ototoxic exposure/treatment. The goal of audiological OtoM is to identify any changes in hearing from baseline as early as possible to allow for discussion, education and/or treatment changes to mitigate further hearing loss and minimise the function impact on the patient.

Despite widespread acknowledgement of audiological OtoM as an effective practice in the management of ototoxic hearing loss, information regarding its implementation remains ad hoc worldwide with reports found in only four countries; the United States of America (USA), South Africa, the United Kingdom (UK), and New Zealand. In the USA, audiologists and medical staff seldom perform thorough audiological OtoM. The most recent survey of perceptions of OtoM showed that all audiologists and department chiefs surveyed felt that some form of OtoM was necessary but only half routinely performed assessments (Konrad-Martin et al. 2023). Another review of monitoring practices showed that only 20% of the audiologists surveyed regularly performed audiological OtoM on patients at risk of ototoxic hearing changes (Dille 2018). Approximately 80% of medical oncologists in this same study were unclear on the referral process required to have their patients hearing monitored for ototoxic changes during their chemotherapy treatment. A separate, large scale study showed that less than 52% of oncology patients were counselled on the potential ototoxic effects of cisplatin chemotherapy and only 24% were referred for a baseline audiogram prior to commencing treatment (Santucci et al. 2021).A review conducted by Konrad-Martin et al. (2018) found reasons for the poor implementation of audiological OtoM in the USA to include inconsistent referrals from the managing physician, scheduling, physical resourcing and staffing limitations for audiologists. Later work confirmed these findings, identifying barriers in three key areas: care and referral coordination with oncology, audiology workload and lack of protocols (Konrad-Martin et al. 2023).

In South Africa, multiple reasons have been suggested for the limited success of audiological OtoM. Ehlert, Heinze, and Swanepoel (2022) found the most prominent challenges to be referral system, environmental noise and the compromised status of the oncology patients requiring monitoring. Poor awareness of audiological OtoM procedures was reported in 100% of surveyed oncology clinics and 14% of surveyed audiology clinics in South Africa (Ehlert, Heinze, and Swanepoel 2022) as well as audiologists not performing a baseline assessment or completing the recommended test battery required to effectively detect changes in hearing for patients at risk of ototoxicity (Ehlert, Heinze, and Swanepoel 2022; Khoza-Shangase and Masondo 2021). Khoza-Shangase (2017) previously suggested that these challenges may be due to lack of involvement by audiologists in the initial evaluation of medication and treatment options specifically, and poor strategies for the management of audiological OtoM and ototoxic hearing loss in South Africa generally.

In the UK, Maru and Malky (2018) reported only 28% of professionals including audiologists, ear nose and throat specialists and general practitioners had an ototoxicity monitoring protocol in place in their centre and were able to identify the process for hearing monitoring in patients at risk of ototoxicity. In this same study, qualitative responses from 134 surveyed participants showed significant variability in referrals, test procedures and testing intervals for patients at risk of ototoxicity. Only 16% of audiologists were able to confirm that baseline testing occurs for all patients prior to treatment, with 56% performing a baseline on some but not all patients. Results from the study confirmed that ototoxicity monitoring occurs but is inconsistent across the UK.

In New Zealand, a survey of oncologists and audiologists across sixteen of their twenty health districts showed inconsistent referrals to audiology for audiological OtoM and inconsistent protocols used by audiology to assess audiological OtoM (Steffens et al. 2014). Local audiological OtoM protocols were in place in nine of the 16 health districts but adherence to these protocols differed significantly amongst sites and clinicians. It was revealed that the protocols in place ranged from independently developed to variations on existing, international ototoxicity monitoring guidelines. This study suggested the lack of standardised, national protocol in New Zealand (Steffens et al. 2014).

While there are many possible reasons for the ad hoc implementation of audiological OtoM, the target of this review is the number and quality rating of existing audiological OtoM guidelines worldwide. Various studies have shown that high quality clinical guidelines can improve healthcare (Hakkennes and Dodd 2008; Medves et al. 2010); however, most audiological professional bodies do not have a formal publication governing the monitoring of ototoxicity or management of ototoxic hearing losses. Of the limited number of audiological OtoM guidelines currently available, none have been formally reviewed despite the presence of as many as 40 guideline assessment tools (Siering et al. 2013) including the tools used in the present study, the AGREE II. Published by the Appraisal of Guidelines for Research and Evaluation (AGREE) collaboration (an international group of guideline developers and researchers), the AGREE II is an instrument used to evaluate the rigour and transparency of guideline development with its reliability and construct validity (Brouwers et al. 2010a, 2010b) seeing it widely applied for guideline evaluation in healthcare worldwide (Bargeri et al. 2021; Brouwers et al. 2010c; Eikermann et al. 2014; Guyatt and Vandvik 2013).

The present study aims to identify all published audiological OtoM guidelines in the English language, and to review their quality against the AGREE II framework for guideline evaluation. An emphasis was placed on audiological OtoM guidelines for oncology patients given the high rates of cancer, the known ototoxic nature of its primary treatments, and the existing roles of audiologists in monitoring hearing in this population. The results of this review will be used to inform the future application of guidelines in clinical settings to better meet the needs of all patients and clinicians involved in the identification and management of ototoxicity.

Method

For the purposes of this review, an audiological OtoM guideline was defined as a document published by a professional body that provided recommendations and/or procedures for the monitoring of hearing in oncology patients receiving ototoxic treatments. Audiological OtoM guidelines were located through an online search of the literature completed between May and June of 2022. The search was conducted via MedLine, Scopus, Web of Science, Google Scholar and Google. Search terms were chosen to cover target patient population, target user and the type of publication (clinical guideline or position statement). The search terms used were ‘oncology’ OR ‘cancer’ AND ‘ototoxicity’ OR ‘hearing loss’ OR ‘audiology’ AND ‘guideline’ OR ‘clinical guideline’ OR ‘clinical practice guideline’ OR ‘position statement’. A further manual search for audiologial OtoM guidelines was completed in MedLine’s National Guideline Clearinghouse (NGC). Guidelines were not restricted by date of publication but were restricted to those published in the English language.

Following identification, included audiological OtoM guidelines were evaluated by three reviewers using the AGREE II tool The number of reviewers chosen is in line with the AGREE Collaboration’s recommendation that each guideline be assessed by a minimum of two and ideally four reviewers (Agree Collaboration 2009; Brouwers, Kerkvliet, and Spithoff 2016). This tool assesses the methodological rigour and transparency in which a guideline was developed, but not the effectiveness or application of the guideline in clinical practice. It contains 23 items rated on a 7-point Likert scale of strongly disagree (score of 1) to strongly agree (score of 7). These 23 items are divided into 6 domains of scope and purpose (3 items, score of 3 to 21), stakeholder involvement (3 items, score of 3 to 21), rigour of development (8 items, score of 8 to 56), clarity of presentation (3 items, score of 3 to 21), applicability (4 items, score of 4 to 28), and editorial independence (2 items, score of 2 to 14). Final domain scores are calculated by summing the scores from each reviewer on each item and each domain and scaling those scores as a percentage of the maximum possible score from all reviewers for each item and each domain (1% to 100%, with 1% being the lowest and 100% being the highest score) (Supplementary material). The AGREE II tool also contains two overall assessment items one using a 7-point Likert scale to classify the quality of the guideline as 1 = lowest possible quality to 7 = highest possible quality; and one using a yes, no or yes with modification scale in response to the statement ‘I would recommend this guideline for use’. These two items are analysed descriptively for all reviewers.

The AGREE II tool was applied to the included audiological OtoM guidelines by three of the authors (GL, WW, BT) of the present study. These reviewers were audiologists, one a practicing clinical audiologist and doctoral student with seven years of experience, and two academic audiologists with over 30 years of experience. All reviewers had between five and 10 years’ experience with audiological OtoM in both clinical and research settings.

To apply the AGREE-II tool, the 3 reviewers met in person to discuss the framework and ensure they were in agreeance on how the tool was to be applied. As per the AGREE-II tool, each guideline was appraised independently in random order and results were collated in person at a follow up meeting with no attempt made to reach consensus. Each reviewer provided scores that reflected his or her individual judgements of the guideline’s quality rating, however discussion ensured mutual understanding of each reviewer’s interpretation of each item. This post-evaluation meeting also provided opportunity for reviewers to provide comment and justification for their scores and identify key areas for future research. All AGREE-II data was analysed descriptively as per the AGREE II tool user manual (Agree Collaboration 2009; Brouwers, Kerkvliet, and Spithoff 2016).

Results

Three OM guidelines were found and included in the review: the Audiologic Management of Individuals Receiving Cochleotoxic Drug Therapy published by the American Speech-Language-Hearing Association (ASHA 1994), the American Academy of Audiology Position Statement and Clinical Practice Guidelines: Ototoxicity Monitoring published by the American Academy of Audiology (AAA 2009), and the Audiological Management of Patients on Treatment That Includes Ototoxic Medications: Guidelines published by the Health Professionals Council of South Africa (HPCSA 2018).

Table 1 shows the scaled scores for each domain derived from the scores and the quality rating of the guideline and recommendation for use provided by the three reviewers (individual reviewer scores are shown in Appendix 1 and the calculation used to scale scores is shown in Appendix 2). The HPCSA audiological lOtoM guideline scored more highly than the ASHA and AAA guidelines in five of the six AGREE II tool domains. All guidelines received average domain ratings of less than 50% with all reviewers recommending all guidelines for use following modification. The three reviewers showed general agreement across most ratings with the exception of the AAA audiological OtoM guideline where some disagreement was noted for Domain 5 (Applicability) due to the reviewers’ different interpretations of the question (one reviewer interpreted resourcing to predominantly mean physical resourcing and clinical space while the other reviewers interpreting it to mean these items plus larger considerations of administration and budgetary considerations). These results reflect the quality of the guideline content and methodological rigour and transparency of their development, and not the effectiveness or application of the guidelines in clinical practice. The application of these guidelines and effectiveness in detecting hearing changes in patients is an important area for future research but was not addressed in this review.

Table 1. Rater scores for the audiological OtoM guidelines using the AGREE II tool (scores rounded to whole percentages).

Guideline	ASHA (1994)			AAA (2009)			HSPCA (2018)
Domain 1: Scope and Purpose	52%			49%			75%*
Domain 2: Stakeholder Involvement	28%			28%			31%*
Domain 3: Rigour of Development	29%			28%			30%*
Domain 4: Clarity of Presentation	67%			59%			85%*
Domain 5: Applicability	30%			57%*			43%
Domain 6: Editorial Independence	15%			24%			31%*
Average Domain Rating (domains 1-6)	37%			41%			49%*
Domain 7: Overall quality of the guideline (out of 7 from each reviewer)	3	3	3	5	4	3	5	5	5
Guideline recommended for use	Yes, with modifications			Yes, with modifications			Yes, with modifications

* Indicates highest score of the three guidelines.

Discussion

The present review identified three published audiological OtoM guidelines in the English language. Whilst identified through a search that emphasised guidelines for oncology patients, all three guidelines were applicable to general audiological OtoM and were not limited to specific conditions or treatments.

The first identified audiological OtoM guideline was ASHA (1994), which was based on the results of numerous, large-scale clinical studies in the 1980s and early 1990s that noted the need for earlier detection of hearing changes caused by antineoplastic-chemotherapeutic agents (Fausti et al. 1984). While the need for hearing monitoring was acknowledged in the ASHA audiological OtoM guideline, there was no consensus among researchers in the field at the time as to how and when to monitor hearing during chemotherapy treatment. This is reflected in the ASHA guideline which acknowledges the risk of changes but lacks specific recommendations for audiological OtoM to limit or prevent ototoxic hearing loss.

The second identified audiological OtoM guideline was AAA (2009). AAA acknowledged ASHA’s (1994) original work (including their appendix with recommendations for the ‘ideal’ test schedule) and the subsequent body of evidence that suggested a predictable pattern of high frequency sensory hearing loss caused by many ototoxic agents. With this knowledge, AAA expanded on ASHA’s findings and included the use of an abbreviated protocol known as the ‘sensitive range for ototoxicity’ (SRO) in their guideline in an attempt to reduce audiological test time for patients undergoing ototoxic treatment. A provision for bedside testing was also added, acknowledging the difficulty patients may have attending audiology clinics while in treatment. Though ASHA and AAA share a number of similarities (including recommendations for when testing should occur), AAA referenced a separate organisational policy that clearly outlined a framework for developing guidelines and formal position statements. AAA (2009) included the SRO protocol in the body of their document and addressed the difficulties identified by ASHA (1994) that accompany extensive and regular audiological OtoM by offering a minimum test battery and provision for bedside testing. Neither document provides a classification for what constitutes a significant, and therefore medically actionable, change in hearing thresholds or concrete intervals for which OtoM should occur (Konrad-Martin et al. 2018).

The third identified audiological OtoM guideline was HPCSA (2018). This more recent guideline offered greater focus on all ototoxic drugs and a broader consideration of culturally appropriate models in response to local needs (with a key example in the South African context being the treatment of Multi-Drug Resistant Tuberculosis). Despite its recency, the HPCSA audiological OtoM guidelines still do not account for more recent and rapid advances in technology and health information management such as digital health records, hearing screening applicationss (such as OtoCalc [Hollander, Joubert, and Schellack 2020], hearTest [Patel et al. 2021] and uHear [Peer and Fagan 2015]), portable audiometers such as OtoID (Dille et al. 2013), and telehealth technologies.

The review of the three identified audiological OtoM guidelines against the AGREE II framework for guideline evaluation found these guidelines did not meet the framework’s standards regarding quality of guideline content and methodological rigour and transparency of development (it is important to note that the present review’s results do not reflect the effectiveness or application of the guidelines in clinical practice). All guidelines scored below 50% overall with concerns raised across multiple domains. The identification of only three formal guidelines worldwide speaks to the dearth of audiological OtoM practice and governance for clinicians, while their review against the AGREE II tool raises issues with the quality of the guidelines that do exist. Three domains were of most concern Domain 6: Editorial Independence and Domain 2: Stakeholder Involvement, with none of the guidelines providing an audit tool or acknowledging the sponsor/funding body or any competing interests of the authors or describing consultation outside of their professional organisation, and Domain 3: Rigour of Development, with methods for searching, selecting considering evidence not clearly described, the guidelines not being externally reviewed, and procedures for updating the guidelines not provided. Of moderate concern was Domain 5: Applicability, with guidelines reasonably describing facilitators and barriers to audiological OtoM and considering the implications of applying guideline recommendations in practice. Of less concern were Domain 1: Scope and Purpose with all objectives and intended populations clearly described, and Domain 4: Clarity of Presentation with key recommendations being unambiguous and easily identifiable and options for management being clearly articulated. Future iterations of these guidelines could be improved through explicit acknowledgement of sponsors and the authors organisation and any competing interests. Consultation outside the authoring organisation to include clinicians, patients and administrators and peer review of final recommendations should improve their AGREE II domain scores.

It is not currently known whether addressing any of the limitations discussed above in the current audiological OtoM guidelines would help clinicians wanting to improve audiological OtoM practices and hearing preservation in cases of ototoxic treatment. For oncology patients in particular, the context within which audiological OtoM guidelines are applied are often complex and encompass an array of issues including patient fragility, tolerance of treatment, their age and the subjective importance of hearing preservation to their ongoing quality of life. Despite the presence of formal audiological OtoM guidelines, effective use of these and regular monitoring of oncology patients at risk of ototoxic hearing changes is seldom reported to be successful with existing literature suggesting that guidelines are poorly or inconsistently applied (Ehlert, Heinze, and Swanepoel 2022; Dille 2018; Khoza-Shangase and Masondo 2021; Maru and Malky 2018; Steffens et al. 2014). Reasons for this may include poor dissemination and advertisement to professionals outside of South Africa and the US, lack of governance and support from other international audiological professional bodies and lack of cultural specificity and consideration of new health management systems and technology.

To improve audiological OtoM guidelines, stakeholder involvement beyond the professional organisations is needed to determine the true value of formal OtoM in the management of hearing loss and quality of life in patients receiving ototoxic treatment. Future research to investigate the application of guidelines, thoughts and personal experiences of clinicians, patients and administrators with lived experience would be beneficial to inform future recommendations and ensure barriers are addressed. Any future versions need to consider advancements in the fields of smart applications and telehealth along with the rapidly expanding area of otoprotectants used to mitigate the effects of ototoxic medications.

The current review of audiological OtoM guidelines was limited by its consideration of audiological OtoM guidelines published in the English language by professional organisations only. It is recognised that many clinicians will be guided by unpublished local site or work unit audiological OtoM guidelines. Further investigation is needed to determine whether audiological OtoM guidelines should be authored and maintained at national levels by professional organisations, or whether creation and governance of audiological OtoM guidelines should be district or site dependant based on what is feasible and applicable to the local population. The review also did not consider recommendations offered outside of published audiological OtoM guidelines such as research papers published in the scientific literature or any publications in the grey literature. The search terms used limited results to audiological OtoM guidelines thus excluding any recommendations for audiological OtoM contained within other clinical guidelines (e.g. the management of ototoxicity as a side effect of medications used to treat infectious diseases or chronic pulmonary conditions or in clinical cancer trials). The study was also biased by its selection of reviewers for appraisal of international guidelines. Three Australian audiologists were chosen for convenience as this review precedes a formal review of audiological OtoM processes in an Australian state public health facility.

Conclusion

Only three published audiological OtoM guidelines in the English language were identified – ASHA (1994), AAA (2009) and HPCSA (2018) – none of which met the AGREE II framework’s quality standards for guideline evaluation. Future guidelines, or revisions to the current guidelines, would most benefit from improved editorial independence, stakeholder involvement and rigour of development. The results of this study made some progress towards explaining the poor uptake of audiological OtoM guidelines and practices internationally and suggested the need for greater involvement of clinicians, patients and administrators to develop high quality, evidence based and culturally relevant audiological OtoM guidelines.

Disclosure statement

No potential conflict of interest was reported by the authors.