Ototoxicity monitoring through the eyes of the treating physician: Perspectives from pulmonology and medical oncology

Abstract

Objectives: Integrating audiological management into the care pathways of clinical specialties that prescribe ototoxic medications for essential, often life-preserving medical care that is critical for early hearing loss identification and remediation. Research shows that successful implementation of a new health service or intervention requires alignment of goals among provider groups, institutional leadership and patients. Thoughtful consideration of the physician’s viewpoints about ototoxicity and its implications for treatment planning is, therefore, important for the implementation and enduring success of an ototoxicity monitoring programme (OMP). Design: This discussion paper uses qualitative methods to explore the perspectives of four physicians on OMP provision in their patient populations. Study sample: Three pulmonologists and one oncologist completed the written survey or survey-based interview described in this report. Results: Each physician indicated that (i) ototoxicity is a potential problem for their patients; (ii) monitoring hearing is important to ensure good quality of life among their patients and (iii) treatment modification would be considered if an alternative treatment option were available. The physicians differed in their approaches to ototoxicity monitoring, from routine referrals to audiology, to relying on patient self-referral. Conclusion: Physician provider input is needed to optimise monitoring schedules and OMP care coordination with audiology.

Key Words:

• Ototoxicity monitoring
• medical audiology
• adult or general hearing screening
• pulmonology
• oncology
• chemotherapy
• cisplatin
• aminoglycoside

Introduction

Pulmonology and medical oncology are medical specialties that use potentially ototoxic medications for the treatment of life-threatening diseases in their distinct patient populations. Pulmonologists may prescribe inhaled or intravenous (IV) aminoglycoside antibiotics for mycobacterial infections such as those associated with bronchiectasis in patients with chronic obstructive pulmonary diseases (COPD), chronic bronchitis and emphysema (Drobnic et al. 2005; Orriols et al. 1999). Aminoglycosides considered to have particularly high cochleotoxic (amikacin) or vestibulotoxic (gentamicin) potential are most often used in cases of multidrug-resistant tuberculosis and non-tuberculous mycobacterial infections. Many patients with cystic fibrosis (CF) use aminoglycosides considered to be less toxic (e.g. tobramicin) on a routine, life-long basis to treat severe infections caused by Pseudomonas aureus or methicillin-resistant Staphylococcus aureus (MRSA; Moore, Smith, and Lietman 1984; Nordstrom and Lerner 1991). The incidence of ototoxicity from these treatments is inconsistent in the literature, ranging from 0–56% in adults with CF (Garinis et al. 2017).

Medical oncologists, on the other hand, use highly ototoxic platinum-based agents for individualised cancer treatments in adult and paediatric patients. For adult patients, the most ototoxic regimens include cisplatin and are used with head and neck or lung cancers, germ cell tumours, bladder cancer, some lymphoma regimens (particularly after relapse) and some gynecological and soft tissue cancers (Chen et al. 2013; Shamseddine and Farhat 2011; Wusthoff, McMillan, and Ablin 2005). Cisplatin ototoxicity varies widely as illustrated in a recent review of cisplatin chemoradiation used in the treatment of head and neck cancer. Theunissen et al. (2015) found hearing loss incidence ranging from 17–88%. Differences in ototoxicity risk can be due to the relative toxicity of a drug, the dosing regimen, duration and mode of administration as well as patient-related factors (e.g. age, renal function, genetics), as discussed in Konrad-Martin et al. (2017).

In the US, the two main governing bodies for audiologists, the American Speech-Language- Hearing Association (ASHA) and the American Academy of Audiology (AAA) have provided the primary guidance for development of ototoxicity monitoring programmes (OMPs) (AAA 2009; ASHA 1994). Evidence suggests that monitoring during treatment with an ototoxic drug remains an inconsistent practice, however among clinics that provide monitoring; various schedules, methods and outcome reporting methods are used (Egelund, Fennelly, and Peloquin 2015; Konrad-Martin et al. 2017; Prescott 2014; Theunissen et al. 2015; Vasquez and Mattucci 2003). Understanding the perspectives of physicians (and other medical professionals, e.g. nurses, pharmacists) providing care in the multiple contexts in which these ototoxicity monitoring guidelines were designed to be applied may be crucial to establishing more efficacious OMPs.

Following the Consolidated Framework for Implementation Research (CFIR; Damschroder et al. 2009) a theory developed to guide implementation of new practices into clinical settings, several physician colleagues were contacted who refer their patients for at least some form of ototoxicity monitoring. The goal was to begin to appreciate the beliefs and practices of pulmonologists and medical oncologists regarding ototoxicity monitoring by facilitating an open discussion with four physician colleagues, guided by a survey developed as part of a larger project evaluating the efficacy of ototoxicity monitoring techniques. Aims were to gain insight into the plurality of approaches to ototoxicity monitoring and determine whether a more detailed study of physician stakeholder perspectives is warranted.

Methods

Survey

The survey instrument was a modified version of a non-validated questionnaire called the “Practitioner Survey of Ototoxicity Monitoring Beliefs” developed at the VA Portland Health Care System, National Center for Rehabilitative Auditory Research (NCRAR).

Sample

Four physician colleagues (three pulmonologists and one oncologist) were selected to participate who could provide insight into the breadth of perspectives on ototoxicity monitoring that might be associated with different patient populations: those receiving highly ototoxic platin-based chemotherapy drugs, highly ototoxic aminoglycoside antibiotics and less ototoxic antibiotics used on a lifelong basis. All physicians were offered the opportunity for a verbal interview or could provide a written response if scheduling limitations precluded a face to face meeting. Two physicians provided verbal interviews (Dr. Fennelly and Dr. Maggiore), which were transcribed verbatim; two provided written responses. Each was emailed an edited version of their responses to ensure that they were happy with it. The first and last authors revised the original survey for clarity and adapted it to more broadly address ototoxicity rather than only cisplatin-induced ototoxicity. They edited the data obtained for semantic and grammatical errors, selected survey questions that elicited the most information for inclusion in this discussion paper, analysed responses for similarities and differences between perspectives and provided introductory and concluding remarks. All authors reviewed and edited this paper.

Results

Table 1 displays the physicians who provided verbal or written responses to the survey. The physician responses to most survey questions are provided below in the text. A few questions routinely elicited redundant or limited feedback and were therefore omitted.

Table 1. Physician contributors to the survey, their institutional affiliations and medical specialty.

Physician name	Institution	Medical specialty
Dr. Alexandra Cornell, M.D.	Oregon Health & Science University	Pediatric pulmonology
Dr. Gopal Allada, M.D.	Oregon Health & Science University	Adult pulmonology
Dr. Kevin Fennelly, M.D., M.P.H.	National Institutes of Health	Pulmonary and occupational-environmental medicine
Dr. Ronald Maggiore, MD	VA Portland Health Care System Oregon Health &  Science University; University of Rochester Medical Center	Adult medical oncology

Based on the physicians responses, the survey instrument was expanded to include questions about how often and in what form audiological information about ototoxic effects is best conveyed. Additionally, questions about ototoxic effects on balance were added along with several questions meant to elicit more specific information about the prevalence of ototoxic hearing loss, tinnitus and balance issues in a provider’s patient base. The revised survey is provided in the Appendix that is available online.

This sample was intentionally diverse in the sense that the risk of ototoxicity varies for the drug treatments used in the disparate patient populations served by these four physicians. Drs. Cornell and Allada see patients routinely as part of the paediatric and adult CF care centres. These patients primarily receive inhaled tobramycin, which is associated with mild ototoxicity in general, but can cause more severe ototoxicity sporadically (Patatanian 2006). In contrast, Dr. Fennelly cares for severely ill patients, many with a drug resistant form of Mycobacterium abscessus that warrants treatment with the antibiotic amikacin, which is associated with a high incidence of ototoxicity, particularly with IV administration (Schacht 2007). Similarly, as an oncologist at a VA medical centre, Dr. Maggiore prescribes a highly ototoxic drug, cisplatin, mainly in patients with high-risk early-stage lung cancer and for patients with head/neck cancer requiring concurrent radiation therapy. Ototoxicity risk among the patient populations served by each physician was considered to be a possible influence on their views on and experience with ototoxicity monitoring.

Question #1: What is your current clinical practice for (or participation with) ototoxicity monitoring/testing hearing for patients receiving ototoxic medications or treatments?

Pulmonologists

Dr. Cornell: Our team often refers patients for hearing testing on an as-needed basis if they are on ototoxic medications.

Dr. Allada: Currently, we are not testing all patients who receive aminoglycosides, but refer those with audiology complaints.

Dr. Fennelly: Normally, we like to get a baseline within the first few weeks, if not before initiation of therapy and then at least monthly if they are on IV medications. If they are on inhaled aminoglycosides (we use a fair amount of inhaled amikacin), I usually like to get a baseline and then get [a follow up] at a month and then judge how frequently it might be worthwhile.

Oncologist

Dr. Maggiore: We refer patients receiving cisplatin for ototoxicity monitoring, particularly head and neck (cancer) patients receiving concurrent radiation therapy as well as patients with stage 1–3 lung cancer because these patients generally are getting cumulative doses that are more likely to be ototoxic.

Question #2: Do you advise patients about the potential for ototoxicity?

Pulmonologists

Dr. Cornell: I warn patients that aminoglycosides can affect hearing over time due to repeated exposure and damage to the inner ear.

Dr. Allada: It has not been in our practice to routinely mention ototoxicity risk with each patient receiving aminoglycoside therapy.

Dr. Fennelly: Yes, absolutely. We warn them that the medicine can cause ototoxicity, and that it might manifest as just tinnitus or it may cause actual hearing loss or symptoms of instability or loss of balance and if they get any of those things, to stop the medication and call us.

Oncologist

Dr. Maggiore: I do tell them there may be hearing changes or hearing loss from their baseline with ongoing cisplatin treatment and also tinnitus. And so I at least recommend a baseline audiology examination, and then (again) at some point during or after treatment depending on what the audiologist says.

Question #3: Have you noticed if your patients have ringing in their ears (tinnitus) when they receive potentially ototoxic treatments? If so, when did you typically notice tinnitus in your patients and what type of medication were they receiving?

Pulmonologists

Dr. Cornell: Yes. They (those affected) have usually received long-term inhaled tobramycin plus repeated courses of IV tobramycin for treatment of chronic Pseudomonas aeruginosa.

Dr. Allada: Yes. We have rarely noticed tinnitus in patients. One patient had it chronically after having had a combination of inhaled aminoglycoside chronically in addition to periodic IV aminoglycoside therapy for acute infections.

Dr. Fennelly: Yes, we see much more tinnitus than actual hearing loss. With IV amikacin -it’s pretty much 100% if we go long enough. Although tinnitus seems rare for inhaled amikacin, it does occur. So we try to stay on top of things. The incidence of tinnitus is quite high and certainly increases with age with patients receiving ototoxic treatments.

Oncologist

Dr. Maggiore: Yes, with cisplatin.

Question #4: Have you noticed if your patients have difficulty hearing when they get potentially ototoxic treatments? If so, when did you typically notice hearing issues in your patients and what type of medication were they receiving?

Pulmonologists

Dr. Cornell: No.

Dr. Allada: It is sometimes difficult to ascertain when patients first had an issue with hearing. By the best of my recollection, the timing seems to be sporadic. However, as I treat adult patients, they have usually had exposure to aminoglycosides prior to my involvement in their care.

Dr. Fennelly: Yes, for both inhaled and IV-tobramycin, amikacin and IV-gentamicin. There were lower percentages for the inhaled treatments, but almost routine for IV. The hearing loss was typically identified by the patient or audiologist.

Oncologist

Dr. Maggiore: Yes. From what I recall, the few patients who reported it were getting adjuvant (post-surgery) cisplatin typically. They typically reported hearing changes notable to them by the third cycle. At that point, they were probably exceeding 200 mg/m² in total. Those who brought it up more, or who reported it when I asked were the adjuvant lung or head and neck (cancer) patients who were also receiving radiation. Not sure of what the objective changes in hearing were. In my experience, I don’t see the same complaints (patients freely reporting [ototoxicity] issues) with carboplatin or oxaliplatin.

Question #5: Are the effects of hearing loss among your patients important to consider during treatments?

Pulmonologists

Dr. Cornell: Yes. As CF patients live longer and healthier lives, hearing loss can dramatically affect their quality of life.

Dr. Allada: It is very important because we give medications that can put patients hearing at risk. Subclinical issues are found much more commonly than problems that interfere with day to day activities, but because these can be potentially serious, it is an issue that is important to consider.

Dr. Fennelly: Yes, absolutely. We don’t, unfortunately have alternative treatments. The art of what we should be doing is trying to maintain quality of life and hearing loss definitely decreases folks quality of life and it can be very distressing to them and to their loved ones.

Oncologist

Dr. Maggiore: Yes, hearing loss I feel is important to at least evaluate and potentially intervene on because it will have an impact on the patients quality of life particularly if it impacts the patients communication skills and (therefore) impacts most everything we do. So for these reasons I feel it is important.

Question #6: Would findings of ototoxicity influence your treatment decisions (e.g. decrease dose, change drug or regimen, order additional hearing tests and assess the need for hearing aids)? Why or why not?

Pulmonologists

Dr. Cornell: Yes. I would consider alternative drug regimens (although for Pseudomonas, this is difficult due to the need for double coverage during exacerbations requiring IV antibiotics and chronic inhaled anti-pseudomonal antibiotic, most typically tobramycin), as well as additional hearing tests and hearing aids if necessary. In terms of alternative antibiotics, inhaled aztreonam is now an option that could be used in the event of hearing loss with tobramycin.

Dr. Allada: When we notice any issues with ototoxicity, we would be very reluctant to aggravate the issue with additional exposure to potentially ototoxic medications.

Dr. Fennelly:Sometimes, it’s a difficult decision. It is a bit like chemotherapy – sometimes if we don’t treat aggressively, we can’t cure them. Sometimes we can’t cure them to begin with and we just try to suppress things. The flip side is that if you make someone deaf and you’re not successful at curing this life threatening infection, then you have made them deaf for their last few months of life.

Oncologist

Dr. Maggiore: Yes. I believe that is where the role of the audiologist is helpful. The treating oncologist or care provider involved in cancer care would appreciate interpretation by an audiologist in terms of changes in serial hearing tests. If the opinion is that those changes are clinically meaningful and could significantly or have a high likelihood of impacting speech understanding and communication ability, I would consider changing the regimen. There have been a few cases where patients have reported hearing loss or tinnitus interfering with their daily activities. In those cases, you feel compelled to lower their dose, but no guidelines exist on how much lowering. We don’t have good consensus on how to modify the dose based on changes in hearing tests. Therefore the input from the audiologist is very important to help guide decision making regarding dose modification or discontinuation.

Question #7: Why do you believe clinics have not implemented standard screening protocols for ototoxicity?

Pulmonologists

Dr. Cornell: Some have and some have not. In terms of why we have not, it is most likely due to time and resource constraints.

Dr. Allada: A significant issue is the cost to garner the resources to serve all our patients. Also, for testing to be conducted at a typical CF clinic visit, it would require additional clinic space due to 4–5 providers already seeing the patient.

Dr. Fennelly: I don’t know. Most of us in the NTM (Non-Tuberculous Mycobacteria disease) community follow similar practices in term of ototoxicity monitoring and I think it is similar to what the CF people do. However, we work with older patients and hearing loss seems to be more prevalent in our population compared to younger CF patients.

Oncologist

Dr. Maggiore: To me, the honest answer is that many cancer centres or divisions do not place as much of an emphasis on supportive care standardised protocols or institutional guidelines, as we do on having newer and better therapeutics available, whether approved or on a research study. And among the short and long term toxicities associated with cancer treatment, probably a lot of oncologists don’t feel (ototoxicity) is as important as other toxicities, such as blood count issues and neuropathy. Supportive care policies may not get the attention they deserve. They should include toxicities, nutrition, oral health, social work, psychology or mental health, physical therapy-rehab, lymphedema and palliative care. With the emphasis on survivorship these issues will become more important as most centres will have to have survivorship care plans. But we are just scratching the surface.

Question #8: Would you modify your current clinical practices to include hearing monitoring? Why or why not?

Pulmonologists

Dr. Cornell: Yes. We absolutely need to modify our clinical practice to include hearing monitoring when children start chronic ototoxic medications such as azithromycin and tobramycin, particularly if they are on more than one medication. If we can identify hearing impairment sooner, then we can offer more sensitive testing and possibly intervention.

Dr. Allada: We currently partner with our audiology department for research and clinical purposes. If we had the support to do more routine clinical testing, this would be a valuable option for our patients.

Dr. Fennelly: We are already monitoring patients.

Oncologist

Dr. Maggiore: At Portland VA, we are currently monitoring hearing in patients on cisplatin.

Question #9: What would be an “actionable” amount of hearing change for you? One that would lead you to consider a treatment change.

Pulmonologists

Dr. Cornell: Not sure. I would defer to our audiology team.

Dr. Allada: Either a meaningful effect for my patients or a change seen on testing that would predict a patient would be a high-risk for having a meaningful effect.

Dr. Fennelly: That’s a tough one. If I understand the question right, how severe a hearing loss or at what level would I stop the therapy? That really depends on how advanced their disease is. Here, I can think of one gentleman… He had been seen by the thoracic surgery service for a thymoma and we were treating him for a Mycobacterium abscessus infection that had been discovered during the course of his evaluation. So, he had had the audiometry that showed that he was starting to lose the high frequencies and his Mycobacterium abscessus infection was not that awful. He had what we considered fairly mild disease. And so, I just said we are going to stop (aminoglycosides). We have a few other drugs we can go with and it reversed.

Oncologist

Dr. Maggiore: Threshold shift that would impact the patient’s speech understanding or daily communication. No specific numerical threshold needs to be followed until we (treating medical oncologists) develop more consensus. I need the input and guidance of the audiologist doing the measure to interpret results. If the American Society of Clinical Oncology weighed in, you would see more uptake. Their practice guidelines have been very helpful that they put out and the evidence base is synthesised in many of those guidelines.

Interviewer follow-up question: “Did anyone provide an in-service for you and your group on hearing loss and what can be done?”

Pulmonologist

Dr. Fennelly: No. We just had discussions where we met with the audiologist one-on-one and shared our mutual interest in developing a monitoring programme. It would help communication with the treating physicians if we plotted each audiometric test results across visits, so we can determine when a change is evident.

Interviewer follow-up question: “Would you like to see a shaded background for what is normal for their age, or what sounds they are missing that are essential for hearing speech and other environmental sounds?”

Pulmonologist

Dr. Fennelly: That would be good. People need simple answers. Some audiologist’s reports are exquisitely detailed, but when you are in a busy clinic, you want the quick answers.

Interviewer follow-up question: “Do treatment changes due to ototoxicity shorten lives?”

Pulmonologist

Dr. Fennelly: Well, fortunately we don’t see that much mortality …I am trying to think…COPD (chronic obstructive pulmonary disease) is the major co-morbidity associated with mortality in our NTM patients (i.e. patients with NTM infections). I can’t think of an instance of where I have backed off or held the aminoglycoside and it resulted in a patients death.

Oncologist

Dr. Maggiore: In my experience treating primarily lung , head and neck cancer, I have not witnessed that lowering a dose or foregoing a fourth cycle of adjuvant therapy has reduced their longevity. We do talk about dose intensity for other drugs in the curative setting. I’m not as aware of the testicular cancer literature, but there is some evidence in the head and neck literature where cisplatin is used together with radiation for a curative intent, that a cumulative dose of less than 200 mg/m² has led to lower survival rates (Strojan et al. 2016). So we need to have a handle on what are the toxicities and how significant they are to warrant intervention (drug change). Most of the time we are not making drug treatment changes solely based on ototoxicity, but rather for other toxicities (e.g. nephrotoxicity, dehydration). Patients are typically ill for a number of reasons. We need good reasons to stop treatment, but may lower the dose, keeping in mind importance of cumulative dose.

Interviewer follow-up question: “Is there anything else you would like to say regarding ototoxicity and monitoring?”

Pulmonologist

Dr. Fennelly: Is there anything we can do to prevent hearing loss? We are sort of stuck with these drugs for now. Until we get some new drugs, what can we do?

To put things in perspective, there is this whole world out there of people treating MDR (multiple drug resistant)and XDR (extensively drug resistant) tuberculosis. They don’t have the luxury there of you or your staff (e.g. medical assistants, nurses). What are ways that people in resource limited settings could monitor for ototoxicity?

Summary and conclusion

Responses from all four physicians indicate that (i) ototoxicity is a potential problem for their patients; (ii) monitoring hearing is important to ensure good quality of life among their patients and that (iii) modification of a treatment regimen would be considered if an alternative treatment option were available. These physicians were known to the interviewers to promote ototoxicity monitoring; others may require education to establish ototoxicity monitoring as a high priority in the treatment plan of their patients. They differed widely in their approaches to monitoring, from making routine referrals to audiology for patients receiving highly ototoxic drug therapies, to relying on patient self-referral. The referral patterns appeared somewhat reflective of the expected risk of ototoxicity in each practitioner’s patient population.

The national audiology governing bodies in the US have general recommendations that do not specify intervals for the monitoring tests. They also provide an ideal monitoring schedule for cisplatin- and aminoglycoside-ototoxicity early detection that may not be feasible (AAA, 2009; ASHA, 1994; Konrad-Martin et al. 2017). Limitations of this discussion paper include a small sample size; however, the anecdotal accounts provided indicate that even in settings where patients are routinely monitored for ototoxicity, monitoring occurs less frequently than suggested by current audiological guidance on ototoxicity early detection. This makes a case for clear OMP guidelines that take physician perspectives into account because, although audiologists perform the ototoxicity monitoring and manage the patient’s audiological care, getting patients referred for testing generally falls to the treating physician. National audiology governing bodies should obtain physician provider input to optimise interdisciplinary care for patients exposed to ototoxic drugs, including to help determine monitoring schedules that maximise patient outcomes while minimising preventable ototoxicity, are tolerable for the patient and logistically feasible. The physician responses were considered rich with information that also could help the individual audiologist in their OMP practice. Further research is warranted on OMP stakeholder perspectives.

Abbreviations
AAA	=	American Academy of Audiology
ASHA	=	American Speech-Language-Hearing Association
CF	=	Cystic fibrosis
CTCAE	=	National Institutes of Health, Cancer Institute, Common Terminology Criteria for Adverse Events
CFIR	=	Consolidated Framework for Implementation Research
COPD	=	Chronic obstructive pulmonary disease
IV	=	Intravenous
MRSA	=	Pseudomonas aureus or methicillin-resistant Staphylococcus aureus
NTM	=	Non-tuberculosis Mycobacterium
OMP	=	Ototoxicity monitoring programme

Declaration of interest

Dawn Konrad-Martin is listed as a co-inventor on patents for a hearing test and mobile device. These patents generate no revenue. No other potential conflicts of interest were reported by the authors.

Supplemental data available online

Acknowledgements

Funding for this work was partially provided DKM by the U.S. Department of Veterans Affairs Office of Rehabilitation Research & Development (RR&D) Service (Grant #C0239R). This research was supported in part (KF) by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, and in part (ACG) by the National Institute on Deafness and other Communication Disorders (NIDCD) of the NIH under (award number R01DC10202).. We thank Dr. Marilyn Dille for allowing us to adapt her survey for use here and Dr. Carmen Brewer for interviewing the pulmonary care specialist (KPF). Dr. Maggiore was at Oregon Health & Science University and VA Portland Health Care System during the interview and transitioned to University of Rochester, Rochester, NY during the writing and editing phase of this manuscript. The opinions and assertions presented are the private views of the authors and are not to be construed as official or as necessarily reflecting the views of the Department of Veterans Affairs or the US Government.