Interview with Kathleen Campbell Professor and Director of Audiology Research Division of Otolaryngology, Department of Surgery, Southern Illinois University School of Medicine

Topic: Ototoxicity

BECK: Hi Kathleen. Thanks for taking the time to meet with me today. Would you please tell me a little about your education and professional experiences?

CAMPBELL: Sure. I got my masters degree at the University of South Dakota in 1977 and then I opened a clinic in the middle of the Canadian Rockies where there had never been audiology services before. I stayed there for 6 years. It was a great experience. After that, I went to the University of Iowa for six years where I was in charge of auditory electrophysiology for the otolaryngology department and simultaneously worked on my PhD.

BECK: What was your dissertation on?

CAMPBELL: It was on electrocochleography in different body positions to distinguish Meniere's disease from perilymphatic fistula.

BECK: That's very interesting. What did you find?

CAMPBELL: I found that if you change the body position of Meniere's people, the SP/AP ratio may or may not be enlarged but remains stable.

BECK: So if someone truly has Meniere's, their body position in space doesn't matter with respect to their ECochG result?

CAMPBELL: That's right.

BECK: Very good. When did you start at Southern Illinois University (SIU)? And can you please tell me a little about the audiology program there?

CAMPBELL: I joined SIU in 1989, so I've been here just over 15 years now. I'm the only PhD audiologist on faculty and I started the program. Before I arrived, the medical school had never employed an audiologist, and the original plan was to have me doing research, administration and teaching, and adding just one clinical audiologist to see patients. SIU now employs six audiologists. I focus on research and teaching now. I'm really trying to get the otoprotective agents to clinical trials and through the FDA approval process.

BECK: And do you also teach for the AuD programs?

CAMPBELL: Yes, I've recorded a couple of lectures for the University of Florida. It was interesting and I think they've gone well. I also do a lot of CEU conferences around the country.

BECK: And you're on the AAA Board?

CAMPBELL: Yes. I am a member-at-large, and my term ends in 2005. I take a lot of students in the research lab, medical students, talented high school students, residents, professors that are on sabbatical. We do enjoy them.

BECK: That's pretty impressive! OK then, let's move to the subject at hand - ototoxicity. How do you define ototoxicity?

CAMPBELL: Any toxin that can damage the peripheral or central auditory system is ototoxic and I include "noise" as ototoxic. Most people think of ototoxic agents as drugs only, but noise produces many auditory and vestibular reactions in the inner ear.

BECK: How do you diagnose ototoxicity? Is it always by history or do you have some things that you look for clinically?

CAMPBELL: As far as an ototoxic change, right now we're relying on the 1994 ASHA guidelines. To define a significant ototoxic event, one of the three following incidences must occur:

a) ³ 20 dB decrease at any one test frequency
b) ³ 10 dB decrease at any two adjacent frequencies, or
c) loss of response at three consecutive frequencies where responses were previously obtained.

and then if those results replicate in 24 hours, then we can say it is an ototoxic change. We'll include the ASHA reference at the end of the interview for the interested readers.

BECK: And can you tell me please, what about high frequency audiometry and ototoxicity?

CAMPBELL: Well that varies. I would say basically we're most interested in the frequencies between 8000 and 16,000 Hz, although some equipment goes up to 20,000. I'm not real fussy about the highest frequencies, but I like to see up to 16K. Unfortunately, what you'll find in a lot of high frequency protocols is that they're not specifying the complete protocol, so it's just hard to read their protocol and evaluate it. In the April JAAA, 2003, we addressed this issue and related issues in detail.

BECK: I think one thing people are concerned with is a lack of normative data with respect to high frequency information.

CAMPBELL: Yes, but that's not really the issue. There are studies out there that do reveal norms for these measures, but more importantly, what you want to do is get a good baseline evaluation and compare the patients to themselves over time!

BECK: Right, excellent point! And as far as special headphones or special audiometers any comments on that?

CAMPBELL: Sure. I don't want to promote any particular brand, but there are available high frequency systems and you do have the right equipment. And again, you don't have to worry about comparing it to normals.

BECK: What about otoacoustic emissions monitoring? Does that play a role in ototoxic monitoring?

CAMPBELL: I started using OAEs back in '90 or '91. I doubt it will completely replace high frequency audiometry, but it is useful and we know it works, however, we don't know how to define a significant change with OAEs just yet, although in certain patients it is somewhat apparent. There's a lot of research being done in that area.

BECK: How often during chemotherapy, or during pharmacologic therapy, should somebody be monitored?

CAMPBELL: With the platinum drugs, it should be just before each round of chemo and that is usually about every 2-4 weeks. And another important category are the aminoglycosides, and that testing is usually once or twice a week depending on the agent being used.

CAMPBELL: Aminoglycosides can decay very quickly but keep in mind that both aminoglycoside and platinum can cause delayed hearing loss and aminoglycosides, in animal studies, may not clear your ear very rapidly. In fact, they can be retained for up to eleven months after discontinuation.

BECK: Wow. What about platinum drugs? How long do they stay in system?

CAMPBELL: We don't know. No one has done the definitive study, but it is known to give hearing loss, and if there is pre-existing hearing loss, it can progress after discontinuation but nobody has really exhaustively studied this yet. It's really important to remember that these patients have life threatening illnesses, and their hearing loss may not be the physician's and patient's top priority , but I don't say that to minimize it, it is very important regarding the patient's quality of life.

BECK: You're getting to the pragmatic issues. When I was at a large medical center I remember oncologists who didn't refer because they must've thought what's the point? They probably thought that having ongoing audiometry on these very sick patients was just adding stress to the lives of the patients, and it wasn't going to change the outcome. I suppose they thought "Why fit somebody with expensive high-end digital hearing aids when you know they have less than twelve months?"

CAMPBELL: Yes, that may be what they're thinking, but the answer is ...So they can have a quality of life during those final twelve months!!! My step-dad died of brain cancer last year, and it was a long haul...radiation, hair loss, pain, and it went on for two years. With the combination of radiation and platinum drugs, I knew what was coming. He already had hearing loss and we fit him with very high end digital hearing aids - but the thing was -- it saved him money because every month we were re-setting them, because as the hearing loss got worse, the hearing aids were able to handle the changing hearing loss, and we reset the hearing aids to the "moving target." These are "quality of life" issues. And when you think about it, these are very sick people, they don't feel like reading, and if they cannot communicate by speaking and listening, they are isolated. They want to speak to their loved ones, in person and on the phone, and they want to get their things in order, but if they cannot communicate due to hearing loss, they are further isolated and lonely at a time of very high stress.

BECK: I agree. With compromised patients you can argue that not addressing hearing loss is adding insult to injury.

CAMPBELL: Absolutely, for oncology patients, one of the biggest quality of life issues is communication.

BECK: For hearing healthcare professionals looking to get involved at medical centers, or for those who might have an office in a professional building where patient are being treated with various ototoxic drugs, how do they get started?

CAMPBELL: Often oncology patients are managed by a team of physicians including not only primary care physicians, but also medical oncology, oncologists, Ob-Gyn and infectious disease physicians are involved too. So it varies location-to-location, but the key in providing these services is to be flexible, and available.

BECK: Kathy, one thing that really impacts us is the Physician's Desk Reference (PDR) and the hundreds or thousands of drugs listed as ototoxic or vestibulo-toxic. Can you comment on that please?

CAMPBELL: Just because a drug is listed as causing tinnitus or hearing loss or dizziness in the PDR, does not necessarily mean that there's good evidence of ototoxicity. Let's put it this way, often times the drug company finds it is more cost effective to list "tinnitus, hearing loss or dizziness" as a possible side effect, if there are patient reports during clinical trials rather than to actually do the extensive research required to determine if it is actually ototoxic. Keep in mind that over a period of time, a certain number of people will develop hearing loss or tinnitus without taking any ototoxic drug. If you are testing a new drug on thousands of patients some unrelated hearing loss or tinnitus may also coincidentally develop. So, if the incidence is not very high, it can take a lot of research to determine if the incidence is higher in the treated versus untreated groups and if it is truly related to the study drug. They might say "We're not going to do a lot of research to find out whether or not it's truly ototoxic. It's much cheaper to just list it as a possible side effect." So you don't want to "over-identify" everything in the PDA as being absolutely ototoxic. There are many levels of risk, and some are pretty insignificant. So don't go around meeting physicians and giving them a list of 200 drugs that are ototoxic! We all know aspirin is ototoxic, but it also serves many health benefits too. It's the same with diuretics. We certainly don't want to cry wolf; we need to be realistic.

BECK: What do you see that makes you think we've come a long way in the last five years?

CAMPBELL: Formal monitoring. If you look at the literature even ten years ago, some of the oncology literature said to do things like the "finger rub" test. Of course that test is not a test, and the "whisper" and "watch" tests have little meaning too! If we're truly concerned about hearing, let's do it the right way and actually derive a real answer.

BECK: What about the issue of audiologists advising patients about drugs and nutritional supplements?

CAMPBELL: In my opinion, at this time it is ill-advised. As licensed healthcare professionals, we need to be certain we are practicing within our training and our scope of practice as mandated by the states, the licensing boards and the national associations, and we have to act within their ethical guidelines too. Basically, audiologists cannot advise patients to take or discontinue meds, or prescribe or over-the-counter meds, and I think the same argument can be made for nutritional supplements. I do think that audiologists need much more training in pharmacology and ototoxicity in general but we are already moving that direction.

BECK: So to summarize, there two reasons to perform ototoxicity monitoring?

CAMPBELL: Exactly right. One is to look for negative consequences of ototoxic drugs with regard to the hearing and balance system, and the other is to help patients communicate, as indicated based on their hearing loss, to improve and perhaps maintain their quality of life.

BECK: Kathy, normally at the end of interviews, we don't list references, but I thought that for this topic, it might be a good idea. So if you would give me a short list of your work, and other recommended readings, that would be great.

CAMPBELL: Sure Doug, happy to do so.






Recommended Readings (alphabetical):

American Speech-Language-Hearing Association Guidelines for the Audiologic Management of Individuals Receiving Cochleotoxic Drug Therapy. ASHA 36 1994;(Suppl 12):11-19.

Beck A, Maurer J, Welkoborsky HJ, Mann W. Changes in transitory evoked otoacoustic emissions in chemotherapy and with cisplatin and 5FU. HNO 1992;40(4):123-7.


Blakley BW, Cohen JI, Doolittle ND, et al. Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 2002;112(11):1997-2001.

Brummett RE, Morrison RB. The incidence of aminoglycoside antibiotic induced hearing loss. Arch Otolaryngol Head Neck Surg 1990;116:406-410.

Campbell, K. Audiologic Monitoring for Ototoxicity. In: Roland P, Rutka J, eds. Ototoxicity. BC Decker Inc: Hamilton, 2004.

Campbell KCM, Kalkanis J, Glatz FR. Ototoxicity: mechanisms, protective agents, and monitoring. Current Opinion in Otolaryngol Head Neck Surg 2000;8:436-440.

Campbell KCM, Durrant J.D. Audiologic Monitoring for Ototoxicity. Otolaryngol Clin North Am 1993;Vol 26, 903-914.

Campbell, KCM Audiologic Monitoring for Ototoxicity in Essential Audiology for Physicians. Singular Publishing San Diego, CA 1998 155-167

Campbell KCM, Kelly E, Targovnik N, et al. Audiologic Monitoring for Potential Ototoxicity in a Phase I Clinical Trial of a New Glycopeptide Antibiotic. J Am Acad Audiol: Special Edition on Ototoxicity 2003a;14(3):157-169.

Campbell KCM, Rybak LP, Meech RP, Hughes L. D-Methionine Provides Excellent Protection from Cisplatin Ototoxicity in the Rat. Hear Res 1996;102:90-98.

Campbell KCM, Meech RP, Rybak LP, Hughes LP. D-Methionine Protects Against Cisplatin Damage to the Stria Vascularis. Hear Res 1999;138:13-28.

Campbell KCM, Meech, RP, Rybak LP, Hughes LF. The Effect of D-Methionine on Cochlear OxidativeState With and without Cisplatin Administration: Mechanisms of Otoprotection. J Am AcadAudiol: Special Edition on Ototoxicity 2003b;14(3):144-156. Campbell, KCM. "Audiologic Monitoring for Ototoxicity" in Ototoxicity edited by Roland P and Rutka J.Decker Publishing

Fausti SA, Henry JA, Helt WJ, et al. An individualized, sensitive frequency range for early detection of ototoxicity. Ear Hear 1999;20(6):497-505.

Fausti SA, Frey RH, Henry JA, et al. Early detection of ototoxicity using high frequency, tone-burst evoked auditory brainstem responses. J Am Acad Audiol.1992a;3: 397-404.

Fausti SA, Flick CL, Bobal AM, et al. Comparison of ABR stimuli for the early detection of ototoxicity: conventional clicks compared with high frequency clicks and single frequency tonebursts. J Am Acad Audiol 2003;14(5):239-250.

Fausti SA, Henry JA, Shaffer HI. High-frequency audiometric monitoring for early detection of aminoglycoside ototoxicity. J Infect Dis 1992c;165:1026-32.

Frank T. High-Frequency Hearing Thresholds in Young Adults Using a Commercially Available Audiometer. Ear Hear 1990;11:450-454.

Frank T. High Frequency (8 to 16 kHz) Reference Thresholds and Intrasubject Threshold Variability Relative to Ototoxicity Criteria Using a Sennheiser HAD 200 Earphone. Ear Hear 2001;22(2):161-168.

Gillette-Cloven N, Re A, McHale, M., Burger, R., DiSaia, P., Rose, S. Campbell K, Fan, H. (2000). Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer. Anticancer Research 20:4205-4210

Katbamna B, Homnick DN, Marks JH. Effects of chronic tobramycin treatment on distortion product otoacoustic emissions. Ear Hear 1999;20(5):393-402.

Kopke, R.D., Coleman, J.K.M., Liu, J., Campbell, K.C.M., and Riffenburgh, R.H. Enhancing Intrinsic Cochlear Stress Defenses to Reduce Noise-Induced Hearing Loss. The Laryngoscope 112:1515-1532, 2002

Kopke R, Liu W, Gabaizedeh R, et al. Use of Organotypic Cultures of Corti¡¦s Organ to Study theProtectiveEffects of Antioxidant Molecules on Cisplatin-Induced Damage of Auditory Hair Cells. Am J Otol 1997; 18:559-571.

Kopelman J, Budnick AS, Kramer MB et al. Ototoxicity of High-Dose Cisplatin by Bolus Administration in Patients with Advanced Cancers and Normal Hearing. Laryngoscope 1988;98(8 Pt 1):858-864.

Kujansuu E, Rahko T, Punnonen R., Karma P. Evaluation of the hearing loss associated with cisplatin treatment by high-frequency audiometry. Gynecol Oncol 1989;33:321-322.

Korver KD, Rybak LP, Whitworth C A, Campbell KCM. (2002). Round window application of D-methionine provides complete cisplatin otoprotection. Otolaryngol Head Neck Surg. 126(6):683-689

Lockwood DS, Ding DL, Wang J, Salvi RJ. Related Articles, Links D-Methionine attenuates inner hair cell loss in carboplatin-treated chinchillas.Audiol Neurootol. 2000 Sep-Oct;5(5):263-6.

Ress BD, Sridhar KS, Balkany TJ, et al. Effects of cis-platinum chemotherapy on otoacoustic emissions: the development of an objective screening protocol. Otolaryngol Head Neck Surg 1999;121(6):693-701.

Sha S, Schacht J. Antioxidants attenuate gentamicin-induced free radical formation in vitro and ototoxicity in vivo: D-methionine is a potential protectant. Hear Res 2000;142:34-40.

Wimmer C, Mees K, Stumpf P, Welsch U, Reichel O, Suckfull M. Related Articles, Links Round window application of D-methionine, sodium thiosulfate, brain-derived neurotrophic factor, and fibroblast growth factor-2 in cisplatin-induced ototoxicity.Otol Neurotol. 2004 Jan;25(1):33-40.

Zorowka PG, Schmitt HJ, Gutjahr P. Evoked Otoacoustic Emissions and Pure Tone Threshold Audiometry in Patients Receiving Cisplatinum Therapy. Int J Pediatr Otorhinolaryngol 1993;25:73-80.