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Journal of Clinical Oncology, Vol 19, Issue 6 (March), 2001: 1658-1663
© 2001 American Society for Clinical Oncology

Recommendations for Cancer Prevention Trials Using Potentially Ototoxic Test Agents

By Lawrence I. Shotland, Frank G. Ondrey, Kristen A. Mayo, Jaye L. Viner

From the Hearing Section, Neuro-Otology Branch, and Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, and the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Otolaryngology, University of Minnesota, Minneapolis, MN; and CCS Associates, Inc, Mountain View, CA.

Address reprint requests to Lawrence I. Shotland, PhD, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 9000 Rockville Pike, Bldg 10, Rm 5C-306, Bethesda, MD 20892.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill.

MATERIALS AND METHODS: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations.

RESULTS: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents.

CONCLUSION: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
DRUGS WITH OTOTOXIC side effects are commonly used in the management of cancer and infectious disease (eg, cisplatin for malignancies; aminoglycosides for infection).1-4 Other therapeutic modalities for cancer, eg, radiation, also have a potential for inducing or exacerbating ototoxicity.5-8 When possible, a compound’s side effects are reduced or eliminated by modifying the route or schedule of administration, or by selecting nontoxic derivatives or new classes of drugs. For life-threatening illnesses, toxicity may be tolerated in the absence of viable alternatives. However, when promising agents first advance into clinical trials, toxicities have yet to be identified or well-defined, particularly for drugs intended for prolonged administration.

Epidemiologic, preclinical, and now clinical data support the use of pharmacologic agents in addition to lifestyle or nutritional modifications to reverse, retard, or halt the process of carcinogenesis.9-13 Consequently, cancer prevention is a topic of intense medical research and public concern, particularly for people at risk for developing specific cancers based on their family or personal history, prevalent presymptomatic disease, genetic testing (eg, BRCA mutations in breast cancer, APC mutation in colorectal cancer), or precursor lesions (eg, adenomatous polyps in colorectal cancer, leukoplakia in squamous head and neck cancer). One agent that is being developed for prevention of specific malignancies, difluoromethylornithine (DFMO) is known to have the potential to cause ototoxic side effects when given at moderate-to-high doses,14,15 although these toxicities have almost always resolved within a few weeks after cessation of drug.12,16-22 Novel schedules and drug combinations of DFMO may increase its ototoxic potential and mandate more stringent clinical monitoring.

Grading of adverse events (AE) in U.S. cancer trials is routinely based on the National Cancer Institute’s Common Toxicity Criteria (http://ctep.info.nih.gov/CTC3/Download/CTCv20%204-30-992.pdf). The current Common Toxicity Criteria, however, are insensitive to small changes in hearing that may be clinically significant. For the protection of patients, investigators may appreciate the more-detailed audiologic monitoring and follow-up recommendations proposed here. The purpose of these recommendations is to (a) enable investigators to identify subjects with or at higher risk for hearing loss (HL) or vestibular problems at baseline; (b) provide a feasible schedule for audiologic monitoring; (c) help investigators distinguish between gradations of HL; (d) aid in distinguishing drug-related HL from HL due to other causes; (e) suggest appropriate steps for evaluating ototoxicity encountered in clinical trials; and (f) raise awareness of an under-recognized problem.

In therapy for advanced malignancy, iatrogenically induced HL may be tolerated in pursuit of cure or palliation. However, in the setting of clinical trials of potentially ototoxic investigational agents, unexplained HL during treatment, particularly in the absence of adequate audiologic monitoring and conservation safeguards, might pose severe problems that could hamper the development of a promising agent. It would be unfortunate if development of an otherwise promising agent for therapy or prevention were to be prematurely aborted because of AEs inappropriately attributed to the agent. Age-adjusted hearing norms, such as those presented in our recommendations, provide criteria for differentiating normal, age-related HL (such as presbycusis—a normal, age-associated increase in hearing threshold) from drug-related HL.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Audiologic Evaluation: Terms
Normal, age-related hearing. Normal hearing measured in decibels (range, 0.5 to 4 kHz) extends to the 95th percentile (inclusive) and is adjusted for age ( Tables 1 and 2). Additionally, separate norms are given for men and women. Although hearing loss is thought to be multifactorial, ample evidence supports environmental noise exposure as a major contributor to the greater hearing loss seen in males.23-25 The data in Tables 1 and 2 are adapted from Morrell et al26 and used highly otologically screened individuals to exclude those with otologic disease and long-term noise exposure, which could affect their hearing. Additional norms are available for frequencies of 0.125 to 8 kHz,27,28 as well as for frequencies as high as 9 to 20 kHz.29 These latter studies used either a less rigorous otologic screening process27 or purposely did not screen for otologic disease.29 Although the lack of otologic screening may be more representative of the overall population, and more inclusive than use of a screened population, our rationale for using an otologically screened population is motivated by a desire to minimize deleterious changes in a study population.


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  		Table 1. Age-Adjusted Normalized Hearing Thresholds for Men at Various Frequencies
 

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  		Table 2. Age-Adjusted Normalized Hearing Thresholds for Women at Various Frequencies
 
Hearing loss. For the purposes of these recommendations, HL is defined as a physiologic function rather than a communication disorder. Using a population-based reference for normal, age-related hearing, thresholds exceeding the 95th percentile constitute HL.

Threshold shift. Threshold shift refers to the relative decibel increase necessary for a subject to hear the stimulus. Threshold shifts are evaluated in the context of an individual’s baseline measure and typically refer to short-term events, ie, ototoxic drug or noise exposure.

Tinnitus. Tinnitus is defined as noise in the ears—described variously as ringing, buzzing, hissing, and so on.

Clinical Application of the Recommendations
Baseline testing. Subjects enrolling in clinical studies using potentially ototoxic investigational agents are at an indeterminate risk for HL. Complete otologic history will initially alert investigators to patients who may be unsuitable for studies with ototoxic agents or who may require special monitoring. Therefore, before the first dose of a study drug, not to exceed 6 weeks, all subjects should be seen for a baseline evaluation consisting of the elements listed below. Subject thresholds should be compared with the appropriate table for the subject’s gender and age group at each frequency to determine whether the subject’s hearing exceeds the 95th percentile. Baseline testing should be followed by regularly scheduled monitoring throughout the course of the study (see below). Appropriate physical examination will be part of the baseline physical evaluation for any clinical trial. Therefore, presumably, examination of potentially affected organ systems will have been performed before enrollment.30

Standard testing. Standard testing includes standardized audiologic and vestibular history, otoscopy, pure-tone air conduction thresholds from 0.25 to 8 kHz., and bone conduction thresholds (0.5 to 6 kHz, including half-octaves as needed), which should be performed when indicated, ie, whenever air conduction thresholds are greater than 10 dB HL. If the type of HL (conductive versus sensorineural) cannot be ascertained, then middle ear immittance should be used (see below).

Additional testing. Additional testing should include speech testing (thresholds and speech recognition) when significant HL is present and overall communication status is unknown, as well as middle ear immittance (when conductive HL or active middle ear pathology may be a contributing factor).

Exclusion criteria. Exclusion criteria are as follows (1) age-related pure-tone thresholds exceeding the 95th percentile of the population distribution; (2) active middle ear pathology; (3) sudden HL (origin known or unknown) regardless of the magnitude; (4) hearing loss associated with closed head trauma; (5) concomitant use of known ototoxic medications ( Table 3); and (6) any diagnosis or treatment for inner ear disorder, ie, hearing or balance (Table 3).


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  		Table 3. Is Hearing Age- and Sex-Appropriate? Eligibility Decision Tree (consult Tables 1 and 2)
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Definition and Grades of Hearing and Balance Dysfunction: Toxicity Criteria
To date, there are no universally accepted threshold shift criteria for chemotherapeutic or chemopreventive agents. The differentiation between a true threshold shift and normal variability is critical in distinguishing true signal from intrinsic and extrinsic background noise.31 Noise is a random phenomenon, therefore thresholds may vary from one test session to the next. A commonly used set of ototoxicity guidelines32 uses stringent AE criteria; however, various authors33-37 have demonstrated that test-retest variability regularly exceeds these criteria. Few studies have systematically examined true-versus false-positive response rates for these tests. Two such studies have used a cisplatin model for investigating the sensitivity of pure-tone audiometry for ototoxic monitoring.35,36 Cisplatin is an excellent model because of its known ototoxicity and high incidence of irreversible HL.3 The data show that a mean threshold shift of at least 15 dB at 6 and 8 kHz provided maximal sensitivity (50%) while eliminating (0%) false-positive results.35 Simpson et al36 suggested the use of multifrequency averaging between 3 and 8 kHz in an effort to reduce false-positive results, but stopped short of a specific recommendation. Our definition and gradations of ototoxic AEs are based on these studies ( Table 4). Frequency recommendations, however, without the benefit of drug-specific data would be premature and therefore are not proposed at this time.


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  		Table 4. Definition and Gradation of Ototoxic Adverse Events
 
Monitoring
Regularly scheduled, on-study audiologic monitoring allows an opportunity to detect early ototoxic side effects with increased sensitivity so they may be arrested or reversed.2,4,5,38-40 Because the optimal duration of treatment with chemopreventive agents may be open-ended, there is potential for cumulative toxicity and need for ongoing vigilance—making audiologic monitoring a necessary safeguard.

Scheduling
It is recommended that pure-tone air conduction threshold testing be performed at baseline and after 1, 6, and 12 months of therapy, and again 3 months after discontinuing drug. Patients should be advised to call the investigator in the event of new-onset HL, tinnitus, or balance disturbance. Subjects who experience ototoxicity should be periodically contacted by study personnel to assess the status of the AE. The interval at which study personnel contact subjects will vary depending on characteristics of the agent and study population.

Tests
For subjects with no hearing complaints and stable pure-tone air conduction thresholds, air conduction testing will suffice to detect subclinical changes. In the event that air conduction thresholds shift by at least 15 dB at two or more contiguous frequencies (grade 1), additional testing should be performed to rule out nonototoxic causes of the HL. Subjects with this magnitude of threshold shift should be retested within 24 hours of the previous test or as soon as possible to confirm the presence of a true threshold shift. Objective vestibular work-up is indicated for subjects complaining of vertigo or loss of balance.

Categories of Possible Adverse Events
Criteria adopted for discontinuing or reducing the dose of an experimental drug in a specific protocol, application, or subject are ultimately a function of the risk-benefit ratio. In general, however, study drug administration should be discontinued or held if the subject exhibits any one of the following possible signs of ototoxicity: hearing loss (grade 1 or higher); presence or worsening of tinnitus (grade 1); dizziness, transient vertigo, or other dysequilibrium (grade 3); or other, at the discretion of the physician or patient.

Implementation of Audiometric Monitoring
Ideally, testing should be performed in a sound suite meeting American National Standards Institute (ANSI) standards41 using a diagnostic audiometer calibrated to ANSI standards.42 If a sound suite is not available, a portable pure-tone audiometer calibrated to ANSI standards can be used for air and bone conduction testing in a quiet room. A daily biologic calibration will be necessary to account for ambient room noise, which is subject to change. Ambient noise may artificially elevate low-frequency air and bone conduction thresholds of patients with sensitive hearing. All follow-up testing should be referred to a regional center that has a sound suite, if none is available on site.

Recommended Adverse Event Follow-Up
Audiograms should be repeated at 1-month intervals until hearing thresholds have returned to within 10 dB of baseline or until hearing stabilizes. For patients who complete the study without threshold shifts, follow-up should be conducted by telephone or physical examination should be performed 3 to 6 months after discontinuing the study drug. For patients with balance disturbance, vestibular tests, at the clinician’s discretion, should be performed until dysequilibrium has resolved or stabilized.43


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The recommendations proposed here take advantage of readily available tools for assessing ototoxicity. Early recognition of an agent’s ototoxic potential, along with sensitive mechanisms for quantifying the magnitude of impairment, may enable clinical investigators to reduce the dose or discontinue investigational agents before the onset of significant HL. Monitoring to limit, and even forestall, ototoxicity as early as possible in the course of clinical trials is clearly in the best interest of subjects and investigators. Naturally, as clinical experience accrues for a particular drug, the magnitude of ototoxic risk will become better defined. If the preponderance of data show minimal risk for HL, then screening and monitoring recommendations can be relaxed accordingly. Conversely, with novel test agents, or in populations at increased ototoxic risk, more intense scrutiny (ie, shorter intervals between audiometric testing) may be warranted. In the case of long-term interventions, one must also bear in mind that even minimal risks for ototoxicity can be magnified over time. This principle applies to other drugs, existing as well as emerging. Regardless of the class of drug, the same clinical questions persist. For example, low-risk cohorts treated on an open-ended basis with loop diuretics for hypertension or deferoxamine mesylate for iron overload are in need of an objective monitoring program for the same reasons as are patients receiving cisplatin or other highly ototoxic agents.

The proposed recommendations are intentionally limited to conventional audiometry, ie, 0.25 to 8 kHz, this being the standard of care. High-frequency audiometry, formerly a research tool, is increasingly used to detect ototoxic changes above 8 kHz, which correspond to early cochlear insults.44-50 High-frequency audiometry clearly detects preclinical ototoxicity with greater sensitivity than conventional audiometry,47-50 and may be used to detect early cochlear insults 44,45. Although such instrumentation is commercially available, it is not universally used. Consequently, high-frequency testing is encouraged, but not required.

Ultimately, patients and clinical investigators must weigh clinical prospects for investigational agents against side effects potentially incurred by that agent—just as they routinely would (or should) with any medication. Fortunately, HL can be objectively measured and, if caught soon enough, may be minimized or even reversed by stopping the drug. Clinical experience to date has shown the utility of monitoring for DFMO12,19,20,22 and other agents.46,48,49 Precisely because chemoprevention may be a long-term process, age-adjusted norms such as those presented here will assist investigators in determining whether a subject is at increased risk for HL and whether observed changes in hearing are drug related, or more likely caused by the normal aging process.


   ACKNOWLEDGMENTS
 
Supported by National Institute on Deafness and Other Communication Disorders intramural research project grant no. DC-00016.

We are indebted to clinical chemoprevention researchers who responded to our solicitation for critiques of early iterations of these recommendations. Drs Ernest T. Hawk and Julia Lawrence provided substantive contributions.


   NOTES
 
Portions of this work were presented at the Twelfth Annual Convention of the American Academy of Audiology, Chicago, IL, March 16-19, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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15. Salzer SJ, Mattox DE, Brownell WE: Cochlear damage and increased threshold in alpha-difluoromethylornithine (DFMO) treated guinea pigs. Hear Res 46: 101-112, 1990[Medline]

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Submitted August 25, 2000; accepted November 20, 2000.




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