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The Five W’s of Ototoxicity Monitoring: Who, What, Where, When, & Why

Gayla L. Poling, Ph.D.

26th Mayo Clinic Audiology Conference

February 6, 2016

“The best interest of the patient is the only interest to be considered.”

-William J. Mayo, M.D.

Ototoxicity

• Certain exposures to medications/chemicals can damage the ear, resulting in hearing loss, ringing in the ear, or balance disorders1

• May progress unnoticed by the patient until a communication problem becomes apparent

• Early intervention becomes critical for the maintenance of quality of life

• Address communication needs while reducing the long-term impacts of hearing loss

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Ototoxicity

• A large number of therapeutic substances and industrial chemicals can cause ototoxicity

• Over 200 medications are reported to be potentially ototoxic2

• Nine million Americans are exposed to ototoxic chemicals3

Ototoxicity Monitoring

• WHO?

• WHAT?

• WHERE?

• WHEN?

• WHY?

WHO? Ototoxicity Monitoring

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Physician

Dose Reductions or Omissions

Change Medication

No Change

Audiologist

Early Intervention

Communication Strategies

Counseling/ Education

Health Care Team

Adapted from http://education.healthcaresource.com/

Role of Audiology4-5

1994

2009

http://www.asha.org/policy/GL1994-00003/

http://www.audiology.org/publications-resources/document-library/ototoxicity-monitoring

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Pediatric Concerns4-8

Delayed Identification

Speech and Language Development

Reasoning Skills

Educational Achievement

Social-Emotional Development

Lifetime of Medical Expenses

Pediatric Considerations9

Increased risk with cisplatin dose

Youngest

Oldest

n=73

Ages: 0 to 20 years

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Veterans10-11

• Treatment with cisplatin can result in permanent cochlear damage in up to 50% of patients

• New tinnitus onset in ~ 40% of patients

Impacts4-8

Speech Communication

Coping Skills Stress

Emotional Well-Being

Quality of Life Delayed

Identification

Speech and Language

Development

Reasoning Skills

Educational Achievement

Social-Emotional

Development

Lifetime of Medical

Expenses

Acro

ss t

he L

ifesp

an

WHAT? Ototoxicity Monitoring

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Ototoxic Agents2,4

• Amikacin

• Gentamicin*

• Neomycin*

• Kanamycin

• Netilmicin

• Streptomycin*

• Tobramycin*

Aminoglycoside Antibiotics

• Erythromycin*

• Vancomycin

• Chloramphenicol

• Furazolidone*

• Polymyxin B and E

• Trimethoprim-sulfamethoxazole

Other Antibiotics

• Ethacrynic acid*

• Furosemide*

• Bumetanide*

Loop Diuretics

• Quinine*

• Chloroquine

• Hydroxychloroquine*

• Primaquine*

• Quinidine*

• Pyrimethamine

Antimalarial Drugs

• Aspirin

• Nonsteroidal anti-inflammatory agents

Salicylates

• Cisplatin

• Carboplatin

• Oxaliplatin

• Nitrogen mustard

• Methotrexate*

• Vincristine

• Dactinomycin

Antineoplastic Drugs

*Also possibly vestibulotoxic

Aminoglycoside Antibiotics

• Common populations:

• Neonatal sepsis

• Gram-negative bacterial infections

• Cystic Fibrosis

• Hearing loss estimated in 2-20%4,12-13

• Cochlear and vestibular hair cells and neurons most vulnerable4

Platinum-based Chemotherapy

• Carboplatin

• Treatment for lung, head and neck, and ovarian cancers

• Risk in combination with cisplatin or at high dose levels4

• Cisplatin

• Treatment for testicular, ovarian, head and neck, cervical, bladder, brain, and lung cancers

• Hearing loss occurs in 40-60%4,10,14

• Ototoxicity is recognized as a severe,

dose-limiting side effect14

• Impacts outer hair cells first4,14

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Cranial Radiation Therapy15-17

• Can be in combination with surgery or chemotherapy

• Increased risk of hearing loss from radiation to head and neck16

• Radiation to the posterior fossa

• Radiation-induced hearing loss

• 40% acute middle ear complications17

• Progressive hearing loss up to 10 years post16

• Late onset hearing loss

WHERE? Ototoxicity Monitoring

Impacts on the Auditory System

• Impacts the structure and function of:

• vestibular & cochlear hair cells and their supporting structures

• the vestibulocochlear (VIIIth) nerve

Adapted from MC4324rev1115 and Dallos & Fakler, 2002

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• Hearing Loss

• Permanent or temporary

• Varying degree and configuration

• Progressing from high to low frequencies

• Tinnitus (“ringing in the ears”)

• Aural fullness/pressure

• Imbalance/dizziness

Symptoms4

• Difficult to predict; poorly correlated with:

• Dosage

• Peak serum levels

• Development of other toxicities (renal toxicity)

• Depends on dosage, age, genetics, and concurrent exposure to noise or other chemicals/drugs

• Effects of multiple ototoxic agents may be synergistic, antagonistic, and nonlinear

Ototoxicity4

Platinum Ototoxicity

• With larger doses4,14: • inner hair cells • supporting cells • stria vascularis • auditory nerve

Adapted from MC4324rev1115 and Dallos & Fakler, 2002

• Outer hair cells

• Several possible methods of entry into the hair cells18

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Symptoms of Platinum Ototoxicity4

• Hearing Loss

• Bilateral, irreversible, progressing from higher (> 8 kHz) to lower frequencies

• Related to cumulative dose, though a single dose may cause hearing loss

• May have a delayed onset

• Tinnitus • Transient or permanent

(with or without hearing loss)

Audiological Evaluation4,5

• Case History

• Otoscopic Examination

• Tympanometry (Acoustic reflexes and decay)

• Behavioral Audiometry (conventional, CPA, VRA)

• Thresholds for pure tones (≤ 8 kHz)

• Extended high frequency (up to 20 kHz)

• Speech Audiometry

• Otoacoustic Emissions (OAEs)

• Byproduct of healthy outer hair cell function

• Auditory Brainstem Response (ABR) testing

Responsive

Full Assessment Subjective Measures Objective Measures

Behavioral Audiometry

Otoacoustic Emissions (OAEs)

Limited

Limited Time Subjective Measures Objective Measures

Limited Behavioral Audiometry

OAEs

Nonresponsive

Objective Measures Only

Auditory Brainstem Response (ABR)

testing

OAEs

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WHEN? Ototoxicity Monitoring

Ototoxicity Monitoring

• Baseline evaluation

• Monitoring evaluations

• Post-treatment evaluations

• Long-term follow-up evaluations

Baseline

M2

TREATMENT

M3 M4 M1

Post- Long-term

follow-up

CASE

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Guidance

1994

2009

Long-term follow-up guidelines. https://childrensoncologygroup.org

2006

ASHA (1994) Significant Change Criteria

• Change in hearing thresholds relative to baseline

• ≥ 20 dB decrease

One Frequency

• ≥ 10 dB decrease

Two Frequencies • No

response

Three Frequencies

• Change confirmed by retest within 24 hours

Scales/Criteria/Grading

• Detection of change for an individual

• No agreed upon grading scale4,6

• Used to rank degree of ototoxicity

• Report adverse events in clinical trials / hearing outcomes in groups

• Provide government agencies with data for drug safety

• Difficult to compare patients, disease groups, assess effectiveness of otoprotective drugs, etc.

ASHA (1994)

NCI-CTCAE v4.03 (2010)

Children’s Cancer Group (1996)

SIOP Boston Scale (2012)

AAA (2009)

Brock Scale (1991)

Chang Scale

(2010)

CHB

(2009)

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ADULT GRADING National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Grade Definition

0

Baseline

1 Threshold shift of 15-25 dB averaged at 2 contiguous test frequencies^ in at

least one ear

2 Threshold shift > 25 dB averaged at 2 contiguous test frequencies^ in at least

one ear

3 Threshold shift > 25 dB averaged at 3 contiguous test frequencies^

in at least one ear OR therapeutic intervention indicated

4 Decrease in hearing to profound bilateral loss (absolute threshold > 80 dB HL at

2 kHz or above^) OR non-serviceable hearing

^ On a 1, 2, 3, 4, 6, and 8 kHz audiogram

(June 14, 2010) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

PEDIATRIC GRADING National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Grade Definition

0

Baseline

1 Threshold shift > 20 dB at 8 kHz in at least one ear

2 Threshold shift > 20 dB at 4 kHz or above in at least one ear

3 Threshold shift > 20 dB at 3 kHz or above in at least one ear, or hearing loss

requiring intervention including hearing aids and/or speech-language services

4 Hearing loss indication for a cochlear implant and/or additional speech-

language services

(June 14, 2010) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

^ On a 1, 2, 3, 4, 6, and 8 kHz audiogram

PEDIATRIC GRADING SIOP Boston Ototoxicity Scale

Grade Parameters

0

≤ 20 dB HL at all frequencies

1 > 20 dB HL (i.e., 25 dB HL or greater) SNHL above 4 kHz (i.e., 6 or 8 kHz)

2 > 20 dB HL SNHL at 4 kHz and above

3 > 20 dB HL SNHL at 2 kHz or 3 kHz and above

4 > 40 dB HL (i.e., 45 dB HL or more) SNHL at 2 kHz and above

Brock PR, Knight KR, Freyer DR, et al. (2012) Platinum-Induced Ototoxicity in Children: A Consensus Review on

Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston

Ototoxicity Scale. J Clin Oncol. 30: 1-11.

^ Based on sensorineural hearing loss (SNHL) in dB HL; bone

conduction or air conduction with normal tympanogram

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Limited/Minimal Evaluations

• Influence of patient cooperation

• Maximizing essential auditory information

• Objective measures of hearing

• Shortened procedures4-6,15,20

• Emphasis on highest frequencies

• Minimal test battery

• Sensitive range for ototoxicity (SRO)

• Highest frequency (≤100 dB SPL)

• Next 6 lower adjacent frequencies in1/6-octave increments (1 octave)

Factors/considerations

• Scheduling/coordination logistics

• Standard monitoring protocol

• Missing critical information

• Conductive component

• Test sequence/prioritization/methodology

• Influence of patient cooperation

• Access to clinical equipment/portability

• Determining a significant change/grading

WHY? Ototoxicity Monitoring

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CASE

Oncology Counseling

• Side effects of chemotherapy;

including but not limited to: • Myelosuppression • Need for transfusion • Risk for transfusion • Nausea • Vomiting • Hair loss • Cardiac toxicity • Low risk of fertility issues • Renal failure • Seizures • Ototoxicity • And many more…

Children’s Oncology Group

Family Handbook

https://childrensoncologygrou

p.org/index.php/cog-family-

handbook

Counseling

• Potential impacts on the auditory system

• Hearing loss

• Realistic expectations

• Other symptoms (tinnitus, fullness, dizziness)

• Signs and symptoms of cochlear damage and potential effects on communication ability

• Potentiating effects such as noise exposure during or following treatment

• Hearing protection

• Informing caregivers (communication strategies)

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Outcomes

• Type of testing (purpose)

• Behavioral and/or objective hearing change noted

(confirmed by re-test)

• ASHA significant criteria

• Frequencies demonstrating ototoxic change

• Grading/Scaling

• Other symptoms (tinnitus, dizziness, etc.)

• Communicating to Health Care Team

• Physician

• Tumor Boards

• Grand Rounds

Future?

Ototoxicity Monitoring

• WHO?

• WHAT?

• WHERE?

• WHEN?

• WHY?

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• There are several medications and chemicals known to be ototoxic

• Hearing loss is known to adversely impact quality of life, psychosocial functioning, and emotional well-being

Summary

• Individual and societal costs of hearing loss are particularly grave in the case of children

• Delayed speech, language, and educational development, need for special educational programs, continued medical care, etc.

• Profound impact on the individual, his/her family, and society at large

Summary

• Ototoxicity monitoring permits:

• Early identification of hearing loss

• Classification of ototoxicity that can guide treatment decisions

• Early intervention for hearing loss

• Prevention of hearing loss

• Critical for the maintenance of quality of life and continued development

• Leading to a reduction in the long-term impact of hearing loss

Conclusions

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References

1. ASHA. Ototoxic Medications (Medication Effects). Obtained 2015 from: http://www.asha.org/public/hearing/Ototoxic-Medications/

2. Campbell KC. (2004) Audiologic Monitoring for Ototoxicity. In P Roland, J Rutka (Eds), Ototoxicity. New York: BC Decker (pp 153-60).

3. U.S. Department of Labor, Occupational Safety & Health Administration, Occupational Noise Exposure,

https://www.osha.gov/SLTC/noisehearingconservation/

4. American Academy of Audiology (AAA). (2009) American Academy of Audiology Position Statement and Clinical Practice Guidelines:

Ototoxicity Monitoring (pp 1–25). Reston, VA.

5. American Speech-Language-Hearing Association (ASHA). Guidelines for the audiologic management of individuals receiving

cochleotoxic drug therapy. ASHA. 1994;36:11-19.

6. Brock PR, Knight KR, et al. (2012) Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition,

and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol. 30: 1-11.

7. Gurney, JG, Tersak, JM, Ness, KK, Landier, W, Matthay, KK, Schmidt, ML. (2007). Hearing Loss, Quality of Life, and Academic

Problems in long-term Neuroblastoma Survivors: A report from the Children’s oncology group. Pediatrics, 120.

8. Dalton DS, et al. The impact of hearing loss on quality of life in older adults. Gerontol. 2003;43:661-668.

9. Li Y, Womer RB, Silber JH. (2004) Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J

Cancer 40(16):2445–2451.

10. Dille et al. (2015). A Store-and-Forward Tele-Audiology Solution to Promote Efficient Screenings for Ototoxicity during Cisplatin

Cancer Treatment. JAAA, 26:750-760.

11. Konrad-Martin et al. (2014) Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP-VA). JRRD,51:81-100.

12. Al-Malky et al., J Cystic Fibros 2015; 14(2):248-54.

13. Fjalstad et al. (2014). High-dose gentamicin in newborn infants: is it safe? Eur J Pediatr 173: 489–495.

14. Bielefeld EC, Henderson D. (2011) Mechanisms of Cisplatin Ototoxicity and Routes for Intervention. ASHA Perspect Hear & Hear Dis.

15: 3-14.

15. Bass & Bhagat (2014). Challenges in ototoxicity monitoring in the pediatric oncology population. JAAA, 25:760-774.

16. Kolinsky et al. (2010). Late onset hearing loss: A significant complication of cancer survivors treated with cisplatin containing

chemotherapy regimens. J Pediatr Hematol Oncol, 32(2):119-123.

17. Jereczek-Fossa BA, Zarowski A, Milani F, Orecchia R. (2003). Radiotherapy-induced ear toxicity. Cancer Treat Rev 29(5): 417–430

18. Brockenbroughet al., 2001

19. Children’s Oncology Group (2006). Long-term follow-up guidelines. https://childrensoncologygroup.org

20. Fausti et al. (1999)