1. Sensitivity of Different Otoacoustic Emission Paradigms for Monitoring Ototoxicity in Patients Receiving Platinum Agents as Treatment
Brittany Vlosich
San Diego State University and University of California, San Diego

2. Ototoxicity of Platinum Derivatives
Platinum derivatives are chemotherapeutic agents
Cisplatin
Carboplatin
Oxaliplatin
Primarily target basal outer hair cells (OHCs)
(Dammeyer et al. 2014; Ding et al., 2012; Ding et al., 1999; Ress et al. 1999; Hofstetter et al., 1997; Saito et al., 1989; Komune et al., 1981)

3. Ototoxic Monitoring
Traditionally monitored with: (Durrant et al., 2009)
Pure-tone audiometry
Conventional and extended-high frequencies
Distortion product otoacoustic emissions (DPOAEs)
Conventional frequencies (≤8 kHz)(Durrant et al., 2009)
DPOAE extended high frequencies (≤16 kHz)
(Dreisbach et al., 2018, 2006; Poling et al., 2014; Yu et al., 2014; Dreisbach & Siegel, 2005)

4. Purpose
Determine sensitivity of different DPOAE paradigms for monitoring ototoxicity in patients receiving platinum chemotherapy

5. Methods: Participants
23 enrolled participants
Ages: 22-79
Receiving: Carboplatin, Oxaliplatin, or Cisplatin
Exclusion criteria
positive history of:
Radiation to head
Abnormal middle ear measures
No response for pure-tone thresholds (1-8 kHz)
Absence of DPOAEs between 2-16 kHz
Retrocochlear pathology
Less than 2 testing sessions for at least 2 paradigms
12 participants analyzed

6. Methods: Procedures
Retrospective Study - data collected at UCSD Moores Cancer Center
Tested in hospital bed in private room in infusion center (reduced noise):
Before treatment (baseline)
During treatment
Following treatment (when possible)
Nine DPOAE paradigms tested
Not all paradigms could be completed in every testing session

7. Methods: Three DPOAE Paradigms
Frequency Sweep
Level Sweep
Ratio Sweep
Both frequencies swept together
Stimulus levels fixed
Stimulus ratio fixed
Level of one or both stimuli varied
Stimulus frequency fixed
Stimulus ratios fixed
Stimulus ratio varied
Frequency fixed (f2)
Stimulus levels fixed
Use phase info to calculate group delay 1 2
Level 1 2
Frequency 1 2
Ratio

8. Paradigms: Frequency Sweeps (n=3)
Gross Frequency Sweep
f2=2-16 kHz
L1/L2=62/52 dB FPL
Concentrated High-Level Sweep
Highest frequency
L1/L2=72/72 dB FPL
Concentrated Mid-Level Sweep 1 2
Frequency
Present DPOAE: SNR ≥6 dB and overall emission > -20 dB SPL
Significant change: +/- 6 dB or more from baseline at a minimum of 2 consecutive frequencies

9. Paradigms: Level Sweeps (Detection Thresholds; n=4)
L1 Held Constant, L2 Level Sweep
2 highest frequencies
L2 Held Constant, L1 Level Sweep 1 2
Level
Present DPOAE detection threshold: SNR ≥6 dB and overall emission > -20 dB SPL
Significant change: +/- > 6 dB from baseline

10. Paradigms: Ratio Sweeps (n=2)
2 highest frequencies
Examine level and phase (group delay) information 1 2
Ratio
Present DPOAE: SNR ≥6 dB and overall emission > -20 dB SPL
Significant change: for levels +/- > 6 dB at a minimum of 2 consecutive frequencies or for group delay +/ msec from baseline

11. Participant Demographics
Subject
Sex
Platinum Agent
Cumulative Dose (mg)
Highest Frequency DPOAE (kHz) 1
Male
Oxaliplatin
519
12.0 2
3669
5.3 3
Female
Carboplatin
Unknown
3.0 4
873
16.0 6
2412
8.0 7
1079
7.3 8
3779
10.6 9
1455 10
1202
9.0 12
Cisplatin
163
6.0 16
1057
13.3 18
3907
13.0

12. Gross Frequency Sweep Changes in DPOAE Level
Results: Gross Frequency Sweep
Patient 9 - Carboplatin
Gross Frequency Sweep Changes in DPOAE Level
Sessions
Frequencies Significantly Changed (kHz)
Direction of Change from Baseline
T1 to T2
and
Decrease
T1 to T3
Group Data
66% showed significant changes
Direction of change
62% showed decreases only
37% showed increases only

13. Results: Concentrated High-Level Frequency Sweep
Patient 9 - Carboplatin
High-Level Frequency Sweep Changes in DPOAE Level
Sessions
Frequencies Significantly Changed (kHz)
Direction of Change from Baseline
T1 to T2
Decrease
T1 to T3
and
Group Data
75% of participants showed significant changes
Direction of change
22% showed decreases only
33% showed increases only
44% showed increases and decreases

14. Results: Concentrated Mid-Level Frequency Sweep
Patient 9 - Carboplatin
Mid-Level Frequency Sweep Changes in DPOAE Level
Sessions
Frequencies Significantly Changed (kHz)
Direction of Change from Baseline
S1 to S2
, , , , and
Decrease
S1 to S3
Group Data
80% of participants showed significant changes
Direction of change
25% showed decreases only
12.5% showed increases only
62.5% showed increases and decreases

15. Results: L1 Held Constant, L2 Swept
Participant 7 - Oxaliplatin
Changes in Detection Threshold (L2 Varied) at 6.6 kHz
Session
Threshold Level
Direction of Change from Baseline 1
44 dB SPL
--- 2
Absent
Increase (worsening) 3
53 dB SPL 4
56 dB SPL
Group Data
90% of participants showed significant changes
Direction of change
78% showed increases (worsening)
22% showed decreases (improvement)

16. Results: L2 Held Constant, L1 Swept
Participant 7 - Oxaliplatin
Changes in Detection Threshold (L1 Varied) at 6.6 kHz
Session
Threshold Level
Direction of Change from Baseline 1
62 dB SPL
--- 2
71 dB SPL
Increase (worsening) 3 4
68 dB SPL
Group Data
66% of participants showed significant changes
Direction of change
50% showed increases (worsening)
50% showed increases (improvement)

17. Results: Ratio Sweep – Level Data
Patient 9 - Carboplatin
Ratio Sweep Changes in DPOAE Level at 16 kHz
Sessions
Frequencies Significantly Changed (kHz)
Direction of Change from Baseline
S1 to S2
, , , , and
Decrease
and
Increase and decrease
S1 to S3
, , , , and
Group Data
77% of participants showed significant changes
Direction of change
71% showed decreases only
29% showed increases and decreases

18. Results: Ratio Sweep - Weighted Group Delay
Participant 7 - Oxaliplatin
Weighted Group Delay at 6.6 and 7 kHz
Trial
GD 6.6 kHz
Direction of Significant Change from Baseline
GD 7 kHz 1
2.86
---
1.80 2
2.09
0.50
Decrease 3
2.89
0.79 4
1.89
Group Data
Highest
33% showed significant changes
All decreases
2nd Highest
37.5% showed significant changes
66% decreases

19. Summary Frequency Sweeps Level Sweeps Ratio Sweeps/Group Delay
More changes with concentrated frequency sweeps
Level Sweeps
More changes with L2 varied
Ratio Sweeps/Group Delay
More changes with levels than group delay
Less changes than frequency or level sweeps
Time intensive

20. Conclusions Any change, positive or negative, is important
Frequencies higher than conventionally tested are important
Ototoxic paradigms
High or mid-level concentrated frequency sweeps
Detection thresholds with L2 varied

21. Limitations Small sample size Incomplete data sets
Non-acoustically treated testing rooms

22. References
Dammeyer, P., Hellberg, V., Wallin, I., Laurell, G., Shoshan, M., Ehrsson, H., Kirkegaard, M. (2014). Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures. Acta Otolaryngol, 134(5), doi: /
Ding, D., Allman, B. L., & Salvi, R. (2012). Review: ototoxic characteristics of platinum antitumor drugs. Anat Rec (Hoboken), 295(11), doi: /ar.22577
Ding, D. L., Wang, J., Salvi, R., Henderson, D., Hu, B. H., McFadden, S. L., & Mueller, M. (1999). Selective loss of inner hair cells and type-I ganglion neurons in carboplatin-treated chinchillas. Mechanisms of damage and protection. Ann N Y Acad Sci, 884,
Dreisbach, L. E., Long, K. M., & Lees, S. E. (2006). Repeatability of high-frequency distortionproduct otoacoustic emissions in normal-hearing adults. Ear Hear, 27(5), doi: /01.aud a
Dreisbach, L. E., & Siegel, J. H. (2005). Level dependence of distortion-product otoacoustic emissions measured at high frequencies in humans. J Acoust Soc Am, 117(5),
Dreisbach, L., Zettner, E., Chang Liu, M., Meuel Fernhoff, C., MacPhee, I., & Boothroyd, A. (2018). High-Frequency Distortion-Product Otoacoustic Emission Repeatability in a Patient Population. Ear Hear, 39(1), doi: /AUD
Hofstetter, P., Ding, D., Powers, N., & Salvi, R. J. (1997). Quantitative relationship of carboplatin dose to magnitude of inner and outer hair cell loss and the reduction in distortion product otoacoustic emission amplitude in chinchillas. Hear Res, 112(1-2),
Komune, S., Asakuma, S., & Snow, J. B. (1981). Pathophysiology of the ototoxicity of cisdiamminedichloroplatinum. Otolaryngol Head Neck Surg, 89(2),
Poling, G. L., Siegel, J. H., Lee, J., & Dhar, S. (2014). Characteristics of the 2f(1)-f(2) distortion product otoacoustic emission in a normal hearing population. J Acoust Soc Am, 135(1), doi: /
Ress, B. D., Sridhar, K. S., Balkany, T. J., Waxman, G. M., Stagner, B. B., & Lonsbury-Martin, B. L. (1999). Effects of cis-platinum chemotherapy on otoacoustic emissions: the development of an objective screening protocol. Third place--Resident Clinical Science Award Otolaryngol Head Neck Surg, 121(6),
Saito, T., Saito, H., Saito, K., Wakui, S., Manabe, Y., & Tsuda, G. (1989). Ototoxicity of carboplatin in guinea pigs. Auris Nasus Larynx, 16(1),
Yu, K. K., Choi, C. H., An, Y.-H., Kwak, M. Y., Gong, S. J., Yoon, S. W., & Shim, H. J. (2014). Comparison of the Effectiveness of Monitoring Cisplatin-Induced Ototoxicity with Extended High-Frequency Pure-Tone Audiometry or Distortion-Product Otoacoustic Emission. In (Vol. 2, pp ). Korea: Korean J Audiol.

23. Acknowledgments
Past and present members of the Auditory Physiology and Psychoacoustic Laboratory
Faculty at San Diego State University and the University of California, San Diego for their support and guidance, especially Dr. Laura Dreisbach Hawe
Thank you for listening!

24. Questions?