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

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)

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)

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

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

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

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

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

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

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 +/- 0.87 msec from baseline

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

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 5.3-7.3 and 9.4-12.0 Decrease T1 to T3 12.0-14.7 Group Data 66% showed significant changes Direction of change 62% showed decreases only 37% showed increases only

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 10.6-11.9 Decrease T1 to T3 14.1-14.7 and 15.8-16.0 Group Data 75% of participants showed significant changes Direction of change 22% showed decreases only 33% showed increases only 44% showed increases and decreases

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 10.7-10.3, 12.6-13.1, 14.1-14.3, 14.8-15.0, and 14.6-16.0 Decrease S1 to S3 11.5-15.8 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

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)

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)

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 1.107-1.151, 1.157-1.159, 1.162-1.177, 1.190-1.192, and 1.195-1.197 Decrease 1.2011-1.213 and 1.241-1.243 Increase and decrease S1 to S3 1.102-1.104 1.107-172, 1.175-1.188, 1.192-1.197, 1.201-1.205, and 1.228-1.238 Group Data 77% of participants showed significant changes Direction of change 71% showed decreases only 29% showed increases and decreases

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

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

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

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

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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!

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