Browsing by Author "Vaughn, David J."
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Item A Phase II Study Assessing the Safety and Efficacy of ASP1650 in Male Patients with Relapsed Refractory Germ Cell Tumors(Springer, 2022) Adra, Nabil; Vaughn, David J.; Einhorn, Lawrence H.; Hanna, Nasser H.; Funt, Samuel A.; Rosales, Matt; Arozullah, Ahsan; Feldman, Darren R.; Medicine, School of MedicineClaudin6(CLDN6) is a tight junction protein of claudin-tetraspanin family and is of the earliest molecules expressed in embryonic epithelium. CLDN6 is frequently aberrantly expressed in testicular germ-cell tumors(GCT). ASP1650 is a chimeric-mouse/human-IgG1 antibody directed against CLDN6. Two-part, open-label, phase-II trial investigating ASP1650 in patients with relapsed/refractory GCT and no curable options. Part1 was a safety lead-in to establish the recommended-phase-II-dose(RP2D). Part2 was a phase-II study designed to evaluate the antitumor effects of ASP1650. CLDN6 expression was centrally assessed on archival tumor tissue using immunohistochemistry. The primary objectives were to establish the RP2D(safety lead-in) and the antitumor activity(phase-II) of ASP1650. Nineteen male patients were enrolled: 6 patients in 1000 mg/m2 safety lead-in group, and 13 in 1500 mg/m2 group. Median age 37.2 years(range,20-58). Histology was non-seminoma in 17/19 patients. Median number of previous chemotherapy regimens was 3. Thirteen patients had prior high-dose chemotherapy. No dose-limiting toxicity events were reported at any study drug dose. A RP2D of 1500 mg/m2 every 2 weeks was established. No partial or complete responses were observed. The study was stopped at the end of Simon Stage-I due to lack of efficacy. 15/16 subjects with available tissue had CLDN6 positive staining. The mean percent membrane staining was 71.6% and the mean membrane H score was 152.6(SD 76). ASP1650 did not appear to have clinically meaningful single-agent activity in relapsed/refractory GCT. CLDN6 expression seems ubiquitous in all elements of GCT and is worthy of investigation as a diagnostic biomarker and therapeutic target.Item Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors(National Comprehensive Cancer Network, 2019-05-01) Abu Zaid, Mohammad; Dinh, Paul C., Jr.; Monahan, Patrick O.; Fung, Chunkit; El-Charif, Omar; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Sesso, Howard D.; Huddart, Robert; Mushiroda, Taisei; Kubo, Michiaki; Dolan, M. Eileen; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Platinum Study Group; Medicine, School of MedicineBackground: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P=.006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P=.011) or ≥30 kg/m2 (OR, 2.36; P=.005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P=.09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P=.07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P=.003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P=.013), and to report erectile dysfunction (19.6% vs 11.9%; P=.018) or peripheral neuropathy (30.7% vs 22.5%; P=.041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P=.07) or anxiety/depression (14.8% vs 9.3%; P=.06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.Item Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors(National Comprehensive Cancer Network, 2018-03) Abu Zaid, Mohammad; Gathirua-Mwangi, Wambui G.; Fung, Chunkit; Monahan, Patrick O.; El-Charif, Omar; Williams, Annalynn M.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Dinh, Paul C., Jr.; Sesso, Howard D.; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Medicine, School of MedicineBackground: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization.Item Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms(American Association for Cancer Research, 2019-07-01) Charif, Omar El; Mapes, Brandon; Trendowski, Matthew R.; Wheeler, Heather E.; Wing, Claudia; Dinh, Paul C.; Frisina, Robert D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Gamazon, Eric R.; Cox, Nancy J.; Huddart, Robert; Ardeshir-Rouhani-Fard, Shirin; Monahan, Patrick; Fossa, Sophie D.; Einhorn, Lawrence H.; Travis, Lois B.; Dolan, M. Eileen; Medicine, School of MedicineCisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n= 762) were dichotomized to cases (moderate/severe tinnitus; n=154) and controls (none; n=608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in GWAS following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P=0.007) and cumulative cisplatin dose (P=0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared to 300 (P=0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P<0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P<0.0001), and reported more vertigo (OR=6.47; P<0.0001) and problems hearing in a crowd (OR=8.22; P<0.0001) than controls. Cases reported poorer health (P=0.0005) and greater psychotropic medication use (OR=2.4; P=0.003). GWAS suggested a variant near OTOS (rs7606353, P=2×10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P=0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q=0.007). Conclusions: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.Item Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy(American Association for Cancer Research, 2019-10-01) Trendowski, Matthew R.; El Charif, Omar; Ratain, Mark J.; Monahan, Patrick; Mu, Zepeng; Wheeler, Heather E.; Dinh, Paul C., Jr.; Feldman, Darren R.; Ardeshir-Rouhani-Fard, Shirin; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Hannigan, Robyn; Strathmann, Frederick; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Dolan, M. Eileen; Medicine, School of MedicinePurpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a bi-exponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13×10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58×10−3). Patients with high residual platinum levels experienced greater Raynaud’s phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6×10−8, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.Item Cognitive function in long-term testicular cancer survivors: impact of modifiable factors(Oxford University Press, 2024) Dinh, Paul C., Jr.; Monahan, Patrick O.; Fung, Chunkit; Sesso, Howard D.; Feldman, Darren R.; Vaughn, David J.; Hamilton, Robert J.; Huddart, Robert; Martin, Neil E.; Kollmannsberger, Christian; Althouse, Sandra; Einhorn, Lawrence H.; Frisin, Robert; Root, James C.; Ahles, Tim A.; Travis, Lois B.; Medicine, School of MedicineNo study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) affecting cognitive function in long-term testicular cancer survivors (TC survivors). TC survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those that assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC survivors (median age = 46; interquartile range [IQR] = 38-54); median time since chemotherapy = 10.9 years, IQR = 7.9-15.9), 13.7% reported cognitive dysfunction. Hearing loss (odds ratio [OR] = 2.02; P = .040), neuropathic pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P < .001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive decline. Factors associated with impaired cognition identify TC survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC survivors.Item Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer(ASCO Journals, 2016-08-10) Frisina, Robert D.; Wheeler, Heather E.; Fossa, Sophie D.; Kerns, Sarah L.; Fung, Chunkit; Sesso, Howard D.; Monahan, Patrick O.; Feldman, Darren R.; Hamilton, Robert; Vaughn, David J.; Beard, Clair J.; Budnick, Amy; Johnson, Eileen M.; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence H.; Lipshultz, Steven E.; Dolan, M. Eileen; Travis, Lois B.; Medicine, School of MedicinePurpose Cisplatin is widely used but highly ototoxic. Effects of cumulative cisplatin dose on hearing loss have not been comprehensively evaluated in survivors of adult-onset cancer. Patients and Methods Comprehensive audiological measures were conducted on 488 North American male germ cell tumor (GCT) survivors in relation to cumulative cisplatin dose, including audiograms (0.25 to 12 kHz), tests of middle ear function, and tinnitus. American Speech-Language-Hearing Association criteria defined hearing loss severity. The geometric mean of hearing thresholds (0.25 to 12 kHz) summarized overall hearing status consistent with audiometric guidelines. Patients were sorted into quartiles of hearing thresholds of age- and sex-matched controls. Results Increasing cumulative cisplatin dose (median, 400 mg/m2; range, 200 to 800 mg/m2) was significantly related to hearing loss at 4, 6, 8, 10, and 12 kHz (P trends, .021 to < .001): every 100 mg/m2 increase resulted in a 3.2-dB impairment in age-adjusted overall hearing threshold (4 to 12 kHz; P < .001). Cumulative cisplatin doses > 300 mg/m2 were associated with greater American Speech-Language-Hearing Association–defined hearing loss severity (odds ratio, 1.59; P = .0066) and worse normative-matched quartiles (odds ratio, 1.33; P = .093) compared with smaller doses. Almost one in five (18%) patients had severe to profound hearing loss. Tinnitus (40% patients) was significantly correlated with reduced hearing at each frequency (P < .001). Noise-induced damage (10% patients) was unaffected by cisplatin dose (P = .59). Hypertension was significantly related (P = .0066) to overall hearing threshold (4 to 12 kHz) in age- and cisplatin dose–adjusted analyses. Middle ear deficits occurred in 22.3% of patients but, as expected, were not related to cytotoxic drug dosage. Conclusion Follow-up of adult-onset cancer survivors given cisplatin should include routine inquiry for hearing status and tinnitus, referral to audiologists as clinically indicated, and hypertension control. Patients should be urged to avoid noise exposure, ototoxic drugs, and other factors that further damage hearing.Item Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study(American Society of Clinical Oncology, 2018-05-20) Kerns, Sarah L.; Fung, Chunkit; Monahan, Patrick O.; Ardeshir-Rouhani-Fard, Shirin; Abu Zaid, Mohammad I.; Williams, AnnaLynn M.; Stump, Timothy E.; Sesso, Howard D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair; Huddart, Robert A.; Kim, Jeri; Kollmannsberger, Christian; Sahasrabudhe, Deepak M.; Cook, Ryan; Fossa, Sophie D.; Einhorn, Lawrence H.; Travis, Lois B.; Biostatistics, School of Public HealthPurpose In this multicenter study, we evaluated the cumulative burden of morbidity (CBM) among > 1,200 testicular cancer survivors and applied factor analysis to determine the co-occurrence of adverse health outcomes (AHOs). Patients and Methods Participants were ≤ 55 years of age at diagnosis, finished first-line chemotherapy ≥ 1 year previously, completed a comprehensive questionnaire, and underwent physical examination. Treatment data were abstracted from medical records. A CBM score encompassed the number and severity of AHOs, with ordinal logistic regression used to assess associations with exposures. Nonlinear factor analysis and the nonparametric dimensionality evaluation to enumerate contributing traits procedure determined which AHOs co-occurred. Results Among 1,214 participants, approximately 20% had a high (15%) or very high/severe (4.1%) CBM score, whereas approximately 80% scored medium (30%) or low/very low (47%). Increased risks of higher scores were associated with four cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR], 1.96; 95% CI, 1.04 to 3.71) or bleomycin, etoposide, and cisplatin (OR, 1.44; 95% CI, 1.04 to 1.98), older attained age (OR, 1.18; 95% CI, 1.10 to 1.26), current disability leave (OR, 3.53; 95% CI, 1.57 to 7.95), less than a college education (OR, 1.44; 95% CI, 1.11 to 1.87), and current or former smoking (OR, 1.28; 95% CI, 1.02 to 1.63). CBM score did not differ after either chemotherapy regimen ( P = .36). Asian race (OR, 0.41; 95% CI, 0.23 to 0.72) and vigorous exercise (OR, 0.68; 95% CI, 0.52 to 0.89) were protective. Variable clustering analyses identified six significant AHO clusters (χ2 P < .001): hearing loss/damage, tinnitus (OR, 16.3); hyperlipidemia, hypertension, diabetes (OR, 9.8); neuropathy, pain, Raynaud phenomenon (OR, 5.5); cardiovascular and related conditions (OR, 5.0); thyroid disease, erectile dysfunction (OR, 4.2); and depression/anxiety, hypogonadism (OR, 2.8). Conclusion Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified AHO clusters could guide the development of survivorship care strategies.Item Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy(American Society of Clinical Oncology, 2017-04) Fung, Chunkit; Sesso, Howard D.; Williams, Annalynn M.; Kerns, Sarah L.; Monahan, Patrick; Abu Zaid, Mohammad; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Kollmannsberger, Christian K.; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Lipshultz, Steve E.; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Department of Medicine, IU School of MedicinePurpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking (P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased (P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.Item Patient-Reported Functional Impairment Due to Hearing Loss and Tinnitus After Cisplatin-Based Chemotherapy(American Society of Clinical Oncology, 2023) Sanchez, Victoria A.; Shuey, Megan M.; Dinh, Paul C., Jr.; Monahan, Patrick O.; Fosså, Sophie D.; Sesso, Howard D.; Dolan, M. Eileen; Einhorn, Lawrence H.; Vaughn, David J.; Martin, Neil E.; Feldman, Darren R.; Kroenke, Kurt; Fung, Chunkit; Frisina, Robert D.; Travis, Lois B.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthPurpose: Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. Patients and methods: Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. Results: HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score (P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). Conclusion: One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.