Objectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL). DESIGN Randomized... Show moreObjectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL). DESIGN Randomized controlled trial. SETTING Tertiary cancer hospital. PATIENTS Adults to be treated with high-dose cisplatin (>= 75 mg/m(2)). INTERVENTION Selected by randomization, 0.1 M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated. Main Outcome Measure: Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a >= 10 dB threshold shift at pure-tone average 8-10-12.5 kHz (PTA(8-12.5)). Response to STS was defined as a threshold shift at PTA(8-12.5) in the STS-treated ear of >= 10 dB smaller than the untreated ear. Results: Twelve patients were treated. Average CIHL at PTA(8-12.5) was 12.7 dB in untreated ears and 8.8 dB SPL in STS-treated ears (p = 0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA(8-12.5) in STS-treated ears was 18.4 dB less compared to untreated ears (p = 0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients. Conclusion: Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale. Show less
Objective: To illustrate a case of sensorineural hearing loss (SNHL) after immunotherapy based on T cell receptor (TCR) gene therapy using modified T cells recognizing melanoma antigen recognized... Show moreObjective: To illustrate a case of sensorineural hearing loss (SNHL) after immunotherapy based on T cell receptor (TCR) gene therapy using modified T cells recognizing melanoma antigen recognized by T cells 1 for disseminated melanoma.Patient: We present a 59-year-old woman with profound subacute bilateral SNHL including unilateral deafness after immunotherapy based on TCR gene therapy using modified T cells recognizing melanoma antigen recognized by T cells 1 for disseminated melanoma. Ten days after treatment, the patient developed hearing loss of 57 dB hearing loss air conduction at pure-tone average 0.5-1-2-4 kHz in the right ear, and >100 dB hearing loss air conduction at pure-tone average 0.5-1-2-4 in the left ear. The right ear recovered partially, while the left ear remained deaf, despite oral prednisolone (1.0 mg/kg) and salvage treatment with three transtympanic injections of 0.5 ml dexamethasone (4.0 mg/ml).Conclusion: Based on our presented case and a vast amount of literature there is circumstantial evidence that TCR gene therapy for melanoma targets the perivascular macrophage-like melanocytes in the stria vascularis, resulting in SNHL. We suggest that SNHL after TCR gene therapy may be caused by a disruption of the blood-labyrinth-barrier and the endolymphatic potential and/or a sterile inflammation of the stria vascularis. In severe cases like our subject, we posit that endolymphatic hydrops or hair cell loss may cause irreversible and asymmetrical deafness. Steroid prophylaxis via transtympanic application is debatable. Show less
Rashid, M.S.; Dreschler, W.A.; Laat, J.A.P.M. de 2017
IMPORTANCE Patients with head and neck cancer may experience chemoradiotherapy-induced hearing loss, but the weighing of involved variables has been subjective. Identification of patient and... Show moreIMPORTANCE Patients with head and neck cancer may experience chemoradiotherapy-induced hearing loss, but the weighing of involved variables has been subjective. Identification of patient and treatment characteristics to predict the absolute posttreatment hearing level is important for effective counseling of patients undergoing chemoradiotherapy.OBJECTIVE To predict treatment-induced hearing loss among patients with head and neck cancer.DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was performed at The Netherlands Cancer Institute. One hundred and fifty-six patients with head and neck cancer treated with concomitant chemoradiotherapy as the primary treatment modality from January 1, 1997, through December 31, 2011, were enrolled. Follow-up was complete on March 1, 2012, and data were analyzed from April 1, 2011, through November 5, 2013.INTERVENTIONS High-dose intravenously administered cisplatin-based concomitant chemoradiotherapy. Cisplatin, 100mg/m(2), was administered in 3 courses on days 1, 22, and 43 during 7 weeks of radiotherapy (total radiation dose, 70 Gy in 35 fractions).MAIN OUTCOMES AND MEASURES Posttreatment bone conduction hearing threshold at pure-tone average frequencies of 1, 2, and 4 kHz, based on pure-tone audiometry after completion of treatment. Predictors included baseline hearing levels, radiation dose to the cochlea, and cisplatin dose. A multilevel mixed-effects linear regression model for predicting whether or not posttreatment hearing was at least 35 dB was established, and cross-validated sensitivity and specificity were obtained.RESULTS Of 156 patients who received high-dose concomitant chemoradiotherapy, 15 were missing the exact radiation dose to the cochlea and 41 had no data on posttreatment pure-tone audiometry. Nineteen patients had a hearing level of at least 35 dB for at least 1 ear before the treatment. The remaining 81 patients (162 ears) had a total cumulative cisplatin dose ranging from 315 to 600 (median, 546) mg. The radiation dose to the cochlea ranged from 1.1 to 70.9 (median, 13.6) Gy. Based on data from the 81 patients (162 ears), the area under the receiver operating characteristic curve was 0.68, with a sensitivity of 29% (95% CI, 13%-51%) and a specificity of 97%(95% CI, 88%-100%), resulting in a positive predictive value of 78%.CONCLUSIONS AND RELEVANCE Patient and treatment characteristics can be used to predict hearing level after concomitant chemoradiotherapy for head and neck cancer. This step may constitute the first in evidence-based individual counseling for treatment-induced hearing loss. Show less
Theunissen, E.A.R.; Bosma, S.C.J.; Zuur, C.L.; Spijker, R.; Baan, S. van der; Dreschler, W.A.; ... ; Rasch, C.R.N. 2015
BackgroundBoth radiotherapy (RT) and cisplatin-based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to... Show moreBackgroundBoth radiotherapy (RT) and cisplatin-based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to provide more insight into SNHL because of CRT compared to RT.MethodsComprehensive search of Medline and Embase with the terms radiotherapy combined with ototoxicity, head and neck squamous cell carcinoma, and synonyms.ResultsOf the 2507 studies found, 21 were included in this study. Pooled analysis could not be committed because of heterogeneity. Incidence rates of SNHL after RT and CRT varied considerably, with percentages ranging from 0% to 43% and 17% to 88%, respectively. Factors that influenced the risk of SNHL were radiation dose to the cochlea, follow-up time, age, baseline hearing level, and cisplatin dose.ConclusionThe wide range of SNHL incidence rates makes it impossible to draw any conclusions on the severity of RT- and CRT-induced ototoxicity. To allow for future comparison of study outcomes, development of uniform criteria is of utmost importance. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 281-292, 2015 Show less
Theunissen, E.A.R.; Zuur, C.L.; Bosma, S.C.J.; Lopez-Yurda, M.; Hauptmann, M.; Baan, S. van der; ... ; Balm, A.J.M. 2014
Objectives/HypothesisThe purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not.Study DesignLong-term (LT) follow-up... Show moreObjectives/HypothesisThe purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not.Study DesignLong-term (LT) follow-up study.MethodsBetween 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n=80) or intraarterial CCRT (n=78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging.ResultsLong-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045).ConclusionCCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment.Level of Evidence4. Laryngoscope, 124:2720-2725, 2014 Show less
Theunissen, E.A.R.; Dreschler, W.A.; Latenstein, M.N.; Rasch, C.R.N.; Baan, S. van der; Boer, J.P. de; ... ; Zuur, C.L. 2014
Objective: This study aimed to propose an ototoxicity grading system sensitive to the effect of ototoxicity on specific daily life situations like speech intelligibility and the perception of ultra... Show moreObjective: This study aimed to propose an ototoxicity grading system sensitive to the effect of ototoxicity on specific daily life situations like speech intelligibility and the perception of ultra-high sounds and to test its feasibility compared to current criteria.Methods: Pure tone averages (PTAs) for speech perception (1-2-4 kHz) and ultra-high frequencies (8-10-12.5 kHz) were incorporated. Threshold shift and hearing level posttreatment were taken into account. Criteria were tested on head and neck cancer patients treated with (chemo-)radiotherapy ([C]RT) and compared with the Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) and the American Speech-Language-Hearing Association criteria (ASHA).Results: Grades 1 and 2 were based on threshold shifts from baseline (in dB) and subjective complaints. Grades 3 and 4 were defined as treatment-induced hearing loss of 35 dB at PTA 1-2-4 kHz and >= 70 dB at PTA 1-2-4 kHz, respectively. In high-dose cisplatin CRT incidences by the new criteria, CTCAEv4 and ASHA were comparable (78%-88%). In RT and low-dose cisplatin CRT, incidences were 36% to 39% in the new criteria versus 22% to 53% in CTCAEv4 and ASHA.Conclusion: The new criteria show an increased sensitivity to ototoxicity compared to CTCAEv4 and ASHA and provide insight into the effect of hearing loss on certain daily life situations. The new grading system seems feasible for clinic and research purposes. Show less
Theunissen, E.A.R.; Zuur, C.L.; Yurda, M.L.; Baan, S. van der; Kornman, A.F.; Boer, J.P. de; ... ; Dreschler, W.A. 2014
Background: Radiation to the inner ear may lead to (irreversible) sensorineural hearing loss. The purpose of this study was to evaluate the long-term effect of radiotherapy on hearing in patients... Show moreBackground: Radiation to the inner ear may lead to (irreversible) sensorineural hearing loss. The purpose of this study was to evaluate the long-term effect of radiotherapy on hearing in patients treated with Intensity Modulated Radiation Therapy (IMRT), sparing the inner ear from high radiation dose as much as possible.Methods: Between 2003 and 2006, 101 patients with head and neck cancer were treated with IMRT. Audiometry was performed before, short-term, and long-term after treatment. Data were compared to normal hearing levels according to the International Organisation for Standardization (ISO). Statistical analysis was done using repeated measurements. None of the patients received chemotherapy.Results: In 36 patients an audiogram at long-term follow-up (median 7.6 years) was available. The mean dose to the cochlea was 17.8 Gy (1.0 66.6 Gy). A hearing deterioration of 1.8 dB at Pure Tone Average (PTA) 0.5 1 2 kHz (p = 0.11), 2.3 dB at PTA 1-2-4 kHz (p = 0.02), and 4.4 dB at PTA 8-10-12.5 kHz (p = 0.01) was found. According to the ISO, the expected age-related hearing loss was 2.7, 4.8, and 8.8 dB at PTA 0.5-1-2 kHz, 1-2-4 kHz, and 8-10-12.5 kHz, respectively.Conclusions: After IMRT with radiation dose constraint to the cochlea, potential long-term adverse effects of IMRT remained subclinical. The progressive hearing loss over time was mild and could be attributed to the natural effects of ageing. Therefore, we recommend that a dose constraint to the cochlea should be incorporated in the head and neck radiotherapy protocols. Show less
