Are There Cochlear Dead Regions Involved in Hearing Loss after Cisplatin Ototoxicity?

BACKGROUND: The most common complaint of patients affected by chemotherapy-induced hearing loss is difficulty understanding speech in noisy environments despite the use of hearing aids. Cochlear dead regions, those areas with damaged or absent inner hair cells and dendrites, may account for this type of hearing loss. However, it is unknown whether this condition is associated with cisplatin agents. OBJECTIVE: The aim of this study was to determine whether cisplatin is associated with hearing loss and cochlear dead regions. METHODS: This prospective cross-sectional study was conducted in patients participating in routine audiological monitoring during and after chemotherapy treatment. Adults undergoing audiological evaluation who had completed chemotherapy treatment were invited to participate. Patients were divided into 3 groups according to pure tone thresholds. Group 1 patients had thresholds over 70 dB (HL) at 2,000 Hz and higher frequencies. Group 2 patients had thresholds below 70 dB (HL) up to 2,000 Hz. Patients in the control group had normal thresholds at all frequencies. The threshold equalizing noise test (TEN[HL]) was used to identify cochlear dead regions by repeating thresholds in the presence of TEN noise played from a compact disc. The presence of cochlear dead regions was established when the masked threshold was 10 dB or greater above the TEN level and 10 dB or greater above the absolute threshold at any frequency. RESULTS: Twelve patients were included in study group 1, 10 patients in study group 2, and 7 patients in the control group. Cochlear dead regions were present in all patients with hearing loss and in none of the control group. For groups 1 and 2, mean differences between absolute and masked thresholds were 21 and 16 dB at 500 Hz; 22 and 15 dB at 1,000 Hz; 31 and 17 dB at 2,000 Hz; 32 and 20 dB at 3,000 Hz; and 31 and 21 dB at 4,000 Hz, respectively. Nevertheless, analysis of variance testing with Bonferroni analysis showed a difference between groups 1 and 2 only at 2,000, 3,000, and 4,000 Hz. CONCLUSION: We found unresponsive or dead cochlear regions in patients who had undergone cisplatin chemotherapy even among patients with mild to moderate hearing loss.

Audiological profile of patients treated for childhood cancer / Perfil audiológico de pacientes tratados de câncer na infância

Abstract Objective: To characterize the hearing loss after cancer treatment, according to the type of treatment, with identification of predictive factors. Methods: Two hundred patients who had cancer in childhood were prospectively evaluated. The mean age at diagnosis was 6 years, and at the audiometric assessment, 21 years. The treatment of the participants included chemotherapy without using platinum derivatives or head and neck radiotherapy in 51 patients; chemotherapy using cisplatin without radiotherapy in 64 patients; head and neck radiotherapy without cisplatin in 75 patients; and a combined treatment of head and neck radiotherapy and chemotherapy with cisplatin in ten patients. Patients underwent audiological assessment, including pure tone audiometry, speech audiometry, and immittancemetry. Results: The treatment involving chemotherapy with cisplatin caused 41.9% and 47.3% hearing loss in the right and left ear, respectively, with a 11.7-fold higher risk of hearing loss in the right ear and 17.6-fold higher in the left ear versus patients not treated with cisplatin (p < 0.001 and p < 0.001, respectively). Children whose cancer diagnosis occurred after the age of 6 have shown an increased risk of hearing loss vs. children whose diagnosis occurred under 6 years of age (p = 0.02). Conclusion: The auditory feature found after the cancer treatment was a symmetrical bilateral sensorineural hearing loss. Chemotherapy with cisplatin proved to be a risk factor, while head and neck radiotherapy was not critical for the occurrence of hearing loss.

Resumo Objetivo: Caracterizar as alterações auditivas após o tratamento do câncer, segundo o tipo de tratamento identificando os fatores preditivos. Método: Foram avaliados prospectivamente duzentos pacientes que tiveram cancer na infância. A idade média ao diagnóstico foi de 6 anos e à avaliação audiométrica de 21 anos de idade. O tratamento incluiu quimioterapia sem uso de derivados de platina ou radioterapia em cabeça e pescoço em 51 pacientes; quimioterapia com uso de cisplatina sem radioterapia em 64 pacientes; radioterapia em cabeça e pescoço sem cisplatina em 75 pacientes; e 10 pacientes receberam o tratamento combinado de radioterapia em cabeça e pescoço e quimioterapia com cisplatina. Os pacientes foram submetidos à avaliação audiológica incluindo audiometria tonal, audiometria vocal e imitanciometria. Resultados: O tratamento envolvendo quimioterapia com cisplatina levou a 41,9% e 47,3% de perda auditiva na orelha direita e esquerda, respectivamente, apresentando risco 11,7 vezes maior de desenvolver perda auditiva na orelha direita e 17,6 vezes na orelha esquerda do que aqueles que não receberam cisplatina (p < 0,001 e p < 0,001; respectivamente). Crianças cujo diagnóstico do câncer ocorreu após os 6 anos de idade mostraram maior risco de apresentar perda auditiva do que crianças menores do que 6 anos de idade (p = 0,02). Conclusão: A característica audiológica encontrada após tratamento oncológico foi perda auditiva sensorioneural bilateral simétrica. A quimioterapia com cisplatina mostrou ser fator de risco, enquanto a radioterapia em cabeça e pescoço não foi determinante para aquisição da perda auditiva.

Audiological profile of patients treated for childhood cancer.

OBJECTIVE: To characterize the hearing loss after cancer treatment, according to the type of treatment, with identification of predictive factors. METHODS: Two hundred patients who had cancer in childhood were prospectively evaluated. The mean age at diagnosis was 6 years, and at the audiometric assessment, 21 years. The treatment of the participants included chemotherapy without using platinum derivatives or head and neck radiotherapy in 51 patients; chemotherapy using cisplatin without radiotherapy in 64 patients; head and neck radiotherapy without cisplatin in 75 patients; and a combined treatment of head and neck radiotherapy and chemotherapy with cisplatin in ten patients. Patients underwent audiological assessment, including pure tone audiometry, speech audiometry, and immittancemetry. RESULTS: The treatment involving chemotherapy with cisplatin caused 41.9% and 47.3% hearing loss in the right and left ear, respectively, with a 11.7-fold higher risk of hearing loss in the right ear and 17.6-fold higher in the left ear versus patients not treated with cisplatin (p<0.001 and p<0.001, respectively). Children whose cancer diagnosis occurred after the age of 6 have shown an increased risk of hearing loss vs. children whose diagnosis occurred under 6 years of age (p=0.02). CONCLUSION: The auditory feature found after the cancer treatment was a symmetrical bilateral sensorineural hearing loss. Chemotherapy with cisplatin proved to be a risk factor, while head and neck radiotherapy was not critical for the occurrence of hearing loss.

Speech recognition and frequency of hearing loss in patients treated for cancer in childhood.

BACKGROUND: The aim of this study was to characterize the audiological profile accompanying oncological treatment in patients who had cancer in childhood and had been free of oncological treatment for at least 8 years. Our main interest lay in identifying the affected frequencies that interfered with speech intelligibility (SI) in those who had acquired hearing loss after treatment. PROCEDURE: Two hundred patients who had cancer in childhood were evaluated. Diagnosis was made at the mean age of 6 years old, and hearing evaluation was performed at a mean age of 21 years. Fifty-one of these patients received chemotherapy without cisplatin, carboplatin or head and neck radiotherapy; 64 received cisplatin without head and neck radiotherapy; 75 received head and neck radiotherapy without cisplatin; and 10 received both head and neck radiotherapy and cisplatin chemotherapy. All patients underwent pure tone audiometry and speech audiometry. RESULTS: Patients who had hearing loss primarily had bilateral symmetric sensorineural hearing loss. Although the average SI for ears with hearing loss in the frequency range from 4 to 8 kHz was normal, the Kruskall-Wallis test showed a significant difference between ears without hearing loss and those with hearing loss between 4 and 8 kHz. The average SI score in ears with hearing loss between 1 and 8 kHz was significantly different from all other ears. CONCLUSIONS: Hearing loss involving frequencies at and above 4 kHz determines a decline in SI.

Quais as frequências audiométricas acometidas são responsáveis pela queixa auditiva nas disacusias por ototoxicidade após o tratamento oncológico? / What are the audiometric frequencies affected are the responsible for the hearing complaint in the hearing loss for ototoxicity after the oncological treatment?

INTRODUÇÃO: A perda auditiva neurossensorial bilateral simétrica resultante do tratamento oncológico é subestimada, pois os pacientes têm a detecção auditiva preservada, relatando queixa em determinadas situações, ou a não compreensão de parte da mensagem. OBJETIVO: Investigar quais as frequências audiométricas acometidas são responsáveis pela presença de queixa auditiva. MÉTODO: Estudo prospectivo avaliando 200 pacientes com câncer na infância fora de tratamento oncológico há no mínimo 8 anos, com idade média ao diagnóstico de 6,21 anos (4,71). Foi aplicada anamnese para investigar a presença de queixa auditiva e realizada audiometria tonal limiar. Para verificar a associação entre queixa e perda auditiva, foi empregado o teste exato de Fisher, com um erro a=5%. Os pacientes foram divididos em: audição normal, perda auditiva em 8kHz, perda em 6-8kHz, perda em 4-8kHz, perda em 2-8kHz e perda em <1-8kHz. RESULTADOS: Encontramos 125 pacientes com audição normal, 10 apresentaram queixa auditiva. Entre os pacientes com perda auditiva, 16 apresentaram perda somente em 8kHz, e 1 com queixa; 22 com perda em 6-8kHz, sendo 3 com queixa; 16 com perda em 4-8kHz, destes 10 com queixa; 15 com perda 2-8kHz, sendo 14 com queixa e 6 com perda em <1-8kHz todos com queixa. Houve relação estatisticamente significante entre perda e queixa auditiva (p<0.001), quando a frequência de 4kHz foi envolvida. CONCLUSÃO: Quanto maior o número de frequências acometidas maior a ocorrência de queixa auditiva, sobretudo quando as frequências da fala estão envolvidas, sendo que o acometimento de 4kHz já determina o aparecimento das queixas.

INTRODUCTION: The neurosensory bilateral simetric hearing loss resulting of the oncological treatment is underestimated, because the patients has the hearing detection preserved, reporting complaints in determined situation, or the not comprehension of part of the message. OBJECTIVE: Investigate which are the audiometric frequencies affected are the responsible by the presence of hearing complaints. METHOD: Prospective study evaluating 200 patients with cancer in the childhood out of the oncological treatment in at least 8 years, with average age to the diagnosis of 6,21 years (4,71). Was applied anamnesis to investigate the presence of hearing complaints and performed a tonal threshold audiometry. To check the association between the complaint and the hearing loss, was applied the Exact test of Fisher, with one error a=5%, the patients were split into: normal hearing, hearing loss in 8kHz, loss in 6-8 kHz, loss in 4-8 kHz, loss in 2-8 kHz and loss in < 1-8 kHz. RESULTS: We found 125 patients with hearing loss, 10 presented hearing complaints. Between the patients with hearing loss, 16 presented loss only at 8kHz, and 1 with complaint; 22 with loss in 6-8 kHz, being 3 with complaint; 16 with loss in 4-8 kHz, from them 10 with complaint; 15 with loss 2-8 kHz, being 14 with complaint and 6 with loss in < 1-8 kHz all with complaints. There were a significant relationship between the loss and hearing complaint (p<0,001), when the frequency of 4 kHz was involved. CONCLUSION: The bigger the number of affected frequencies the bigger the occurrence of hearing complaint, most of all when the speech frequencies are involved, and the involvement of 4 kHz already determines the appearing of the complaints.

Evaluation of ototoxicity in children treated for retinoblastoma: preliminary results of a systematic audiological evaluation.

BACKGROUND: The objective of this study was to identify the ocurrence of hearing loss in children treated for retinoblastoma using a multidisciplinary approach. PATIENTS AND METHODS: Thirty-two children were evaluated pre- and post-treatment. Eleven children were treated exclusively with enucleation, fifteen with carboplatin and six with cisplatin. Otoacoustic emissions were performed with the ILO 88, before and after the treatment. RESULTS: In our study we found 5 children (24%) with hearing loss among the 21 evaluated. However in the group of children treated with carboplatin (N=15), 1 case (6.6%) presented hearing loss, while among those treated with cisplatin (N=6) we found 4 cases (66.6%) with hearing loss (p=0.0114). CONCLUSION: We concluded that patients who are treated with cisplatin are at risk for developing hearing loss.

Hearing loss and complaint in patients with head and neck cancer treated with radiotherapy.

OBJECTIVE: To investigate occurrences of hearing loss and hearing complaints among patients with head and neck tumors who underwent radiotherapy. DESIGN: Prospective case-control study. SETTING: Tertiary care hospital. PARTICIPANTS: Two hundred eighty-two participants underwent evaluation, including 141 with head and neck tumors and 141 as an age-matched control group. The controls had never undergone oncological treatment that put their hearing at risk. MAIN OUTCOME MEASURES: Results of audiological evaluation, including the Hearing Handicap Inventory for the Elderly questionnaire and pure-tone, speech, and immittance audiometry, and radiation dose received by the auditory system (based on the percentage of the external auditory canal included in the radiation field). RESULTS: We observed occurrences of hearing loss in 102 (72.3%) of the participants exposed to radiotherapy and 69 (48.9%) of the control group (P < .001). Hearing losses were mostly sensorineural and of mild degree, but those exposed to radiotherapy more frequently presented with severe and mixed-type hearing losses (P < .001). Of the participants exposed to radiotherapy, 19.1% had a severe handicap (P < .001). CONCLUSION: Patients undergoing radiotherapy in the head and neck region have a higher incidence of hearing loss and more severe hearing handicap. Trial Registration  clinicaltrials.gov Identifier: NCT01102621.

Report on hearing loss in oncology.

UNLABELLED: Cisplatin is used frequently as an antineoplastic drug in the treatment of many different cancers. However, when used in doses over 360mg/m(2), ototoxicity may ensue, resulting in loss of hearing. Criteria for identifying and quantifying hearing loss have been devised. AIM: To describe the features of different hearing loss classification systems and to identify their implications and use in oncologic patients. METHOD: Hearing loss was classified in 31 patients before and after chemotherapy, according to different criteria, assessing the sensitivity and specificity of each classification system. RESULTS: Hearing loss results were highly variable (ranging from 29% to 61%). Only 4 of 31 subjects with post-therapy hearing loss were identified by all the methods. A few subjects with hearing loss were classified as normal hearing in some of the criteria. A normal PTA was found in 18 of 31 subjects in the post-treatment evaluation. CONCLUSION: None of the criteria assesses the complaints of patients. The criteria described in this study were inadequate to identify hearing loss following chemotherapy, requiring additional information for physicians to better understand the hearing losses and their implications for the quality of life of patients.

Report on hearing loss in oncology / Classificações das perdas auditivas em Oncologia

Cisplatin is used frequently as an antineoplastic drug in the treatment of many different cancers. However, when used in doses over 360mg/m², ototoxicity may ensue, resulting in loss of hearing. Criteria for identifying and quantifying hearing loss have been devised. AIM: To describe the features of different hearing loss classification systems and to identify their implications and use in oncologic patients. METHOD: Hearing loss was classified in 31 patients before and after chemotherapy, according to different criteria, assessing the sensitivity and specificity of each classification system. RESULTS: Hearing loss results were highly variable (ranging from 29 percent to 61 percent). Only 4 of 31 subjects with post-therapy hearing loss were identified by all the methods. A few subjects with hearing loss were classified as normal hearing in some of the criteria. A normal PTA was found in 18 of 31 subjects in the post-treatment evaluation. CONCLUSION: None of the criteria assesses the complaints of patients. The criteria described in this study were inadequate to identify hearing loss following chemotherapy, requiring additional information for physicians to better understand the hearing losses and their implications for the quality of life of patients.

A cisplatina é um antineoplásico muito utilizado no tratamento de diferentes neoplasias, porém quando utilizada em doses acima de 360mg/m² pode causar ototoxicidade. Esta produz lesões cocleares que resultam em perda auditiva. Existem critérios que visam identificar e quantificar as perdas auditivas. OBJETIVO: Descrever as características das classificações e identificar implicações e aplicações de cada uma, dentro das necessidades do acompanhamento ao paciente oncológico. MATERIAL E MÉTODO: Avaliamos 31 pacientes pré e pós-tratamento quimioterápico. Classificamos as perdas auditivas de acordo com os critérios e verificamos a sensibilidade e especificidade de cada um. RESULTADO: Houve grande variabilidade na detecção das alterações auditivas (de 29 por cento a 61 por cento). Somente 4 dos 31 indivíduos com alterações auditivas no exame pós-tratamento foram identificados por todos os critérios. Por vezes o indivíduo portador de perda auditiva era classificado com normal por algum critério. Dos 31 indivíduos, 18 apresentaram PTA normal no exame pós-tratamento. CONCLUSÃO: Nenhum dos critérios considera a queixa do paciente. Os critérios descritos mostraram inadequações para descrever as alterações auditivas encontradas, fazendo-se necessária a descrição de informações adicionais, para que o médico compreendesse a natureza da perda auditiva. É importante o refinamento desses instrumentos para melhor compreensão e tratamento dos pacientes oncológicos, assim como de sua qualidade de vida.

Audiologic consequences of ototoxicity: case report with deterioration of the intelligibility of speech

Hearing is a channel of extreme importance for life because it enables the development of oral language; acquiring the knowledge to communicate with the world. Hearing loss can occur due to innumerous factors and can be expressed in various forms, according to its type and degree, and any impediment in the transport of sound to the central auditory nervous system implies a loss of part or all of the message content. Cisplatin chemotherapy treatment has ototoxicity as one of its described side effects. For that reason, the monitoring of the hearing of individuals submitted to cisplatin chemotherapy treatment has been a growing concern, especially in children presenting retinoblastoma. This study had as objective to describe the consequences of a hearing loss due to ototoxicity in the speech intelligibility of a child diagnosed as having retinoblastoma diagnosed at 22 months of age. Audiological monitoring showed a progressive hearing loss as well as deterioration of speech intelligibility. We have verified that the use of accumulative doses of cisplatin can compromise neural components of the auditory system resulting in a deterioration of speech intelligibility. The early detection of hearing loss in these cases is fundamental to avoid deafness progression as well as to conduct an adequate orientation for the school and family of the patient.

Auditory effects after organ preservation protocol for laryngeal/hypopharyngeal carcinomas.

OBJECTIVE: To investigate the prevalence of hearing loss after concomitant radiochemotherapy in patients enrolled in a larynx preservation protocol. DESIGN: Prospective study. SETTING: Consecutive patients treated in a tertiary cancer center hospital between 2001 and 2002. PATIENTS: Eligible subjects included patients prospectively enrolled in an organ preservation protocol based on concomitant radiotherapy and chemotherapy (cisplatin and paclitaxel). MAIN OUTCOME MEASURES: Descriptive analysis of the results of audiologic evaluations, including pure-tone audiometry and immitance audiometry, which were performed prior to and 8 months after treatment. Change in hearing sensitivity was computed relative to baseline measures. Criteria to indicate hearing decrease after the treatment were defined as either a 20-dB decrease at any single test frequency or a 10-dB decrease at any 2 adjacent test frequencies. RESULTS: A total of 11 patients were analyzed. Four patients (36%) had hearing loss after the treatment. CONCLUSION: Our results suggest that the prevalence of hearing loss after radiochemotherapy in larynx preservation protocols is high (36%); however, it was usually mild and asymptomatic.

Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones.

With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition data of 52 paullone entities, which were aligned by a docking routine into the ATP-binding cleft of a CDK1/cyclin B homology model. Variation of grid spacing and column filtering were used during the optimization of the models. The predictive ability of the models was shown by a leave-one-out cross-validation and the prediction of an independent set of test compounds, which were synthesized especially for this purpose. Besides paullones with the basic indolo[3,2-d][1]benzazepine core, the test set comprised novel thieno[3',2':2,3]azepino[4,5-b]indoles, pyrido[2',3':2,3]azepino[4,5-b]indoles, and a pyrido[3',2':4,5]pyrrolo[3,2-d][1]benzazepine. The best statistical values for the CoMSIA were obtained for the CDK1-models (r(2)() = 0.929 and q(2)() = 0.699), which were clearly superior to the models for CDK5 (r(2)() = 0.874 and q(2)() = 0.652) and GSK-3 (r(2)() = 0.871 and q(2)() = 0.554).