Article

Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study

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  • Princess Maxima Center for Pediatric oncology (PMC)
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... Survivors of cancer in children treated with cisplatin developed hearing loss. However, the risk of hearing loss was not increased in those children treated with aminoglycosides in addition to cisplatin [162]. ...
... Several preclinical studies have shown that cisplatin ototoxicity is greatly increased when combined with a loop diuretic [165][166][167][168]. Clinical studies revealed that the risk of increased ototoxicity in patients treated with a combination of furosemide and cisplatin seem to depend on patient age. A significant increased risk of ototoxicity in survivors of pediatric cancers treated with furosemide and cisplatin was reported [162]. However, in adult patients treated with furosemide combined with cisplatin with higher doses, did not exhibit increased risk of ototoxicity compared to patients treated with cisplatin alone [169]. ...
... But among patients who received both cisplatin and carboplatin, the incidence of hearing loss was 75%. Thus, there appears to be a synergistic ototoxicity among children treated with both drugs [162]. ...
Article
Introduction Cisplatin is a highly effective chemotherapeutic agent against a variety of solid tumors in adults and in children. Unfortunately, a large percentage of patients suffer permanent sensorineural hearing loss. Up to 60% of children and at least 50% of adults suffer this complication that seriously compromises their quality of life. Hearing loss is due to damage to the sensory cells in the inner ear, primarily the outer hair cells and cells of the stria vascularis and spiral ganglion. The mechanisms of cochlear damage are still being investigated. However, it appears that most damage to the inner ear is triggered by reactive oxygen species (ROS) formation and inflammation. Areas covered In this review we discuss a number of potential therapeutic targets that can be addressed to provide hearing protection. These strategies include enhancing the endogenous antioxidant pathways, heat shock proteins, G protein coupled receptors and counteracting enzymes that produce ROS and reactive nitrogen species, and blocking pathways that produce inflammation, including TRPV1 and STAT1. Expert opinion A number of potential protective agents show promise in animal models by systemic or local administration by transtympanic or intracochlear injection. However, clinical trials have not shown much efficacy to date with the exception of sodium thiosulfate administration in two studies of pediatric tumors. There is an urgent need to discover safe and effective protective agents that do not interfere with the efficacy of cisplatin against tumors yet preserve hearing.
... 9 Risk factors for developing CIHL are not well-characterized; apart from cumulative cisplatin dose, very few risk factors for CIHL have been consistently identified across case series. 3,[9][10][11][12][13][14] Identification of populations and risk factors for CIHL from past reports is complicated by studies with relatively small numbers of cisplatin-treated patients, single-institution cohorts, and variability among studies in timing of audiology assessments, methods of audiologic evaluation, and even the definition of hearing loss. [9][10][11][12]14 Similarly, genomic studies of pediatric CIHL have used relatively small and varied cohorts, regimens, and hearing endpoints. ...
... 3,[9][10][11][12][13][14] Identification of populations and risk factors for CIHL from past reports is complicated by studies with relatively small numbers of cisplatin-treated patients, single-institution cohorts, and variability among studies in timing of audiology assessments, methods of audiologic evaluation, and even the definition of hearing loss. [9][10][11][12]14 Similarly, genomic studies of pediatric CIHL have used relatively small and varied cohorts, regimens, and hearing endpoints. The resultant inconsistent phenotyping has resulted in few genes implicated in CIHL being replicated among studies. ...
... In examining CIHL as a surrogate marker of chemotherapy tumor efficacy, there was no difference in PFS or OS between patients who developed moderate/severe CIHL at EOT versus those who did not ( Figures 2C-D, Appendix, pp. [13][14]. ...
Article
Background Cisplatin is used to treat a wide range of childhood cancers and cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity. We aimed to address persistent knowledge gaps in CIHL by establishing benchmarks for the prevalence of and risk factors for CIHL. Methods In this multi-institutional cohort study, children (age 0–14 years), adolescents, and young adults (age 15–39 years) diagnosed with a cisplatin-treated tumour from paediatric cancer centres, who had available cisplatin dosing information, and primary audiology data for central review from consortia located in Canada and the USA were eligible for inclusion. Audiology was centrally reviewed and CIHL graded using the consensus International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale. We assessed the prevalence of moderate or severe CIHL (SIOP grade ≥2) at latest follow-up and end of therapy, in each demographic, diagnosis, and treatment group and their relative contributions to risk for CIHL. Secondary endpoints explored associations of cisplatin dose reductions and CIHL with survival. We also examined whether cisplatin dose reductions and CIHL were associated with survival outcomes. Findings We included 1481 patients who received cisplatin. Of the 1414 (95·5%) participants who had audiometry at latest follow-up (mean 3·9 years [SD 4·2] since diagnosis), 620 (43·8%) patients developed moderate or severe CIHL. The highest prevalence of CIHL was seen in the youngest patients (aged <5 years; 360 [59·4%] of 606 patients) and those with a CNS tumour (221 [50·9%] of 434 patients), hepatoblastoma (110 [65·9%] of 167 patients), or neuroblastoma (154 [62·1%] of 248 patients). After accounting for cumulative cisplatin dose, higher fractionated doses were associated with risk for CIHL (for each 10mg/m² increase per day, adjusted odds ratio [aOR] 1·15 [95% CI 1·07–1·25]; for each 50 mg/m² increase per cycle aOR 2·16 [1·37–3·51]). Vincristine exposure was newly identified as a risk factor for CIHL (aOR 3·55 [2·19–5·84]). Dose reductions and moderate or severe CIHL were not significantly associated with survival differences. Interpretation Using this large, multicentre cohort, benchmarks were established for the prevalence of CIHL in patients treated with cisplatin. Variations in cisplatin dosing confer additive risk for developing CIHL and warrant investigation as a potential approach to decrease the burden of therapy. Funding US National Institutes of Health and National Institute on Deafness and Other Communication Disorders, US National Institutes of Health and National Cancer institute, St Baldrick's Foundation, Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Canada Foundation for Innovation, University of British Columbia, British Columbia Children's Hospital Research Institute, British Columbia Provincial Health Services Authority, Health Canada, and C17 Research Network.
... [5][6][7] Research on hearing loss after platinum-based chemotherapy among CCS is extensive; however, evidence from representative nationwide samples is limited. 8 Previous studies were often singlecenter [9][10][11][12][13][14][15][16] or included selected clinics. [17][18][19][20][21][22][23] Most studies had relatively small samples, 10,12,14 were restricted to specific diagnostic groups, 11,15,17,19,23 or had short follow-up time. ...
... Both categorizations were based on previous studies. 8,35 Other exposures that may increase the risk for hearing loss or modify the risk of ototoxic treatments were age at cancer diagnosis, 8,18,21 year of cancer diagnosis 2 as a proxy for changing treatment regimens, and HSCT. 36 We separated age at cancer diagnosis into three categories (<5, 5-9, and ≥10 years) 18,21 and divided ...
... Both categorizations were based on previous studies. 8,35 Other exposures that may increase the risk for hearing loss or modify the risk of ototoxic treatments were age at cancer diagnosis, 8,18,21 year of cancer diagnosis 2 as a proxy for changing treatment regimens, and HSCT. 36 We separated age at cancer diagnosis into three categories (<5, 5-9, and ≥10 years) 18,21 and divided ...
Article
Background: Hearing loss is a potential side effect from childhood cancer treatment. We described the severity of hearing loss assessed by audiometry in a representative national cohort of childhood cancer survivors (CCS) and identified clinical risk factors. Procedure: We included all CCS from the Swiss Childhood Cancer Registry who were diagnosed ≤18 age and treated with platinum-based chemotherapy between 1990 and 2014. We extracted audiograms, treatment-related information, and demographic data from medical records. Two reviewers independently assessed the severity of hearing loss at latest follow-up using the Münster Ototoxicity Scale. We used ordered logistic regression to identify clinical risk factors for severity of hearing loss. Results: We analyzed data from 270 CCS. Median time from cancer diagnosis to last audiogram was 5 years (interquartile range 2.5-8.1 years). We found 53 (20%) CCS with mild, 78 (29%) with moderate, and 75 (28%) with severe hearing loss. Higher severity grades were associated with (a) younger age at cancer diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI]: 2.5-12.0 for <5 years); (b) treatment in earlier years (OR 4.8, 95% CI: 2.1-11.0 for 1990-1995); (c) higher cumulative cisplatin doses (OR 13.5, 95% CI: 4.7-38.8 for >450 mg/m2 ); (d) concomitant cranial radiation therapy (CRT) (OR 4.4, 95% CI: 2.5-7.8); and (e) hematopoietic stem cell transplantation (HSCT) (OR 2.7, 95% CI: 1.0-7.2). Conclusion: Three of four CCS treated with platinum-based chemotherapy experienced some degree of hearing loss. We recommend closely monitoring patient's hearing function if treated at a young age with high cumulative cisplatin doses, and concomitant CRT as part of long-term care.
... 4,5 Treatment-induced ototoxicity typically presents as hearing loss of high-frequency sounds, often accompanied by tinnitus. [6][7][8][9] Platinum-based compounds (eg, cisplatin and carboplatin) have been shown to be highly effective for a variety of paediatric malignancies, such as osteosarcoma, neuroblastoma, hepatoblastoma, brain tumours, and malignant germ cell tumours. In addition, head and brain radiotherapy is a crucial part of treatment for several head and neck tumours, most brain tumours, and relapsed leukaemia. ...
... [ie, high-quality] evidence). 7,[29][30][31][32][33] Evidence sug gests that the risk of hearing loss is higher in survivors treated with platinum-based drugs who were younger (cutoff age not defined) at the time of diagnosis (level B evidence), although a cutoff age for an increased risk for ototoxicity cannot be defined. 5,7,28,[30][31][32][33]41,47 No evidence of any effect of sex on the risk of hearing loss (level B evidence) was available. ...
... 7,[29][30][31][32][33] Evidence sug gests that the risk of hearing loss is higher in survivors treated with platinum-based drugs who were younger (cutoff age not defined) at the time of diagnosis (level B evidence), although a cutoff age for an increased risk for ototoxicity cannot be defined. 5,7,28,[30][31][32][33]41,47 No evidence of any effect of sex on the risk of hearing loss (level B evidence) was available. 32,34,40,41,43 No studies evaluated ototoxicity risk after treatment with only carboplatin or oxaliplatin by multivariable analysis. ...
Article
Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems—such as speech and language, social–emotional development, and learning difficulties—for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.
... Thirty studies were selected based on the inclusion criteria after full-text screening. Seven were RCTs (Table S3), [28][29][30][31][32][33][34] 20 were cohort studies (Table S4) [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] and 3 were cross-sectional studies (Table S5). [55][56][57] Within the RCTs, one study 33 had a low risk of bias, whereas the other six RCTs had a high or unclear risk of bias (Table S6). ...
... Cross-sectional aetiology studies were performed in healthy children 57 and children with hearing loss. 55,56 Amikacin, 32,35,[42][43][44][45][46]48,50,53 gentamicin, [28][29][30][34][35][36][41][42][43]48,50,52,55,56 streptomycin 39,46,51,57 and tobramycin 31,33,35,[41][42][43]50 were the most frequently administered aminoglycosides, whereas vancomycin was the only administered glycopeptide antibiotic ( Figure 3). 38 (Tables S3 and S4). ...
... Cross-sectional aetiology studies were performed in healthy children 57 and children with hearing loss. 55,56 Amikacin, 32,35,[42][43][44][45][46]48,50,53 gentamicin, [28][29][30][34][35][36][41][42][43]48,50,52,55,56 streptomycin 39,46,51,57 and tobramycin 31,33,35,[41][42][43]50 were the most frequently administered aminoglycosides, whereas vancomycin was the only administered glycopeptide antibiotic ( Figure 3). 38 (Tables S3 and S4). ...
Article
Full-text available
Background Ototoxicity has been reported after administration of aminoglycosides and glycopeptides. Objectives To identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children. Materials and methods Systematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies. Results Twenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%–57%, whereas the frequency of tinnitus and vertigo ranged between 0%–53% and 0%–79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication. Conclusions In children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication.
... Several factors may increase the risk of developing ototoxicity and HL following platinum-based chemotherapy. Cisplatin seems to be considerably more ototoxic than carboplatin and when patients receive both cisplatin and carboplatin, an increased rate of HL is reported [51]. The ototoxicity of other platinum compounds is less studied, but oxaliplatin seems to be less ototoxic than its predecessors [3]. ...
... The ototoxicity of other platinum compounds is less studied, but oxaliplatin seems to be less ototoxic than its predecessors [3]. Incidence of platinum-induced ototoxicity is dose-dependent [1,51] and elderly and pediatric populations are more susceptible to sensorineural HL following treatment [1,4,51]. Aging is one of the most important risk factors for developing malignancies but also for acquired HL [52]. ...
... The ototoxicity of other platinum compounds is less studied, but oxaliplatin seems to be less ototoxic than its predecessors [3]. Incidence of platinum-induced ototoxicity is dose-dependent [1,51] and elderly and pediatric populations are more susceptible to sensorineural HL following treatment [1,4,51]. Aging is one of the most important risk factors for developing malignancies but also for acquired HL [52]. ...
Article
Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.
... The degree of hearing loss is highly variable among children treated for cancer with cisplatin [25]. The currently known non-genetic risk factors, such as platinum dose and compound, short-time infusion, renal dysfunction, age, concomitant use of other ototoxic drugs, cranial irradiation and pretherapeutic hearing loss, only partially explain the interindividual variability [26,27]. This led to the hypothesis that genetic factors may render certain individuals more susceptible to the adverse effects of platinum compounds. ...
... From the Swiss Childhood Cancer Survivor Study came a report of a significantly decreased prevalence of hearing loss after cisplatin for children treated more recently, suggesting that new treatment regimens with lower doses are benefitting survivors [46]. Seven paediatric oncology centres in the Netherlands reported that higher cumulative doses of cisplatin, young age and furosemide chemotherapy are independently associated with hearing loss [27]. These results will all be taken into account in analyses of the pan-European PanCareLIFE data set. ...
Article
Aims: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. Methods: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. Results: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. Conclusions: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.
... When loop diuretics were coadministered with cisplatin, hearing loss was exacerbated in guinea pigs (McAlpine and Johnstone 1990). In young cancer patients too, cotreatment with furosemide increased the risk of hearing loss (Clemens et al. 2016). The CTR1 and OCT2 transporters have been observed in stria vascularis but not in the spiral ligament, suggesting their possible involvement in cisplatin transport across the BLB into the endolymph (Ciarimboli et al. 2010;More et al. 2010;Waissbluth and Daniel 2013). ...
... Cisplatin also damages supporting cells in the mammalian vestibular system (utricle), and blocks the proliferation of resident stem cells in the utricle, reducing the potential to regenerate hair cells (Slattery et al. 2014). Inflammation potentiates cisplatin-induced ototoxicity, as do loop diuretics (McAlpine and Johnstone 1990;Oh et al. 2011;Clemens et al. 2016). ...
Article
Ototoxicity refers to damage of inner ear structures (i.e., the cochlea and vestibule) and their function (hearing and balance) following exposure to specific in-hospital medications (i.e., aminoglycoside antibiotics, platinum-based drugs), as well as a variety of environmental or occupational exposures (e.g., metals and solvents). This review provides a narrative derived from relevant papers describing factors contributing to (or increasing the risk of) aminoglycoside and cisplatin-induced ototoxicity. We also review current strategies to protect against ototoxicity induced by these indispensable pharmacotherapeutic treatments for life-threatening infections and solid tumors. We end by highlighting several interventional strategies that are currently in development, as well as the diverse challenges that still need to be overcome to prevent drug-induced hearing loss.
... Hearing impairment in children can enhance learning problems by influencing speech and language development as children have difficulty understanding speech and sounds, especially in the presence of ambient noise [5,6]. The overall reported incidence of platinum-induced ototoxic- ity in children approaches 60% [1,7,8] and is influenced by younger age, higher cumulative cisplatin or cranial radiotherapy doses, and concomitant treatment with aminoglycosides and furosemide [9][10][11][12]. Although carboplatin is considered less ototoxic than cisplatin, hearing impairment can occur, especially with high doses [13][14][15]. ...
... Therefore, the classification scales are not interchangeable. Nevertheless, it is important to take into consideration that platinum-induced hearing loss, regardless which grading scale used, can have significant complications for children [6,10]. In both psychosocial and develop- mental areas, difficulties can arise [5,8,31]. ...
Article
Full-text available
Childhood cancer patients treated with platinums often develop hearing loss and the degree is classified according to different scales globally. Our objective was to compare concordance between five well-known ototoxicity scales used for childhood cancer patients. Audiometric test results (n = 654) were evaluated longitudinally and graded according Brock, Chang, International Society of Pediatric Oncology (SIOP) Boston, Muenster scales and the U.S. National Cancer Institute Common Technology Criteria for Adverse Events (CTCAE) version 4.03. Adverse effects of grade 2, 3 and 4 are considered to reflect a degree of hearing loss sufficient to interfere with day-to-day communication (> = Chang grade 2a; > = Muenster grade 2b). We term this "deleterious hearing loss". A total number of 3,799 audiograms were evaluated. The prevalence of deleterious hearing loss according to the last available audiogram of each patient was 59.3% (388/654) according to Muenster, 48.2% (315/653) according to SIOP, 40.5% (265/652) according to Brock, 40.3% (263/652) according to Chang, and 57.5% (300/522) according to CTCAEv4.03. Overall concordance between the scales ranged from ĸ = 0.636 (Muenster vs. Chang) to ĸ = 0.975 (Brock vs. Chang). Muenster detected hearing loss the earliest in time, followed by Chang, SIOP and Brock. Generally good concordance between the scales was observed but there is still diversity in definitions of functional outcomes, such as differences in distribution levels of severity of hearing loss, and additional intermediate scales taking into account losses <40 dB as well. Regardless of the scale used, hearing function decreases over time and therefore, close monitoring of hearing function at baseline and with each cycle of platinum therapy should be conducted.
... The degree of cisplatin-induced ototoxicity is variable. Previous epidemiological studies have identified several environmental and clinical risk factors that can increase the risk of platinum-induced ototoxicity, including the type of platinum agent and drugdosing conditions, such as single and cumulative cisplatin dose [8][9][10]. Cisplatin-induced hearing loss is particularly serious in pediatric and elderly patients [8,9,11]. ...
... Previous epidemiological studies have identified several environmental and clinical risk factors that can increase the risk of platinum-induced ototoxicity, including the type of platinum agent and drugdosing conditions, such as single and cumulative cisplatin dose [8][9][10]. Cisplatin-induced hearing loss is particularly serious in pediatric and elderly patients [8,9,11]. In addition, concomitant cranial radiation may aggravate cisplatininduced ototoxicity [9,12,13]. ...
Article
Full-text available
Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8–21.5; P = 5.6 × 10⁻⁷) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m²: OR: 2.4; 95% CI: 1.3–4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04–14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07–2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
... Quatro estudos utilizaram apenas a audiometria tonal (convencional, condicionada ou com reforço visual) 4,26,35,38 , e apenas um estudo considerou a avaliação da audiometria de altas frequências 33 . ...
... Dentre os fatores mais destacados como de maior risco para desenvolver perda auditiva induzida por platina, pode-se citar o diagnóstico de osteossarcoma 26 e a dosagem cumulativa de cisplatina 8,20,22,27 , maior do que 400 mg/m² 26 , embora dosagens superiores à 200 mg/m² já tenham se mostrado ototóxica 12 . Foi mencionada também a influência do fator idade, bem como o uso concomitante da furosemida 38 . ...
Article
Full-text available
Purpose: to identify and analyze the effects of chemotherapy on the auditory system of children and/or adolescents with cancer treated with cisplatin and carboplatin, assessed through standardized audiological procedures. Methods: studies in Brazilian Portuguese and in English were searched for, as available in the databases Science Direct, PubMed, LILACS, BIREME, Embase, SciELO, Web of Science and Cochrane. The descriptors were: Hearing Loss, Audiology, Child Cancer, Chemotherapy, and Child. Articles with levels 1 and 2 of scientific evidence, published in the last 20 years (1997 to 2017), were considered, of which the audiological results were analyzed, as well as the prevalence of hearing loss in children with cancer undergoing chemotherapy. Results: 3,625 articles were found, of which only 23 were selected for analysis in the present review. Studies have shown a high incidence of sensorineural hearing loss and decrease or even loss of otoacoustic emissions in children and adolescents with cancer, even after the first dose of chemotherapy drugs, with high frequencies being the most affected. Conclusion: there is evidence that both carboplatin and especially cisplatin from the first doses may impair the hearing of children and adolescents, mainly affecting the cochlear function, thus, the importance of long-term audiological monitoring.
... The most relevant determinant of future health status of survivors appears to be the different effects of cytostatics on organ toxicity in age-dependent groups. For example, cisplatin and/ or carboplatin, which have ototoxic and nephrotoxic effects, are commonly used to treat embryonal tumors [12][13][14][15]. ...
... Platinum agents used to treat various solid tumors (e.g., bone tumors, germ cell tumors) in younger children and adolescents lead to long-term or permanent hearing loss or deafness. This problem is most significant in younger patients as it is associated with future impaired speech, language, and intellectual development [13]. Some large epidemiologic studies of cohorts of NBL survivors have emphasized that neurosensory, endocrine, and musculoskeletal problems were most common [16,[18][19][20][21]. ...
Article
Full-text available
Background The effect of age on the incidence of late sequelae that occur after anticancer treatment in childhood is still not fully elucidated. In this multicenter study of long-term survivors diagnosed before age of three, we investigated the prevalence of late effects many years after treatment. Methods The study group (n = 561) was selected from the Polish National Childhood Cancer Survivors Registry (n = 1761) created in 2007. A survivor was defined as an individual who has survived at least 5 years after completion of anticancer treatment. All children were diagnosed between 1991 and 2016, mean age at diagnosis was 1.82 years (range 0.03–2.99) and median follow up time - 9.85 years (range 5.0–23.6). They were treated in accordance with international protocols approved by the Polish Pediatric Leukemia and Lymphoma Group and Polish Solid Tumor Group. Chemotherapy alone was used in 192 (34.2%), chemotherapy and radiotherapy – 56 (10%), chemotherapy and surgery – 176 (31.4%), chemotherapy, radiotherapy, and surgery – 79 (14.1%), and surgery alone in 58 patients (10.3%). Results Of all patients enrolled to the study, only 94 (16.8%) had normal function of all organs. Seventy-six (13.5%) children developed dysfunction in one organ, another 83 (14.8%) had symptoms or complaints suggestive of dysfunction in two organs or systems, 88 (15.7%) had abnormalities in three organs, and 220 (39.2%) had at least four or more dysfunctions. In the entire study group, dysfunctions most frequently (> 20% of cases) involved the following organs/systems: circulatory – 21.8%, urinary – 30.8%, gastrointestinal – 20.8%, immune – 23.5%, vision – 20.7%, hearing – 21.8%, and oral and masticatory dysfunction – 26.9%. We did not find any significant differences in organ dysfunction between children diagnosed under the age of 1 and those diagnosed at the age of 1–3, except for a lower incidence of thyroid abnormalities (p = 0.007) and the higher prevalence of liver dysfunction in youngest patients. In the subset with longer follow-up period (> 10 years) more frequent thyroid abnormalities (p = 0.019), male (p = 0.002) and female (p = 0.026) gonads dysfunction, as well as musculoskeletal problems (p < 0.001) were observed. Among subjects who received radiotherapy compared to those who did not, short stature (p = 0.001), and dysfunction of the following systems/organs – circulatory (p = 0.049), urinary (p = 0.012), thyroid gland (p < 0.0001), nervous (p = 0.007), immunological (p = 0.002), liver (p = 0.03), dental or chewing difficulties (p = 0.001), hearing (p = 0.001) and musculoskeletal (p = 0.026) were more frequently reported. When multimodal therapy was applied (chemotherapy, radiotherapy, and surgery) a higher incidence of short stature (p = 0.007), urinary system disorders (p < 0.0001), thyroid dysfunction (p < 0.0001), hearing loss (p < 0.0001), and skin problems (p = 0.031) were observed. Conclusion This study confirms that radiotherapy and some specific toxicity of cytostatics are the most important factors affecting organ function. Apart from a higher incidence of liver dysfunction in the youngest patients, there were no significant differences in organ and system toxicities between children diagnosed under the age of 1 and those diagnosed at the age of 1–3. We have shown that this group requires systematic, careful and long-term follow-up.
... 8,[10][11][12] In addition, hearing loss seems more prevalent in children who are younger at the time of cancer diagnosis compared with older children (see Supporting Table 1). 11,[13][14][15][16][17][18][19][20] To date, however, investigations into whether patterns of CIHL over time are affected by age have been limited. ...
... Previous studies have reported that young age (eg, <5 years) at the time of cisplatin treatment is a risk factor for hearing loss, 14,[17][18][19] but data on the course of CIHL development over time and the association with age are limited. In this study, the cumulative incidence of CIHL development over time was higher in patients aged <5 years compared with older patients, reaching up to 75% and 48% at 3 years after the start of cisplatin treatment, respectively. ...
Article
Background: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. Methods: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. Results: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time. Conclusions: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.
... 45 Cisplatin increases the risk of hearing loss and renal dysfunction. 46 Alkylating agents increase the risk of gonadal injury and infertility. 38 ...
Article
Progress in therapy has made survival into adulthood a reality for most children, adolescents, and young adults with a cancer diagnosis today. Notably, this growing population remains vulnerable to a variety of long-term therapy-related sequelae. Systematic ongoing follow-up of these patients is, therefore, important to provide for early detection of and intervention for potentially serious late-onset complications. In addition, health counseling and promotion of healthy lifestyles are important aspects of long-term follow-up care to promote risk reduction for physical and emotional health problems that commonly present during adulthood. Both general and subspecialty health care providers are playing an increasingly important role in the ongoing care of childhood cancer survivors, beyond the routine preventive care, health supervision, and anticipatory guidance provided to all patients. This report is based on the guidelines that have been developed by the Children's Oncology Group to facilitate comprehensive long-term follow-up of childhood, adolescent, and young adult cancer survivors (www.survivorshipguidelines.org).
... Literature data show that between 40 and 80% of cisplatin-treated patients experience permanent hearing loss (10,11). Some authors report that cisplatin-induced ototoxicity has been observed in 7 and 90% of cases at standard doses (12), as well as at different doses and in various age groups (13), including children (14). Clinically, ototoxicity manifests itself as bilateral hearing loss accompanied by tinnitus (15). ...
Article
Full-text available
Melanotic neuroectodermal tumor of infancy (MNTI) is a rare infantile tumor that originates from mesenchymal-neuroectodermal cells, the treatment of which uses platinum derivatives that can affect hearing loss. The present study evaluated the long-term effects of ototoxicity following chemotherapy with cisplatin, vincristine, cyclophosphamide, teniposide and adriamycin in a 10-year-old patient after surgical removal of a MNTI tumor at the age of 8 months. Audiometric tests (high-frequency tonal audiometry, speech audiometry, speech acoustics, tympanometry and absorbance measurements) were performed during a 10-year follow-up after receiving chemotherapy. Hearing disorders in the high-frequency range (6,000 to 16,000 Hz range) were demonstrated for both ears, indicating that these may be the long-term effects of chemotherapy with use of platinum compounds during the treatment of infants.
... Several studies have shown dose-dependent effects of RT on hearing outcomes; associated risk factors include treatment with aminoglycosides, platinum agents, craniospinal fluid (CSF) shunts, and cranial surgery [4,5,[7][8][9][10][11][12]. Recent studies have also examined the independent ototoxic effects of platinum therapy and showed early onset, bilateral high-frequency loss following treatment [13][14][15]. However, few studies examined the ototoxic effects of RT independent of platinum therapy using objective audiometric testing over long-term follow-up [6,9,16]. ...
Article
Full-text available
The ototoxic effects of radiotherapy have been poorly characterized. We examined adult survivors of childhood cancer who were treated with radiotherapy, which included the head, before the age of 22 years and between 1952 and 2016. Those who received platinum chemotherapy were excluded. Demographic, diagnosis, and treatment outcomes were captured. Audiograms were graded using the Chang and International Society of Paediatric Oncology ototoxicity (SIOP) scales. Among 276 patients with a history of radiation to sites that included the brain, orbit, nasopharynx, and total body irradiation, the median age at treatment was 10.1 years and 59% were male. Of 51 survivors who had post-treatment audiograms, 19 demonstrated severe hearing impairment according to both the Chang and SIOP scales after a median follow-up of 16.6 years. Of those with severe impairment, 10 were using hearing aids. Among the 23 patients with more than one audiogram, five had normal hearing on the first audiogram but hearing loss upon subsequent study. Ototoxic effects of radiotherapy are present in a significant portion of survivors, but impairment may present over time, and our results suggest that many are not being screened. Further, among patients with severe hearing loss, use of hearing aids is not universal. Expansion of access to audiology testing and hearing interventions may be warranted.
... Neuropathy from vinka alkaloids is a more common adverse effect (16-78%) (5,8). Cisplatin and carboplatin are ototoxic drugs, which can cause permanent high-frequenting hearing loss (42-71%) and consequently severe learning and developmental impairments in young children (5,(9)(10)(11)(12)(13)(14). Among patients, who received cisplatin and carboplatin therapy for brain tumors, 4 patients with glioma (57%), 15 with medulloblastoma (88%) and 3 with primitive neuroectodermal tumor (50%) had ototoxicity. ...
Article
Full-text available
Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.
... Hearing loss is frequently encountered in childhood cancer patients and survivors treated with platinum derivatives such as cisplatin and carboplatin [5][6][7][8][9]. Studies have shown that 45% to 60% of CCS treated with cisplatin develop irreversible hearing loss and almost half of them may require hearing aids [10,11]. Platinum-induced hearing loss usually starts in the high frequencies but can eventually affect the lower frequencies, including speech frequencies [12]. ...
Article
Full-text available
Background Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication. Objective We describe the design of the PanCareLIFE consortium’s work packages that address the genetic susceptibility of platinum-induced ototoxicity. Methods As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening. Results This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020. Conclusions Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies. International Registered Report Identifier (IRRID) DERR1-10.2196/11868
... As described earlier, furosemide is known to induce ototoxicity especially when combined with cisplatin. 17,20 Unfortunately, the use of furosemide was not registered in our population. Patients treated with high-dose cisplatin receive more fluid for prehydration and posthydration than patients with intermediate-dose cisplatin, which conceivably could have led to more furosemide use. ...
... Concernant le carboplatine, nous avons confirmé les résultats de l'étude du DCOG concernant l'absence d'effet significatif de la dose cumulée de carboplatine sur la perte d'audition. 153 Ces résultats semblent être en contradiction avec les rapports antérieurs. 146 ...
Thesis
Les progrès thérapeutiques en oncologie pédiatrique ont permis une amélioration des taux de survie qui dépassent aujourd’hui 80%. De façon à augmenter les taux de guérison et diminuer les complications et séquelles des traitements, des efforts collaboratifs internationaux ont permis le développement de protocoles thérapeutiques stratifiés sur les facteurs pronostiques majeurs incluant des facteurs biologiques tumoraux issus des analyses moléculaires et notamment génomiques. Cependant, si les traitements utilisés prennent de plus en plus en compte la biologie tumorale, leur adaptation aux facteurs individuels reste marginale. La thèse ici présentée cherche à mieux comprendre comment les caractéristiques tumorales et individuelles des patients modifient l’efficacité et la toxicité des thérapeutiques anticancéreuses utilisées en oncologie pédiatrique.Plusieurs travaux ont été réalisés :1- Etude de l’impact pronostique des facteurs tumoraux : évaluation de l’impact pronostique de la décroissance du marqueur tumoral alphafoetoprotéine (AFP) dans les tumeurs germinales malignes de l’enfant et de l’adolescent traitées par chimiothérapie ; 2- Etude de l’impact pronostique des facteurs constitutionnels : (i) évaluation de l’effet du sexe sur l’efficacité et la toxicité des agents alkylants ; (ii) évaluation de l’impact pronostique de polymorphismes génétiques de gènes impliqués dans le métabolisme du méthotrexate sur l’efficacité et/ou la toxicité du méthotrexate haute dose dans le traitement de l’ostéosarcome ;3- Etude des facteurs de risque de toxicité tardive : analyse de la de toxicité auditive sévère dans la cohorte des survivants à long terme de cancers pédiatriques (FCCSS).
... Cisplatin is taken up via OCT2 and accumulates in hair cells, the stria vascularis, and spiral ganglion cells after which these structures are (irreversibly) destroyed leading to hearing loss mostly in the high frequency range [132]. Although aminoglycosides and furosemide do not belong to the group of drugs classified as chemotherapy, these medications do lead to ototoxicity and can aggravate the effects of platinum agents on the cochlea [133,134]. ...
Article
Full-text available
Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible.
... Highdose furosemide leads to proximal tubular necrosis and its use with cisplatin may aggravate the nephrotoxicity (21,22). In addition, furosemide causes edema of the stria vascularis, disrupts the blood-ear barrier, and enhances the entry of ototoxic drugs into the inner ear, known to potentiate cisplatin-induced hearing loss (23)(24)(25). Therefore, many researchers have sought less toxic methods for administering cisplatin without furosemide (26,27). ...
Article
Background: To survey the prevalence of potential drug-drug interactions (DDIs) between anticancer drugs and non-anticancer drugs and evaluate the risk factors associated with these drug-drug interactions in China. Methods: All discharged patients in the Department of Oncology were collected from Jun to Dec in 2016 with the Hospital Information System of the Chinese people's Liberation Army General Hospital. Drugs were screened for interactions by Micromedex solutions database. Descriptive statistics were generated and logistic regression was used to identify the associated factors. Results: Among 6578 eligible patients, 1979 potential drug interactions were found in 1830 patients (27.82%). The most common drug-drug interaction was cisplatin and furosemide. Erlotinib was most likely to interact with various non-anticancer drugs. Most interactions were classified as pharmacodynamics (71.60%), major severity (97.02%) and were supported by fair documentation evidence (86.21%). In multivariate analysis, increasing number of medications, lung cancer and patients with stage IV had a higher risk for potential drug-drug interactions. Conclusion: Potential drug-drug interactions between antineoplastic drugs and non-antineoplastic drugs occur frequently in cancer patients of Chinese hospitals. Doctors should fully consider potential risk associated with DDIs. Further research should be performed to evaluate real clinical significance of these drug-drug interactions.
... Some common late effects of childhood cancer include: secondary breast cancer after chest radiation; cardiomyopathy after treatment with anthracyclines, or chest radiation; premature ovarian insufficiency after treatment with alkylating agents, or radiotherapy to ovaries; impaired sperm production after gonadotoxic chemotherapy, or radiotherapy to testes; secondary thyroid cancer after radiation therapy involving the thyroid; ototoxicity after platinumbased chemotherapy, or cranial irradiation (6)(7)(8)(9)(10). Some late effects are more likely to manifest in later adulthood. ...
Technical Report
Full-text available
Survivorship after Childhood Cancer, National Needs Assessment
... After platinum exposure, special attention for hearing function is needed throughout infancy [58]. It is anticipated, based on animal models as well as childhood cancer studies, that combining platinum exposure with aminoglycosides or furosemide adds to the risk [83,84]. ...
Article
Full-text available
Objectives: We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Methods: Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Results: Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow up of the infants. Non-ionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. Conclusions: More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary box 1) is encouraged.
... Ototoxicity was reported in 17% of children who survived cancer treatment compared to 45% of those treated with cisplatin. Patients receiving both drugs were found to have a 75% incidence of hearing loss (Clemens et al., 2016). Ototoxicity from carboplatin in children has been associated with cumulative doses in excess of 400 mg/m 2 (Grewal et al., 2010). ...
Chapter
This chapter presents current information on various types of sensorineural hearing loss (SNHL). SNHL represents the second most common sensory disorder in humans, affecting nearly half a billion persons in the world. This affliction can cause major disabilities, particularly in children. SNHL results from damage to cells in the inner ear. The loss of sensory cells in the cochlea is permanent—they cannot regenerate. The various types of SNHL are presented as a brief overview. A more detailed presentation of SNHL from environmental causes includes a review of noise-induced SNHL and environmental toxins comprising heavy metals. A detailed summary of SNHL caused by ototoxic drugs is presented. The two major classes of ototoxic drugs include the chemotherapeutic agent cisplatin and the aminoglycoside antibiotics. These drugs are used to treat cancer patients and individuals with life-threatening infections, respectively. Results of both animal and human publications are presented. Exciting new investigations of putative protecting agents offer promising approaches to these challenging disorders. Obstacles to the treatment of SNHL include the presence of a barrier system in the inner ear called the blood-labyrinth barrier. This barrier system restricts the access of systemically administered drugs to the cochlea. Novel methods to address these challenges are summarized. These could lead to effective treatments to prevent or reverse SNHL in patients.
... Hearing loss is one of the most common adverse effects of cancer treatment [1][2][3] . Several studies have shown that hearing loss is a prevalent late effect of cisplatin or carboplatin chemotherapy and radiotherapy to the cochlea. ...
Article
Background: Hearing loss is a prevalent late effect among cancer survivors. Despite the significant social costs, there is a noted delay in seeking care and to the authors' knowledge there are limited data regarding the lived experiences of cancer survivors with hearing loss. The objective of the current study was to explore the lived experience of hearing loss in survivors of childhood and young adult cancers to guide survivorship care. Methods: A total of 24 survivors participated in semistructured telephone interviews. Inclusion criteria consisted of a clinical visit at the Adult Long-Term Follow-Up Program at Memorial Sloan Kettering Cancer Center in New York City between September 2005 and January 2019; exposure to cranial radiotherapy, platinum chemotherapy, or both; and hearing loss as evidenced by clinical notes, use of hearing aids, or audiogram levels consistent with severe ototoxicity. Results: Three primary themes emerged from the interviews. First, posttreatment hearing loss is associated with isolation and feelings of exclusion. Second, clinicians play an important role in providing survivors with education regarding hearing loss and hearing aids. Finally, hearing loss for survivors may be deprioritized because it is a reminder of the cancer history and is interpreted within the context of other treatment-related late effects. Conclusions: Clinicians play an important role in initiating the discussion regarding hearing loss with survivors given the importance of hearing in maintaining social relationships, the availability of hearing care interventions, and the invisibility of hearing loss. Education regarding the value of treatment may have implications for how survivors choose to prioritize hearing loss and seek care.
... However, the evidence regarding cardiac function on children prenatally exposed to anthracyclines is reassuring: non-clinically relevant differences in echocardiographic findings have been reported in exposed children compared with non-exposed ones [8,42,51,52]. Concerns related to hearing function throughout infancy are mainly based on data from young cancer survivors [53,54]. However, on indication, the use of carboplatinum during pregnancy is preferred, as there are case reports of impaired hearing in children prenatally exposed to cisplatin [8,41,55]. ...
Article
Full-text available
Purpose of review: Cancer diagnosis in young pregnant women challenges oncological decision-making. The International Network on Cancer, Infertility and Pregnancy (INCIP) aims to build on clinical recommendations based on worldwide collaborative research. Recent findings: A pregnancy may complicate diagnostic and therapeutic oncological options, as the unborn child must be protected from potentially hazardous exposures. Pregnant patients should as much as possible be treated as non-pregnant patients, in order to preserve maternal prognosis. Some approaches need adaptations when compared with standard treatment for fetal reasons. Depending on the gestational age, surgery, radiotherapy, and chemotherapy are possible during pregnancy. A multidisciplinary approach is the best guarantee for experience-driven decisions. A setting with a high-risk obstetrical unit is strongly advised to safeguard fetal growth and health. Research wise, the INCIP invests in clinical follow-up of children, as cardiac function, neurodevelopment, cancer occurrence, and fertility theoretically may be affected. Furthermore, parental psychological coping strategies, (epi)genetic alterations, and pathophysiological placental changes secondary to cancer (treatment) are topics of ongoing research. Further international research is needed to provide patients diagnosed with cancer during pregnancy with the best individualized management plan to optimize obstetrical and oncological care.
... 94,95 Enhanced ototoxicity can also occur when cisplatin is coadministered with aminoglycosides, loop diuretics, and cranial radiation. [96][97][98][99] Thus, when dosing with multiple drugs simultaneously, all therapeutics should be examined for toxic interactions, including potentiated or synergistic ototoxic effects, and alternative dosing regimens identified where possible. ...
Article
Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of environmental exposures (eg, lead, cadmium, solvents). This article reviews the fundamental mechanisms underlying ototoxicity by clinically relevant, hospital-prescribed medications (ie, aminoglycoside antibiotics or cisplatin, as illustrative examples). Also reviewed are current strategies to prevent prescribed medication-induced ototoxicity, with several clinical or candidate interventional strategies being discussed.
... Recent data from a large cohort of childhood cancer survivors revealed ototoxic change in 45% of subjects treated with cisplatin and 17% treated with carboplatin [84]. Another recent review of ototoxicity in pediatric patients estimated 60-70% of pediatric patients experienced cisplatin-induced ototoxicity, with 80-90% affected when cisplatin and carboplatin were used in combination [85]. ...
Article
Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.
... 12 Carboplatin did not appear to be associated with tinnitus in the current study. This platinum agent has ototoxic potential but generally causes less cochlear damage compared to cisplatin, 28 which may explain the low frequency of tinnitus in CCS treated with carboplatin. Furthermore, previously administered cranial irradiation/TBI was associated with the occurrence of tinnitus, but not the total radiation dose. ...
Article
Full-text available
Background Tinnitus is a serious late effect of childhood cancer treatment. The aim of this study was to determine the occurrence and risk factors for tinnitus in a national cohort of childhood cancer survivors (CCS). Methods Data were collected within the national DCOG-LATER cohort by a self-reported health questionnaire among 5,327 Dutch CCS treated between 1963-2002. Siblings (N=1,663) were invited to complete the same questionnaire. Relevant patient characteristics and treatment factors were obtained from the Dutch LATER database. Occurrence of tinnitus in survivors was compared to siblings. To study the effect of risk factors, multivariate logistic regression models were estimated. Results In total, 2,948 CCS and 1,055 siblings completed the tinnitus item. Tinnitus was reported in 9.5% of survivors and in 3.7% of siblings (OR 3.0, 95% CI 2.9-3.1). Risk factors associated with tinnitus in CCS were total cumulative dose cisplatin ≥400 mg/m 2 (OR 2.4, 95% CI 1.4-4.0), age at diagnosis (≥10 years: OR 2.1, 95% CI 1.6-2.8), cranial irradiation/total body irradiation (TBI) (OR 1.9, 95% CI 1.5-2.5), and neuro/ear, nose, throat (ENT) surgery (OR 1.8, 95% CI 1.1-2.9). Fifty-one percent of CCS with tinnitus had received treatment with either cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery. Conclusions Tinnitus in CCS was present nearly three times more often than in siblings. Awareness in CCS previously treated with cisplatin, cranial irradiation/TBI and/or neuro/ENT surgery is warranted. As only half of affected CCS had a history of these treatments, it seems that other factors might be associated with tinnitus occurrence in this population.
... Some survivors face a range of medical challenges relating to late treatment effects. They are at heightened risk of complications such as recurrence of their primary cancer, secondary cancers, cardiac disease, infertility, ototoxicity or bone disease (Clemens et al., 2016;den Hoed et al., 2015;Gibson et al., 2018;Khan et al., 2018;Taylor et al., 2009;Wasilewski-Masker et al., 2008). This can result in frequent ongoing contact with the health service and repeated hospitalisations (Brewster et al., 2014;de Fine Licht et al., 2017). ...
Article
Full-text available
Objective To establish the major expressed psychological needs of adult survivors of childhood cancer living in Ireland. Methods Seven focus groups were conducted with adult survivors of childhood cancer and their parents in 2018. Survivors were invited to participate if they were diagnosed with cancer before age 18. Results Thirty‐three participants (15 survivors, 18 parents; 27 female, 6 male) were included. They had experienced a range of haematological and solid tumours. Five themes were generated: (a) Enduring psychological impact on survivors; many survivors experience delayed trauma and mental health crises in adulthood. (b) Enduring psychological impact on family members; parents and siblings have unmet psychological needs relating to the family's experience of cancer. (c) Enduring impact on family dynamics; survivors and parents expressed fear and guilt relating to cancer which impacted on family interactions. (d) Challenges accessing support; psychological support services are inadequate to meet expressed needs. (e) Desired model of care; no single service model appeals to all survivors, and flexibility is required in the delivery of psychological support. Conclusion Adult survivors of childhood cancer and their family members experience enduring psychological effects relating to their diagnosis and treatment. Psychological support services are inadequate to meet the expressed needs of this growing population.
... Cisplatin has also been related to ototoxicity in adults and children with cancer [23]. Ototoxicity is associated with declines on intellectual and academic performances and worse social and langauge development [24,25]. Where possible, cisplatin should be replaced by carboplatin with a more favourable toxicity profile. ...
Article
Full-text available
Background Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. Methods In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. Results In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5–101.8, versus 104.4, 95% CI: 100.4–108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6–4.3, versus 4.5, 95% CI: 4.1–4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). Conclusions Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. Clinical trial registration The study is registered at ClinicalTrials.gov, NCT00330447.
... En la serie de pacientes que presentamos se encontró que un 21,05% de los niños desarrollaron una hipoacusia como secuela del tratamiento con platinos, radioterapia craneal y/o intervención neuroquirúrgica. En estudios previos se reportan porcentajes mayores, en torno al 50% 7,9,20 reflejo de que los estudios son heterogéneos en relación con la definición de hipoacusia, test diagnósticos realizados, características de los pacientes, tipos de tratamientos oncológicos, otros fármacos ototóxicos administrados y la duración del seguimiento 22 . ...
Article
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Resumen Introducción La ototoxicidad se presenta en diversos porcentajes según estudios tras el tratamiento con quimioterapia basada en platino y/o radioterapia craneal. El objetivo es mostrar nuestra experiencia en la monitorización de la ototoxicidad. Material y métodos Se realizó una revisión del 1999 al 2019 en el registro de pacientes oncológicos pediátricos de nuestro hospital y remitidos a la Unidad de Hipoacusia Infantil. Resultados 46 pacientes fueron remitidos a nuestra unidad. 41 pacientes recibieron platinos como parte de su tratamiento, 17 pacientes fueron sometidos a una intervención neuroquirúrgica y 18 pacientes recibieron radioterapia craneal. A todos se les realizó una anamnesis y otoscopia, y la monitorización se llevó a cabo con una audiometría tono-verbal y/o productos de distorsión. Se objetivó una hipoacusia como secuela del tratamiento en ocho pacientes (21,05% de los pacientes remitidos para seguimiento audiológico). Fue imposible determinar la situación audiológica al finalizar el tratamiento en ocho pacientes. La adaptación audioprotésica fue necesaria en dos pacientes. En la coordinación con Oncología Pediátrica, se consideró oportuno el cambio de cisplatino por carboplatino por ototoxicidad importante durante el tratamiento en un único paciente. Conclusión Es imprescindible una adecuada coordinación con Oncología Pediátrica para realizar una vigilancia activa de la ototoxicidad y modificar, si es posible, la dosificación o el tipo de quimioterápico en caso de verse afectada la audición. En nuestra experiencia, y siguiendo las recomendaciones actuales, realizamos una valoración pretratamiento, una monitorización durante el tratamiento, al finalizarlo y después de forma anual por el riesgo de desarrollo diferido de una hipoacusia.
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Intensive treatments including high-dose chemotherapy (HDC) with autologous stem cell rescue have improved high-risk neuroblastoma (HRNB) survival. We report the long-term health status of 145 HRNB survivors, alive and disease-free 5 years post HDC. Median follow-up was 15 years (range = 5–34). Six patients experienced late relapses, 11 developed second malignant neoplasms (SMNs), and 9 died. Event-free and overall survivals 20 years post HDC were 82% (95% CI = 70%–90%) and 89% (78%–95%), respectively. Compared with the French general population, the standardized mortality ratio was 19 (95% CI = 8.7–36.1; p < 0.0001) and the absolute excess risk was 37.6 (19.2–73.5). Late effects were observed in 135/145 patients (median = 3 events/patient); 103 had at least one severe event. SMNs arose at a median of 20 years post HDC and included carcinoma (n = 5), sarcoma (2), acute myeloid leukemia (2), melanoma (1), and malignant glioma (1). Non-oncologic health events included dental maldevelopment (60%), severe hearing loss (20% cumulative probability at 15 years), hepatic focal nodular hyperplasia (14%), thyroid (11%), cardiac (8%), and renal (7%) diseases and growth retardation (height-for-age z-score ≤ −2 for 21%). Gonadal insufficiency was near-universal after busulfan (40/43 females, 33/35 males). Severe late effects are frequent and progressive in HRNB survivors needing systematic very long-term follow-up.
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Introduction Platinum-based chemotherapeutics play an important role in the treatment of cancer at different levels and are the most cited ototoxic agents when scientific evidence is analyzed. Objective To present scientific evidence based on a systematic literature review, PRISMA, in order to systematize information on the ototoxic effects of using antineoplastic drugs. Methods For the selection of studies, the combination based on the Medical Subject Heading Terms (MeSH) was used. The Medline (Pubmed), LILACS, SciELO, SCOPUS, WEB OF SCIENCE and BIREME databases were used, without restriction of language, period, and location. Evaluation of the quality of the articles was carried out, which included articles with a minimum score of 6 in the modified scale of the literature. The designs of the selected studies were descriptive, cohort, and cross-sectional, which were related to the research objective. Results Three articles were included in this systematic review. The ototoxicity caused by cisplatin alone varied from 45% to 83.3%, while that caused by the use associated with carboplatin varied from 16.6% to 75%. There was a significant variation in the cumulative doses of these antineoplastic agents, both in isolated and in combination. Auditory changes, especially at high frequencies, were evident after completion of treatment. Conclusion Auditory changes after the use of platinum-based antineoplastic drugs were found, however, there was an important heterogeneity regarding the frequency of ototoxicity and the cumulative dose of the drugs used.
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Polymorphisms in genes can affect the efficacy of drugs in individual patients as well as their risk for adverse drug reactions. This particularly applies for life-saving drugs with narrow therapeutic ranges, which can induce irreversible disabling side effects.
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Multimodal osteosarcoma therapy according to past and current European and American protocols is described. This includes both local treatment (usually surgery) and systemic antineoplastic therapy, which is often based on high-dose methotrexate, doxorubicin (Adriamycin), cisplatin, and sometimes ifosfamide. As all must be employed at relatively high doses, early and late adverse effects have long been a major research focus. Their long-term late effects on organ function are described, and recommendations for lifelong follow-up are given. These are meant to comply with the evidence-based recommendations of the International Guideline Harmonization Group. Follow-up after surgery of the primary tumor and (endoprosthetic) reconstruction require the expertise of specialized centers.
Article
Background: Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during treatment. Up to now, several risk factors have been identified that may contribute to ototoxicity, such as platinum derivates, cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal. Currently, knowledge is lacking on the prevalence of ototoxicity. Objective: The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors. Methods: The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution of antibiotics and diuretics on ototoxicity. Results: This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417/M). Currently, we are in the process of recruitment for this study. Conclusions: The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are currently being prepared. Trial registration: Netherlands Trial Register NL8881; https://www.trialregister.nl/trial/8881. International registered report identifier (irrid): DERR1-10.2196/34297.
Article
Ototoxicity and other neurologic toxicities are potential consequences of exposure to common therapeutic agents used during treatment of childhood cancer, including platinum and vinca alkaloid chemotherapy, cranial radiation, surgery involving structures critical to cochlear and neurologic function, and supportive care medications such as aminoglycoside antibiotics and loop diuretics. This article provides an overview of ototoxicity and other neurologic toxicities related to childhood cancer treatment, discusses the challenges that these toxicities may pose for survivors, and presents an overview of current recommendations for surveillance and clinical management of these potentially life-altering toxicities in survivors of childhood cancers.
Article
Background Tinnitus can occur during and after treatment for childhood cancer. Studies on the occurrence of, and risk factors for tinnitus during and after childhood cancer treatment are scarce. The aim of this study is to get insight into the frequency and risk factors of tinnitus during and after childhood cancer therapy, based on a review of all previously reported literature. Materials and methods Systematic electronic literature searches that combined childhood cancer with different treatments and tinnitus terms were performed in the databases EMBASE, Medline, Cochrane, Web of Science, and Google Scholar. Studies were included based on reporting the frequency of tinnitus during and/or after childhood cancer, with 75% of participants being under the age of 25 at time of diagnosis, diagnosed with any type of childhood malignancy and treated with any type of chemotherapy and/or radiotherapy. A risk of bias assessment per research question was performed. Results Tinnitus incidence rates were reported up to 15.9 (95% CI 11.8–21.4) during therapy and up to 5.4 (95% CI 4.3–6.9) more than 5 years after diagnosis. The relative risk of developing tinnitus as compared to siblings during and after childhood cancer therapy were reported up to 17.2 (95% CI 11.8–25.0) during therapy and up to 3.7 (95% CI 2.7–5.1) more than 5 years after diagnosis. Independent risk factors for tinnitus development included high dose cranial radiation and platinum based chemotherapy. Conclusion The frequency of and risk to develop tinnitus seems to be higher in childhood cancer patients and survivors as compared to the normal population. Regular tinnitus screening before, during and after therapy with standardized questionnaires for early detection seems therefore reasonable in order to identify high-risk patients and eventually develop successful clinical preventive, supportive and management strategies.
Article
PURPOSE Hearing loss is a significant late effect among childhood cancer survivors. Recent guidelines note insufficient evidence to quantify its natural history or risk associated with specific exposures. We examined the long-term incidence and predictors of hearing loss requiring hearing amplification devices (HADs) using population-based health care data. METHODS In Ontario, Canada, HAD costs are subsidized by the Assistive Devices Program (ADP). Ontario children < 18 years of age at cancer diagnosis between 1987 and 2016 were identified and linked to ADP claims. Cumulative HAD incidence was compared between cases and matched controls. Patient, disease, and treatment predictors of HAD were examined. RESULTS We identified 11,842 cases and 59,210 controls. Cases were at higher risk for HAD (hazard ratio [HR], 12.8; 95% CI, 9.8 to 16.7; P < .001). The cumulative incidence of HAD among survivors was 2.1% (95% CI, 1.7% to 2.5%) at 20 years and 6.4% (95% CI, 2.8% to 12.1%) at 30 years post-diagnosis. The 30-year incidence was highest in neuroblastoma (10.7%; 95% CI, 3.8% to 21.7%) and hepatoblastoma (16.2%; 95% CI, 8.6% to 26.0%) survivors. Predictors of HAD in multivariable analyses included age 0-4 years at diagnosis ( v 5-9 years; HR, 2.2; 95% CI, 1.4-3.3; P < .001). Relative to no cisplatin exposure, patients receiving < 200 mg/m ² were not at greater risk, unlike those receiving higher cumulative doses. Relative to no cranial or facial radiation, those who had received ≤ 32.00 Gy were at no higher risk, unlike those who had received > 32.00 Gy. Carboplatin exposure was not associated with HAD. CONCLUSION Childhood cancer survivors are at elevated risk for requiring HAD, which continues to increase between 20 and 30 years after diagnosis. Thresholds of cisplatin and radiation exposure exist, above which risk substantially increases. Prolonged monitoring and trials of otoprotective agents are warranted in high-risk populations.
Article
Nicht nur Aminoglykoside und Platin-haltige Medikamente, sondern auch häufiger verwendete Medikamente wie Schleifendiuretika können das Gehör und das Gleichgewichtsorgan schädigen. Auch eine ungünstige Auswirkung einer langfristigen Schmerzmittel-Verabreichung ist möglich.
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Background For extracranial malignant germ cell tumours (MGCTs) in the UK, the GCII study used carboplatin-based chemotherapy (JEb) and demonstrated equivalent survival to cisplatin-containing protocols. GCIII, a single-arm observational study, used new risk stratification, replaced consolidation chemotherapy with a standard number of cycles and introduced surveillance for all stage I MGCTs. Pure teratomas were registered to understand their natural history. Methods Patients with MGCTs were stratified to three risk groups – low risk (LR), intermediate risk (IR) and high risk (HR), using stage and prognostic factors. Patients with alpha fetoprotein (AFP) >10,000 kU/L, stage IV disease (except testis <5 years and all germinomas) or stage II-IV mediastinal tumour were classified HR. Stage I tumours (LR) received chemotherapy only if disease progressed. IR and HR patients received 4 and 6 JEB cycles, respectively. Carboplatin dose was calculated using glomerular filtration rate to give an area under the curve of 7.9 ml/m².min. Results Eighty-six patients with MGCTs were enrolled from 2005 to 2009: 59% female, median age, 5.7 years. Twenty-five patients were LR, 21 IR and 38 HR. Seven LR patients had disease progression; all were successfully treated with chemotherapy. Overall survival (OS) for the whole group was 97%; 5-year event-free survival for JEb-treated patients was 92%, and OS, 95%. JEb was well tolerated with no observed significant hearing or renal side-effects. There was no discernible difference in carboplatin dose whether calculated by body surface area or creatinine clearance. Forty-seven patients with teratoma were managed with surgery and one had malignant transformation. Conclusion Carboplatin-based chemotherapy as part of a risk-stratified approach leads to excellent survival in paediatric MGCTs, minimising potential burden of long-term effects.
Article
Introduction Ototoxicity occurs in different percentages in patients after treatment with platinum-based chemotherapy or cranial radiation therapy. The aim of this study was to present our experience in ototoxicity monitoring. Material and methods A review was made of the registry of paediatric cancer patients referred to the Children’s Hearing Loss Unit from 1999 to 2019. Results Of the 46 patients referred to this unit, 41 had received platinum as part of their treatment, 17 patients underwent neurosurgery, and 18 patients received cranial radiation therapy. An anamnesis and otoscopy were performed on all of them, and the monitoring was carried out with tone-verbal audiometry and/or distortion products. Hearing loss was observed in eight patients (21.05% of patients referred for audiological follow-up) as a consequence of the treatment. It was impossible to determine the audiological situation in eight patients at the end of treatment. Hearing aid adaption was necessary in two patients. In coordination with Paediatric Oncology, a change from cisplatin to carboplatin due to bilateral grade two ototoxicity was considered appropriate during treatment in one patient. Conclusion Adequate coordination with Paediatric Oncology is essential to carry out active surveillance for ototoxicity and to modify, if possible, the dosage or type of chemotherapy in case hearing is affected. In our experience, and following current recommendations, a pre-treatment assessment is usually performed, as well as monitoring during treatment, at the end of treatment, and annually thereafter due to the risk of a later development of hearing loss.
Article
Purpose: Platinum-derived chemotherapy is one of the cornerstones in the treatment of central nervous system tumors in children. We aimed to assess the incidence of hearing loss in children after the exposure to platinum drugs. Material and methods: Retrospective study of prospectively collected data on children consecutively diagnosed with brain tumors and treated with platinum derivatives at a tertiary referral hospital between January 2006 and December 2015. We analyzed multiples variables, such as: age at diagnosis, tumor location, hydrocephalus, platinum drug type, radiotherapy, and follow-up time. The final sample size was 51 patients. Results: The median age at diagnosis was 6 years. The median overall follow-up time was 75 months. The incidence of ototoxicity was 23.5%. Rates of hearing loss with carboplatinum were lower than with cisplatinum. A statistically significant association occurred between the presence of hydrocephalus, radiotherapy exposure, infratentorial tumor location, and ototoxicity after treatment with platinum derivatives. Conclusions: Childhood central nervous system tumors nowadays exhibit improved cure and survival rates. However, the ototoxicity resulting from the chemotherapy treatment may accompany patients for the rest of their lives. This study reveals that this occurrence is not negligible, and the association of radiotherapy and the presence of hydrocephalus can be potentiating factors.
Article
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Platinum-based chemotherapeutic agents cisplatin and carboplatin are widely used in cancer treatment worldwide and may result in ototoxic hearing loss. The high incidence of cancer and salient ototoxic effects of platinum-based compounds pose a global public health threat. The purpose of this study was twofold. First, to estimate the prevalence of ototoxic hearing loss associated with treatment with cisplatin and/or carboplatin via a systematic review and meta-analysis. Second, to estimate the annual global burden of ototoxic hearing loss associated with exposure to cisplatin and/or carboplatin. For the systematic review, three databases were searched (Ovid Medline, Ovid Embase, and Web of Science Core Collection) and studies that reported prevalence of objectively measured ototoxic hearing loss in cancer patients were included. A random effects meta-analysis determined pooled prevalence (95% confidence intervals [CI]) of ototoxic hearing loss overall, and estimates were stratified by treatment and patient attributes. Estimates of ototoxic hearing loss burden were created with published global estimates of incident cancers often treated with platinum-based compounds and cancer-specific treatment rates. Eighty-seven records (n = 5077 individuals) were included in the meta-analysis. Pooled prevalence of ototoxic hearing loss associated with cisplatin and/or carboplatin exposure was 43.17% [CI 37.93-48.56%]. Prevalence estimates were higher for regimens involving cisplatin (cisplatin only: 49.21% [CI 42.62-55.82%]; cisplatin & carboplatin: 56.05% [CI 45.12-66.43%]) versus carboplatin only (13.47% [CI 8.68-20.32%]). Our crude estimates of burden indicated approximately one million individuals worldwide are likely exposed to cisplatin and/or carboplatin, which would result in almost half a million cases of hearing loss per year, globally. There is an urgent need to reduce impacts of ototoxicity in cancer patients. This can be partially achieved by implementing existing strategies focused on primary, secondary, and tertiary hearing loss prevention. Primary ototoxicity prevention via otoprotectants should be a research and policy priority.
Article
Hypothesis: Furosemide alters the permeability of the intrastrial fluid-blood barrier. Background: The cochlear sensory cells are protected by the blood-perilymph and intrastrial fluid-blood barriers, which hinder substances, including gadolinium-based contrast agents (GdCAs), to enter the endolymphatic space. High-dose furosemide causes transient shift of hearing thresholds and morphological changes in stria vascularis. Furosemide is also known to enhance drug-induced ototoxicity. Methods: Furosemide (400 mg/kg b.w.) was injected i.v. in Balb/C mice (n = 20). Twenty minutes later, the GdCA gadobutrol, gadopentetic acid, or gadoteric acid was injected i.v. The distribution of GdCA to the perilymphatic and endolymphatic spaces was studied with MRI (9.4 T) for 250 minutes. Results: The perilymphatic and endolymphatic spaces were signal-enhanced in all animals. Gadopentetic acid and gadoteric acid yielded similar signal enhancement in all three scalae, while gadobutrol yielded significantly higher enhancement in scala tympani than scala media (p = 0.043) and scala vestibuli (p = 0.043). The signal enhancement reached a plateau but did not decrease during the time of observation. Conclusion: Treatment with a high dose of furosemide before injection of a GdCA resulted in enhancement of the MRI signal in the endolymphatic space as well as the perilymphatic space, which supports our hypothesis that furosemide alters the permeability of the intrastrial fluid-blood barrier.
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Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.
Article
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Purpose This review article summarizes our current understanding of the mechanisms underlying acquired hearing loss from hospital-prescribed medications that affects as many as 1 million people each year in Western Europe and North America. Yet, there are currently no federally approved drugs to prevent or treat the debilitating and permanent hearing loss caused by the life-saving platinum-based anticancer drugs or the bactericidal aminoglycoside antibiotics. Hearing loss has long-term impacts on quality-of-life measures, especially in young children and older adults. This review article also highlights some of the current knowledge gaps regarding iatrogenic causes of hearing loss. Conclusion Further research is urgently needed to further refine clinical practice and better ameliorate iatrogenic drug-induced hearing loss.
Article
Background: Cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity for childhood cancer survivors. Understanding provider perspectives is crucial to developing otoprotection studies that are both informative and feasible. Two international trials (ACCL0431 and SIOPEL6) investigated the drug sodium thiosulfate (STS) as an otoprotectant, but definitive interpretation of the findings of these trials has been challenging. Adoption of STS has therefore been uneven, and provider perspectives on its role are unknown. Procedure: The Children's Oncology Group (COG) Cancer Control and Supportive Care Neurotoxicity Subcommittee therefore conducted a survey of providers at COG institutions to determine perspectives on pediatric otoprotection practices and research surrounding three major themes: (1) prevalence of routine use of STS with cisplatin-based regimens, (2) application of audiometry to cisplatin therapy, and (3) preferred modalities for otoprotection research. Results: Survey respondents (45%, 44/98 surveyed institutions) were of diverse institutional sizes, practice settings, and geographical locations primarily in the United States and Canada. Overall, respondents considered CIHL an important toxicity and indicated strong enthusiasm for future studies (98%, 40/41). Results indicated that while STS was the current or planned standard of care in a minority of responding institutions (36%, 16/44), most sites were receptive to its inclusion in appropriate study designs. Application of audiometry for ototoxicity monitoring varied widely across sites. For otoprotection research, systemic agents were preferred (68%, 28/41) as compared with intratympanic approaches. Conclusion: These results suggest that pediatric otoprotection trials remain of interest to providers; the emphasis of these trials should remain on systemic and not intratympanic therapy.
Article
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Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed. Audiological evaluations were reviewed for 379 patients with newly diagnosed medulloblastoma (ages 3-21 years). Each patient was enrolled on one of two St. Jude clinical protocols that included craniospinal radiation therapy and four courses of 75 mg/m(2) cisplatin chemotherapy. The latest audiogram conducted 5.5-24.5 months post-protocol treatment initiation was graded using the Chang and SIOP ototoxicity criteria. Clinically significant hearing loss was defined as Chang grade ≥2a and SIOP ≥2. Hearing loss was considered serious (requiring a hearing aid) at the level of Chang grade ≥2b and SIOP ≥3. A strong concordance was observed between the Chang and SIOP ototoxicity scales (Stuart's tau-c statistic = 0.89, 95% CI: 0.86, 0.91). Among those patients diagnosed with serious hearing loss, the two scales were in good agreement. However, the scales deviated from one another in classifying patients with less serious or no hearing loss. Although discrepancies between the Chang and SIOP ototoxicity scales exist primarily for patients with no or minimal hearing loss, the scales share a strong concordance overall. Pediatr Blood Cancer 2014;61:601-605. © 2013 Wiley Periodicals, Inc.
Article
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Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study. Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m(2); exposure one) or after cisplatin (400 mg/m(2)) plus carboplatin (1,700 mg/m(2); exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]). Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection. Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.
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Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26-16.27) years. Follow-up was 6.97 (IQR, 0.87-15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m(2). Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m(2) and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m(2); IQR, 240-360 mg/m(2) and median carboplatin dose: 1200 mg/m(2); IQR, 600-3000 mg/m(2)). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m(2), six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.
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Background: High doses of cisplatin and cranial radiotherapy (CRT) have been reported to cause irreversible hearing loss. The objective of this study was to examine the influence of cranial irradiation on cisplatin-associated ototoxicity in children with pediatric malignancies. Methods: Serial audiograms were obtained for 33 children, age <16 years, treated with cisplatin-based chemotherapy (90-120 mg/m(2) per cycle) with or without CRT. Eligible patients included those with normal baseline audiometric evaluations and without significant exposure to other ototoxic drugs. We defined significant hearing loss as a hearing threshold ≥30 dB at 2,000-8,000 Hz frequencies. Results: The median age of our study population was 4.9 years (range 6 weeks to 16 years), and the male to female ratio was 0.8:1. The study population consisted of 15 Caucasians, 17 African-Americans, and 1 Hispanic. Fourteen patients had brain tumors, and 19 had other solid tumors. Thirteen patients were exposed to CRT, and 20 were not. Bilateral hearing loss was observed in 24/33 (73%) patients, with severe/profound (≥70 dB) impairment in 10/33 (30%) of all patients. Young age (<5 years), CRT, and brain tumors were independent prognostic factors predicting hearing loss. Conclusion: The study demonstrated a high incidence of hearing loss in children treated with cisplatin and CRT. Consequently, we recommend monitoring these children for the early detection of hearing loss.
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Carboplatin-induced ototoxicity remains poorly defined but is of potential great consequence in children with retinoblastoma. We retrospectively assessed the incidence of ototoxicity and its risk factors in children with retinoblastoma who were treated with carboplatin. We reviewed the audiologic test results of 60 patients with retinoblastoma who received front-line treatment with systemic carboplatin and vincristine according to the St Jude RET-3 protocol (n = 23) or best clinical management (n = 37). Ototoxicity was evaluated by three different grading systems. Twelve patients (20%) developed ototoxicity at some time after treatment initiation; however, ototoxicity resolved in two patients, and thus,10 patients (17%) had sustained hearing loss as documented at their most recent audiologic evaluation. Nine of these 10 patients had grade 3 or 4 ototoxicity, and nine patients were less than 6 months of age at the start of chemotherapy. Age at the start of chemotherapy was the only risk factor identified as a significant predictor of sustained hearing loss. Younger age was associated with an increased incidence of hearing loss. The different ototoxicity grading systems showed good overall agreement in the identification of patients with ototoxicity. Agreement was greatest between the Brock and Children's Cancer Group systems. We found that young patients with retinoblastoma who were treated with systemic carboplatin had a higher incidence of ototoxicity than previously reported. Younger patients (< 6 months of age at the start of treatment) were more likely to have ototoxicity than were older patients. Children treated with carboplatin should routinely undergo thorough, long-term audiologic monitoring.
Article
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The aim of this study was to investigate long-term development of hearing in subjects who had received platinum-based chemotherapy in childhood or adolescence. Another aim was to assess the self-reported hearing loss handicap and compare it to audiometric measurements. Medical records from individuals diagnosed with childhood cancer and treated with platinum-based chemotherapy between 1985 and 2000 at the University Hospital in Lund Sweden were reviewed retrospectively. Fifteen subjects, who fulfilled the eligibility criteria set for the study, underwent a thorough audiometric evaluation. The results show that the hearing loss, in subjects with ototoxicity had increased after the end of treatment, to include also the lower frequencies. The largest deterioration in hearing thresholds, up to 55 dB HL, was found at frequencies above 2 kHz. The findings also reveal that the subjects have a considerably greater hearing loss handicap and disability than would be expected from the results of the audiometric evaluations. The conclusion of this study is that children and adolescence treated with platinum-based chemotherapy should have regular audiometric follow-up examinations, also many years after the end of treatment. Furthermore, assessments of self-reported hearing disability should be made during and after chemotherapy.
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We present a new ototoxicity grading system that has clearly defined and frequency-specific audiometric criteria. The purpose of this study was to validate this grading system by assessing its correspondence to audiology treatment recommendations and comparing it with the currently utilized Common Terminology Criteria for Adverse Events (CTCAE). A retrospective chart review was conducted using audiologic, demographic, and clinical data from 134 children receiving 149 courses of chemotherapy consisting of cisplatin and/or carboplatin. Pure-tone audiograms were evaluated using both our proposed grading criteria and the CTCAE criteria. The resulting grades were then compared with charted audiologic interventions and a number of clinical parameters to assess the clinical validity of the grading scale. Chang grade 2a or higher predicted audiologic intervention. Although both the Chang and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices such as hearing aids and/or frequency modulated systems (P < .0001), the Chang scale was more specific, with the CTCAE scale diverging from clinical recommendation at higher grades. As expected, patients receiving cisplatin had more severe hearing loss with concurrent carboplatin administration, radiation therapy exposure, younger age, smaller body-surface area, longer treatment exposure, and more severe disease. This grading system provides robust and clinically useful criteria to represent clinical hearing loss induced by ototoxicity with regard to the impact on speech and language and the need for assistive hearing devices. It is both more specific and more sensitive than the traditional CTCAE criteria for identifying clinically significant ototoxicity.
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Objectives: The purpose of this study was to evaluate the severity of hearing loss after cisplatin and/or carboplatin treatment in young children and to analyze its evolution and its relation to different therapy schedules. Methods: One hundred twenty patients treated in the Pediatrics Department at the Institut Gustave-Roussy from 1987 to 1997 for neuroblastoma, osteosarcoma, hepatoblastoma, or germ cell tumors were analyzed. Median age at diagnosis was 2.6 (range 0-17) years. Median follow-up was 7 (1-13) years. Chemotherapy regimens contained cisplatin and/or carboplatin. Three patients also received high-dose carboplatin. Cisplatin was administered at a dose of 200 mg/m/course in 72% of cases. The median cumulative dose was 400 mg/m for cisplatin and 1,600 mg/m for carboplatin. Hearing loss of grade 2 or above, according to Brock's grading scale, was revealed with pure tone audiometry and behavioral techniques. Results: Carboplatin alone was not ototoxic. Deterioration of hearing of grade 2 or above was observed in 37% of patients treated with cisplatin and 43% of patients treated with cisplatin plus carboplatin (P = NS). Fifteen percent of patients experienced grade 3 or 4 ototoxicity. Ototoxicity was most often observed after a total cisplatin dose of at least 400 mg/m. No improvement was observed with time; on the contrary, worsening or progression of hearing loss at lower frequencies was detected during follow-up. Only 5% of audiograms showed toxicity of at least grade 2 before the end of therapy; in contrast, this level was observed in 11% of early post-therapy evaluations and in 44% after more than 2 years of follow-up. Conclusions: Children treated with cisplatin at cumulative doses approaching 400 mg/m require long-term surveillance to avoid overlooking hearing deficits. Carboplatin, at a standard dose, does not appear to be a significant risk factor for ototoxicity even in patients who have already been treated with cisplatin.
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Background The antineoplastic agents cisplatin and carboplatin are widely-used and highly-effective against a variety of pediatric cancers. Unfortunately, ototoxicity is a frequently encountered side effect of platinum-based chemotherapy. There is currently no treatment or prevention for platinum-induced ototoxicity and development of hearing loss may lead to devastating consequences on the quality of life of pediatric cancer survivors. The objective of this study is to determine the incidence of platinum-induced ototoxicity in a large series of pediatric patients and to evaluate the incidence of progression of ototoxicity after completion of treatment. ProceduresA retrospective chart review of pediatric patients treated with cisplatin or carboplatin between 2000 and 2012 was conducted. The incidence of ototoxicity was determined based on the American-Speech-Language-Hearing Association (ASHA) criteria and severity was based on the Chang classification. ResultsFour hundred and sixty-six patients received platinum-based chemotherapy. Patients were excluded due to congenital hearing loss (n=1) and insufficient data for calculating the platinum dose (n=24) or for assessing ototoxicity (n=135). Three hundred and six patients were included in the analysis. Post-chemotherapy ototoxicity was detected in 148 (48%) patients, and clinically-significant ototoxicity was present in 91 (30%). In addition, based on the ASHA criteria, 48% of patients (97/204) with long-term follow-up had further deterioration of their hearing after completion of treatment. Conclusions Ototoxicity following chemotherapy with cisplatin or carboplatin is common and can frequently progress after the completion of treatment. Long-term follow-up is strongly recommended. Pediatr Blood Cancer 2014;61:2012-2017. (c) 2014 Wiley Periodicals, Inc.
Article
Cisplatin is an effective chemotherapeutic agent against pediatric cancers; however, ototoxicity is a concern. This study describes the frequency, severity, and clinical course of hearing loss in Japanese pediatric patients treated with cisplatin-based multimodal therapy. A total of 55 children who received cisplatin-based therapy from 1983 to 2012 underwent audiologic evaluations. Data were analyzed to determine the onset, time-to-progression, and severity of hearing loss. Thirty-five patients, 12 of 16 older patients (4 y or older), and 23 of 39 younger patients (under 4 y), including 7 of 8 patients treated with cisplatin, carboplatin, and radiotherapy, developed hearing loss. Ten of 18 patients who received a cumulative cisplatin dose of <360 mg/m developed hearing loss at a minimum dose of 200 mg/m. Median time to onset after the last cisplatin dose was 71 days; 6 patients developed hearing loss after ≥2 years. Four patients required hearing aids, 6 patients developed progressive hearing loss with time, and 4 patients exhibited persistent hearing failure at low frequencies. Risk factors for acquired hearing loss and its severity may be associated with a combination of factors such as cisplatin and carboplatin therapy, radiotherapy, age at diagnosis, and genetic background. Our results suggested that all pediatric patients treated with cisplatin would have their hearing evaluated regularly, irrespective of the cumulative cisplatin dose as a suggestion, and that further prospective studies regarding ototoxicity including genetic polymorphisms analysis were required.
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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.
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BackgroundA secondary end point of the NBL90 protocol (Rubie H et al. Pediatr Oncol 2001;36:247–250) was the concern in this infant population for possible carboplatin-(CBDCA) induced late side effects including impaired renal and hearing functions.ProcedureGlomerular filtration rate (GFR), tubular function (TF), pure tone audiometry (PTA), high-frequency, and transient evoked-otoacoustic emission were prospectively assessed in 30 children alive and disease-free 6 years after the end of the treatment.ResultsMedian age at diagnosis and at assessment was 4.7 months and 7 years, respectively. Blood pressure was ≤97.5 centile in all children. The mean estimated GFR was 114 ± 13 ml/min/1.73 m2 by Schwartz formula [range 87–145]. TF assessment failed to demonstrate any impairment. 29/30 children had grade 0 ototoxicity and all transient evoked otoacoustic emission were normal.Conclusions With a 6-year follow-up the combination of VP16 and carboplatin given at conventional doses is safe on renal and hearing functions in infants with unresectable neuroblastomas treated according to SFOP NB90. Pediatr Blood Cancer 2005; 45:32–36. © 2005 Wiley-Liss, Inc.
Article
Objective: To describe hearing changes in a group of 28 children (age range, 8-180 mo) undergoing protocol-based cisplatin therapy. Methods: Conventional, play audiometry, visual reinforcement audiometry (VRA), immittance audiometry, transient click evoked otoacoustic emissions (OAEs), and auditory brainstem response (ABR) evoked potentials were used to assess peripheral sensitivity and for threshold determination. Results: Bilateral symmetrical high-frequency sensorineural hearing loss was noted in 9 of the 28 children (26%). Hearing loss was evident as early as 1 month after chemotherapy and as late as 50 months and was not dependent on individual or cumulative dosage of cisplatin. Conclusions: 1) Presence of sensorineural hearing loss was independent of individual and/or cumulative dosage of cisplatin; 2) audiologic assessment should be incorporated into a child's periodic medical evaluations after chemotherapy treatment, as onset of sensorineural hearing loss cannot be predicted; 3) personal hearing aids may be indicated for those children with hearing loss affecting the low- to mid-frequencies; a personal assistive listening device (frequency modulated system) may be more appropriate for losses above 3000 Hz; and 4) evaluation and intervention by a speech-language pathologist may be indicated to address possible articulation or language development problems consequent to hearing loss.
Article
Background Slight high frequency hearing loss following cisplatin chemotherapy can be proof of an ototoxic effect even when hearing ability is not yet clinically affected. To answer scientific questions, such as the relationship between cisplatin ototoxicity and drug regime or individual tolerance, early detection of ototoxicity and a classification relating to intensity and the affected frequencies are required. A search for relevant literature resulted the WHO-classification (1991) describing clinically relevant hearing loss and two high frequency hearing loss classifications published by Khan et al. (1982) and Brock et al. (1991). Their application is compared to a new, proprietary classification. Patients and methods 55 patients (32 boys, 23 girls) undergoing cisplatin chemotherapy at Muenster University Hospital from 1999 to 2004 underwent audiometric tests in our department. From this data we developed a grading system, that was based on the WHO classification, but paid special attention to early ototoxic effects, to intensity of hearing loss and to the frequencies affected: Grade 0 (normal hearing) includes hearing loss of not more than 10 dB in all frequencies. Grade 1 (beginning hearing loss) encompasses >10 dB up to 20 dB in at least one frequency or tinnitus. Grade 2 (moderate impairment) describes hearing loss ≥4 kHz and differentiates 2a (>20 to 40 dB), 2b (>40 to 60 dB) and 2c (>60 dB). Hearing loss <4 kHz >20 dB in grade 3 (severe impairment, hearing aids needed) is further classified according to grade 2 in a, b and c. Grade 4 (loss of function) finally decribes average hearing loss <4 kHz of at least 80 dB. This classification is compared to the two high frequency hearing loss classifications (Khan et al. and Brock et al.). Results The Muenster classification, compared to Khan et al. and Brock et al., demonstrated the best results in the early detection of hearing loss: All children with hearing loss of at least 20 dB after therapy had already shown pathological audiograms during treatment, when those audiograms were assessed by our classification. All children whose audiograms were flagged as pathological by our classification finally developed hearing loss. In terms of the prediction of hearing loss, our classification evualated processing audiograms with a sensitivity, specifity and efficiency of 1.0. Progressive hearing loss was detected in 45 patients (Khan et al. 30, Brock et al. 38). Therefore our classification showed a better suitability for monitoring hearing loss than the other classifications. Conclusion The Muenster classification is a suitable new basis for scientific questions concerning cisplatin ototoxicity. It detects hearing loss earlier and maps progression of hearing loss more precisely than the existing high frequency classifications (Khan et al. and Brock et al.).
Article
During and after 233 cycles of cis-diamminedichloroplatinum (II) (CDDP), 197 serial audiograms were obtained in 48 patients and compared with baseline audiograms. Use was made of three dose schedules (20 mg/m2, 25–50 mg/m2 and 70–120 mg/m2), two regimens (single-day or daily for 5 days) and three modes of administration (rapid infusion, 2- or 3-hr infusion, 24-hr infusion). Clinical hearing loss occurred in 12.5% and tinnitus in 25% of all patients. The incidence of audiographic changes (65% overall, 81% bilaterally) increased with increasing cumulative CDDP dose independent of treatment schedule. The incidence was correlated with the daily dose (P = 0.0037) and changes were more severe after single high doses. No difference was found between the single low dose and the daily for 5 days regimen. Rapid infusion of a single high dose was more ototoxic than a 24-hr infusion of the same dose (P = 0.0015). It is concluded that, compared with the single high-dose regimen, the daily low dose for 5 days is preferable in cases where the patient might be cured by a regimen including CDDP.
Article
Cisplatin is an effective chemotherapy agent against several pediatric malignancies. One of its side effects is irreversible sensorineural hearing damage that is highly variable with a reported incidence of 22-70%. The aim of this study was to evaluate the incidence and identify clinical predictors of cisplatin-related ototoxicity. We performed a retrospective chart review of 102 pediatric patients who had completed cisplatin therapy for osteosarcoma, neuroblastoma, hepatoblastoma, or germ cell tumor. Patients were diagnosed at Riley Hospital for Children between January 1995 and June 2008, were less than 18 years old at diagnosis, and had normal hearing prior to therapy. Audiograms were scored using the Brock scale (0-4), a validated grading system for cisplatin-related hearing loss. Forty-two percent of the patients experienced hearing loss and 28% had moderate to severe ototoxicity (Brock score ≥2). Males were at significantly greater risk for developing hearing loss than were females (P = 0.005, OR 4.812). Age at cancer diagnosis was inversely related to severity of ototoxicity. Patients who suffered Brock grade 3 ototoxicity had a mean age of 4.5 years versus 11.5 years and 7.2 years for grades 1 and 2, respectively (P = 0.02). Cumulative cisplatin dose was also identified as a risk factor for development of ototoxicity (P = 0.03). Gender and cumulative dose are important clinical biomarkers of cisplatin ototoxicity. Severity of ototoxicity may be inversely related to age at time of exposure, with very young patients exhibiting higher grades of hearing loss following cisplatin therapy.
Article
The objective is to describe progressive changes in hearing and cochlear function in children and adolescents treated with platinum-based chemotherapy and to begin preliminary evaluation of the feasibility of extended high-frequency audiometry and distortion product otoacoustic emissions for ototoxicity monitoring in children. Baseline and serial measurement of conventional pure-tone audiometry (0.5 to 8 kHz) and evoked distortion product otoacoustic emissions (DPOAEs) were conducted for 32 patients age 8 months to 20 years who were treated with cisplatin and/or carboplatin chemotherapy. Seventeen children also had baseline and serial measurement of extended high-frequency (EHF) audiometry (9 to 16 kHz). Audiologic data were analyzed to determine the incidence of ototoxicity using the American Speech-Language-Hearing Association criteria, and the relationships between the different measures of ototoxicity. Of the 32 children, 20 (62.5%) acquired bilateral ototoxicity in the conventional frequency range during chemotherapy treatment, and 26 (81.3%) had bilateral decreases in DPOAE amplitudes and dynamic range. Of the 17 children with EHF audiometry results, 16 (94.1%) had bilateral ototoxicity in the EHF range. Pilot data suggest that EHF thresholds and DPOAEs show ototoxic changes before hearing loss is detected by conventional audiometry. EHF audiometry and DPOAEs have the potential to reveal earlier changes in auditory function than conventional frequency audiometry during platinum chemotherapy in children.