Prevalence and risk factors for cisplatin-induced hearing loss in children, adolescents, and young adults: a multi-institutional North American cohort study,The Lancet Child & Adolescent Health

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Prevalence and risk factors for cisplatin-induced hearing loss in children, adolescents, and young adults: a multi-institutional North American cohort study
The Lancet Child & Adolescent Health ( IF 36.4 ) Pub Date : 2021-02-12 , DOI: 10.1016/s2352-4642(21)00020-1
Diana J Moke ₁ , Chunqiao Luo ₂ , Joshua Millstein ₂ , Kristin R Knight ₃ , Shahrad R Rassekh ₄ , Beth Brooks ₅ , Colin J D Ross ₆ , Michael Wright ₇ , Victoria Mena ₈ , Teresa Rushing ₉ , Adam J Esbenshade ₁₀ , Bruce C Carleton ₁₁ , Etan Orgel ₁

Affiliation

Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA; Department of Pediatrics, University of Southern California, Los Angeles, CA, USA.
Department of Preventive Medicine, Division of Biostatistics, University of Southern California, Los Angeles, CA, USA.
Department of Pediatric Audiology, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR, USA.
Division of Pediatric Hematology, Oncology, Bone Marrow Transplant, University of British Columbia, Vancouver, BC, Canada; British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
School of Audiology and Speech Sciences, University of British Columbia, Vancouver, BC, Canada; British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Health Science Center, University of Tennessee, Memphis, TN, USA.
Cancer and Blood Diseases Institute, Division of Rehabilitation Services, Hearing and Speech, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Department of Pharmacy, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Division of Pediatric Hematology and Oncology, Vanderbilt University Medical Center and the Vanderbilt Ingram Cancer Center, Nashville, TN, USA.
Department of Pediatrics, Division of Translational Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

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.

中文翻译：

儿童、青少年和年轻人中顺铂引起的听力损失的患病率和危险因素：一项多机构北美队列研究

背景

顺铂用于治疗多种儿童癌症，顺铂引起的听力损失 (CIHL) 是一种常见且使人衰弱的毒性。我们旨在通过为 CIHL 的流行和风险因素建立基准来解决 CIHL 中持续存在的知识差距。

方法

在这项多机构队列研究中，儿童（0-14 岁）、青少年和年轻成人（15-39 岁）从儿科癌症中心诊断出患有顺铂治疗的肿瘤，他们有可用的顺铂剂量信息，以及初级来自加拿大和美国联合体的用于中央审查的听力学数据符合纳入条件。使用国际儿科肿瘤学会 (SIOP) 波士顿耳毒性量表对听力学进行集中审查和 CIHL 分级。我们评估了每个人口、诊断和治疗组中中度或重度 CIHL（SIOP ≥2 级）在最近随访和治疗结束时的患病率，以及它们对 CIHL 风险的相对贡献。次要终点探讨了顺铂剂量减少和 CIHL 与生存的关系。

发现

我们纳入了 1481 名接受顺铂的患者。在最近一次随访（自诊断后平均 3·9 年 [SD 4·2]）进行听力测试的 1414 名 (95·5%) 参与者中，620 名 (43·8%) 患者发展为中度或重度 CIHL。CIHL 的最高患病率见于最年轻的患者（年龄 <5 岁；606 名患者中的 360 名 [59·4%]）和患有 CNS 肿瘤（434 名患者中的 221 名 [50·9%]）、肝母细胞瘤（110 [65·9%] 的 167 名患者）或神经母细胞瘤（154 [62·1%] 的 248 名患者）。考虑到累积顺铂剂量后，较高的分次剂量与 CIHL 风险相关（每天每增加 10mg/m ²，调整优势比 [aOR] 1·15 [95% CI 1·07–1·25]；对于每 50 mg/m ²每个周期增加 aOR 2·16 [1·37–3·51]）。新发现长春新碱暴露是 CIHL 的一个危险因素（aOR 3·55 [2·19–5·84]）。剂量减少和中度或重度 CIHL 与生存差异无显着相关性。