Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group

Abstract

Purpose: 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.

Patients and methods: 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]).

Results: 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.

Conclusion: 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.

Fig 1.

COG (Children's Oncology Group) A3973 trial evaluable postplatinum audiologic data.

Fig 2.

Audiometric testing time points in relation to protocol-delivered platinum. CPM, cyclophosphamide; DOXO, doxorubicin; ETOP, etoposide; Exp 1, exposure one (cisplatin ≤ 400 mg/m²); Exp 2, exposure two (cisplatin 400 mg/m² and carboplatin 1,700 mg/m²); MEL, melphalan; VCR, vincristine.

Fig 3.

Prevalence of (A) any hearing loss and (B) severe hearing loss and (C) degree of hearing loss by exposure and grading scale; (D) percentage of children requiring a hearing aid by exposure. ASHA, American Speech-Language-Hearing Association; CTCAEv3, Common Terminology Criteria for Adverse Events, version 3; Exp 1, exposure one (cisplatin ≤ 400 mg/m²); Exp 2, exposure two (cisplatin 400 mg/m² and carboplatin 1,700 mg/m²).

Fig 4.

Results of unconditional multivariable logistic regression of risk factors for severe hearing loss (carboplatin conditioning, hospitalization for infection); controlled for race/ethnicity, sex, age at diagnosis, time from most recent platinum to auditory testing, preconsolidation glomerular filtration rate, and chemotherapy dose reduction during induction. CTCAEv3, Common Terminology Criteria for Adverse Events, version 3.