Elsevier

European Journal of Cancer

Volume 40, Issue 16, November 2004, Pages 2445-2451
European Journal of Cancer

Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose

https://doi.org/10.1016/j.ejca.2003.08.009Get rights and content

Abstract

The aim of this study was to determine the risk factors for high-frequency hearing loss in children treated with cisplatin. We scored off-treatment pure-tone audiograms from 153 children (age 6 months to 18 years) who had completed cisplatin therapy (40–200 mg/m2/cycle) for germ cell tumours, hepatoblastoma, neuroblastoma or osteosarcoma. The risk of developing bilateral moderate to severe high-frequency hearing loss was significantly related to the age at treatment (P < 0.001), and individual and cumulative cisplatin dosages (both P < 0.005). Logistic regression showed that children younger than 5 years were at a greater risk of sustaining cisplatin ototoxicity than children older than 15 years, controlling for individual and cumulative doses of cisplatin (Odds Ratio (OR)=21.17, 95% Confidence Interval (CI): 2.48–180.94). Age at treatment and the cumulative dose of cisplatin were the two most important risk factors in predicting moderate to severe high-frequency hearing loss in children treated with cisplatin.

Introduction

Cisplatin is known to cause high-frequency hearing loss in adults and in children 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. The ototoxicity is non-reversible, appears soon after therapy, and may worsen after repeated doses 3, 5, 8, 9, 10. As cisplatin is an important chemotherapy agent for childhood cancer, and as less ototoxic alternative (e.g., carboplatin) treatments are sometimes inappropriate or unavailable, there is a continuing need to achieve a fuller understanding of the risk of cisplatin ototoxicity related to patient characteristics and treatment regimens.

Several important risk factors have been identified. The prevalence of hearing loss after paediatric cisplatin therapy ranges widely. This is in part due to the difficulty in monitoring hearing loss in hepatoblastoma and neuroblastoma patients, who have a median age at diagnosis of less than 18 months [11]. Pure-tone audiometry has low reliability at this young age. Other measures such as oto-acoustic emissions may not detect the changes in the inner hair cells due to carboplatin in a multi-agent therapy 12, 13.

Brock's [1] grade 2+ hearing losses have been observed in 18% of infants who received cisplatin (median age at diagnosis 8 months; range 1–11.5 median cumulative dose at 400 mg/m2; range 105–1000) [11]. Other studies reported a risk of 48% (median age 2 years 2 months; range 1 month–13.5 years; median cumulative dose 540 mg/m2; range 120–1860) [1], 34% [14], and 41% (mean age 13 years; range 7–19; median cumulative dose 542 mg/m2; range 312–1072) [15]. More recently, a risk of 21% was found in an international collaboration (20 with grade 2+ per 96 for whom audiometric data were available; median age 16.5 months; range new born –155 months; highest cumulative dose 480 mg/m2) [16].

Larger individual and cumulative doses are the leading risk factors 1, 2, 3, 4, 6, 8, 15, 17, 18, 19. Age is important and hearing loss is more prevalent in younger children 2, 5, 20, 21. The findings derived from these risk factors tend to be repetitive and analyse the same factors in different diagnoses. Other risk factors have been examined. It has been found that rapid chemotherapy administration (e.g., bolus administration) causes more severe ototoxicity in adults [4]. The European trend for the last decade has been to administer cisplatin to children in a 24-h infusion instead of 6 h or less 15, 16, although there has been no definitive proof of its superiority. Other risk factors are also significant, including potential genetic causes [22] and prior cranial irradiation 21, 23.

Advances have been made in understanding how children may develop hearing loss after cisplatin chemotherapy, although to date many important questions remain unanswered. The potential interactions between patients' characteristics and treatment regimens—which can be very important in the patients' clinical management—are not well understood.

This article aims to build a predictive model that estimates a child's risk in sustaining what Brock considers ‘moderate to severe’ losses as a function of patient risk factors. The focus is on developing a practical procedure in constructing a risk model: several common risk factors are analysed individually, followed by a logistic regression model that simultaneously considers risk factors that show statistical significance. In particular, we examined the extent to which younger age and higher cumulative dose of cisplatin increase the risks of developing hearing loss.

Section snippets

Patients and methods

The study was approved by the Institutional Review Board at The Children's Hospital of Philadelphia. The data came from two sources. One was the records of audiometric findings from 80 paediatric patients who participated in two Intergroup clinical trials for treating germ cell tumours (Children's Cancer Group (CCG) protocols 8882 and 8891). We obtained single off-treatment audiograms for 80 patients who had completed the protocols. Approximately half the patients were assigned to a regimen of

Patient's characteristics

Table 1 summarises the patients' characteristics. The CHOP and CCG patients developed similar levels of hearing losses (Fisher's test, P=0.47). Overall, 72 patients (47%) developed grade 0 hearing loss, 26 (17%) developed grade 1 loss, and 54 (35%) developed grade 2 or worse hearing losses. Approximately half of the patients were male. Fifty percent of them were younger than 5 years at the time of their treatment. The median time of the first off-treatment audiogram was measured at 8 months

Discussion

Cisplatin ototoxicity in children is highly dependent on age and the cumulative cisplatin dose. The increased risk due to larger individual doses was not statistically significant after adjusting for the cumulative dose.

Previous studies evaluated how cisplatin ototoxicity disproportionately affected younger children, but they were limited in their sample size: a recent review of 11 published studies showed that 10 of them included less than 60 children 3, 20. Conflicting results have also been

Acknowledgements

This study was funded by the National Institute on Deafness and Other Communication Disorders, grant number R03DC04486-03. We thank the Children's Cancer Group for providing the audiograms, and Shantae Ockimey for her help in conducting this research.

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