Original ResearchDeterminants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study
Introduction
Late-effects of cancer treatment have gained more attention because of the increasing number of survivors. A Dutch study showed that 75% of 1362; 5-year survivors of childhood cancer treated before 1996 had at least one low burden side-effect [1]. Problems with ear, nose and throat, including ototoxicity, were reported in 108 survivors of which 17% showed mild to severe problems. Ototoxicity is an important side-effect of platinum-based chemotherapy. This is characterised by irreversible, bilateral loss of high frequencies and is commonly accompanied by tinnitus [2]. This is relevant, as hearing impairment in children seriously influences speech, language and subsequent social-emotional development. Furthermore, it enhances the risk of learning difficulties [3], [4], [5], [6].
Cisplatin and carboplatin are effective chemotherapy agents for a variety of pediatric malignancies, but they are also notorious for ototoxic side-effects. However, several previous studies showed a wide range in the frequency of reported ototoxicity (11%–73%) [2], [3], [4], [5], [7], [8], [9], [10], [11], [12], [13], [14]. Most of these studies were small-scale [3], [4], [15] and focused on patients who got cranial radiotherapy [3], [8], [9], [16]. Because cranial radiotherapy is a very strong determinant of ototoxicity, it is hard to examine the independent ototoxic effects of cisplatin and carboplatin. Therefore studies focused on patients that were not treated with cranial radiotherapy are needed. Children receiving chemotherapy are often given diuretics to attain diuresis or antimicrobial drugs to treat infections. It has been suggested from adult studies that this co-medication may increase the risk of ototoxicity. Vancomycin has been associated with ototoxicity in adults, mice and guinea pigs [17], [18], [19], [20], but there have been no studies on this type of co-medication in childhood cancer survivors (CCSs). The lack of published results highlighting the risk of ototoxicity from non-chemotherapeutic ototoxic co-medication in platinum-treated pediatric patients, impedes the assessment of independently associated potential risk factors (Table 1) [8], [10], [12], [13], [14], [21], [22], [23], [24], [25].
The aim of the present study was to determine the frequency and the determinants of ototoxicity (including the role of co-medication) in a large national multicenter cohort of survivors of childhood cancer who received platinum, but not cranial irradiation for the treatment of childhood cancer.
Section snippets
Patients and methods
Survivors of childhood cancer, <19 years at diagnosis, treated between 1980 and 2012 in The Netherlands participated if they met the following inclusion criteria: (1) received platinum agents; (2) not irradiated cranially or locally to ear/neck region; (3) available audiogram after stop treatment; (4) normal hearing before start of chemotherapy as assessed by medical records or hearing test. Data collection included demographics, cancer diagnosis, type and total cumulative dose (TCD) of
Cohort characteristics
We identified 795 CCS who received platinum agents for a primary malignancy but not cranial irradiation. In total, 451 CCS were included in the study based on inclusion criteria (Fig. 1). Median age at diagnosis was 4.9 years (range: 0.01–19 years). In a previous study [29], we observed that hearing impairment after cessation of platinum treatment seemed to be irreversible. Therefore, we considered to use audiological data from stop treatment onwards. Clinical characteristics of the included
Discussion
The purpose of this study was to analyse the frequency and determinants of ototoxicity in a cross-sectional multicenter analysis of Dutch platinum-treated non-cranially irradiated CCS. We showed that 42% of the survivors of childhood cancer who received platinum agents, but not cranial irradiation, developed ototoxicity. The occurrence of Münster ≥ 2b ototoxicity was independently associated with younger age at diagnosis, higher TCD cisplatin, treatment with both platinum agents, and
Ethical standards
This study has been submitted by the medical ethical committee and was approved as a non-WMO study (MEC-2015-269) because only data were retrieved from databases and medical records.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030 (EC and SMP), and from the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands (ADV, SMP).
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2022, Brazilian Journal of OtorhinolaryngologyCitation Excerpt :In another paper selected for this study,27 there was also no improvement in hearing loss in the evaluations performed during the follow-up. One of the studies included in this systematic review showed that younger age at diagnosis is associated with an increased risk of ototoxicity,28 corroborating what was found in other studies,14,32,33 but contrasting with what was found in research that did not find age as a risk factor for ototoxicity.15 Li et al.40 found that children under the age of five at the time of treatment were 21 times more likely to acquire moderately severe high-frequency hearing loss compared to patients aged 15–20 years.