Elsevier

European Journal of Cancer

Volume 69, December 2016, Pages 77-85
European Journal of Cancer

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

https://doi.org/10.1016/j.ejca.2016.09.023Get rights and content

Highlights

  • A higher total cumulative dose cisplatin is associated with a higher risk of ototoxicity.

  • The risk of ototoxicity increased significantly up to a total cumulative dose cisplatin of 300 mg/m2.

  • Children with younger age at diagnosis have an increased risk of ototoxicity after platinum treatment.

  • Co-treatment with furosemide is independently associated with ototoxicity.

Abstract

Platinum-containing chemotherapeutics are efficacious for a variety of pediatric malignancies, nevertheless these drugs can induce ototoxicity. However, ototoxicity data on large cohorts of childhood cancer survivors (CCSs) who received platinum agents, but not cranial irradiation are scarce. Therefore, we have studied the frequency and determinants of ototoxicity in a cross-sectional multicenter CCS cohort, including the role of co-medication since it has been suggested that these play a role in ototoxicity.

We have collected treatment data and audiograms from the medical records of CCS treated in the seven pediatric oncology centres in The Netherlands. Ototoxicity was defined as Münster grade ≥2b (>20 dB at ≥4–8 kHz).

Four-hundred-fifty-one CCS who received platinum agents, but not cranial irradiation (median age at diagnosis: 4.9 years, range: 0.01–19 years) were included. The overall frequency of ototoxicity was 42%. Ototoxicity was observed in 45% of the cisplatin-treated CCS, in 17% of the carboplatin-treated CCS and in 75% of the CCS that had received both agents. Multivariate analysis showed that younger age at diagnosis (odds ratio [OR]: 0.6, 95% confidence interval [CI]: 0.5–0.6 per 5 years increase); higher total cumulative dose cisplatin (OR: 1.2, 95% CI: 1.2–1.5 per 100 mg/m2 increase); and co-treatment with furosemide (OR: 2.3, 95% CI: 1.4–3.9) were associated with ototoxicity.

We conclude that treatment with (higher total cumulative dose of) cisplatin, young age and furosemide co-medication independently are associated with an increased risk of ototoxicity in CCS. Future prospective studies are necessary to confirm the additive risk of co-medication on the development of ototoxicity.

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).

References (42)

  • Y. Li et al.

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

    Eur J Cancer

    (2004)
  • K. Hirose et al.

    Comparative analysis of combination kanamycin-furosemide versus kanamycin alone in the mouse cochlea

    Hear Res

    (2011)
  • J.B. Vermorken et al.

    Ototoxicity of cis-diamminedichloroplatinum (II): influence of dose, schedule and mode of administration

    Eur J Cancer Clin Oncol

    (1983)
  • M.M. Geenen et al.

    Medical assessment of adverse health outcomes in long-term survivors of childhood cancer

    JAMA

    (2007)
  • K.R. Knight et al.

    Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions

    J Clin Oncol

    (2007)
  • P. Bertolini et al.

    Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss

    J Pediatr Hematol Oncol

    (2004)
  • J.B. Dean et al.

    Hearing loss in pediatric oncology patients receiving carboplatin-containing regimens

    J Pediatr Hematol Oncol

    (2008)
  • K.R. Knight et al.

    Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development

    J Clin Oncol

    (2005)
  • S. Grewal et al.

    Auditory late effects of childhood cancer therapy: a report from the Children's Oncology Group

    Pediatrics

    (2010)
  • W. Stohr et al.

    Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system

    Cancer Invest

    (2005)
  • E.J. Einarsson et al.

    Long term hearing degeneration after platinum-based chemotherapy in childhood

    Int J Audiol

    (2010)
  • P.R. Brock et al.

    Cisplatin ototoxicity in children: a practical grading system

    Med Pediatr Oncol

    (1991)
  • P.P. Coradini et al.

    Ototoxicity from cisplatin therapy in childhood cancer

    J Pediatr Hematol Oncol

    (2007)
  • N. Yasui et al.

    Cisplatin-induced hearing loss: the need for a long-term evaluating system

    J Pediatr Hematol Oncol

    (2014)
  • A. Yancey et al.

    Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients

    Pediatr Blood Cancer

    (2012)
  • M.J. Lewis et al.

    Ototoxicity in children treated for osteosarcoma

    Pediatr Blood Cancer

    (2009)
  • C. Bergeron et al.

    Long-term renal and hearing toxicity of carboplatin in infants treated for localized and unresectable neuroblastoma: results of the SFOP NBL90 study

    Pediatr Blood Cancer

    (2005)
  • A.L. Berg et al.

    Ototoxic impact of cisplatin in pediatric oncology patients

    Laryngoscope

    (1999)
  • M. Rybak et al.

    Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists

    Am J Health Syst Pharm

    (2009)
  • A. Forge et al.

    Ultrastructural and electrophysiological studies of acute ototoxic effects of furosemide

    Br J Audiol

    (1982)
  • R. Warrier et al.

    Cisplatin and cranial irradiation-related hearing loss in children

    Ochsner J

    (2012)
  • Cited by (64)

    • Neurologic complications in the treatment of childhood malignancies

      2022, Neurological Complications of Systemic Cancer and Antineoplastic Therapy
    • Ototoxic effects of antineoplastic drugs: a systematic review

      2022, Brazilian Journal of Otorhinolaryngology
      Citation 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.

    View all citing articles on Scopus
    View full text