Ototoxicity monitoring in children treated with platinum chemotherapy

Abstract

Objective: To review the prevalence, mechanisms, clinical presentation, risk factors and implications of platinum-induced ototoxicity in paediatric cancer patients based on published evidence, discuss options for monitoring hearing in young children during treatment and review long-term follow-up guidelines. Design: Narrative literature review. Results: Children treated with cisplatin are at high risk of hearing loss and early, accurate identification of ototoxicity is important for medical decision making and hearing rehabilitation. Challenges of monitoring hearing in young children during cancer treatment and options for monitoring hearing are discussed. Conclusion: Hearing loss has important consequences for the survivors of childhood cancer including communication, learning, cognition and quality of life. Due to the presentation and configuration of ototoxic hearing loss, the test frequencies that are prioritised and the sequence of testing may differ from standard paediatric hearing evaluations. Hearing should be monitored during treatment and after completion of therapy.

Key Words:

• Hearing loss
• ototoxicity
• children
• cisplatin
• carboplatin

Introduction

The alkylating platinum chemotherapeutics, cisplatin and carboplatin, are the mainstay of therapy for several types of childhood and adolescent cancers, despite their toxicities. The most common childhood cancers treated with cisplatin include medulloblastoma, osteosarcoma, hepatoblastoma, neuroblastoma and germ cell tumours. Although these life-threatening illnesses affect a relatively small number of children and adolescents each year, the impact on children and their families is significant. Platinum chemotherapeutics and other free-radical inducing therapies, such as radiotherapy, can cause multiple systemic and neurological side effects.

In children, ototoxicity is the primary toxicity of cisplatin chemotherapy. The prevalence of cisplatin-induced ototoxicity, measured with standard audiometry to 8 kHz, is approximately 60–70% in paediatric patients (Knight et al, 2005; Bass et al, 2014; Peleva et al, 2014). Carboplatin is significantly less ototoxic, but hearing loss can occur with high-dose treatment (Punnett et al, 2004; Qaddoumi et al, 2012). When both drugs are used in combination, ototoxicity approaches 80–90% (Landier et al, 2014). Individual risk factors for acquiring hearing loss from cisplatin therapy are age less than 5 years (Li et al, 2004), cisplatin cumulative dose and dose intensity (Lewis et al, 2009; Yancey et al, 2012), prior or concurrent cranial radiation (Warrier et al, 2012), concomitant treatment with other ototoxins, such as myeloablative carboplatin, aminoglycosides and loop diuretics (Parsons et al, 1998; Landier et al, 2014) and genetic susceptibility (Rednam et al, 2013; Carleton et al, 2014; Lee et al, 2016). Several studies suggest that platinum-induced hearing loss can worsen after treatment is completed (Bertolini et al, 2004; Einarsson et al, 2010) and survivors who received cranial radiation prior to cisplatin therapy appear to be at the highest risk (Bass et al, 2016; Kolinsky et al, 2013). Additional study is needed to evaluate the time course of changes in hearing after ototoxic therapy and it is important to take a careful history for each patient to ascertain if there are additional risk factors related to disease, treatment, or other potential causes of hearing loss such as noise exposure. Long-term follow-up guidelines for late effects of childhood cancer treatment include audiological monitoring (Children’s Oncology Group, 2006).

Mechanisms of platinum ototoxicity

The hearing loss caused by cisplatin and carboplatin is due to degeneration of the cochlear hair cells and supporting cells (Rybak et al, 2007; Brock et al, 2012). The outer hair cells are damaged before the inner hair cells, and platinum initially affects hair cells at the base of the cochlea, where high-frequency sounds are encoded (Ramirez Camacho et al. 2004). Clinically, this is seen as a loss of hearing sensitivity that begins in the high-frequency range that worsens and progresses to lower frequencies with continued exposure. Hearing loss associated with cisplatin ototoxicity is typically bilateral, high-frequency, steeply sloping and symmetrical (Rybak et al, 2007). In addition to loss of hearing sensitivity, damage to cochlear hair cells impacts one’s ability to recognise subtle differences in sound frequency; this results in difficulty understanding speech, especially in noise (Summers et al, 2013). Persistent tinnitus is also associated with platinum-induced ototoxicity and it is likely under-reported and under-appreciated in children (van As et al, 2016). Ototoxic high-frequency hearing loss may not be readily apparent to caregivers and medical providers. While hearing aid technology can help mitigate the negative consequences that result from the loss of acoustic information, it is not a replacement for normal hearing (Sininger et al, 2010).

Genetics of platinum ototoxicity

Screening for genetic predisposition to cisplatin ototoxicity may identify individuals who are at increased risk for hearing loss. Pharmacogenomic studies investigating genetic variants in methyltransferases (thiopurine S-methyltransferase gene [TPMT] (Ross et al, 2009), catechol-o-methyltransferase gene [COMT]) (Ross et al, 2009) cisplatin transporters (ATP-binding cassette sub-family C member 3 [ABCC3], CTR1) (Pussegoda et al, 2013), glutathione-S-transferases (GSTs) and megalin (LRP2) (Choeyprasert et al, 2013) have found mixed results, likely due to variability of patient populations and treatment regimens. Genetic variants in TPMT were strongly associated with cisplatin ototoxicity in three independent paediatric cohorts (Ross et al, 2009; Pussegoda et al, 2013) and it has been recommended that all children receiving cisplatin therapy have testing for genetic variants in TPMT, ideally before the initiation of therapy (Lee et al, 2016). However, despite the high predictive value of TPMT (92%), only approximately 25% of children who acquire cisplatin-associated ototoxic hearing loss have a genetic variant in TPMT. A recent genomewide association study identified a variant in ACYPT2 that was strongly associated with ototoxicity (Xu et al, 2015). The field of pharmacogenomics is rapidly changing. Audiologists are encouraged to watch for updates to the use of pharmacogenomic markers for ototoxicity.

Impact of platinum ototoxicity

Hearing loss acquired from ototoxic therapy may negatively impact a child’s language development and communication, speech development, socialisation, cognition, learning, lifetime earnings and quality of life. Gurney et al (2007) investigated academic and quality of life outcomes in survivors of childhood cancer who were treated with cisplatin and carboplatin for neuroblastoma, an embryonal nerve cell tumour. Neuroblastoma most often originates from the adrenal glands, abdomen, chest or spine and treatment does not typically include cranial radiation. In this cohort, hearing loss was associated with lower school functioning scores, greater need for special education services and poorer child-reported quality of life (Gurney et al, 2007). In a series of 165 survivors who received cranial radiation and cisplatin for the treatment of medulloblastoma, a malignant primary brain tumour, hearing loss serious enough for hearing aid use was independently associated with declines in cognition and educational performance up to five years after completion of therapy (Schreiber et al, 2014). Brinkman et al. (2015) studied 226 adults who received platinum chemotherapy for non-central nervous system (CNS) tumours in childhood. Approximately 37% of this patient group had cranial radiation. Participants with hearing loss that included frequencies below 4  kHz were at twice the risk of non-independent living and unemployment or not graduating from high school compared to those whose hearing was not as severely affected (Brinkman et al, 2015).

Audiologic monitoring for platinum ototoxicity

There are two primary reasons for audiologic monitoring during platinum therapy. The first is to inform treatment management. In some treatment regimens, the dose of cisplatin may be decreased to avoid further hearing loss. Dose modification guidelines are typically specified by the cancer treatment protocol and the guidelines vary by disease and treatment regimen. Secondly, monitoring serves to inform family, caregivers and the medical team about changes in hearing so that communication strategies can be recommended and intervention can be initiated as soon as possible. With family permission, the child can also be informed about changes in their hearing, the impact on understanding and practical strategies they can use to improve communication. Generally, it has been our experience that facilitating a discussion between parents and children, even as young as four or five years old, about the frustrations in communication that they may be experiencing helps them become knowledgeable observers of different listening environments and gives them a shared understanding of problem-solving skills.

Children receiving ototoxic therapy should have a baseline audiologic evaluation before treatment begins. Pre-existing hearing loss is sometimes identified and it has important ramifications for determining ototoxic change and possibly treatment. A valid baseline may not always be feasible for very young or ill children or when therapy must begin immediately. Children treated with cisplatin often have monitoring evaluations after each cisplatin cycle. Patients receiving carboplatin may have monitoring evaluations less frequently during treatment and the schedule for testing is often directed by the treatment protocol. An end-of-treatment evaluation should be completed 4–6 weeks after the final course of platinum. Patients treated with cranial radiation typically have a baseline evaluation and a post-treatment evaluation but do not usually have ototoxicity monitoring during radiation therapy since ear and hearing problems due to radiation are generally of latent onset (Williams et al, 2005; Bass et al, 2016).

The methods for ototoxicity monitoring in children include behavioural pure tone audiometry, speech audiometry, immittance, acoustic reflexes, otoacoustic emissions, extended high-frequency audiometry and electrophysiological testing. By contrast, audiological test protocols for paediatric clinical cancer trials are developed to maximise the amount of standardised collectible data in large groups of patients across multiple participating institutions. Clinical trial test protocols are not intended to be the recommended standard of care in paediatric audiology.

Behavioural pure tone audiometry, including standard audiometry, conditioned play audiometry and visual reinforcement audiometry, is widely available and routinely employed. The quality and extent of behavioural test results may be limited by the child’s age, health status, development, cooperation and energy level. Ototoxicity evaluations differ from standard paediatric hearing assessments both in the test frequencies that are prioritised and the sequence of testing. For young children, a team-testing approach often results in a more complete evaluation because the test-assist is able to change play activities quickly when needed, provide positive reinforcement and encourage continued participation. Because cisplatin and carboplatin initially affect high-frequency hearing, testing the high-frequency range first (2 kHz and above) will likely detect ototoxicity. When cisplatin dose modification is included in the treatment protocol, the frequencies that are most important for informing treatment, usually 2 and 4 kHz, should be measured at the beginning of the evaluation. It may be preferable to establish thresholds for each ear at each test frequency, rather than measuring all frequencies for one ear and then the other. Including the inter-octave frequencies 3 and 6 kHz is recommended whenever possible, since platinum-induced hearing loss is typically steeply sloping.

An algorithm intended to guide a minimal test battery for children receiving ototoxic medications was developed by the Ototoxicity Monitoring and Grading Workgroup at the 42nd International Society of Pediatric Oncology Congress in Boston in 2010 (Brock et al, 2012) and is presented in Figure 1. Although this tool was intended largely to capture the degree of ototoxic change for reporting purposes (i.e. grading), when a clinician anticipates a test will be incomplete, this minimal test battery can be used to direct testing to those frequencies critical to identifying ototoxicity. Children who are tested with a minimal test battery will require a complete evaluation as soon as the child is able.

Figure 1. SIOP minimal test battery algorithm. Decision matrix for a minimal test battery when the clinician feels a complete evaluation is unlikely (Brock et al, 2012). If hearing is normal or if hearing status is unknown, begin testing at 4000 Hz. Establish threshold in each ear (or in sound field if the earphones are not tolerated); if threshold is ≤20 dB HL, test 8000 Hz; if threshold is >20 dB HL, test 2000 Hz. Continue testing, as indicated.

Sound field testing is necessary when a child cannot tolerate earphones or headphones. Due to standing wave issues, typically testing can only be done up to 6 kHz; effort should be made to test 3 and 6 kHz as well as octave intervals. Sound field test results are not ear-specific and may miss unilateral or asymmetric hearing loss which has been reported in 16% of patients with platinum ototoxicity (Chang & Chinosornvatana, 2010). A benefit of sound field testing is that the caregiver(s) in the test booth with the child is able to directly observe what the child is and is not able to hear. If time and the child’s energy allows, sound field testing can be a useful adjunct to ear-specific test data, to provide both a cross check of ear-specific responses and as a reference for counselling.

Auditory brainstem response (ABR) or auditory steady-state response (ASSR) can be used for the estimation of hearing thresholds when behavioural audiometry is not possible due to the child’s age, development or health status. Testing typically requires sedation. Patients undergoing treatment for childhood cancer often receive sedation for other medical procedures or diagnostic tests; it may be possible to coordinate ABR/ASSR with those procedures. Click-evoked ABRs are not adequate for detecting ototoxicity; a frequency-specific measurement is required. Although frequencies above 4 kHz are not routinely measured with ABR/ASSR, testing at 6 or 8 kHz can provide earlier detection of ototoxicity (Fausti et al, 1992).

For young children and patients with developmental delays or who are medically compromised, hearing threshold levels may be difficult to obtain. Instead, the audiologist may screen at levels consistent with normal hearing, such as 15 or 20 dB HL, so that other additional data can be obtained given the potential limitations of patient interest and attention. This is also common practice for ABR/ASSR testing, to maximise the amount of information obtained and to avoid prolonging sedation. However, this screening protocol has potential implications for ototoxicity classification systems that are based on changes in hearing thresholds (e.g. ASHA, NCI CTCAE; see accompanying article on grading scales in this issue) and the audiologist should clearly indicate on the test form or report that actual hearing threshold is less than or equal to the level measured.

The measurement of otoacoustic emissions (OAEs) to evaluate cochlear outer hair cell function is part of the standard paediatric audiologic evaluation. OAEs are objective, ear-specific, can be measured fairly quickly and are usually well-tolerated. Because the outer hair cells are among the first structures of the inner ear that are damaged by platinum drugs (Ramirez Camacho et al, 2004), OAEs may provide an indirect measurement of early ototoxic changes in cochlear function in patients treated with ototoxic medications (Bhagat et al, 2010; Al-Noury, 2011). Distortion-product OAEs (DPOAEs) are preferred for ototoxicity monitoring over transient-evoked OAEs (TEOAEs) because DPOAEs can measure into a high-frequency range. Ototoxic damage is initially seen as decreases in DPOAE amplitudes and signal-to-noise ratios and then loss of DPOAE responses. Studies of DPOAEs in children receiving platinum chemotherapy have shown high correlations between DPOAE levels and hearing thresholds (Dhooge et al, 2006). Reductions in DPOAE amplitudes can be observed before changes in hearing are apparent on conventional pure tone audiometry (Coradini et al, 2007; Knight et al, 2007). Because there is no clear temporal relationship between OAE and hearing changes, there is no widely-accepted ototoxic change criteria for OAEs and, as a result, they currently cannot be used to estimate hearing thresholds clinically. This limits their utility as a stand-alone diagnostic measure.

OAEs are, however, especially helpful in augmenting behavioural test results in young children. Some children are very sensitive to touch and have great difficulty tolerating earphones or ear tips, especially if they are not feeling well and are undergoing other medical interventions. Although ear-specific audiometry is recommended whenever possible, for some children it may be preferable to evaluate audiometry in the sound field and obtain ear-specific measurements with OAEs. A child may be more easily distracted when they are not also required to attend, listen and follow directions.

Tympanometry should be included at each evaluation to assess middle ear function. Otitis media is relatively common in the paediatric population and the prevalence of middle ear dysfunction is increased in patients receiving cranial radiation and who are immunosuppressed (Grewal et al, 2010). Middle ear pathology can confound audiometric results and will prevent valid measurement of OAEs. Bone conduction audiometry distinguishes sensorineural from conductive hearing losses up to 4 kHz, but not all children provide threshold measurements or will comply with wearing the bone conduction oscillator.

The measurement of acoustic reflexes provides information about neural pathway function in addition to middle ear function. Ipsilateral reflex measurement for 1 and 2 kHz at intensity levels of 85–95 dB HL, or broad-band noise at intensity levels of 75–90 dB HL, is well tolerated by most children. Additional diagnostic assessment can be completed if reflexes are absent. The presence of acoustic reflexes reflects a degree of integrity of the auditory pathways, while asymmetry may be an indicator of retrocochlear involvement. There is increased value in obtaining acoustic reflex information in children who are neurologically compromised or who have posterior fossa tumours or other cancers of the CNS, which can be associated with retrocochlear auditory dysfunction.

Extended high-frequency (EHF) audiometry is the measurement of hearing thresholds >8 kHz and it can be used for monitoring in most children who are generally 4–5 years or older (Beahan et al, 2012), and for some younger children. Because cisplatin and carboplatin initially damage hair cells at the base of the cochlea, testing at the highest frequencies will detect ototoxic damage earlier than standard audiometry. In studies that have simultaneously evaluated standard audiometry, EHF audiometry and DPOAEs in children during ototoxic therapy, ototoxicity was first detected by EHF audiometry, second with DPOAEs and third by conventional audiometry (Knight et al., 2007; Abujamra et al, 2013). EHF audiometry requires instrumentation that may not be available at all clinics and testing requires additional test time. When monitoring children, the standard frequency range is typically measured first in case the child’s cooperation or attention is limited. EHF testing provides a more sensitive signal and earlier identification of ototoxic damage, but at this time a change in hearing >8 kHz generally will not impact treatment. Baseline measures are important as there is greater inter-subject variability in EHFs than in the standard frequency range (Frank, 2001).

Suprathreshold speech recognition testing is an essential component in the evaluation of a patient’s hearing ability. Children who lose hearing to ototoxicity have pre-existing listening, speech, and language skills. When low- and mid-frequency hearing has been preserved, it may be remarkably difficult for the children, their families and their teachers to fully appreciate the impact of the loss of access to high-frequency acoustic energy. Whenever possible, measures of speech recognition should be conducted at baseline, at the end of therapy or before the child resumes attending school, and at annual long-term follow-up appointments. The purpose of speech recognition testing is not for determining ototoxic change or for informing treatment, but to assess speech perception and the functional impact of ototoxicity. Speech recognition testing for words presented at 50 dB HL in quiet can be a poor indicator of the functional impact of ototoxic hearing loss. Measures of speech recognition in noise may better reflect communication difficulties (Einarsson et al, 2011). If the parent or caregiver is present, this type of testing can be helpful for allowing them to observe the child’s ability in the two different contexts and may provide an opportunity for discussion about the various conditions in which individuals communicate and how hearing loss impacts understanding. For younger children, speech recognition could be assessed with the Ling sounds (Ling, 1989) plus the phonemes/k/ and/t/, or the University of Western Ontario Plurals Test (Glista & Scollie, 2012). High-frequency word lists, such as the Gardner high-frequency word list (Gardner, 1971) could also be used instead of the more commonly used phonemically balanced word lists. The Bamford-Kowal-Bench Speech-in-Noise (BKB-SIN) test (Bench et al. 1979) and Quick Speech in Noise (QuickSIN) test (Killion et al, 2004) are speech-in noise measures that can be used in this population. A summary of suggested ototoxicity monitoring protocols are presented in Table 1.

Table 1. Suggested paediatric ototoxicity monitoring protocols.

Developmental age	Time point	Tests to include
5 years and older	Baseline evaluation	PTA 500–8000 Hz*EHF audiometryOtoscopy and immittanceDPOAEsSpeech recognition testing
	Monitoring evaluations	PTA 500–8000 Hz*EHF audiometryOtoscopy and immittanceDPOAEsSuprathreshold speech recognition testing, as clinically appropriateQuestion about tinnitus
	End of therapy or school re-entry	PTA 500–8000 Hz*EHF audiometryOtoscopy and immittanceDPOAEsSpeech recognition testingQuestions or questionnaire about tinnitus
8 months – 5 years	Baseline	PTA 500–8000 Hz*Otoscopy and immittanceDPOAEsSpeech recognition testing when possibleEHF audiometry when possible
	Monitoring	PTA 500–8000 Hz*Otoscopy and immittanceDPOAEsEHF audiometry when possibleSuprathreshold speech recognition testing as clinically appropriate
	End of therapy	PTA 500–8000 Hz*Otoscopy and immittanceDPOAEsSpeech recognition testing when possible
Infant or unresponsive patient	Baseline	Tone-evoked ABR/ASSR (>4000 Hz if possible)DPOAEsOtoscopy and immittance
	Monitoring	DPOAEsOtoscopy and immittanceBehavioural audiometry as soon as the patient is ableRepeat ABR/ASSR if DPOAEs become absent at frequencies that inform treatment
	End of treatment	Repeat ABR/ASSRDPOAEsOtoscopy and immittance

*Include pure tone bone conduction thresholds when hearing loss and/or conductive middle ear pathology is present or suspected.

ABR: auditory brainstem response; ASSR: auditory steady-state response; DPOAEs: distortion product evoked otoacoustic emissions; EHF: extended high-frequency audiometry; PTA: pure tone audiometry.

A gentle approach in assessment is advocated, as children will likely be seen for multiple evaluations during treatment and many will need ongoing long-term audiologic care. Allowing children and caregivers to make choices and have some control, when appropriate (such as which ear to measure tympanometry first, what games are used for play audiometry, whether OAEs and immittance or audiometry are done first) can be helpful. Patients and caregivers should be counselled regarding noise exposure during ototoxic therapy, since exposure to loud sounds can potentiate ototoxic damage (DeBacker et al, 2017). The family should be asked how and when they would like to receive hearing evaluation results and whether or not they would like to have their child present and included in the initial discussion of results. Audiologists and the healthcare team should determine the preferred method for communicating results among providers when ototoxicity occurs.

It can be challenging to provide paediatric ototoxicity monitoring services due to logistic difficulties in scheduling same-day or urgent appointments, or coordinating testing around other medical appointments and admissions. It is helpful to have a point person who can readily coordinate and accommodate hearing evaluations. Portable equipment (including a portable audiometer, tympanometer, OAEs, ABR/ASSR) is essential when testing outside the audiology clinic, such as at bedside or in the oncology clinic; control of environmental noise is necessary to obtain reliable hearing results.

When hearing loss that impacts communication is acquired, audiologists can connect patients and families with educational and community resources for children and adolescents with hearing loss, including hearing technology. More research is needed regarding hearing technology outcomes for children with hearing loss secondary to platinum therapy. Children with a history of cranial radiation may have co-existing cognition changes that may also impact communication and learning. Audiologists work collaboratively with oncologists and neuropsychologists to try and disentangle the effects of hearing loss from neurocognitive consequences of cancer and its treatment.

Children treated with platinum therapy and/or cranial radiation should have long-term follow-up evaluations to monitor for late onset and progressive hearing loss. It is important to inform families about the need for long-term audiologic follow-up. Parents may need to advocate for these services so that their child is not lost to follow up once they enter survivorship. In addition to monitoring hearing status, audiological counselling can be provided to help children and young adults understand their hearing status, its impact on communication and learning, hearing conservation, and their options for ongoing management. The Children’s Oncology Group has published Long-Term Follow-up Guidelines for late effects related to childhood cancer treatment: http://www.survivorshipguidelines.org/. Audiology should be included in Pediatric Cancer Survivorship Programs where these programmes are established.

Declaration of interest

No potential conflict of interest was reported by the authors.