Pediatr Blood Cancer 2006;47:120–122

COMMENTARYPreventing Platinum-Induced Ototoxicity in Children—Is There a

Potential Role for Sodium Thiosulfate?

Ototoxicity due to platinum-based cytotoxic drugs

is characterised by bilateral, symmetrical, sensorineural

hearing loss. While cisplatin is the commonest cause of this

complication, carboplatin is responsible in some patients.

The pathogenetic mechanisms underlying platinum-induced

ototoxicity remain unclear, but outer hair cell degeneration in

the lower turns of the cochlea is a consistent finding in

pathological studies, suggesting that the platinum agent or a

metabolite may cause direct toxic damage. Hearing loss

caused by carboplatin is less frequent and usually much less

severe than that caused by cisplatin. Nevertheless, consider-

able hearing loss may occur after high-dose carboplatin or in

patients with pre-existing hearing impairment.

Most of the published literature describing platinum

ototoxicity is based on cisplatin-based chemotherapy proto-

cols. Although the majority of studies have focused on adult

patients, an increasing number of reports have described the

features and consequences of cisplatin-induced ototoxicity in

children [1–5]. Higher frequency hearing loss (�6,000 Hz)

occurs earlier and to a greater extent than impairment of

lower frequency hearing (500–2,000 Hz), but the latter

range, which is crucial for speech discrimination, tends to be

involved progressively with higher cumulative cisplatin

doses. Clinical symptoms are uncommon, even in children

with documented auditory toxicity, although a few suffer

from tinnitus. Nevertheless, moderate or severe deafness

detected by audiometry is common [1–5]. Unfortunately, but

not surprisingly given the pathological lesions observed,

nearly all reports of cisplatin ototoxicity in children have

found no evidence of recovery up to 4 years post-treatment,

and it appears that, once established, such hearing loss is

irreversible. Indeed, a recent study suggested that the

frequency of moderate or severe ototoxicity might increase

with time after completion of cisplatin treatment [6].

The incidence of platinum ototoxicity varies according to

the patient group studied, the platinum drug and dose

received, the patient age at this treatment, other potentially

ototoxic treatment received (e.g. aminoglycoside antibiotics,

cranial radiotherapy), and the criteria by which hearing

impairment is defined. Furthermore, ototoxicity appears to be

common in the presence of pre-existing hearing impairment

(often due to previous cisplatin treatment). Many paediatric

series have shown that a hearing loss of 15–25 dB or greater

at high frequencies (4,000 Hz and above) occurs in 50–70%

of children receiving cisplatin doses above 450–600 mg/m2,

while up to 30%may develop similar loss at 2,000 Hz after a

dose of 720 mg/m2 [1–5].

In contrast to this high frequency of ototoxicity after

cisplatin, most series of children investigated for hearing loss

after carboplatin treatment have shown no [7] or only

infrequent and mild hearing impairment [8]. Nevertheless,

there is growing awareness of the occurrence of signifi-

cant carboplatin-induced ototoxicity in certain patient

groups, especially children receiving high dose carboplatin

(usually in the context of autologous stem cell transplanta-

tion, most often for neuroblastoma) [9], [10]. Children with

brain tumours treated with carboplatin also appear to be at

higher risk of ototoxicity [11]. Both these groups often have

additional risk factors (prior cisplatin treatment and/or

cranial radiotherapy).

Platinum ototoxicity leads to a considerable risk of

delayed speech development in infants and younger children

due to impaired recognition of higher frequency consonant

sounds. This may have devastating consequences for a young

child’s social and educational development [12].

So how can we reduce the frequency and severity of

hearing loss suffered by children treated formalignancy? It is

unlikely that paediatric oncologists will stop using cisplatin

and carboplatin in the foreseeable future owing to their

considerable efficacy.Carboplatin has assumed a leading role

in many paediatric solid tumours (especially brain tumours),

whilst cisplatin retains an important role in other malig-

nancies (e.g. osteosarcoma). Therefore, we must seek

alternative methods to allow continued use of these drugs

but with reduced ototoxicity. Three main strategies may be

adopted—improved prediction and hence avoidance of the

risk of hearing impairment with current treatment, develop-

ment of less ototoxic but nevertheless efficacious platinum

analogues, or the use of otoprotective drugs alongside the

established platinum agent.

Some progress has been made in terms of predicting

cisplatin ototoxicity. A recent study of 153 children found

that children less than 5 years old at treatment with cisplatin

and those receiving a cumulative dose of over 400mg/m2 had

an increased risk of moderate to severe ototoxicity (Brock

� 2005 Wiley-Liss, Inc.DOI 10.1002/pbc.20627

——————Roderick Skinner is a Consultant and Honorary Clinical Senior

Lecturer in Paediatric Oncology.

*Correspondence to: Roderick Skinner, Department of Paediatric and

Adolescent Oncology, Newcastle upon Tyne Hospitals NHS Trust,

Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne,

NE1 4LP, United Kingdom. E-mail: Roderick.Skinner@ncl.ac.uk

Received 18 August 2005; Accepted 22 August 2005

grades 2–4) [13]. Furthermore, the raw data was used to

develop a statistical model that enables prediction of the risk

of developing grade 2–4 ototoxicity at any given age and

cumulative cisplatin dose. This may permit the design of

future chemotherapy protocols with lower ototoxic potential,

but this will necessitate the use of lower cumulative doses.

Disappointingly, although much preclinical and early

clinical research has been performed in the search for a non-

ototoxic platinum analogue that retains the cytotoxic efficacy

of cisplatin, to date this ideal solution remains elusive.

However, a promising (but so far unproven, at least in

children) approach may be the use of protective agents that

allow continued use of optimal platinumchemotherapywhile

reducing the risk of ototoxicity.

One randomised study has found a reduced incidence of

cisplatin-induced ototoxicity in adults given amifostine

cytoprotection, although the difference did not attain

statistical significance [14]. Recent guidelines do not support

the use of amifostine to reduce platinum-induced ototoxicity

[15]. Therefore, considerable uncertainty remains about the

potential role of this agent in preventing ototoxicity in both

adults and children receiving platinum drugs [16]. However,

the article by Neuwelt et al in this issue of Pediatric Blood

and Cancer, describing the use of sodium thiosulfate (STS)

as an otoprotective agent, offers an alternative and promising

approach. STS is a reactive thiol agent that is thought to bind

directly with and hence inactivate platinum cytotoxic agents.

After initial experience in adult patients, the authors

treated a series of 12 children (aged 17 months to 11 years)

with brain tumours with intra-arterial carboplatin (200 mg/

m2/day for 2 consecutive days) alongside intravenous

mannitol with the aim of osmotically but temporarily

‘‘opening’’ the blood–brain barrier (BBB) to optimise

carboplatin delivery to the tumour. This was then followed

by intravenous STS given initially at either 2 or 4 hr after

carboplatin. Previous work by the authors had suggested that

the BBB regained normal functional integrity within 1 hr of

mannitol treatment, so it was hypothesised that STS given

after this time would protect the inner ear (which is outside

the BBB) but not the brain tumour itself (i.e. anti-tumour

cytotoxicity would not be reduced). The first four children

participated in a dose escalation study of STS given 2 hr post-

carboplatin, which resulted in a standard STS dose of 16 g/m2

for children under 12 years old. Thereafter, the treatment

protocol was amended to include a second STS dose (4 hr

after the first) if baseline audiometry showed a defined level

of (relatively mild) impairment or if significant hearing loss

occurred during treatment. Five of the next eight children

received two STS doses per carboplatin dose after fulfilling

these criteria.

Apart from mild transient hypernatraemia, no significant

toxicity attributable to STS was observed. Unfortunately, the

changes in STS dosage, number and timing of doses as the

protocol evolved, along with minor protocol deviations,

complicate evaluation of the otoprotective effect of STS in

this small series, so the authors have instead provided

descriptive results only. Themost impressive findingwas that

later administration of STS at 4 (or 4 and 8 in those patients

receiving two doses) hr to six patients (four of whom had

impaired baseline hearing) resulted in protection from

subsequent hearing loss in 4 of the 6, whereas earlier STS

given at 2 (or 2 and 6) hr in 5 patients (all ofwhomhad normal

baseline hearing) was associated with carboplatin-induced

ototoxicity in 3. Inspection of the data suggests that this

difference is not explained by differences in patient age or

cumulative carboplatin dose. The effect that this difference in

STS scheduling appears to have on the efficacy of

otoprotection is intriguing and may offer clues about the

mechanism of platinum-induced ototoxicity.

Importantly, there was no suggestion that STS treatment

protected the tumour, and the authors provide two detailed

case reports to demonstrate that sustained responses were

possible even in extensively pre-treated patients with

relatively chemoresistant tumours.

What is the importance of these findings? This may be

viewed at two different levels. First, specifically with relation

to the occurrence of ototoxicity, they suggest that there is

genuine hope that STS may offer otoprotection to children

receiving platinum chemotherapy. This is of particular

importance to younger children who have not yet acquired

speech development. However, it is prudent to sign a note of

caution since these results have been obtained with

carboplatin (albeit in a protocol known to be associated with

a substantial risk of ototoxicity), and it remains to be seen

whether similar otoprotection will be afforded to children

receiving cisplatin. Nevertheless, given the paucity of

previous evidence supporting the use of specific protective

strategies to reduce treatment-associated toxicity in children

with cancer, this study represents a very important early step

in a new therapeutic direction. Second, this report illustrates a

very important principle, namely that of the intention of

paediatric oncologists to cure their patients at least cost [17].

Survival rates can be only be optimised by the use of the

most efficacious chemotherapy, but the desire to reduce

potentially serious long-term toxicity may be aided by

protective strategies such as that proposed by Neuwelt et al.

These important early results need to be confirmed

by randomised controlled studies that have sufficient

statistical power to investigate the potential otoprotective

role of STS in platinum-based treatment protocols in children

and to confirm that there is no adverse impact on cytotoxic

efficacy.

Roderick Skinner, MBChB, PhD, FRCPCH*

Department of Paediatric

and Adolescent Oncology

Newcastle upon Tyne Hospitals NHS Trust

Royal Victoria Infirmary

Newcastle upon Tyne

United Kingdom

Pediatr Blood Cancer DOI 10.1002/pbc

Platinum-Induced Ototoxicity in Children 121

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