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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: [email protected]
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
REFERENCES
1. McHaney VA, Thibadoux G, Hayes FA, et al. Hearing loss in
children receiving cisplatin chemotherapy. J Pediatr 1983;102:
314–317.
2. Schell MJ,McHaney VA, Green AA, et al. Hearing loss in children
and young adults receiving cisplatin with or without prior cranial
irradiation. J Clin Oncol 1989;7:754–760.
3. Brock PR, Bellman SC, Yeomans EC, et al. Cisplatin ototoxicity in
children: A practical grading system. Med Pediatr Oncol 1991;19:
295–300.
4. Skinner R, Pearson ADJ, Amineddine HA, et al. Ototoxicity of
cisplatinum in children and adolescents. Br J Cancer 1990;1990:
927–931.
5. Ruiz L, Gilden J, Jaffe N, et al. Auditory function in pediatric
osteosarcoma patients treated with multiple doses of cis-diammi-
nedichloroplatinum(II). Cancer Res 1989;49:742–744.
6. Bertolini P, Lassalle M, Mercier G, et al. Platinum compound-
related ototoxicity in children: Long-term follow-up reveals
continuous worsening of hearing loss. J Pediatr Hematol Oncol
2004;26:649–655.
7. StohrW, Langer T, Kremers A, et al. Hearing function in soft tissue
sarcomapatients after treatmentwith carboplatin:A report from the
Late Effects Surveillance System. Oncol Rep 2004;12:767–771.
8. Bergeron C, Dubourg L, Chastagner P, 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;45:32–36.
9. Parsons SK, Neault MW, Lehmann LE, et al. Severe ototoxicity
following carboplatin-containing conditioning regimen for auto-
logous marrow transplantation for neuroblastoma. Bone Marrow
Transplant 1998;22:669–674.
10. Punnett A, Bliss B, Dupuis LL, et al. Ototoxicity following
pediatric hematopoietic stem cell transplantation: A prospective
cohort study. Pediatr Blood Cancer 2004;42:598–603.
11. Doolittle ND, Muldoon LL, Brummett RE, et al. Delayed sodium
thiosulfate as an otoprotectant against carboplatin-induced hearing
loss in patients withmalignant brian tumors. Clin Cancer Res 2001;
7:493–500.
12. Skinner R. Best practice in assessing ototoxicity in children with
cancer. Eur J Cancer 2004;40:2352–2354.
13. Li U, Womer RB, Silber JH. Predicting cisplatin ototoxicity in
children: The influence of age and cumulative dose. Eur J Cancer
2004;40:2445–2451.
14. Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment
for protection against cyclophosphamide-induced and cisplatin-
induced toxicities: Results of a randomized control trial in patients
with advanced ovarian cancer. J Clin Oncol 1996;14:2101–
2112.
15. Schuchter LM, Hensley MT, Meropol NJ, et al. 2002 update
of recommendations for the use of chemotherapy and radio-
therapy protectants: Clinical practice guidelines of the American
Society of Clinical Oncology. J Clin Oncol 2002;20:2895–
2903.
16. Fisher MJ, Lange BJ, Needle MN, et al. Amifostine for children
with medulloblastoma treated with cisplatin-based chemotherapy.
Pediatr Blood Cancer 2004;43:780–784.
17. Craft AW, Pearson AJ. Three decades of chemotherapy for
childhood cancer: From cure at any cost to cure at least cost.
Cancer Surveys 1989;8:605–629.
Pediatr Blood Cancer DOI 10.1002/pbc
122 Skinner