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International Journal of Pediatric Otorhinolaryngology (2007) 71, 16311638

www.elsevier.com/locate/ijporl

CASE REPORT

Recovery from cisplatin-induced ototoxicity:

A case report and review
Mai Thy Truong a,b,1, Jody Winzelberg a,2, Kay W. Chang a,b,1,*

a
Lucile Packard Childrens Hospital, United States
b
Stanford Hospital and Clinics, United States

Received 4 April 2007; accepted 28 June 2007

Available online 15 August 2007

KEYWORDS Summary We present a pediatric case report of cisplatin-induced ototoxicity with

Cisplatin; subsequent recovery. The patient experienced tinnitus and fluctuating mild high-
Ototoxicity; frequency sensorineural hearing loss (SNHL) with a concomitant decrease in distortion
Pediatric; product otoacoustic emissions (DPOAE). There was recovery of hearing loss and return
Recovery of DPOAE at 1 year after completion of cisplatin therapy. Reports of recovery from
cisplatin-induced ototoxicity in humans are limited in the literature, especially in the
pediatric population. A review of cisplatin ototoxicity and mechanisms of recovery are
discussed, with an emphasis on the particular chemotherapy regimen and dosing
schedule in this case, given at 411 week intervals.
# 2007 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Ototoxic hearing loss has been described as high

Cisplatin is widely used for the treatment of osteo-
sarcoma, hepatoblastoma, neuroblastoma, germ cell
tumors, head and neck cancers and some central
nervous system tumors. Multiple toxicities have been
reported including, peripheral neuropathy, nephro-
toxicity, nausea/vomiting and ototoxicity. Ototoxi-
city has been generally characterized as progressive,
irreversible, bilateral hearing loss with tinnitus [1].
* Corresponding author. Tel.: +1 650 736 1314;
fax: +1 650 498 2734.
E-mail addresses: mttruong@stanford.edu (M.T. Truong),
jwinzelberg@lpch.org (J. Winzelberg),
kchang@ohns.stanford.edu (K.W. Chang).
1
801 Welch Road, Stanford, CA 94305, United States.
Tel.: +1 650 736 1314; fax: +1 650 498 2734.
2
1000 Welch Road, Palo Alto, CA 94304, United States.
Tel.: +1 650 498 2738; fax: +1 650 736 4327.
frequency, sensorineural with progression to lower
frequencies. The incidence of hearing loss has been
reported to be 42% of those receiving higher doses
(7085 mg/m2, cumulative dose of 420 mg) with
critical cumulative doses described as low as
200 mg and up to 400 or 600 mg [2,3].
Children have been reported to be more suscep-
tible to ototoxicity, especially with higher dose
regimens (200400 mg/m2) [4,5]. High-frequency
loss is associated with loss of consonant sounds or
fricatives [6]. Hearing loss in children can lead
to speech and language delay, as well as academic
difficulties. As more children are surviving their
childhood neoplasms, hearing preservation is
imperative as well as early identification of hearing
loss for appropriate management [7]. It has
been recommended that close follow-up with pure
tone audiometry be performed so alterations in

0165-5876/$ see front matter # 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijporl.2007.06.021
1632
chemotherapy doses can be made to preserve hear-
ing. It has also been proposed that monitoring
DPOAE is a more sensitive means of monitoring
ototoxicity, with earlier detection than audiometry.
Evidence shows that the cumulative cisplatin dose
as well as method of infusion play roles in extent of
ototoxicity [8]. In this case we show that dosing
schedule also plays a significant role in ototoxicity.
We present a case of ototoxicity that presented with
tinnitus, fluctuating high-frequency hearing loss and
concomitant fluctuating DPOAE with nearly com-
plete recovery of both pure tone thresholds and
DPOAE at 1 year post treatment.
2. Case report
The patient, a 16-year-old male, was referred to
Lucile Packard Childrens Hospital after noting right
shoulder pain while playing basketball. After several
weeks of continued pain and swelling, an AP X-ray of
the right humerus showed a large soft tissue mass.
An MRI confirmed a large primary bone tumor, 7 cm
in the long axis, and 6.2 cm in diameter. There was
no evidence of metastatic disease on further
workup. An open biopsy confirmed the diagnosis
of osteosarcoma.
Fig. 1 Baseline audiogram. Prior to cisplatin induction, the patients hearing thresholds on pure tone audiometry were
within normal limits. dBHL = decibel hearing level, SRT = speech reception threshold, and WR% = percent word recognition.
M.T. Truong et al.
Table 1 Cisplatin dose schedule
1. 4/8/04: 216 mg
2. 2/28/04: 212 mg
3. 12/11/03: 212 mg
4. 11/03/03: 214 mg
The patient then began chemotherapy according
to the POG Protocol 9351, receiving 120 mg/m2 of
cisplatin planned to be given once approximately
every 5 weeks for four treatments. The patient
received a total cumulative dose of 854 mg
(Table 1). Baseline audiologic evaluation including
pure tone thresholds and DPOAE were performed
prior to initiation of cisplatin and were normal
(Fig. 1). The patient developed tinnitus immedi-
ately following infusion of cisplatin. The first mon-
itoring audiogram performed after initiation of
cisplatin (12/18/03) demonstrated a mild sensori-
neural hearing loss above 2 kHz bilaterally, though
the patient denied any appreciable subjective
hearing loss (Fig. 2). DPOAE revealed reduced/
absent emissions at 3.5 kHz in the left ear (AS)
and at 33.2, 44.5 and 5.5 kHz in the right ear
(AD). On follow-up 5 weeks later, (1/22/04) with no
additional cisplatin treatment, the patients tinni-
tus had stopped and his hearing sensitivity and
Cisplatin-induced ototoxicity 1633

Fig. 2 Audiogram performed after initiation of cisplatin therapy. Pure tone audiometry shows a bilateral mild high-
frequency sensorineural hearing loss. Dashed-dotted line shows previous thresholds for comparison. dBHL = decibel
hearing level, SRT = speech reception threshold, and WR% = percent word recognition.

DPOAE were completely within normal limits bilat-
erally (Fig. 3).
He was subsequently followed 1 week after
administration of his third dose of cisplatin therapy.
He again reported significant tinnitus bilaterally. His
pure tone thresholds demonstrated a 1015 dB
decrease from 1 to 8 kHz AD and a 1025 dB
decrease from 1 to 8 kHz AS. DPOAE were reduced
across all frequencies in both ears (AU). Three
weeks later the tinnitus had once again resolved.
There was a very mild residual hearing loss above
4 kHz AD, however, the DPOAE were now robust and
repeatable from 1 to 6 kHz AU and the other pure
tone thresholds were once again within normal
limits bilaterally.
After the fourth and final course of treatment,
the above reported pattern of results persisted.
Tinnitus occurred with sensorineural decrease in
hearing although less of an effect was realized in
terms of diminished DPOAE. Three weeks later, the
tinnitus had subsided with a residual mild loss above
4 kHz and present and robust DPOAE across the
frequency range AU at the end of his treatment
regimen. However, the patient did not develop
complete recovery of his pure tone thresholds. Six
months post treatment the patient still had a
mild SNHL above 2 kHz AD and above 6 kHz AS.
DPOAE were reduced at 4 and 5.56 kHz and absent
at 33.2 kHz in the right ear and absent only at
3.5 kHz in the left ear. One year post treatment the
patients audiogram improved to a mild hearing loss
at 68 kHz AD and at 8 kHz AS. DPOAE amplitudes
were also slightly improved. Fig. 4 summarizes
the time course of changes in the 8 kHz pure tone
threshold and the 6 kHz DPOAE in relation to the
cisplatin infusion times.
3. Discussion
We present a case of a 16-year-old patient treated
with cisplatin for osteosarcoma who reported
bilateral tinnitus immediately following cisplatin
infusion, followed by bilateral fluctuating high-
1634
Fig. 3 Audiogram performed 5 weeks after initiation of cisplatin therapy. Pure tone audiometry shows a return of
thresholds to baseline. Dashed-dotted line shows previous thresholds for comparison. dBHL = decibel hearing level,
SRT = speech reception threshold, and DNT = did not test.
frequency sensorineural hearing loss (HFSNHL) with
reduced/absent DPOAE. He received four doses of
cisplatin for a cumulative dose of 854 mg over 23
weeks, given in 411 week intervals. The patient
demonstrated a pattern of tinnitus, hearing loss,
and reduced/absent DPOAE that showed recovery
over the subsequent weeks. This pattern would
repeat itself with the each cycle of cisplatin. After
the fourth dose, he maintained a mild HFSNHL at
6 months, with partial recovery at 1-year post
treatment.
In this case report, we document the fluctuating
nature of cisplatin-induced ototoxic hearing loss,
with interval periods of recovery, followed by recov-
ery at 1-year post treatment. This may represent a
dosing schedule that allows for cochlear recovery,
demonstrating that ototoxicity is not irreversible,
but may occur as a graduated process, and that dose
and dosing schedule may affect the permanence of
the loss and the ability of the cochlea to recover.
This report also illustrates the potential utility of
DPOAE to monitor ototoxicity.
M.T. Truong et al.
4. Cisplatin ototoxicity
Platinum compounds were first recognized by Rosen-
burg and Calalieri in 1964 for their therapeutic
potential, though clinical trials of cisplatin as a
chemotherapeutic agent did not begin until 1971.
Final approval for its use in human cancer therapy
was achieved in 1978. Ototoxicity was recognized
early in case reports in 1972, and cisplatin has been
identified as the most ototoxic of all platinum com-
pounds [9]. Predisposing factors for ototoxicity
reported are dose, duration, mode of administra-
tion, age extremes, previous or concurrent cranial
irradiation, previous history of hearing loss, renal
disease, concurrent use of other ototoxic agents,
and volume status. Cisplatin ototoxicity has been
characterized clinically (Table 2) [10].
Cisplatin is a square-planar platinum molecule
with pairs of chlorine atoms and amine groups
arranged in a cis position, allowing for binding to
the N7 atom of purine nucleic acids in DNA. This cross-
linking inhibits proper DNA replication and transcrip-
Cisplatin-induced ototoxicity 1635

Table 2 Classic clinical presentation of cisplatin ototoxicity

Tinnitus
Bilateral hearing loss
High-frequency sensorineural hearing loss with progression to lower frequencies
Permanent and irreversible loss in humans, with recovery documented in animal studies
Ototoxicity after a total cumulative dose of >200 mg/m2, but reported as low as 60 mg/m 2
Lowered endocochlear potential
Decrease in DPOAE
Decrease in cochlear microphonic

tion, ultimately leading to apoptosis [11]. Binding
also occurs in non-DNA targets such as essential
proteins, inducing free radical generation and anti-
oxidant inhibition [12,13]. It is likely that this anti-
neoplastic mechanism is the same mechanism
responsible for the ototoxic, nephrotoxic, neurotoxic
and gastro-intestinal side effects [10]. Cisplatin
undergoes urinary excretion, concentrates in the
liver, and has a low penetration to the CNS. The
half-life is variable due to extensive plasma binding,
ranging from 6 to 47 days [14]. The incidence of
hearing loss has been reported to be 42% of those
receiving higher doses (7085 mg/m2, cumulative
dose of 420 mg) with critical cumulative doses
described as low as 200, 400, or 600 mg [2,3].
Cisplatin ototoxicity has clearly been associated
with outer hair cell (OHC) death. Early studies in
rhesus monkeys demonstrated OHC loss in basal
turns of the cochlea by histopathology [15]. Animal
studies have further characterized histopathologi-
cal changes in the cochlea. Nakai et al. described
changes seen by SEM and TEM in the guinea pig
model, summarized in Table 3 [16]. Human cadaver
studies of the temporal bones have confirmed these
cochlear findings [17]. Low dose cisplatin has also
been reported to cause damage to OHC stereocilia
[17]. OHC damage and loss of OHC function has been
suggested to trigger hyperactivity in the dorsal
cochlear nucleus, a potential cause for ototoxi-
city-related tinnitus [18].
5. Pathophysiology of cisplatin
ototoxicity: early damage to the stria
vascularis progresses to OHC death
Several studies have shown that damage to the stria
vascularis precedes OHC loss in cisplatin ototoxicity
[1921]. It has been proposed that damage to the
marginal cells of the stria vascularis secondarily
causes damage to the OHC [22,23]. In a study by
Miyasha et al., photochemically induced damage to
the cochlea with Rose Bengal dye and green light
irradiation resulted in marginal cell extrusion and
rupture, followed by OHC damage 12 or more hours
after strial insult as seen by TEM. OHCs were noted
to have disruption of the cell membrane at the
cuticular plate, followed by disappearance of OHCs
by 30 days. The mechanism of this damage is
reported to be the photochemical production of a
reactive oxygen species leading to endothelial
damage, platelet aggregation, thrombus formation,
and ischemic changes leading to marginal cell
damage. In a follow-up study demonstrating delayed
OHC damage and concurrent increase in compound
action potential (CAP) thresholds after photoche-
mically induced strial damage, Ocho et al. proposed
that hair cell damage is secondarily caused by strial
degeneration.
Thomas et al. identified accumulation of plati-
numDNA adducts by immunoflorescence exclu-
sively in the nuclei of marginal cells in the stria
vascularis 448 h after infusion of cisplatin in gui-
nea pigs [1921]. This study clearly identifies strial
marginal cells as the main target of cisplatin-
induced ototoxicity. No staining was seen in OHCs,
demonstrating that OHCs had no accumulation of
cisplatinDNA adducts. Thomas proposed that mar-
ginal cell damage leads to impaired potassium
secretion into endolymph. This change in cochlear
current is reflected in a decrease in endocochlear
potential (EP) after cisplatin infusion, which
directly affects sensorineural transduction by hair
cells. Fluctuating changes in EP following cisplatin
infusion in guinea pigs has been described [24].
Similarly, ethacrynic acid, furosemide and ouabain

Table 3 Histopathological characteristics of cisplatin ototoxicity (Nakai et al., 1982)

OHC loss in the first turn of the cochlea, with progression to the 2, 3, and 4th turns with higher doses
OHC loss in a sporadic fashion with lower doses of cisplatin progressing to continuous OHC loss with higher doses
Evidence of damage of remaining OHC: blebs on the surface, enlargement of vacuoles, denaturation of mitochondria
and leakage of cellular contents with surrounding cells
Vacuole enlargement and thinning of stria vascularis
1636
Fig. 4 Summary of audiometric and DPOAE results over
time. Fluctuating hearing loss after cisplatin therapy is
demonstrated in each ear. Hearing loss is shown as changes
from baseline in decibels and can be correlated to time of
cisplatin infusion (red arrows). (For interpretation of the
references to color in this figure legend, the reader is
referred to the web version of the article.)
infusion have been shown to decrease the potassium
concentration in endolymph, with a measured
decrease in EP, and subsequent hair cell degenera-
tion [25,26].
Marginal cells of the stria are hexagonal cells
facing the endolymphatic space containing high
concentrations of sodiumpotassium ATPases and
mitochondria, which are required for pumping
potassium into the endolymph [10,27]. The stria
vascularis is also rich in capillary supply. The high
cellular activity and rich vascular supply may make
these cells more susceptible to ototoxic damage.
6. Recovery of ototoxicity
Why cisplatin accumulates in strial marginal cells in
not clear, though it is hypothesized that cisplatin is
actively transported into these cells and trapped
[21]. The exact mechanism of strial damage leading
M.T. Truong et al.
to outer hair cell damage and death is also unclear.
However, the progression from strial damage to OHC
loss may be a graduated process that may provide a
mechanism to explain the reversibility of hearing
loss that has been described in animal models as
well as few human case reports including this report
[8,2830]. Marginal cells are capable of DNA repair
and reducing peak platinum adduct burden via
reparative mechanisms as described by Siddik
et al. [11]. Cisplatin-induced reversible acute hear-
ing loss may be due to reversible strial failure,
whereas the survival of the OHC determines the
final degree of functional recovery [31]. Ototoxicity
may be reversible if sufficient time for reparative
processes to occur is provided (Fig. 5).
Recovery of electrophysiological cochlear poten-
tial from cisplatin ototoxicity has been described in
the guinea pig [32,33]. Recovery in humans has been
reported by Aguilar-Markus, Laurell, and Vermorken
[8,28,29]. More recently, Zuur et al. described 27
ears that demonstrated recovery of hearing loss at
1, 2, and 4 kHz after chemoradiation for head and
neck cancer patients [30].
Fig. 5 Proposed mechanism of reversible and irreversi-
ble cisplatin ototoxicity. Marginal cell death leads to
fluctuations in endocochlear potential that result in hear-
ing loss which may be reversible. Cisplatin given without
sufficient time for cell reparative mechanisms will lead to
outer hair cell death resulting in permanent hearing loss.
Cisplatin-induced ototoxicity
7. Monitoring for ototoxicity: pure
tone audiometry, ABR, DPOAE
Pure tone behavioral audiometry remains the stan-
dard means to monitor for ototoxicity and hearing
loss. Since cisplatin ototoxicity preferentially
affects the basal end of the cochlea, high-frequency
audiometry is a more sensitive method of detecting
early ototoxicity [34,35]. The pediatric oncology
population is frequently difficult to test behavio-
rally, and therefore auditory brainstem response
(ABR) and DPOAE are sometimes useful objective
studies that can be obtained. Tone burst threshold
ABR studies are preferred, since the broadband click
stimulus may miss isolated high-frequency loss
which is typical for cisplatin ototoxicity. High-fre-
quency tone-burst-evoked ABR have been found to
be even more useful in identifying early ototoxicity
changes [36,37]. A number of researchers have
found DPOAE, a specific measure of OHC activity,
a particularly useful and more easily administered
modality to monitor for early cisplatin otoxicity
[3840]. As seen in this case (Fig. 4), high-frequency
(6 kHz) DPOAE amplitudes correlate well with
changes in high-frequency audiometric thresholds,
while the low frequency (1 kHz) DPOAE amplitudes
are stable and can be used as a verification of the
validity of the OAE measure.
8. Conclusions
In this case report, we present a pediatric case of
recovery of mild high-frequency sensorineural hear-
ing loss after cisplatin ototoxicity. The patient
reported tinnitus immediately following the initia-
tion of cisplatin therapy, followed by a dosing sche-
dule of 411 week intervals between doses, allowing
for appropriate time for reparative processes in the
cochlea. In this case, DPOAE did not provide earlier
detection of hearing loss, however correlated very
closely to audiometric threshold changes. Following
documented hearing loss or clinical complaints of
tinnitus, delay of the next dose of cisplatin should
be considered until clinical improvement is shown.
Allowing the stria vascularis to recover may result in
less OHC loss, and thus lesser degree of permanent
irreversible hearing loss.
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