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Role of Otoacoustic Emission in Early Detection of Cisplatin Induced

Ototoxicity

Article  in  Indian Journal of Otolaryngology and Head & Neck Surgery · July 2020
DOI: 10.1007/s12070-020-01933-7

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Role of Otoacoustic Emission in Early
Detection of Cisplatin Induced Ototoxicity

Shama Shetty, Satheesh Kumar

Bhandary, Vadisha Bhat, Rajeshwary
Aroor, Jayarama Shetty & T. Dattatreya

Indian Journal of Otolaryngology and

Head & Neck Surgery

ISSN 2231-3796

Indian J Otolaryngol Head Neck Surg

DOI 10.1007/s12070-020-01933-7

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 Author's personal copy
Indian J Otolaryngol Head Neck Surg
https://doi.org/10.1007/s12070-020-01933-7
ORIGINAL ARTICLE
Role of Otoacoustic Emission in Early Detection of Cisplatin
Induced Ototoxicity
Shama Shetty1,2 • Satheesh Kumar Bhandary1 • Vadisha Bhat1 • Rajeshwary Aroor1
Jayarama Shetty1 • T. Dattatreya3
Received: 5 February 2020 / Accepted: 23 June 2020
! Association of Otolaryngologists of India 2020
Abstract Cisplatin is a chemotherapeutic agent effective
against head and neck carcinoma but unfortunately it is
cochleotoxic. This study has been designed to investigate
the efficacy of OAE in identifying early effects of cisplatin
on the cochlea and the importance of protocol for audio-
logical monitoring of cisplatin induced ototoxicity. This is
a prospective observational study conducted from October
2012 to September 2014 on 70 patients, receiving Cisplatin
for various malignant conditions. Audiological criteria for
ototoxicity was considered as a difference of 10 d B or
more in pure tone thresholds of two or more adjacent fre-
quencies in conventional audiometry and in DPOAE-Sig-
nal noise ratio less than 6 dB or DPOAE amplitude less
than 20 dBSPL (irrespective of SNR [ 6 dB). According
to PTA, 60.7% patients showed ototoxicity after comple-
tion of chemotherapy. In DPOAE, according to SNR and
amplitude criteria more than 60% patients showed oto-
toxicity after first cycle of cisplatin at high frequencies
(4–8 kHz). DPOAEs is a sensitive tool for early detection
of ototoxicity and protocol is necessary for monitoring
ototoxicity in patients receiving cisplatin to improve the
quality of life.
Keywords Cisplatin ! Ototoxicity ! Otoacoustic emission !
OAE
& Shama Shetty
shamashetty20@yahoo.com
1
Department of ENT, KSHEMA, Mangalore, India
2
Present Address: Department of ENT, Kasturba Medical
College, Manipal, India
3
Nitte Institute of Speech and Hearing, Mangalore, India
•
Introduction
Ototoxicity is defined by Gray and Hawthorn [1], as the
damage to cochlear and/or vestibular part of the inner ear
by drugs.
Cisplatin is a chemotherapeutic agent effective against
many solid tumours, including head and neck carcinoma.
There are lots of chemotherapeutic agents nowadays which
have less side effects but cisplatin is still more effective
than most of these agents, and is also less expensive, so it is
still being used widely in countries like India [2]. Oto-
toxicity is one of the main factors which limits the use of
cisplatin.
Otoacoustic emissions (OAEs) are acoustic signals
emitted from cochlea which is generated by active
mechanical contraction of outer hair cells, spontaneously or
in response to sound.
As the survival rates are increasing nowadays, attention
is focused on ototoxicity by cisplatin aiming at its pre-
vention and /or early detection. In order to achieve that, a
protocol should be established that can be of high predic-
tive value [3].
This study has been designed to investigate the efficacy
of OAE in identifying early effects of cisplatin on the
cochlea and the imporatance of protocol for audiological
monitoring of cisplatin induced ototoxicity.
Methods
The study was conducted from October 2012 to September
2014 on 70 patients receiving Cisplatin for any malignant
conditions without any active or recent ear diseases. All
cases in this study were subjected to complete history
taking and clinical examination followed by audiological
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 Author's personal copy
examination with PTA, Immittance audiometry and
DPOAE.
Baseline audiological evaluation was done prior to drug
administration using Pure tone audiometry, Immittance
audiometry including Tympanometry and acoustic reflex
thresholds and DPOAE. Using PTA, air and bone con-
duction thresholds are calculated for both the ears from
250 Hz to 8 kHz in octaves for AC and 250 Hz to 4 kHz
for BC).
Distortion product otoacoustic emissions (DPOAE’s)—
is recorded with a microphone that is placed in the sealed
external auditory canal. The sealed probe also includes
tube for sound delivery to the ear canal. The microphone
records all sounds in the ear canal which includes in
DPOAEs, sound evoking the OAEs, and other patient—
generated sounds. DPOAEs are formed in the cochlea in
response to two simultaneous pure tone stimuli (primary
tones). This tonal response is not present in the eliciting
stimuli, and is therefore referred to as distortion. The pri-
mary tones (f1 and f2) are separated in frequency within
one third octave (typically f2 = f1 9 1.2) and the distor-
tion product is then typically at a frequency of 2 f1 - f2.
Because the 2f1-f2 DPOAEs have been shown to originate
from the region of the cochlea that maximally responds to
the primary tones, DPOAEs are typically presented in a
magnitude /frequency plot, in which frequency is deter-
mined by f2 (at low levels) or the geometric mean of f1 and
f2, and magnitude is determined for the DPOAEs at the
2f1 - f2 frequency bin. This is called DP-gram [4].
In this study DPOAE’s were collected using custom
software (Audera Grason Stadler PC software version
2.6.5.2116) run on a computer. The software utilized a card
deluxe digital signal processing board to generate stimuli
and record responses. The two DPOAE stimulus frequen-
cies (f1 and f2, where f1 \ f2) were separately digitized,
delivered to sealed ear canal through separate ports in the
probe assembly.
The probe also contained a microphone to record
DPOAE responses. The signal recorded by microphone
was amplified 20 dB by the ER-10B ? preamplifier, digi-
tized in 64-ms time windows, and stored in two interleaved
buffers, which were averaged in the time domain.
The DPOAE level at 2f1 - f2 was estimated from a
Fast Fourier transform of the grand average of two
response buffers ([A ? B]/2). Measurement—based stop-
ping rules were used such that any test frequency, sampling
stopped when the noise floor was \ - 20 dBSPL.
Both DPOAE’s and stimulus levels were measured at
the plane of microphone near the entrance to the ear canal.
DPOAEs, response elicited using two tones, and intensity
adjusted to 65/55 dBSPL. The frequencies tested ranged
from 0.5 to 8 kHz.
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Indian J Otolaryngol Head Neck Surg
DPOAE responses were considered valid and present if
they met all of the following criteria:
1. DPOAE amplitude was greater than - 20 dBSPL, a
conservative estimate of the system distortion.
2. DPOAE amplitude should be of at least 6 dB or
greater than the measured noise floor.
The results of baseline evaluation are used as a reference
criterion for comparison with post-therapy follow up
evaluation.
Chemotherapy protocol used was a single agent Cis-
platin [Cisplatin; Cipla, India] (40 mg/m2 weekly once for
4–6 weeks) along with radiation (Intensity modulated
radiation therapy).
Follow up evaluations was repeated using PTA and
DPOAES after scheduled chemotherapeutic dose regimen
within 24 h of Cisplatin administration.Post treatment
follow up monitoring is done after 1 month and 3 months
to study a possible change in the amplitude of the response.
Audiological criteria for Ototoxicity was considered as a
difference of 10 d B or more in pure tone thresholds of two
or more adjacent frequencies in conventional audiometry
[5] and DPOAE-Signal noise ratio less than 6 dB or
DPOAE amplitude less than – 20 dBSPL (irrespective of
SNR ratio).
Statistical Analysis
Mean, standard deviation and paired t test were used for
statistical evaluation. Significance was accepted at the p
B 0.01. The results from the left and right ears were treated
as independent data. Statistical software used is SPSS
version 20 v.
Results
The study was conducted on 70 patients including 52
(74%) males and 18 (26%) females. The age of patients
varied from 31 to 72 year. Twenty seven (38.6%) patients
belonged to age group of 31–45 year, 30 (42.9%) patients
belonged to 46–60 year, and 13 (18.6%) belonged to more
than 60 year.
In this study males and females were separately com-
pared with respect to right and left ears to study any sig-
nificant difference among them.
In right ear of 52 male patients, average of pure tone
thresholds was increasing at all frequencies during course
of cisplatin,but it was statistically significant after com-
pletion of cisplatin course in 1 and 2 kHz; and from first
cycle in 4, 6 and 8 kHz. In right ear of 18 female patients,
average of pure tone thresholds was increasing at all fre-
quencies during course of cisplatin, but it was statistically
 Author's personal copy
Indian J Otolaryngol Head Neck Surg
significant after completion of cycle in 1 kHz; after second
cycle in 2 and 4 kHz and from first cycle in 6 and 8 kHz.
In left ear of 52 male patients, average of pure tone
thresholds was increasing at all frequencies during course
of cisplatin, but it was statistically significant after com-
pletion of cisplatin course in 1 and 2 kHz; and from second
cycle in 4, 6 and from first cycle in 8 kHz. In left ear of 18
female patients, average of pure tone thresholds was
increasing at all frequencies during course of cisplatin, but
it was statistically significant after second cycle in 4 kHz
and from first cycle in 6 and 8 kHz.
According to ASHA criteria, deterioration of pure tone
thresholds of 10 dB or more at two or more adjacent fre-
quencies is an ototoxic damage. In our study, 20.7%, 45%,
60.7% of ears showed ototoxicity after first cycle, second
cycle and after completion of cycle respectively. After
1 month follow up, this increased to 66.4% and further
after 3 months there was no change from results of
1 month follow up (Table 1).
DPOAE-SNR Ratio Results
In right ear of 52 male patients, average of SNR ratio
(DPOAE) was reduced at all frequencies during course of
cisplatin, and statistically significant at all frequencies. In
right ear of 18 female patients, average of SNR ratio
(DPOAE) was reduced at all frequencies during course of
cisplatin, and was statistically significant at all frequencies.
In left ear of 52 male patients, average of SNR ratio
(DPOAE) was reduced at all frequencies during course of
cisplatin, and statistically significant at all frequencies. In
left ear of 18 male patients, average of SNR ratio (DPOAE)
was reduced at all frequencies during course of cisplatin,
and statistically significant at all frequencies (Tables 2, 3).
In this study, more than 50% of ears of patients show
ototoxicity at 6 and 8 kHz from first cycle of cisplatin and
from second cycle at 4 kHz. Lower frequencies are affec-
ted in less than 27% of patients.
Table 1 Number of ears showing Ototoxicity based on ASHA cri-
teria in PTA
Course of cisplatin No. of ears showing ototoxicity
After 1st cycle 29 (20.7%)
2nd cycle 63 (45%)
After completion 85 (60.7%)
1 month 93 (66.4%)
3 month 93 (66.4%)
ASHA American speech hearing association, PTA pure tone
audiogram
Dpoae Amplitude (dBSPL) Results
In right ear of 52 male patients, average of amplitude
(DPOAE dBSPL) was reduced at all frequencies during
course of cisplatin, and statistically significant at 1and
2 kHz. In higher frequencies as number of cases reduced p
value was not significant.
In right ear of 18 female patients, average of amplitude
(DPOAE-dBSPL) was reduced at all frequencies during
course of cisplatin, and statistically significant (p " 0.001)
at all frequencies. In the left ear of 52 male patients,
average of amplitude (DPOAE-dBSPL) was reduced at all
frequencies during course of cisplatin, and statistically
significant at 0.5, 1 and 2 kHz. At higher frequencies p
value was not significant as number of cases was reduced.
In left ear of 18 female patients, average of amplitude
(DPOAE-dBSPL) was reduced at all frequencies during
course of cisplatin and statistically significant at all fre-
quencies except 8 kHz because number of cases was
reduced.
This study shows ototoxicity in more than 45% of
patients at 4 kHz from second cycle of cisplatin and from
first cycle at 6 and 8 kHz.
Discussion
Anticancer drugs containing platinum are the basis for
chemotherapy for a wide range of malignant tumours.
Cisplatin, which is the first generation platinum drug is
widely used and is very effective against many cancers.
Cisplatin is used as a radiosensitizer as a standard protocol
during concurrent radiotherapy [2]. Cisplatin (CDDP-cis
diamine dichloroplatinum) was synthesized in 1845 by
Peyrone and thereafter it was named as Peyrone’s chloride
[6]. In 1978 cisplatin was approved as a chemotherapeutic
agent by Food and Drug Administration (FDA) [7]. How-
ever, it is also considered to be the most ototoxic com-
pound in clinical use [8]. It has been suggested that cause
of the apical to base difference in outer hair cell sensitivity
to ototoxic substances is because of the apical to basal
differences in levels of intracellular antioxidants in the
cochlea [9]. An ototoxic insult may affect the hearing,
vestibular function or both, depending upon the type of
chemical and its dose [10].
Though the risk for developing hearing loss from oto-
toxic drugs depends on the dose, duration, frequency, and
route of administration, there is marked individual vari-
ability in these relationships [11] It has also been observed
that concomitant exposure to other toxins such as noise,
chemicals, other ototoxic medications as well as genetic
factors and physiological factors can lead to increased rates
of ototoxicity [12, 13]. This damage is in the form of
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Indian J Otolaryngol Head Neck Surg

Table 2 Number of ears showing ototoxicity based on criteria, DPOAE-Signal noise ratio less than 6 dB
Frequency (kHz) After 1st cycle After 2nd cycle After completion After 1 month After 3 month

0.5 0 3 (2.1%) 5 (3.6%) 5 (3.6%) 5 (3.6%)

1 4 (2.9%) 12 (8.6%) 24 (17.1%) 28 (20%) 28 (20%)
2 4 (2.9%) 21 (15%) 36 (25.7%) 37 (26.4%) 38 (27.1%)
4 35 (25%) 74 (52.9%) 103 (73.6%) 103 (73.6%) 103 (73.6%)
6 75 (53.6%) 81 (57.9%) 118 (84.3%) 120 (85.7%) 120 (85.7%)
8 81 (57.9%) 110 (78.6%) 131 (93.6%) 132 (94.2%) 132 (94.2%)
DPOAE distortion product otoacoustic emission

Table 3 Number of ears showing Ototoxicity based on the criteria, DPOAE amplitude less than -20dBSPL (irrespective of signal noise ratio)
Frequency(kHz) After 1st cycle After 2nd cycle After completion After 1 month After 3 month

0.5 0 3 (2.1%) 5 (3.5%) 5 (3.5%) 5 (3.5%)

1 0 7 (5%) 13 (9.2%) 13 (9.3%) 13 (9.3%)
2 1 (0.7%) 13 (9.3%) 26 (18.6%) 26 (18.6%) 28 (20%)
4 32 (22.9%) 65 (46.4%) 95 (67.9%) 95 (67.9%) 96 (68.6%)
6 62 (44.3%) 90 (64.38%) 106 (75.7%) 111 (79.3%) 111 (79.3%)
8 82 (58.6%) 103 (73.6%) 125 (89.1%) 125 (89.1%) 125 (89.1%)
DPOAE distortion product otoacoustic emission

functional impairment due to cellular degeneration of tis-
sues of the inner ear and especially of the end organs and
neurons of the cochlear and vestibular divisions of the
eighth cranial nerve [14].
For incipient detection, change criteria developed by the
American Speech Language Hearing Association (ASHA)
and described in ‘‘Guidelines for the Audiologic Manage-
ment of Individuals Receiving Cochleotoxic Drug Ther-
apy’’ (ASHA 1994) are the most widely used (AAA 2009).
Otoacoustic emission (OAE) testing has been proposed
as an objective indicator of ototoxic damage because OAE
generation depends on the physiological status of the outer
hair cells [15]. There are 4 types of Otoacoustic Emissions:
Spontaneous otoacoustic emission, transient evoked otoa-
coustic emissions, distortion product otoacoustic emis-
sions, stimulus frequency otoacoustic emissions [16]. The
evoked otoacoustic emission is provided by a mechanism
of electro motility observed in cochlear outer hair cells
Distortion products are an objective method of hearing
assessment that provides a rapid way to evaluate the
functional status of the cochlea, so they are ideal for
monitoring drug ototoxicity.
We studied the role of OAE in evaluating early detec-
tion of cisplatin induced ototoxicity in 70 patients. In this
study PTA and DPOAE were used for detection of cisplatin
induced ototoxicity.
After first and second cycle of chemotherapy there was
no significant change in PTA hearing thresholds. After full
course of chemotherapy there showed significant audio-
metric elevation of hearing thresholds at 4, 6 and 8 kHz in
42.9, 52.9 and 62.7% of patients respectively. After
1 month and 3 months of follow up there was no signifi-
cant change in results. This result shows ototoxicity mainly
in high frequency ranges which are consistent with the
observations of Stavroulaki et al., who concluded that there
was elevation of hearing thresholds at 4–8 kHz in children
receiving cisplatin [3].
Durant et al. reported that frequencies above speech
range were most severely affected in patients receiving
cisplatin therapy [17]. It is also consistent with Hallmark
et al. who found that among affected patients hearing loss
was above speech range with no effect on the word dis-
crimination score [18]. This was consistent with our results
where high frequencies were more affected (4–8 kHz) from
first cycle of cisplatin and lower frequencies (1and 2 kHz)
were affected after completion of cisplatin course. After
1 month follow up there was increase in number of ears
showing ototoxicity from 60.7% to 66.4%. While after
3 months there was no change in results compared with
1 month follow up.
While comparing with DPOAE amplitude, ototoxicity
was seen after first course at 6 and 8 kHz in 44.3 and
58.6% of ears respectively, after second course at 4, 6 and
8 kHz in 46.4, 64.6 and 73.6% ears respectively and after
completion of chemotherapy at 4, 6 and 8 kHz in 48.6,
68.6, 76.4 and 88.6% ears respectively. While considering

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Indian J Otolaryngol Head Neck Surg
the average of amplitude value among ears of patients with
amplitude more than - 20dBSPL, there was decrease in
amplitudes during course of cisplatin and it was statisti-
cally significant in all frequencies in both right and left ear.
According to SNR criteria of less than 6 dB for oto-
toxicity, 53.6% and 57.9% of ears showed ototoxicity at
4,6 and 8 kHz respectively after first cycle, 52.9%, 57.9%
and 78.6% at 4,6 and 8 kHz after second cycle and
73.6%,84.3% and 93.6% showed ototoxicity at 4, 6 and
8 kHz after completion of course. In lower frequencies (0.5
2 kHz) less than 30% of ears were affected. While taking
average SNR ratio, it was statistically significant
(p \ 0.001) in all frequencies from first cycle of cisplatin.
This study shows ototoxicity in high frequency range
(4–8 kHz) where more than 50% of ears showed ototoxi-
city compared to the observations of Plinkert et al. where
there was a reduction in overall response level of OAEs in
patients treated with cisplatin [19]. These results show that
the measurement of OAE makes it possible to detect cis-
platin induced ototoxic effects, prior to any change in
conventional audiometry.
Orts et al. showed that Cisplatin produced little effect on
audiometric thresholds and an evident effect on the
amplitude of distortion products which was consistent with
this study [20]. In our study average PTA thresholds
showed significant ototoxicity in more than 60% of patients
after completion of course of cisplatin and it was statisti-
cally significant at higher frequencies (4–8 kHz). Based on
DPOAE SNR ratio and amplitude criteria, ototoxicity is
seen from first cycle in more than 60% of patients and it
was statistically significant at all frequencies(0.5–8 kHz).
According to Biro k et al., in patients receiving Cisplatin
dose of 300 mg/m2 or lesser than300mg/m2, no amplitude
changes were detected. In patients receiving Cisplatin dose
of 400 mg/m2 or more than 400 mg/m2 significant hearing
impairment was detected at lower frequencies that are
important for speech perception. At 400 mg/m2, significant
amplitude change was detected at 3 kHz; at 500–600 mg/
m2, significant amplitude change was detected at 1.5, 2 and
3 and at 700 mg/m2 significant amplitude change was
detected at 3 kHz [21].
In this study significant amplitude changes were seen at
all frequencies with cisplatin dose of 240–480 mg/ m2 but
ototoxicity was proven according to DPOAE amplitude
criteria in more than 60% of patients at high frequencies
(4–8 kHz).
If hearing changes are identified, physicians may alter
dosages or discontinue treatment with current medications,
switch to less toxic medications, or continue treatment and
prepare the patient and family to cope with hearing loss. If
no hearing changes are noted, physicians may aggressively
treat the disease. Early identification and monitoring of
ototoxic hearing loss provides opportunities for counselling
regarding communication strategies, the synergistic effects
of noise exposure with ototoxic medication and imple-
mentation of auditory rehabilitation.
In designing treatment protocols, the health care pro-
fessionals should consider the roles of hearing and balance
in maintaining quality of life following therapy. Permanent
hearing loss caused by ototoxic drugs can have serious
vocational, educational, and social consequences. An
effective monitoring program should detect ototoxic dam-
age before the patient becomes aware of ototoxic
symptoms.
Conclusion
Cisplatin produces bilateral, symmetrical sensorineural
hearing loss affecting mostly high frequency range. The
early detection of ototoxic induced hearing loss is therefore
essential to patients undergoing chemotherapy with cis-
platin. DPOAEs are a sensitive and time efficient tool for
early detection of ototoxicity, which do not require beha-
vioural response. Ototoxic monitoring provides opportu-
nities to consider alternative treatment regimen to
minimize or prevent hearing loss and its progression. If no
hearing changes are noted, physicians may aggressively
treat the disease with the same medication. Audiological
management of such patients can be an integral part of
therapeutic plan, improving the quality of life during and
after treatment.
Cisplatin produces ototoxicity and DPOAE detects
ototoxicity is a known fact. This paper proposes that
DPOAE detects early ototoxicity and requires no beha-
vioural response as compared to PTA. This paper also
proposes to integrate audiological monitoring protocol for
patients receiving Cisplatin. New born screening with OAE
has been effective tool in diagnosing Deafness and
managing thereafter, similarly monitoring ototoxicity by
DPOAE protocol will help in improving quality of life of
malignancy patients.
Summary
• Cisplatin produces bilateral, symmetrical sensorineural
hearing loss affecting mostly high frequency range
• PTA detects ototoxicity only after completion of
chemotherapy
• DPOAEs are a sensitive and time efficient tool for early
detection of ototoxicity, which do not require beha-
vioural response.
• Ototoxic monitoring protocol provides opportunities to
consider alternative treatment regimen to minimize or
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prevent hearing loss and its progression or counsel the
patient for continuation of chemotherapy.
Funding This research received no specific grant from any funding
agency, commercial or not-for-profit sectors.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical Statement Ethics committee approval has been obtained
from Institutional ethics committee for the study.
Informed Consent Informed consent was obtained from all indi-
vidual participants included in the study.
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