Original Cisplatin-based chemotherapy: Add high-

Article
frequency audiometry in the regimen
Arora R, Thakur JS, Azad RK, Mohindroo NK, Sharma DR, Seam RK1
Departments of Otorhinolaryngology-Head and Neck Surgery and 1Radiation Oncology, I G Medical
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0

College, Shimla, India

hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024

Correspondence to: Dr Jagdeep S Thakur, E-mail: anujagdeep@yahoo.co.in

Abstract
BACKGROUND: Cisplatin-induced ototoxicity shows high interindividual variability and is often accompanied by transient
or permanent tinnitus. It is not possible to identify the susceptible individuals before commencement of the treatment.
We conducted a prospective, randomized and observational study in a tertiary care centre and evaluated the effects of
different doses of cisplatin on hearing. MATERIALS AND METHODS: Fifty-seven patients scheduled for cisplatin-based
chemotherapy were included in the study. All patients were divided into three groups depending on the dose of cisplatin
infused in 3 weeks. RESULTS: The subjective hearing loss was found in seven patients, while six patients had tinnitus
during the chemotherapy. The hearing loss was sensorineural, dose dependent, symmetrical, bilateral and irreversible.
Higher frequencies were first to be affected in cisplatin chemotherapy. ConClusion: As use of high-frequency audiometry
is still limited in research work only, we need a strict protocol of adding high-frequency audiometry in the cisplatin-based
chemotherapy regimen.

Key words: Audiometry, cisplatin, hearing loss

DOI: 10.4103/0019-509X.55551 PMID: *****

Introduction before commencement of the treatment is not possible;

Cisplatin contributed significantly in the early success
of modern chemotherapy for solid tumors and today,
cisplatin is a primary drug for testicular cancer,
medulloblastoma, osteogenic sarcoma, cervix and ovarian
cancers.
however, early ototoxic effects can be detected by high-
frequency audiometry[7] and otoacoustic emission.[8-10]
We conducted a prospective, randomized and
observational study and evaluated the effects of different
doses of cisplatin on hearing.

Cisplatin is a cell cycle-nonspecific cytotoxic drug Materials and Methods

and has a toxic profile that is different from other
important cytotoxic drugs. High doses of cisplatin cause
nephrotoxicity, gastrointestinal toxicity, neurotoxicity and
ototoxicity. Ototoxicity is one of the dose-limiting side
effects of cisplatin because it increases with increase in
the dose.[1,2] Initially,[2,3] it normally manifests as high-
frequency sensorineural hearing loss that may progress
to affect frequencies within the speech range later in
the treatment. Cisplatin-induced ototoxicity is often
accompanied by transient or permanent tinnitus [4,5]
and shows high interindividual variability. [6] Exact
etiopathogenesis of this high intraindividual variability
is still unknown but pharmacokinetic differences,
genetic factors and metabolic status of the individuals
are implicated. Identification of susceptible individuals
This study was conducted in the Departments
of Otolaryngology- Head and Neck Surgery, and
Radiation-Oncology (Regional Cancer Centre).
Fifty-seven patients scheduled for cisplatin-based
chemotherapy were included in the study.
We divided all the subjects into three groups:
• Group 1 (Low -dose group): Patients receiving a
total dose of cisplatin at ≤60 mg/m2 in 3 weeks.
This group consisted of 10 patients (7 male and 3
female) with carcinoma of the larynx and received
single dose of cisplatin (50 mg/m2).
• Group 2 (Middle-dose group): Patients receiving a
total dose of cisplatin at 61-80 mg/m2 in 3 weeks.

Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4 311

311 CMYK
 Arora, et al.: Cisplatin based chemotherapy

Group 2 comprised 35 patients (21 male and 14
female) of whom 23 had various head and neck
cancer (excluding larynx) and the remaining 12 were
suffering from carcinoma of the cervix. All these
patients received cisplatin 40 mg/m2 on days 1 and 2.
• Group 3 (High-dose group): Patients receiving a total
dose of cisplatin at ≥81 mg/m2 in 3 weeks. Group
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0
threshold data (up to 16 KHz) was obtained by a
pure-tone audiometer (Clinical audiometer AC 40,
manufactured by Interacoustics A/S, DK-510, Assens,
Denmark) installed in a sound-proof room of the
otolaryngology department. Patients were reassessed
after 1 and 3 months of last cisplatin infusion. The
frequency spectrum of hearing loss (HL) was recorded

3 consisted of 12 patients (9 male and 3 female) of in each subject. Statistical package SPSS 13.0 was
which 10 had carcinoma of the lung and received used to evaluate the probability of significance.
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024

cisplatin 30 mg/m 2 on days 1-3; 2 patients had Postchemotherapy, a increase of 10 dB at Fisher’s

carcinoma of the testis and received cisplatin 20 mg/
m2 on days 1- 5.
All patients received radiation after chemotherapy.
No patient had distant metastasis, and hence none
underwent cranial radiation for treatment. During
radiation for the head and neck cancers, ipsilateral
temporal bone and ear of patients were protected by
beam-modification devices (shielding block made up of
lead) so as to avoid any affect of radiation on hearing.
An informed consent was obtained from each patient.
Patients with ear pathology, history of acoustic/noise
exposure, trauma and suffering with chronic diseases
such as diabetes mellitus, hypertension and those who
were taking any ototoxic drugs were excluded from the
study. All included patients underwent a detailed history,
clinical examination, hearing (tuning fork tests and pure
tone audiometry) and vestibular functions assessment
(bithermal caloric, positioning and positional tests),
blood (complete hemogram, liver and renal function
tests) and urine analysis.
scale (mean value of hearing thresholds at speech
frequencies, i.e., 0.5, 1 and 2 KHz) and increase of 20
dB at individual frequency from the baseline hearing
threshold was considered significant (P < 0.05 was
observed at 95% CI using chi-square test). During
baseline audiometry, a frequency with absent response
(hearing threshold >120 dB) was excluded from the
observations. On follow-up, if a subject with previous
response at a frequency develops an absent response on
that frequency then this was significant, and a value of
121 dB was taken for chart preparation.
Results
In this study, patient age ranged from 19 to 76 years,
with the majority of patients aged 40-50 years. The
mean age of presentation was 48 years. The male to
female ratio was 1.8:1. In 57 subjects (114 ears), mean
baseline hearing threshold at all tested frequencies was
54.4 dB, which increased to 73.1 dB after 3 months
[Table 1].

Prior to the start of chemotherapy, a baseline hearing During follow-up, seven patients complained of

Table 1: Data with respect to total number of ears (n = 114) tested (total no. of patients = 57)
Frequency Follow-up 0-20 21-40 41-60 61-80 81-100 101-120 >120 dB (No response,
dB dB dB dB dB dB Limit of audiometer)
4 KHz Baseline 37 48 16 9 3 1 0
At 3rd month 6 20 37 36 12 3 0
6 KH Baseline 11 45 36 18 4 0 0
At 3rd month 0 7 23 44 31 6 3
8 KHz Baseline 8 38 36 20 12 0 0
At 3rd month 0 4 13 36 41 14 6
12 KHz Baseline 0 1 18 44 33 9 9
At 3rd month 0 0 1 2 32 23 56
16 KHz Baseline 0 0 2 11 58 22 21
At 3rd month 0 0 0 0 1 23 90
Frequency Follow-up 0-25 dB 26-40 dB 41-55 dB 56-70 dB 71-90 dB >90 dB
Fisher Scale Baseline 86 21 5 2 0 0
At 3rd month 44 51 15 2 2 0

312 Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4

312 CMYK
 Arora, et al.: Cisplatin based chemotherapy

subjective hearing loss and six had tinnitus at the time maximum increase of 40 dB at 12 KHz in the hearing
of first follow-up but none had both complaints. The threshold of right ear in a 19-year-old patient [Figure
tinnitus was present in one subject of Group 1 (50-year- 4A]. In the left ear, uniform increase of about 30 dB
old male) and group 3 (34-year-old male), while group was observed in hearing threshold at all frequencies in
2 had 4 patients (mean age 50 years). There was no all age groups [Figure 4B].
statistical correlation between age and dose of cisplatin.
There was no subjective or objective vertigo in any Group 3 [Tables 1 and 2; Figure 5] had a mean age of
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0

patient. 45.16 years. Eight patients had significant hearing loss

at Fisher’s scale and this loss was observed in 11 of
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024

Group 1 [Tables 1, 2 and Figure 1] had mean age of 12 patients at 4 and 6 KHz. All subjects in this group
45.82 years and all 10 subjects received cisplatin at 50 had hearing loss at 8, 12 and 16 KHz. The maximum
mg/m2. All subjects had insignificant changes at Fisher’s
increase in hearing threshold was >60 dB at 6 KHz in
scale. Of 10 patients, 3 had significant hearing loss at 4
both ears of a 63-year-old patient [Figure 6A and B].
and 6 KHz. Of 9 patients, 6 had significant hearing loss
at 8 and 12 KHz, while only 4 of 7 patients showed
Figure 7 (A-C) shows baseline, first and final
significant hearing loss at 16 KHz. The maximum
audiograms of a 48-year-old patient (mean age of
increase in the hearing threshold after cisplatin was 45
study) while Figure 8 (A-C) shows similar audiogram
dB at 8 KHz in both ears in the 41-50 year age group,
which had only 1 patient [Figure 2 A and B]. of a patient belonging to Group 3. In all three
groups, hearing loss was sensorineural, irreversible and
Group 2 [Table 1, 2 and Figure 3] had a mean age of symmetrical, and there was no sex predilection.
49.47 years and all patients received cisplatin at 80 mg/
m2. In this group, 4 patients had significant hearing in Discussion
the Fisher’s scale. Hearing loss observed in all patients
was > 8 KHz. In this group, cisplatin caused the Cisplatin induced ototoxicity compromises, [11]
development of language, cognitive functions, learning
Low dose group ability, communication and quality of life in terms of
12 isolation and depression. The exact cause of cisplatin
10 toxicity is still unclear.[12] The unbound cisplatin in the
plasma is responsible for its toxicity. Cisplatin blocks
No. of patients

8
transduction channels within the outer hair cells of the
6
Significant cochlea and causes progressive destruction of outer hair
4 Non significant
cells, inner hair cells and supporting cells within the
organ of Corti. Hair cell loss in the vestibular labyrinth
2 No response

0 and injury to the stria vascularis also occurs. Cisplatin

Fisher
scale
4 khz 6 khz 8 khz 12 khz 16 khz
ototoxicity is also associated with the generation
Frequency of reactive oxygen species, depletion of intracellular
glutathione and interference with antioxidant enzymes
Figure 1: Hearing loss distribution in Group 1 within the cochlea.

Table 2: Hearing loss in each group, with different frequencies

Frequency Group 1 (≤60 mg/m2 Group 2 (61-80 mg/m2 Group 3 (≥81 mg/m2
in 3 weeks in 3 weeks) in 3 weeks)
Significant Non No Significant Non No Significant Non No
significant Response significant response significant response
Fisher scale 0 10 0 4 31 0 8 4 0
4 KHz 3 7 0 25 10 0 11 1 0
6 KHZ 3 7 0 33 2 0 12 0 0
8 KHz 6 3 1 35 0 0 12 0 0
12 KHz 6 3 1 33 0 2 11 0 1
16 KHz 4 3 3 32 0 3 9 0 3

Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4 313

313 CMYK
 Arora, et al.: Cisplatin based chemotherapy

140 140

120 120

100 100
31-40(n=3) 31-40(n=3)
80 31-40CPL 80 31-40CPL
41-50 (n=1) 41-50(n=1)
41-50CPL 41-50CPL
60 51-60 (n=6) 60 51-60 (n=6)
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0

51-60CPL 51-60CPL
40 40
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024

20 20

0 0
Fisher Scale 4KHz 6KHz 8KHz 12KHz 16KHz Fisher Scale 4KHz 6KHz 8KHz 12KHz 16KHz

Figure 2A: Baseline and post chemotherapy (denoted as ‘CPL’) in Figure 2B: Baseline and post chemotherapy ( denoted as ‘CPL’)
right ear of Group 1 in left ear of Group 1

140
Medium dose group
120
40 0-20(n=1)
35 0-20CPL
No. of patients

100
30 21-30(n=3)
21-30CPL
25 80 31-40(n=7)
20 31-40CPL
15 Significant 41-50(n=8)
60 41-50CPL
10 No significant 51-60(n=8)
5 No response 40 51-60CPL
0 61-70(n=7)
61-70CPL
Fisher 4 khz 6 khz 8 khz 12 khz 16 khz 20
scale
0
Frequency Fisher Scale 4KHz 6KHz 8KHz 12KHz 16KHz

Figure 3: Hearing loss distribution in Group 2 Figure 4A: Baseline and postchemotherapy hearing threshold of
right in Group 2

140 High dose group

120 14
0-20(n=1)
0-20CPL 12
No. of patients

100 21-30(n=3)
21-30CPL
10
80
31-40(n=7) 8
31-40CPL
41-50(n=8) 6 Significant
60 41-50CPL
51-60(n=8) 4 No significant
40
51-60CPL
2
61-70(n=7) No response
61-70CPL 0
20
Fisher 4 khz 6 khz 8 khz 12 khz 16 khz
0 scale
Fisher Scale 4KHz 6KHz 8KHz 12KHz 16KHz
Frequency
Figure 4B: Baseline and postchemotherapy hearing threshold of Figure 5: Hearing loss distribution in Group 3
left ear in Group 2

In this study, hearing assessment was done before
starting cisplatin therapy and at one and three months
after cisplatin infusion. In majority of the patients,
hearing loss was found at the time of first follow-up,
i.e., one month after cisplatin administration. This
hearing loss was progressive and irreversible on second
follow-up, i.e., three months after cisplatin infusion.
Berg et al.[13] conducted a study of cisplatin in children
and also observed hearing losses in children as early as
one month. Few studies[14,15] involving follow-up to two
years had also found irreversible hearing loss by cisplatin.
We found no correlation between age and hearing loss
or between baseline hearing level and cisplatin-induced
hearing loss. These findings indicate that cisplatin
ototoxicity is independent of age and pre-chemotherapy
hearing status of the individuals.
We found that a low dose (50 mg/m2) of cisplatin does
not affect speech frequencies. However, it affects the higher

314 Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4

314 CMYK
 Arora, et al.: Cisplatin based chemotherapy

140 140

120 120
21-30(n=1) 21-30(n=1)
21-30CPL 21-30CPL
100 31-40(n=3) 100 31-40(n=3)
31-40CPL 31-40CPL
41-50(n=6) 41-50(n=6)
80 80
41-50CPL 41-50CPL
51-60(n=1) 51-60(n=1)
60 51-60CPL 60 51-60CPL
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0

61-70(n=1) 61-70(n=1)
61-70CPL 61-70CPL
40 40
71-80(n=1) 71-80(n=1)
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024

71-80CPL 71-80CPL
20 20

0 0
Fisher Scale 4KHz 6KHz 8KHz 12KHz 16KHz Fisher Scale 4KHz 6KHz 8KHz 12KHz 16KHz

Figure 6A: Baseline and postchemotherapy hearing threshold of Figure 6B: Baseline and postchemotherapy hearing threshold of
right in Group 3 left ear in Group 3

Figure 7A: Baseline audiogram of 48-year-old male (mean age of Figure 7B: Audiogram of same patient at first follow-up
study).

et al., [16] who found hearing loss in 22% patients at

4-6 KHz. Fausti SA et al.[17] reported significant high
frequency (>8 KHz) of hearing loss in 71% patients.

Cisplatin at 80 mg/m 2 has little effect on lower

Figure 7C: Audiogram of same patient at final follow-up
frequencies (≥4 KHz) as 30% patient were observed to
have significant loss at 4-6 KHz, 67% at 8-12 KHz and
57% at 16 KHz. The maximum increase in the hearing
threshold after cisplatin administration was 45 dB at 8
KHz in both ears of a 43-year-old patient. This hearing
loss was bilateral, symmetrical and sensorineural. These
observations were comparable to the study by Laurall
frequencies; however, hearing impairment starts appearing
at >8 KHz frequencies as hearing loss was observed in
100% cases of Group 2 at >8 KHz. This observation was
comparable to study by Godofredo et al.[18] who, using
similar dose, found hearing loss at higher frequencies in
seven of eight children. In Group 2, cisplatin caused a
maximum increase of 40 dB in the hearing threshold at
12 KHz in the hearing threshold of right ear in a 19-year-
old patient. In the left ear, uniform increase of about 30
dB was observed in hearing threshold at all frequencies in
all age groups. These observations are suggestive of dose-
dependent ototoxicity. Although compared with Group
1 (50 mg/m2), less increase in the hearing threshold was
observed at a frequency but ototoxic effect was widespread
at 80 mg/m2.
The hearing loss increased more than 60 dB at the
doses of >80 mg/m 2 (90-100 mg/m 2) of cisplatin.

Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4 315

315 CMYK
 Arora, et al.: Cisplatin based chemotherapy
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024
Figure 8A: Baseline audiogram of a patient of Group 3
Figure 8C: Audiogram of same patient of Group 3 at final follow-up
We observed significant changes at Fisher’s scale in
66.66% cases. The ototoxicity increased in 91.66%
patients at 4-6 KHz and at 8-16 KHz; 100% cases had
hearing loss. These observation were comparable to the
study done by Laurell et al.,[16] who found significant
hearing loss in 81% of 54 patients receiving cisplatin
chemotherapy (100-120 mg/m²). A study done by
Koplemon et al. [3] found that 1-2 doses of cisplatin
(150-225 mg/m²) caused hearing loss in all patients
at >9 KHz and repeated administration of high-dose
cisplatin involved lower frequencies also.
Cisplatin ototoxicity is symmetrical, progressive,
irreversible (follow-up period 3 months) and dose-
dependent as hearing loss increases with increase in the
dose. CM Schmidt et al.[19] found left-right asymmetry
in 55 children after cisplatin. The left ear and boys had
more hearing loss compared with the right side and girls.
Few authors[20,21] have found relationship between free
circulating cisplatin in plasma with time. They found
that cisplatin infusion during afternoon and evening
316
316 CMYK
Figure 8B: Audiogram of same patient of Group 3 at first follow-up
results in low plasma levels of free cisplatin, and
hence cisplatin administrated during the early evening
hours results in fewer side effects including ototoxicity.
Measurement of correlation between time and plasma
concentration was beyond the scope of this study.
Cisplatin ototoxicity can present with tinnitus.[5,4,22] In
this study, about six patients had tinnitus irrespective of
the dose of cisplatin. The mean age of presentation was
49 years. We found no correlation of tinnitus with the
dose of cisplatin or age, which was comparable to the
study by Moroso et al.[22] As cisplatin does not affect
the vestibular system, [23] none of the patients in this
study had any vestibular symptom.
The risk of permanent hearing damage from platinum
chemotherapy is stimulating the development of
otoprotectants for coadministration with platinum to
reduce hearing damage without affecting the antitumor
activity of the platinum agent. There are numerous
otoprotectant agents under research, which include
aspirin, antioxidants,[24] intratympanic dexamethasone[25]
and hyperbaric oxygen therapy,[26] Ginkgo biloba extract,[27]
diethyldithiocarbamate, [28] lipoic acid, [29] adenosine
agonist,[30] vitamin E[31] and sodium thiosulfate.[32]
Cisplatin isused as a frontline anticancer drug in our
Department of Radiotherapy-Oncology (Regional cancer
centre). Although, the importance of high-frequency
audiometry in cisplatin chemotherapy was established about
25 years earlier,[33] but in majority of the centers including
our department, it is used only during research work.
However, lack of infrastructure, non-availability of high-
frequency audiometer and audiologist is a major problem
in these centers, especially in our country. Until we find
a substitute of cisplatin, strict protocol of adding high-
frequency audiometry in cisplatin regimen should be made
so that patients can be alerted for further precautions, e.g.,
avoidance of noise, ototoxic drugs and trauma.
Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4
 Arora, et al.: Cisplatin based chemotherapy
To conclude, we all know that cancer patients are
living in physical and mental agony and cisplatin-
induced ototoxicity further enhances this morbidity.
Audiological monitoring is an essential part of the
management of adults and children receiving platinum-
based chemotherapy. Although few authors[12,34,35] found
distortion product otoacoustic emission as a better method
Downloaded from http://journals.lww.com/indianjcancer by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0
of detecting cisplatin-induced early ototoxicity but high-
frequency pure-tone audiometry is the first choice due to
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/19/2024
its high sensitivity. High-frequency monitoring alerts the
physician of early ototoxic effects, who has opportunity
to change a patient’s course of treatment. Therefore,
high-frequency audiometry should be included in the
cisplatin-based chemotherapy regimen. Increase in the dose
of cisplatin lead to increase in ototoxicity that warrants
further research to find therapeutic efficacy of low-dose
cisplatin or a better substitute of cisplatin. Otoprotective
drugs are still at experimental level but may be beneficial
in cisplatin ototoxicity.
Acknowledgment
Dr RS Minhas provided general help in this research work.
References,
1. Li Y, Womer RB, Silber JH. Predicting cisplatin ototoxicity in
children: The influence of age and the cumulative dose. Eur J Cancer
2004;40:2445-51.
2. Vantrappen G, Rector E, Debruyne F. The ototoxicity of cisplatin: A
clinical study. Acta Otorhinolaryngol Belg 1990;44:415-21.
3. Kopelman J, Budnick AS, Sessions RB, Kramer MB, Wong GY.
Ototoxicity of high-dose cisplatin by bolus administration in
patients with advanced cancers and normal hearing. Laryngoscope
1988:858-64.
4. Moroso MJ, Blair RL. A review of cis-platinum ototoxicity. J
Otolaryngol 1983;12:365-9.
5. Domènech J, Cuchí MA, Carulla M. High-frequency hearing loss in
patients with tinnitus. Adv Otorhinolaryngol 1990;45:203-5.
6. Laurell G, Jungnelius U. High-dose cisplatin treatment: Hearing
loss and plasma concentrations. Laryngoscope 1990;100:724-34.
7. Fausti SA, Larson VD, Noffsinger D, Wilson RH, Phillips DS, Fowler
CG. High-frequency audiometric monitoring strategies for early
detection of ototoxicity. Ear Hear 1994;15:232-9.
8. Ozturan O, Jerger J, Lew H, Lynch GR. Monitoring of cisplatin
ototoxicity by distortion-product otoacoustic emissions. Auris Nasus
Larynx 1996;23:147-51.
9. Coradini PP, Cigona L, Selitre SG, Resito LS, Brunetto AL. Ototoxicity
from cisplatin therapy in childhood cancer. J Pediatr Hematol Oncol
2007;29:355-60.
10. Stavroulaki P, Apostolopoulos N, Segas J, Tsakanikos M,
Adamopoulos G. Evoked otoacoustic emissions--an approach for
monitoring cisplatin induced ototoxicity in children. Int J Pediatr
Otorhinolaryngol 2001;59:47-57.
11. Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving
platinum chemotherapy: Underestimating a commonly occurring
toxicity that may influence academic and social development. J Clin
Oncol2005;23:8588-96.
12. Leary SO. Ototoxicty. In: Gleeson M, editor. Scott Browns
Otorhinolaryngology, Head and Neck Surgery. Vol 3, 7th ed, Hodder
Arnold. London: 2008. p. 3567-73.
13. Berg AL, Spitzer JB, Garvin JH Jr. Ototoxic impact of cisplatin in
pediatric oncology patients. Laryngoscope 1999;109:1806-14.
Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4
14. Toral-Martinñon R, Collado-Corona MA, Mora-Magaña I, Leal-Leal
C, Gutiérrez-Castrellón P, González-de Leo S. Evaluation of cisplatin
ototoxicity by the audiometric curve in retinoblastoma. Cir Cir
2006;74:79-82.
15. Bertolini P, Lassalle M, Mercier G, Raquin MA, Izzi G, Corradini N,
et al. Platinum compound-related ototoxicity in children: Long-term
follow-up reveals continuous worsening of hearing loss. J Pediatr
Hematol Oncol 2004;26:649-55.
16. Laurell G, Borg E. Ototoxicity of cisplatin in gynaecological cancer
patients. Scand Audiol 1988;17:241-7.
17. Fausti SA, Henry JA, Schaffer HI, Olson DJ, Frey RH, Bagby GC
Jr. High-frequency monitoring for early detection of cisplatin
ototoxicity. Arch Otolaryngol Head Neck Surg 1993;119:661-6.
18. Borges GC, Borges RH, Baraúna GN, Lopes Filho O. Cisplatin
Ototoxicity in Children: Retrospective study. Revista Brasileira
de Otorrinolaringologia 2001;67:292-5.
19. Schmidt CM, Knief A, Lagosch AK, Deuster D, Zehnhoff-Dinnesen
A. Left-right asymmetry in hearing loss following cisplatin therapy
in children--the left ear is slightly but significantly more affected.
Ear Hear 2008;29:830-7.
20. Hrushesky WJ. Circardian timing of cancer chemotherapy. Science
1985;228:73-5.
21. Hecquet B, Meynadier J, Bonneterre J, Adenis L, Demaille A. Time
dependency in plasmatic protein binding of cisplatin. Cancer Treat
Rep 1985;69:79-83
22. Vermorken JB, Kapteijn TS, Hart AA, Pinedo HM. Ototoxicity of
cis-diamminedichloroplatinum (II): influence of dose, schedule
and mode of administration. Eur J Cancer Clin Oncol 1983;19:53-8.
23. Dutta A, Venkatesh MD, Kashyap RC. Study of the effect of
chemotherapy on auditory function. Indian J Otolaryngol Head Neck
Surg 2005;57:226-8.
24. Rybak LP, Ramkumar V. Ototoxicity. Kidney Int 2007;72:931-5.
25. Hill GW, Morest DK, Parham K. Cisplatin-induced ototoxicity:
effect of intratympanic dexamethasone injections. Otol Neurotol
2008;29:1005-11.
26. Yassuda CC, Righetti AE, Cury MC, Hyppolito MA, de Oliveira
JA, Féres O. The role of hyperbaric oxygen therapy (hot) as an
otoprotection agent against cisplatin ototoxicity. Acta Cir Bras
2008;23:72-6.
27. Huang X, Whitworth CA, Rybak LP. Ginkgo biloba extract (EGb 761)
protects against cisplatin-induced ototoxicity in rats. Otol Neurotol
2007;28:828-33.
28. Rybak LP, Husain K, Morris C, Whitworth C, Somani S. Effect
of protective agents against cisplatin ototoxicity. Am J Otol
2000;21:513-20.
29. Husain K, Whitworth C, Somani SM, Rybak LP. Partial protection by
lipoic acid against carboplantin-induced ototoxicity in rats. Biomed
Environ Sci 2005;18:198-206.
30. Whitworth CA, Ramkumar V, Jones B, Tsukasaki N, Rybak LP.
Protection against cisplatin ototoxicity by adenosine agonists.
Biochem Pharmacol 2004;67:1801-7.
31. Kalkanis JG, Whitworth C, Rybak LP. Vitamin E reduces cisplatin
ototoxicity. Laryngoscope 2004;114:538-42.
32. Zuur CL, Simis YJ, Lansdaal PE, Hart AA, Schornagel JH, Dreschler
WA, et al. Ototoxicity in a randomized phase III trial of intra-
arterial compared with intravenous cisplatin chemoradiation in
patients with locally advanced head and neck cancer. J Clin Oncol
2007;25:3759-65.
33. Tange RA, Dreschler WA, van der Hulst RJ. The importance of high-
tone audiometry in monitoring for ototoxicity Arch Otorhinolaryngol
1985;242:77-81.
34. Knight KR, Kraemer DF, Winter C, Neuwelt EA. Early changes in
auditory function as a result of platinum chemotherapy: use of
extended high-frequency audiometry and evoked distortion product
otoacoustic emissions. J Clin Oncol 2007;25:1190-5.
35. Biró K, Noszek L, Prekopp P, Nagyiványi K, Géczi L, Gaudi I, et
al. Detection of late ototoxic side effect of cisplatin by distortion
otoacoustic emission (DPOAE). Magy Onkol 2007;50:329-35.
Source of Support: Nil, Conflict of Interest: None declared.
317
317 CMYK