Download Effect of cisplatin on distortion product otoacoustic emissions in

The Laryngoscope
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Rhinological and Otological Society, Inc.
Effect of Cisplatin on Distortion Product Otoacoustic Emissions
in Japanese Patients
Peem Eiamprapai, MD; Norio Yamamoto, MD, PhD; Harukazu Hiraumi, MD, PhD;
Eriko Ogino-Nishimura, MD; Morimasa Kitamura, MD; Shigeru Hirano, MD, PhD; Juichi Ito, MD, PhD
Objectives/Hypothesis: Although it is well known that cisplatin is associated with ototoxicity, there is still a lack of
knowledge concerning the ototoxicity of cisplatin, especially in Japanese head and neck cancer patients. The objectives of this
study were to determine the incidence rate of cisplatin ototoxicity and to determine the threshold dose causing ototoxicity in
the Japanese population.
Study Design: Before-and-after study in a tertiary referral hospital.
Methods: The distortion product otoacoustic emission (DPOAE) was measured 1 week after each administration of cisplatin in 44 Japanese head and neck cancer patients treated at Kyoto University Hospital. We determined the incidence and
threshold dose of cisplatin ototoxicity according to DPOAE data.
Results: The incidence of ototoxicity detected by DPOAE was 77.3%. The average DPOAE value was significantly lower
in patients who received more than 200 mg/m2 cisplatin than the baseline DPOAE value. The threshold dose for cisplatin ototoxicity was lower in Japanese patients than in European patients.
Conclusions: Our data suggest that Japanese patients are more susceptible to cisplatin-induced ototoxicity. This is presumably caused by a genetic difference.
Key Words: Distortion product otoacoustic emissions, cisplatin, head and neck cancer, ototoxicity.
Level of Evidence: 4
Laryngoscope, 122:1392–1396, 2012
INTRODUCTION
Cisplatin,
or
cis-diamminedichloroplatinum
(CDDP), is a potent chemotherapeutic agent for the
treatment of head and neck cancer. Chemoradiotherapy
using CDDP in head and neck cancers is widely recognized for its ability to preserve organs.1 However, CDDP
has strong side effects such as neutropenia, acute renal
failure, and ototoxicity. CDDP-induced sensorineural
hearing loss starts in the higher frequencies, usually
progresses bilaterally, and sometimes results in permanent hearing disability and/or tinnitus.2 Early detection
of ototoxicity by CDDP is important to avoid permanent
hearing loss because recent animal studies have demonFrom the Department of Otolaryngology, Head and Neck Surgery,
Graduate School of Medicine (P.E., N.Y., H.H., E.O.-N., M.K., S.H., J.I.), Kyoto
University, Kyoto City, Kyoto, Japan; and Department of Otolaryngology,
Faculty of Medicine, Mahasarakham University (P.E.), Umpur Meung,
Mahasarakham Province, Thailand.
Editor’s Note: This Manuscript was accepted for publication March
9, 2012.
This study was supported by an International Fellowship Program
from Takeda Science Foundation (P.E.), a Grant-in-Aid for Young Scientists (B) (22791595) (N.Y.), a Grant-in-Aid for Scientific Research (C)
(22591907) (M.K.), a Grant-in-Aid for Scientific Research (C) (21592192) to
(S.H.), and a Grant-in-Aid for Scientific Research (S) (23229009) to (J.I.)
from the Ministry of Education, Culture, Sports, Science and Technology.
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Send correspondence to Norio Yamamoto, MD, PhD, Department
of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine,
Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto city, Kyoto
606-0815, Japan. E-mail: [email protected]
DOI: 10.1002/lary.23336
Laryngoscope 122: June 2012
1392
strated that the administration of a protective reagent
can attenuate hearing impairment,2 although CDDPinduced hearing loss is sensorineural hearing loss that
is considered irreversible once established. Among the
several existing tests for hearing function, distortion
product otoacoustic emission (DPOAE) is an appropriate
tool for detecting ototoxicity by CDDP for two reasons.
First, DPOAE measurement is based on outer hair cell
activity, which is affected in CDDP-induced hearing
loss3 before pure-tone audiometry (PTA) demonstrates
the elevation of auditory threshold, indicating that
DPOAE is more sensitive than PTA for the detection of
ototoxicity by CDDP.4 Second, the results of DPOAE, as
an objective test, are not affected by the patient’s condition, which often deteriorates with the progression of
malignant tumor.
Although susceptibility to ototoxicity by CDDP is
affected by genetic differences,5,6 almost all published
studies have been performed with European subjects;
the incidence of ototoxicity and its risk factors have
never been explored for Asian populations. The aim of
this study was to determine the incidence rate and the
threshold dose of CDDP for ototoxicity in Japanese head
and neck cancer patients.
MATERIALS AND METHODS
Subjects
Fifty-five patients received CDDP to treat head and
neck cancer between June 2009 and August 2010 at the
Eiamprapai et al.: CDDP Ototoxicity in Japanese Patients
Department of Otolaryngology Head and Neck Surgery,
Kyoto University Hospital, Kyoto, Japan. Among them, two
patients showing type B tympanograms before the administration of CDDP were excluded from this study. Nine patients
had no follow-up audiologic evaluation; therefore, finally,
44 patients were included in the analysis. In all patients,
the average thresholds of PTA before CDDP administration
were within 50 dBHL, and the DPOAE showed a normal
response.
In this study, CDDP was used in different ways depending
on the malignant tumor stage. For patients with stage I and II
head and neck cancers, CDDP was used in concurrent chemoradiotherapy. CDDP (80 mg/m2) was administered on days 1, 22,
and 43 of the course of radiotherapy. The total dose of 66 to
70 Gy was delivered in conventional fractionation (5 2 Gy/
week). In contrast, patients with stage III and IV cancer
underwent one to two cycles of induction chemotherapy, followed by surgery or chemoradiotherapy. The induction
chemotherapy regimen was as follows: 60 mg/m2 CDDP and
60 mg/m2 docetaxel (Taxotere, Sanofi Aventis, Paris, France)
given as a bolus intravenous injection on day 1, followed by
600 mg/m2 per day of 5-fluorouracil (5-FU) on days 1 to 4.
The protocol of chemoradiotherapy was the same as that for
stage I and II head and neck cancer patients. Postoperative
radiotherapy or adjuvant chemotherapy with 48 to 60 mg/m2
CDDP per dose was optional. In patients with low kidney
function, renal adjustment was calculated, and a smaller
amount of CDDP was administered.
Audiologic Evaluation
The hearing evaluation was scheduled 1 workday before
starting chemotherapy and about 1 week after each course of
chemotherapy. The external auditory canal and tympanic
membrane were examined by an otoscope. Middle ear status
was evaluated by tympanogram. Hearing function was
evaluated by DPOAE (CuBeDIS 2000, Mimosa Acoustics,
Champaign, IL), with two simultaneous pure tones presented
to the ear at two different frequencies (f1 and f2, where the
frequency ratio [f2/f1] was set to 1.2). The levels of f1 and f2
were 65 and 55 dB SPL, respectively. The f2 frequency range
was 516 to 8,016 Hz.
Determination of Ototoxicity
To determine the incidence rate of ototoxicity, a significant
deterioration in DPOAE (i.e., due to an ototoxic change) was
defined according to the test–retest criteria.7,8 At f2 frequencies
below 1 kHz, a decrease in the signal-to-noise ratio (SNR),
which is the difference between amplitude of DPOAE and noise
floor of each test f2 frequency, greater than 14 dB was regarded
as significant. At f2 frequencies above 1 kHz, an SNR decrease
greater than 7 dB was considered a significant clinical change.
The correlation between CDDP dose and the proportion of
patients with DPOAE change was presented using the KaplanMeier survival curve.
Determination of the Cumulative CDDP Dose
Causing DPOAE Shift
To determine the CDDP dose that causes a significant
DPOAE shift, the cumulative dose of CDDP at the time of each
DPOAE test was classified into three categories: categories 1, 2,
and 3 contained data from patients administered <100 mg/m2,
101 to 200 mg/m2, and >200 mg/m2 of CDDP, respectively. The
SNR values of DPOAE in each f2 frequency tested from each
category were subject to analyses.
Laryngoscope 122: June 2012
Fig. 1. Kaplan-Meier survival function curve showing the correlation between the cumulative dose of cisplatin (CDDP) and the ratio of patients without significant change in distortion product
otoacoustic emission (DPOAE). About half the patients exhibited
significant DPOAE change with the administration of less than
120 mg/m2 CDDP.
Statistical Analyses
Logistic regression analysis was performed to detect factors other than CDDP that might possibly cause ototoxic
changes; these factors included renal function; history of hypertension, heart disease, or liver disease; concurrent radiation
therapy; and 5-FU or docetaxel administration with CDDP. The
correlations between ototoxicity and other side effects including
renal insufficiency were also analyzed.
To determine the CDDP threshold dose causing a DPOAE
shift, the DPOAE SNR data in each category were compared
with those before CDDP administration for each f2 frequency
using two-way repeated measures analysis of variance. All analyses were performed using SPSS version 17.0 software (SPSS,
Inc., Chicago, IL).
RESULTS
The mean age of the 44 patients (11 women and
33 men) before CDDP administration was 59.7 years
(range, 27–74 years; median, 61 years). The average follow-up period was 78.95 days (range, 10–274 days). The
average dose of CDDP was 156.1 6 77.17 mg/m2 (range,
48–360 mg/m2). The incidence rate of ototoxicity was
77.3% (34 out of 44 patients). Among these, 14 patients
had bilateral ototoxic change and 21 had ototoxic
changes with less than 100 mg/m2 CDDP. However, most
of these patients did not have subjective inner ear symptoms. Only one patient complained of tinnitus after
completing a course of CDDP. The Kaplan-Meier survival function curve showed that the ratio of patients
with unchanged DPOAE decreased as cumulative CDDP
dose increased (Fig. 1).
Factors other than CDDP that might affect hearing deterioration were analyzed; however, no
statistically significant risk factors were detected. Furthermore, neither a correlation between DPOAE
amplitude with changes in creatinine value nor the
occurrence of acute renal insufficiency during treatment was detected.
CDDP doses lower than 200 mg/m2 had no significant effect on DPOAE SNR amplitude (F ¼ 0.106,
Eiamprapai et al.: CDDP Ototoxicity in Japanese Patients
1393
DISCUSSION
Fig. 2. Comparison of the signal-to-noise ratio (SNR) of distortion product otoacoustic emission (DPOAE) before and after
administration of various amounts of cisplatin (CDDP). A comparison between the average amplitudes of DPOAE SNR before
(baseline, dashed lines) and after (CDDP, solid lines) the administration of each categorized dose of CDDP (<100, 100–200,
and >200 mg/m2 in A, B, and C, respectively) is shown. The
bars represent standard error of mean. Significant DPOAE shifts
were observed after CDDP doses exceeding 200 mg/m2 were
administered (asterisk in C, P < .05, two-way repeated analysis
of variance).
df ¼ 1, P ¼ .746 for CDDP doses less than 100 mg/m2
and F ¼ 0.135, df ¼ 1, P ¼ .715 for CDDP doses 100–
200 mg/m2) (Fig. 2A and 2B). Meanwhile, CDDP doses
more than 200 mg/m2 had a significant effect on
DPOAE SNR amplitude (F ¼ 6.521, df ¼ 1, P ¼ .017)
(Fig. 2C).
Laryngoscope 122: June 2012
1394
CDDP treatment is one of the most potent chemotherapeutic agents for the treatment of head and neck
and other types of cancer. But CDDP has been reported
to cause irreversible sensorineural hearing loss.9 Most of
the reports related to hearing loss caused by CDDP
treatment have used conventional PTA10 to describe the
ototoxicity. From the animal experiment, CDDP administration caused outer hair cell loss from the basal turn,
where higher frequency sound is perceived.3 Utilizing
these characteristics of CDDP ototoxicity, DPOAEs that
detect the activity of outer hair cells11 and extended
high-frequency PTA8 became used recently to achieve
early detection of the ototoxicity. In this study we chose
DPOAE to detect CDDP-induced ototoxicity because of
its objectivity. An objective test is especially useful for
cancer patients because they sometimes have poor performance for the subjective tests, including PTA, owing
to their poor systemic condition.
In the current study, the incidence rate of ototoxicity detected as a result of a significant DPOAE
amplitude change was 77.3%. Only one previous study
determined the incidence rate of ototoxicity caused by
CDDP using DPOAE8; that study used the same DPOAE
diagnostic criteria as ours and reported the incidence of
ototoxicity to be 81.3% among 32 children and adolescent
patients with various malignant tumors. Their results
are comparable to ours, although their patients were
administered a larger average dose of CDDP (420 mg/
m2) and were younger (mean, 8.4 years) and more susceptible to CDDP. The incidence rate of ototoxicity due
to CDDP based on PTA is reported to be around
45%,12,13 which is lower than the present DPOAE
results.
The effect of cumulative doses of CDDP has been
pointed out as a factor that contributes to the incidence of
CDDP-induced ototoxicity.9 Despite numerous studies
concerning the ototoxicity of CDDP having been performed, most have determined the critical dose on the
basis of the patients’ self-reported symptoms (i.e., hearing
impairment and tinnitus) or PTA, which is less sensitive
than DPOAE. Therefore, the critical dose of CDDP
remains controversial. In a pediatric patient series, ototoxic changes in PTA occurred in 50% of patients with a
single dose of CDDP as low as 50 mg/m2.14 However in
adult patients, significant changes in DPOAE amplitude
were found only after administration of 400 mg/m2 CDDP
in testicular cancer patients (n ¼ 223).15 Another study
that used extended high-frequency PTA, which is more
sensitive than DPOAE, to detect ototoxicity due to CDDP,
determined the average cumulative dose of CDDP causing a hearing ability change to be 343.6 mg/m2 (n ¼ 36).11
In our study, we found that cumulative doses less than
100 mg/m2 of CDDP caused ototoxic changes in about half
of the Japanese adult patients (Fig. 1). These results
show that CDDP induces inner ear damage beginning
with less than 100 mg/m2 of CDDP in some patients. In
addition, group analysis revealed that DPOAE SNR amplitude decreased significantly when patients received
more than 200 mg/m2 cumulative CDDP dose (Fig. 2).
Eiamprapai et al.: CDDP Ototoxicity in Japanese Patients
Considering that the maximum CDDP dose in our
study was 360 mg/m2, the cumulative CDDP dose causing ototoxicity in our study is lower than that in two
previous studies.11,14 In addition, we found an incidence
of ototoxicity due to CDDP in a Japanese adult series
(77.3%) that was comparable to that in a previous child
and adolescent study with greater CDDP doses (81.2%).8
These discrepancies can be attributed to differences
in ethnicity5 or other risk factors causing hearing loss,
including younger age, cranial irradiation, and use
of vincristine.2,13 However, the possibility of the latter
factors occurring in our study is quite low. All of
our patients were adults and never received vincristine. In our study series, radiation field did not
involve the cranial area, using an intensity-modulated
radiation therapy technique, which is proven to reduce
hearing loss by avoiding the cochlea.2 Therefore, the
difference in susceptibility due to CDDP between ours
and previous studies can be attributed to ethnic
differences.
The interindividual difference in CDDP ototoxic
susceptibility between Japanese and European populations might be explained by genetic variability.2 A
previous study using cultured cell samples showed
genetic differences between European and African populations with respect to susceptibility to CDDP toxicity.6
Correlations between a few families of genes and CDDP
ototoxic susceptibility have also been discovered.2,5,16,17
One family of genes worth mentioning is the glutathione-S-transferase (GST) gene family. The genes of this
family encode enzymes associated with the cellular
detoxification of CDDP and free radicals.2,5 Individuals
who lack the expression of some GST family genes,
namely GSTT1 and GSTM1, have an increased risk of
CDDP toxicity, including ototoxicity.17 The prevalence of
the deleted genotype of GSTT1 in Asians (Chinese,
64.4%; Koreans, 60.2%) was higher than that in other
ethnic groups (African-Americans,21.8%; Europeans,
20.4%; Mexican-Americans. 9.7%).16 Aside from GSTs,
megalin (which is associated with the accumulation of
CDDP in the cochlea),18 thiopurine S-methyltransferase
(TPMT, which inactivates thiopurine compounds that
bind to CDDP and cause DNA damage), and catechol Omethyltransferase (COMT, unknown function)19 are
associated with CDDP-induced ototoxicity. The ethnic
difference in the prevalence for one or some of these
gene polymorphisms may be the underlying cause of the
higher susceptibility of Japanese people to CDDP in our
study series.
By determining the critical ototoxic CDDP dose, the
early detection of CDDP-induced ototoxicity and its prevention become feasible. Animal studies elucidated that
ototoxicity caused by CDDP was mediated through the
production of reactive oxygen species that resulted in
the induction of outer hair cell apoptosis.20 Candidates
for materials to prevent the CDDP-induced ototoxicity
are materials with antioxidative effects including hydrogen,21 N-acetyl cysteine,22 D-methionine,23 and
salicylate24 or antiapoptotic reagents including caspase
inhibitors25 and X-linked inhibitor of apoptosis.26 It will
be necessary to administer these materials before the cuLaryngoscope 122: June 2012
mulative dose of CDDP reaches the critical dose
determined.
CONCLUSION
In conclusion, our data suggest that the Japanese
population is more susceptible to the ototoxic side effects
of CDDP. Results from studies in the European population may not be generalizable to Japanese and other
Asian populations. This may be explained by differences
in the Asian genetic background. It may be necessary to
conduct basic research on responses to CDDP toxicity as
well as long-term large population studies concerning
the responses and toxicities of CDDP in Asian
populations.
Acknowledgment
The authors thank Yasuaki Hayashino MD, DMSc,
MPH, and Bundit Thinkhamrop, PhD, for providing statistical advice, Kyoko Shimizu and Yoshiko Hosomi for distortion product otoacoustic emission measurement, and
Arpakorn Kositwattanarerk and Pimyupa W. Praphan for
assistance in manuscript preparation.
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