The Journal of Laryngology & Otology (2015), 129, 767–772.

MAIN ARTICLE
© JLO (1984) Limited, 2015
doi:10.1017/S0022215115001632

Sensorineural hearing loss following induction

chemotherapy plus concurrent chemoradiotherapy
for advanced nasopharyngeal carcinoma

V ATCHARIYASATHIAN, K PRUEGSANUSAK, S WONGSRIWATTANAKUL

Department of Otolaryngology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand

Abstract
Objective: To compare the incidence of sensorineural hearing loss between those treated with docetaxel, cisplatin
and 5-fluorouracil induction chemotherapy followed by carboplatin concurrent chemoradiotherapy and those treated
with conventional concurrent chemoradiotherapy for advanced nasopharyngeal carcinoma.
Methods: Serial pure tone audiometry was conducted in 36 nasopharyngeal carcinoma patients who were
randomised into 2 groups. The first group received docetaxel, cisplatin and 5-fluorouracil induction
chemotherapy followed by carboplatin concurrent chemoradiotherapy. The second group received conventional
concurrent chemoradiotherapy.
Results: The incidence of sensorineural hearing loss at speech frequency in the first group was 10 per cent and in
the second group was 50 per cent ( p = 0.0027). Bone conduction thresholds were significantly increased after
completion of the treatment at 2–4 kHz in the first group and at all frequencies in the second group.
Conclusion: The docetaxel, cisplatin and 5-fluorouracil induction chemotherapy regimen followed by concurrent
chemoradiotherapy was associated with a lower incidence of sensorineural hearing loss than conventional
concurrent chemoradiotherapy. This regimen may be the preferred choice of treatment for hearing preservation.

Key words: Sensorineural Hearing Loss; Nasopharyngeal Carcinoma; Chemoradiotherapy

Introduction chemotherapy with docetaxel, cisplatin and 5-fluorour-

Nasopharyngeal carcinoma (NPC) is a common head
and neck cancer in Southeast Asia. Platinum-based
concurrent chemoradiotherapy is the recommended
treatment for NPC stage III or IV.1–5 Hearing loss
that may impact quality of life is one of the major com-
plications of the chemoradiotherapy.
Many studies have reported individual ototoxicity
effects of cisplatin or cisplatin plus carboplatin and
radiation.6–8 In a study by Bertolini et al., 15 per
cent of 120 children treated with a median cumulative
dose of 400 mg/m2 of cisplatin and 1600 mg/m2 of
carboplatin developed hearing loss at 1–8 kHz.7 The
rate of hearing loss is expected to increase with the
use of combined modality therapy.9–12 Pearson et al.
reported that more than 50 per cent of the patients
had a change in pure tone average (PTA) of more
than 10 dB or greater, and more than 85 per cent of
the patients had high frequency hearing loss.9
Many clinical trials of induction chemotherapy with
taxanes have been conducted to provide a new che-
motherapeutic regimen with less toxicity that improves
efficacy for treating advanced NPC.13,14 Induction
acil followed by concurrent chemoradiotherapy is a
modality of treatment for advanced NPC conducted
in a tertiary centre.15 This has resulted in excellent
overall survival and locoregional control, with accept-
able toxicity.16–19
To date, there has been no direct comparative study
of the rate of hearing loss between such treatments in
NPC patients. This study aimed to compare the inci-
dence of sensorineural hearing loss (SNHL) between
those treated with docetaxel, cisplatin and 5-fluoroura-
cil induction chemotherapy followed by concurrent
chemoradiotherapy and those treated with concurrent
chemoradiotherapy followed by adjuvant chemotherapy
for advanced NPC.
Materials and methods
Thirty-six patients were clinically defined as having
advanced nasopharyngeal carcinoma stage IIB–IVB
at the time of receiving treatment (at the Department
of Otolaryngology, Songklanagarind Hospital), from
2010 to 2012.

Accepted for publication 20 January 2015 First published online 26 June 2015
768 V ATCHARIYASATHIAN, K PRUEGSANUSAK, S WONGSRIWATTANAKUL

The patients were classified into two groups by com-
puter randomisation. The first group (arm 1) consisted
of 17 patients who received induction chemotherapy
with docetaxel, cisplatin and 5-fluorouracil followed
by carboplatin concurrent chemoradiotherapy. The
second group (arm 2) consisted of 19 patients who
received conventional treatment; that is, cisplatin con-
current chemoradiotherapy followed by adjuvant cis-
platin and 5-fluorouracil regimen.
Patients with a second primary carcinoma, evidence
of metastasis or recurrent tumour, carcinoma involve-
ment of the middle or inner ear, severe sepsis, or an
Eastern Cooperative Oncology Group performance
status of more than 1, and those who had undergone
previous radiation or chemotherapy, were excluded.
Patients who participated in this study signed an
informed consent form that was approved by the Ethics
Committee (Faculty of Medicine, Prince of Songkla
University). After the medical history had been taken,
and physical examination and laboratory investigation
data had been recorded, all patients were treated in
either arm 1 or arm 2 (Figure 1).
In arm 1, serial audiometry and/or tympanometry
were performed: before the treatment (pre-treatment),
4 weeks after induction therapy (post-induction), 4
weeks after concurrent chemoradiotherapy (post con-
current chemoradiotherapy) and 12 weeks after concur-
rent chemoradiotherapy (post-treatment). In arm 2,
serial audiometry and/or tympanometry were per-
formed: before the treatment (pre-treatment), 4 weeks
after concurrent chemoradiotherapy (post concurrent
chemoradiotherapy), 4 weeks after adjuvant treatment
(post-adjuvant) and 12 weeks after adjuvant treatment
(post-treatment) (Figure 2).
Baseline hearing characteristics and post-treatment
scattergrams relating average air conduction PTA thresh-
olds to word recognitions score were reported according
to the American Academy of Otolaryngology – Head
and Neck Surgery hearing outcomes reporting guide-
lines. The reported PTA was calculated using 0.5, 1, 2
and 3 kHz air conduction thresholds.
The incidence of SNHL at speech frequencies and
bone conduction threshold changes were compared
between the two groups. The SNHL at speech frequen-
cies was defined as an increase in bone conduction
thresholds at 0.5, 1, 2 and 4 kHz of more than 10 dB
after treatment completion. The presence of otitis
media with effusion was also recorded. We used bone
conduction thresholds measured at 0.5–4 kHz that
were less affected by outer- or middle-ear lesions to
evaluate the SNHL.
Statistical analysis
Bone conduction threshold changes during treatment,
post-treatment and between the two groups were
assessed for significance using the Wilcoxon rank

FIG. 1
Flow diagram of the study, which compares ototoxicity effects between patients in arm 1 (treated with docetaxel, cisplatin and 5-fluorouracil
induction chemotherapy followed by carboplatin concurrent chemoradiotherapy) and arm 2 (concurrent chemoradiotherapy followed by a cis-
platin and 5-fluorouracil regimen).
SENSORINEURAL HEARING LOSS FOLLOWING NASOPHARYNGEAL CARCINOMA TREATMENT 769

FIG. 2
Schematic of study design. Audiometry and tympanometry were performed before and 12 weeks after treatment in both arms. Serial audiometry
was performed four weeks after induction and concurrent chemoradiotherapy in arm 1, and four weeks after concurrent chemoradiotherapy and
adjuvant treatment in arm 2. Wks = weeks; CCRT = concurrent chemoradiotherapy; A = audiometry; T = tympanometry

sum test. Fisher’s exact test was used to assess other score. In arm 2, 12 of the 24 ears had a decrease in
discrete data. A p-value of less than or equal to 0.05 PTA and a worse word recognition score.
was considered statistically significant. The incidence of otitis media with effusion post-
treatment was 25 per cent (7 of the 28 ears) in arm 1
Results
Demographic data for the 36 patients in both arms of
the study are shown in Table I. Ten patients (three
from arm 1 and seven from arm 2) were excluded
because of the toxicity of the treatment, which resulted
in prolonged febrile neutropenia, severe renal failure
and severe electrolyte imbalance. The mean follow-
up period was seven months and the mean radiation
dose was 7000 cGy.
Baseline hearing characteristics of those in arm 1 (28
ears) and arm 2 (24 ears) are shown in Figure 3. The
incidence of otitis media with effusion pre-treatment
was 50 per cent (14 of the 28 ears) in arm 1 and
54 per cent (13 of the 24 ears) in arm 2 ( p = 0.98).
Hearing outcomes after completion of the treatment
are shown in Figure 4. In arm 1, 9 of the 28 ears had
a decrease in PTA and a worse word recognition

TABLE I
DEMOGRAPHIC DATA
Characteristic Arm 1∗ Arm 2†

Age (years)
– Mean ± SD 42.53 ± 10.74 48.47 ± 11.75
– Range 23–59 24–63
Sex (n)
– Male 11 15
– Female 6 4
Staging (n)
– Stage IIB 1 4
– Stage III 6 10
– Stage IVA 6 1
– Stage IVB 4 4 FIG. 3
∗ † Scattergram of pre-treatment hearing results for patients in arm 1 (a)
n = 17; n = 19. SD = standard deviation and arm 2 (b). Values in squares represent numbers of ears.
770 V ATCHARIYASATHIAN, K PRUEGSANUSAK, S WONGSRIWATTANAKUL

FIG. 5
Bone conduction threshold changes for patients in arm 1. Data
are shown as means (standard error) ( p < 0.05). ∗ Pre-treatment
versus post-induction; †post-induction versus post concurrent
chemoradiotherapy; ‡post concurrent chemoradiotherapy versus
post-treatment; §pre-treatment versus post-treatment. CCRT =
concurrent chemoradiotherapy

cancer (NPC). The effect of the treatment on hearing

loss has been reported in many studies, with high fre-
quency thresholds being more affected than the
FIG. 4 speech frequencies.6–12 Sensorineural hearing loss
Post-treatment scattergram showing change in hearing of patients in and/or otitis media effusion were the cause of post-
arm 1 (a) and arm 2 (b). Values in squares represent numbers of ears. treatment hearing loss in our study. Hearing outcomes
following completion of treatment in this study are
and 54 per cent (13 of the 24 ears) in arm 2. The inci- shown in Figure 4. There were more patients in arm 2
dence of SNHL at speech frequencies was 10 per cent
(3 of the 28 ears) in arm 1 and 50 per cent (12 of the 24
ears) in arm 2 ( p = 0.0027).
In arm 1, significant differences between mean base-
line and post-treatment bone conduction thresholds
were observed at 2–4 kHz ( p < 0.05). During treat-
ment, bone conduction threshold changes were
observed at 4 kHz after induction chemotherapy and
following concurrent chemoradiotherapy (Figure 5).
In arm 2, significant differences between the
mean baseline and post-treatment bone conduction
thresholds were observed at all speech frequencies
(0.5–4 kHz) ( p < 0.05). During treatment, bone con-
duction threshold changes were observed at 1–4 kHz
following concurrent chemoradiotherapy and adjuvant
chemotherapy (Figure 6).
There was a significant difference in the mean difference
of bone conduction thresholds pre- and post-treatment
between arm 1 and arm 2 at 0.5–4 kHz (p < 0.05)
FIG. 6
(Figure 7).
Bone conduction threshold changes for patients in arm 2. Data
are shown as means (standard error) ( p < 0.05). ∗ Pre-treatment
Discussion versus post concurrent chemoradiotherapy; †post concurrent
chemoradiotherapy versus post-adjuvant; ‡post-adjuvant versus
Platinum-based concurrent chemoradiotherapy is the post-treatment; §pre-treatment versus post-treatment. CCRT =
recommended treatment for advanced nasopharyngeal concurrent chemoradiotherapy
SENSORINEURAL HEARING LOSS FOLLOWING NASOPHARYNGEAL CARCINOMA TREATMENT
FIG. 7
Comparison of bone conduction threshold changes after completed
treatment between patients in arm 1 and arm 2. ∗ p < 0.05
that had a decrease in PTA and a worse word recogni-
tion score than in arm 1.
This study aimed to compare the rate of SNHL at
speech frequencies between the new modality of treat-
ment and the conventional treatment; therefore, bone
conduction threshold changes at 0.5, 1, 2 and 4 kHz
of more than 10 dB following treatment completion
were used to determine SNHL.
There was a significantly lower incidence of SNHL
at speech frequencies (10 per cent) in arm 1 patients,
who received induction chemotherapy with docetaxel,
cisplatin and 5-fluorouracil followed by concurrent
chemoradiotherapy, when compared to arm 2 patients
(50 per cent). The first reason for this finding is the
lower total dose of cisplatin in arm 1 (225 mg/m2)
than in arm 2 (540 mg/m2). A cumulative cisplatin
dose greater than 400 mg/m2 is associated with
increased risk of cisplatin-induced ototoxicity.7 The
second reason is the evidence to suggest that using car-
boplatin during concurrent chemoradiotherapy (as in
arm 1) at a standard dose does not appear to be a sig-
nificant risk factor for ototoxicity, even in patients
who have already been treated with cisplatin or
radiation.7,12
There was a significant change in bone conduction
thresholds only at 4 kHz after induction chemotherapy
and following concurrent chemoradiotherapy in arm 1.
This may be the effect of cisplatin, which initially
impairs hearing in the higher frequencies and pro-
gresses to lower frequencies with an increasing cumu-
lative dose.
Taxanes, the new generation of antineoplastic agents,
are now frequently given to patients for various types of
malignancies, especially NPC patients who have the
highest risk of SNHL from receiving radiation to coch-
lear structures and platinum-based chemotherapy.
Few studies have investigated the ototoxic effects of
taxanes. Atas et al. demonstrated that taxol causes
mild to moderate hearing loss in mice, and histopatho-
logical studies showed degenerative changes in the
771
cochlea.20 Ridwelski et al. reported ototoxic effects
of taxanes when used with cisplatin in 2 of 39 non-
head and neck cancer patients.21 Our study also
showed that cisplatin and 5-fluorouracil induction
with docetaxel, followed by concurrent chemo-
radiotherapy, in head and neck cancer has minimal oto-
toxic effects, although this side effect could also be
attributed to platinum compounds. In one study that
evaluated the ototoxicity of only taxanes in 101
breast and ovarian cancer patients, 2 of the patients
(1.9 per cent) had SNHL in the 4–8 kHz range.22
• This study investigated sensorineural hearing
loss (SNHL) rates in advanced
nasopharyngeal cancer (NPC) patients
• A docetaxel, cisplatin and 5-fluorouracil
induction chemotherapy plus concurrent
chemoradiotherapy regimen was compared
with a conventional concurrent
chemoradiotherapy regimen
• Incidence of SNHL was lower after docetaxel,
cisplatin and 5-fluorouracil induction
chemotherapy plus concurrent
chemoradiotherapy in the short-term
follow up
• Half of NPC patients had reduced hearing
ability and SNHL at speech frequencies
following conventional concurrent
chemoradiotherapy
In arm 2 of the current study, the incidence of SNHL at
speech frequencies was 50 per cent. Changes in bone
conduction thresholds were observed in the 0.5–4
kHz range after treatment. In addition, the mean differ-
ence in bone conduction thresholds pre- and post-treat-
ment in arm 2 was significantly higher than that in arm
1 at all frequencies. Cheng et al. reported a similar inci-
dence (57 per cent) of SNHL at the range of speech fre-
quencies for patients receiving combined modality
treatment for NPC.10 The major risk factors for
SNHL in arm 2 are the combined effects of radiation
and cisplatin, which have been reported in many
studies.9–12 Based on our findings, half of NPC
patients may have reduced hearing ability after conven-
tional concurrent chemoradiotherapy. The new modal-
ity of treatment may be an alternative treatment for
high-risk patients to reduce the incidence of irreversible
hearing loss and to optimise cancer control.
The limitations of our study are the small number of
patients and the short follow-up period. The incidence
of SNHL may be higher in long-term follow up
because the radiation-induced ototoxicity develops
within 6–12 months and progresses within 2 years
after completion of the treatment.23 Additionally,
other potential confounding factors may be the baseline
hearing threshold and concurrent use of medication.
772
Conclusion
Induction chemotherapy with docetaxel, cisplatin and
5-fluorouracil followed by concurrent chemoradiother-
apy has a lower incidence of SNHL at speech frequen-
cies than conventional concurrent chemoradiotherapy.
This regimen may be the preferred choice of treatment
for hearing preservation.
References
1 Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Voung T
et al. Chemoradiotherapy versus radiotherapy in patients with
advanced nasopharyngeal cancer: phase III randomized inter-
group study 0099. J Clin Oncol 1998;16:1310–17
2 Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase
III study of concurrent chemoradiotherapy versus radiotherapy
alone for advanced nasopharyngeal carcinoma: positive effect
on overall and progression-free survival. J Clin Oncol 2003;
21:631–7
3 Chan AT, Leung SF, Ngan RK, Teo PM, Lau WH, Kwan WH
et al. Overall survival after concurrent cisplatin-radiotherapy
compared with radiotherapy alone in locoregionally advanced
nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97:536–9
4 Zhang L, Zhao C, Peng PJ, Lu LX, Huang PY, Han F et al.
Phase III study comparing standard radiotherapy with or
without weekly oxaliplatin in treatment of locoregionally
advanced nasopharyngeal carcinoma: preliminary results.
J Clin Oncol 2005;23:8461–8
5 Lee AW, Lau WH, Tung SY, Chau DT, Chappell R, Xu L et al.
Preliminary results of a randomized study on therapeutic gain by
concurrent chemotherapy for regionally-advanced nasopharyn-
geal carcinoma: NPC-9901 Trial by the Hong Kong
Nasopharyngeal Cancer Study Group. J Clin Oncol 2005;23:
6966–75
6 Musial-Bright L, Fengler R, Henze G, Hernáiz DP. Carboplatin
and ototoxicity: hearing loss rates among survivors of childhood
medulloblastoma. Childs Nerv Syst 2011;27:407–13
7 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
8 Dean JB, Hayashi SS, Albert CM, King AA, Karzon R, Hayashi
RJ. Hearing loss in pediatric oncology patients receiving carbo-
platin-containing regimens. J Pediatr Hematol Oncol 2008;30:
130–4
9 Pearson SE, Meyer AC, Adams GL, Ondrey FG. Decreased
hearing after combined modality therapy for head and neck
cancer. Am J Otolaryngol 2006;27:76–80
10 Chen WC, Jackson A, Budnick AS, Pfister DG, Kraus DH, Hunt
MA et al. Sensorineural hearing loss in combined modality
treatment of nasopharyngeal carcinoma. Cancer 2006;106:
820–9
11 Sumitsawan Y, Vaseenon V, Hanprasertpong J,
Roongrotwattanasiri K, Chitapanarux I, Isaradisaikul S. High
frequency hearing loss following treatment for nasopharyngeal
carcinoma. J Med Assoc Thai 2010;93:324–9
12 Oh YT, Kim CH, Choi JH, Kang SH, Chun M. Sensory neural
hearing loss after concurrent cisplatin and radiation therapy for
nasopharyngeal carcinoma. Radiother Oncol 2004;72:79–82
V ATCHARIYASATHIAN, K PRUEGSANUSAK, S WONGSRIWATTANAKUL
13 Ekenel M, Keskin S, Basaran M, Ozdemir C, Meral R, Altun M
et al. Induction chemotherapy with docetaxel and cisplatin is
highly effective for locally advanced nasopharyngeal carcin-
oma. Oral Oncol 2011;47:660–4
14 Kong L, Zhang YW, Hu CS, Guo Y. Neoadjuvant chemother-
apy followed by concurrent chemoradiation for locally advanced
nasopharyngeal carcinoma. Chin J Cancer 2010;29:551–5
15 NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®). Head and Neck Cancers, Version 2.2013. In:
http://oralcancerfoundation.org/treatment/pdf/head-and-
neck.pdf [3 June 2015]
16 Bossi P, Orlandi E, Bergamini C, Locati LD, Granata R,
Mirabile A et al. Docetaxel, cisplatin and 5-fluorouracil-based
induction chemotherapy followed by intensity-modulated radio-
therapy concurrent with cisplatin in locally advanced EBV-
related nasopharyngeal cancer. Ann Oncol 2011;22:2495–500
17 Bardet E, Bourhis J, Cals L, Fayette J, Guigay J, Hans S et al.
Locally advanced head and neck cancers: recommendations of
an expert panel and perspectives for the use of TPF regimen
(docetaxel, cisplatin and fluoro-uracil) as induction therapy [in
French]. Bull Cancer 2009;96:1013–28
18 Bae WK, Hwang JE, Shim HJ, Cho SH, Lee JK, Lim SC et al.
Phase II study of docetaxel, cisplatin, and 5-FU induction
chemotherapy followed by chemoradiotherapy in locoregionally
advanced nasopharyngeal cancer. Cancer Chemother
Pharmacol 2010;65:589–95
19 Guo L, Lin HX, Xu M, Chen QY, Wang CT, Huang PY. Phase I
study of TPF neoadjuvant chemotherapy followed by radical
radiotherapy in advanced nasopharyngeal carcinoma. Chin J
Cancer 2010;29:136–9
20 Atas A, Agca O, Sarac S. Investigation of ototoxic effects of
Taxol on a mice model. Int J Pediatr Otorhinolaryngol 2006;
70:779–84
21 Ridwelski K, Gebauer T, Fahlke J, Kroning H, Kettner E, Meyer F.
Combination chemotherapy with docetaxel and cisplatin for
locally advanced and metastatic gastric cancer. Ann Oncol 2001;
12:47–55
22 Sarafraz M, Ahmadi K. Paraclinical evaluation of side-effects of
Taxanes on auditory system. Acta Otorhinolaryngol Ital 2008;
28:239–42
23 Grau C, Overgaard J. Postirradiation sensorineural hearing loss:
a common but ignored late radiation complication. Int J Radiat
Oncol Biol Phys 1996;36:515–17
Address for correspondence:
Dr Viraporn Atchariyasathian,
Department of Otolaryngology,
Prince of Songkla University,
15 Karnjanavanit Road,
Songkhla, Thailand 90110
Fax: +66 74 429 620
E-mail: aviraporn@gmail.com
Dr V Atchariyasathian takes responsibility for the integrity
of the content of the paper
Competing interests: None declared