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Contents lists available at ScienceDirect

Auris Nasus Larynx

journal homepage: www.elsevier.com/locate/anl

Olfactory bulb volume and olfactory function after radiotherapy in

patients with nasopharyngeal cancer
Bayram Veyseller a, Berke Ozucer MDa,*, Nazan Degirmenci MDa, Defne Gurbuz MDb,
Makbule Tambas MDc, Musa Altun c, Fadullah Aksoy a, Orhan Ozturan a
a
Bezmiâlem Vakif University, Medical Faculty, Department of Otolaryngology, Fatih, Istanbul, Turkey
b
Okmeydanı Research and Training Hospital, Department of Radiology, Istanbul, Turkey
c
Istanbul University, Istanbul Medical Faculty, Department of Oncology, Çapa, Istanbul, Turkey

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Radiotherapy is the primary method of treatment for nasopharyngeal cancer (NPC) and many
Received 20 November 2013 side effects were reported in patients receiving radiation to this area. This study was conducted to
Accepted 7 February 2014 evaluate the long-term effects of radiotherapy following NPC on olfactory bulb (OB) volume and
Available online xxx
olfactory function.
Methods: Twenty-four patients with NPC who received radiotherapy at least 12 months ago were
Keywords: recruited. Fourteen healthy subjects with similar demographical characteristics were recruited as the
Olfactory function
healthy control group. All volunteers were subjected to a nasoendoscopical examination, and
Nasopharynx cancer
Olfactory dysfunction
abnormalities that could potentially cause olfactory dysfunction were the exclusion criteria from the
Smell study. An experienced radiologist segmented the MRI coronal, axial and sagittal slices manually for
Olfactory bulbus three-dimensional OB volume measurement in a blinded manner. Olfactory function was assessed using
Radiotherapy the Connecticut Chemosensory Clinical Research Center (CCCRC) test, and average score (0: worst, 7:
Dysosmia best) was calculated as the total CCCRC olfactory score.
Results: The mean CCCRC score was 5.5  1.1 for the nasopharyngeal cancer patients, whereas the mean
score of healthy control group was 6.4  0.4. There was a significant difference in the olfactory scores
(p = 0.003). The mean OB volume in the NPC group was 46.7  12.1 mm3. Among the patients with NPC, the
cisplatin receiving group had a mean OB volume of 47.2 mm3, whereas the cisplatin + docetaxel receiving
group had a mean OB volume of 46.5 mm3, and they were similar. The MRI measurement of the healthy
control group was 58.6  13.8 mm3. The OB volumes of the healthy control group were significantly higher
(p < 0.05).
Conclusion: Radiotherapy following nasopharyngeal cancer results in a diminished OB volume and
deteriorated olfactory function. Chemosensory olfactory dysfunction might be a contributing factor to
lack of appetite, cancer cachexia and consequent lowered quality of life in NPC patients.
ß 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Radiotherapy (RT) is the primary method of treatment for all
types of nasopharyngeal cancer (NPC). RT to the head and neck
region can result in serious consequences because important tissues
are often included in the field of irradiation [1–4]. Dental problems,
xerostomia, gustatory dysfunction and mucositis eventually con-
tribute to poor nutritional status and cancer cachexia and
consequently lead to low quality of life in patients [5–8].
* Corresponding author. Tel.: +90 5309635939; fax: +90 2125332326.
E-mail address: berkeozucer@gmail.com (B. Ozucer).
The olfactory nerve is purely sensory and is specialized for the
sense of smell. The olfactory system is connected to the cortical
olfactory area, also known as the rhinencephalon, via olfactory
nerve endings and the olfactory bulb and tract. Afferent nerve
endings are situated in the olfactory epithelium and olfactory bulb
(OB) and are primarily responsible for the plasticity of the olfactory
system [5–9].
RT used in the treatment of NPC, apart from other head and neck
tumors, is directed and focused especially to the region of nasal
mucosa, receptor cells and nerve endings in the olfactory bulb. This
study was conducted to evaluate the long-term side effects of
radiotherapy on the olfactory bulb and olfactory function in NPC
patients.

http://dx.doi.org/10.1016/j.anl.2014.02.004
0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Veyseller B, et al. Olfactory bulb volume and olfactory function after radiotherapy in patients with
nasopharyngeal cancer. Auris Nasus Larynx (2014), http://dx.doi.org/10.1016/j.anl.2014.02.004
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2. Materials and methods
This study was performed with the approval of the local ethics
committee following the National Health and Medical Research
guidelines and in accordance with the Declaration of Helsinki. All
volunteers were provided information about the procedures, and
written informed consents were obtained from them before
participating in the study.
2.1. Patient characteristics
Twenty-four patients with histologically proven NPC who
received radiotherapy at least 12 months earlier were recruited in
the study. All of the patients received additional chemotherapy
with either cisplatin or cisplatin and docetaxel. Fourteen healthy
subjects with similar demographical characteristics were recruited
as the control group. The participants underwent a detailed
nasoendoscopical examination, and any patient with a condition
that could cause olfactory dysfunction, such as septum deviation,
nasal polyposis, congenital olfactory dysfunction, septum surgery,
head trauma, chronic rhinosinusitis, allergic rhinitis, or psychiatric
or neurological disorders, such as Parkinson’s and Alzheimer’s
disease, was excluded from the study.
2.2. Oncological evaluation
The TNM classification system of the American Joint Committee
for Cancer Staging (AJCC) was used and accordingly the disease
extent was T1: 8, T2: 10, T3: 1, and T4: 4 for T classification and N0: 3,
N1: 2, N2: 17, and N3: 1 for N classification. None of the patients had
distant metastatic disease at presentation.
All except two patients received 2D conventional RT with
shrinking fields with a 60Co treatment unit. In most cases, a beam
of 6–13 meV electrons was applied for supplemental doses after
spinal cord tolerance. The primary tumor in the nasopharynx and
all its direct extensions defined by CT or MRI were treated with two
opposed lateral fields, using 60Co. The margins included the base of
the skull, the nasopharynx, the oropharynx, and the upper neck.
After 50 Gy the fields were reduced to include the nasopharynx and
paranasopharyngeal area and the base of the skull. A total dose of
70 Gy was administered in daily fractions of 2 Gy, 5 days a week in
all of the patients except two of the 24 patients who received 6880
and 7230 cGy total dose with 180 cGy/fraction. The spinal cord was
shielded after 46 Gy and the posterior lymphatic chains were
treated with electron beams. The lower cervical and supraclavi-
cular regions were treated using 60Co with a single anterior portal
and a median shield to protect the larynx and the spinal cord, with
doses of 46–50 Gy. Clinically involved neck areas were boosted
with direct oppositional fields with doses of 66–70 Gy using 6–
13 MeV electrons. The dose to the uninvolved neck area was 50 Gy
in 5 weeks with conventional fractionation. The other two patients
received IMRT with 6 MV photons, using simultaneous integrated
boost technique in 33 fractions of 69.96 Gy. Target volume
definition and treatment planning were performed according to
the recommendations of the International Commission on Radia-
tion Units and Measurements Reports 50 and 62 [10,11].
All patients received chemotherapy in addition to radiotherapy;
eight patients received three doses of 100 mg/m2 concomitant
cisplatin, whereas 16 patients received 3 doses of 100 mg/m2
docetaxel in addition to cisplatin. Olfactory tests and OB volume
measurements were conducted individually.
2.3. Evaluation of olfactory function
The Connecticut Chemosensory Clinical Research Center
(CCCRC) test was conducted as described previously elsewhere
Please cite this article in press as: Veyseller B, et al. Olfactory bulb volume and olfactory function after radiotherapy in patients with
nasopharyngeal cancer. Auris Nasus Larynx (2014), http://dx.doi.org/10.1016/j.anl.2014.02.004
[12,13]. The CCCRC test is composed of n-butanol odor threshold
test and odor identification test. Olfactory tests were conducted
individually and were scored out of 7 (0: worst, 7: best olfaction)
and mean score was calculated as the total CCCRC test score. Test
scores were categorized as previously defined [12] and the patients
were evaluated as anosmic, severely hyposmic, moderately
hyposmic, mildly hyposmic or normosmic.
2.4. Evaluation of olfactory bulb volume
OB volumes were measured with a 1.5-Tesla General Electric
Signa Excite MRI scanner. Each consecutive cross-section was
taken with 2-mm slice thickness (gap = 0) and 8-channel head coil
was used. Coronal, axial and sagittal slices were manually
segmented and measured by an experienced radiologist (DG) on
T2W TSE cross-sections for three-dimensional evaluation of
olfactory bulb volume (Fig. 1). Measurements were carried out
individually on the right and left olfactory bulbs in a single-blinded
fashion, and the mean olfactory bulb volume was calculated in
cubic millimeters. Posttraumatic parenchymal or meningeal
hemosiderin accumulation in MRI T2W GRE cross-sections was
a criteria for exclusion from the study. T2W TSE images were
scrutinized for other organic disorders, and detection of any
pathological finding was a criterion for exclusion from the study.
2.5. Statistical analysis
Data were analyzed using Medcalc Software v. 12.3 (Mar-
iakerke, Belgium). All values were calculated as mean  standard
deviation. Mann Whitney U test was used for statistical analysis for
independent groups; a p-value of less than 0.05 was accepted as
statistically significant.
3. Results
The mean age of the NPC group was 48.7  11.4 years; 10 were
women (43.5%) and 14 were men (56.5%). Mean age of the healthy
control group was 48.8  7.0 years; nine were women (64.3%)
and five were men (35.7%). There was no statistical significance in
terms of age between the two groups. Olfactory tests and MRI scans
were carried out 66.0  48.6 (range, 14–218) months (mean  SD)
following the conclusion of radiotherapy and chemotherapy in the
NPC group.
3.1. Olfactory function tests
The mean CCCRC score was 5.5  1.1 (range, 3.5–7) for the NPC
group, whereas the CCCRC score of the control group was 6.4  0.4
(range, 5.5–7). There was a significant difference in the olfactory
scores (p = 0.003, Z = 2.984) (Fig. 2). Detailed n-butanol odor
threshold and odor identification scores are presented in Table 1.
According to the CCCRC scores, 11 (45.8%) patients were
classified as normal, 7 (29.2%) as mildly hyposmic, 3 (12.5%) as
moderately hyposmic, and 3 (12.5%) as severely hyposmic. The
healthy control group consisted of 13/14 (92.9%) normosmic
patients; only one patient (7.1%) was mildly hyposmic (Fig. 3).
3.2. OB volume analyses
The mean of right and left OB volume in the NPC group was
46.7  12.1 (range, 24–65.5) mm3. The MRI measurement of the
healthy control group was 58.6  13.8 (range, 42–91). A comparison
of the olfactory bulb volumes revealed a significant difference in
olfactory volumes (p < 0.05) (Fig. 4). OB volumes of the cisplatin
receiving and cisplatin + docetaxel receiving group were 47.2 and
46.5 mm3, respectively, and the difference was insignificant.
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Fig. 1. Three-dimensional olfactory bulb volume evaluation. (a–c) Cross-sections of right olfactory bulb (volume, 58 mm3) of a healthy control patient cancer patient. (d–f)
Cross-sections of right olfactory bulb (volume, 26 mm3) of an NPC patient. Each patient was evaluated individually in a single-blinded fashion.

4. Discussion examination and therefore conductive etiology was discarded at

Olfactory dysfunction, similar to hearing loss, can be either
conductive or sensorineural in nature. Conductive dysfunction
can be the result of septum deviation, nasal polyposis or
iatrogenic stenosis following septum surgery. Sensorineural
olfactory dysfunction is due to defects in the olfactory nerve
fibers, receptors, olfactory bulb and orbitofrontal cortex. The
participants in our study underwent a detailed nasoendoscopical
Fig. 2. Total CCCRC test score (out of 7, healthy control group versus NPC group).
Significant difference in terms of total CCCRC score (p = 0.003).
the time of olfactory assessment. In addition, significantly
diminished olfactory bulb volume measurements objectively
substantiate that olfactory dysfunction was most likely sensori-
neural and not conductive in nature.
Olfactory dysfunction shown with the identification and
threshold tests can be interpreted as either the result of damage
to the olfactory mucosa or the effect of radiotherapy to primarily
the OB and other olfactory centers. This study shows the long-term
effects of radiotherapy on olfactory bulb for the first time in the
literature.
Radiation doses above 60 Gy can consequently cause impaired
cell cycles and basal cell depletion in olfactory epithelium, which
will eventually result in mucositis. Edema and mucositis as the
result of radiotherapy can influence the stimuli to the olfactory
region [14]. Mucositis of the nasal cavity has been shown to have
detrimental effects on nasal airflow [15,16]. Lack of stimuli as the
result of diminished nasal airflow can be a contributing factor for
olfactory dysfunction.
Previous studies on this matter have contradictory results and
are limited in terms of the duration of follow-up [17–21]. Previous
studies have shown that similar to the development of other
neurological changes that have been observed following radio-
therapy, the changes in olfaction had a delayed onset of 1 year after
irradiation, which was the rationale behind the methodology of
the study [17–21]. This present study therefore focused on the
long-term side effects of radiotherapy on olfactory function, and
olfactory bulb was assessed in addition.
Ho et al. studied the effects of RT for NPC on olfactory
function prospectively; patients were assessed before the start of

Please cite this article in press as: Veyseller B, et al. Olfactory bulb volume and olfactory function after radiotherapy in patients with
nasopharyngeal cancer. Auris Nasus Larynx (2014), http://dx.doi.org/10.1016/j.anl.2014.02.004
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Table 1
Olfactory bulbus volume (in mm3) measurements and olfactory function evaluation.

n OB volume (mm3) CCCRC total score N-butanol odor threshold score Odor identification score

HC group 14 58.6  13.8 6.4  0.4 6.4  0.5 6.4  0.7

NPC group 24 46.7  12.1* 5.5  1.1* 5.8  1.1* 5.2  1.6*
Cisplatin receiving group 8 47.2 5.41 5.69 5.13
CIS + docetaxel receiving group 16 46.5 5.59 5.94 5.25

Olfactory evaluation (0: worst, 7: best olfaction).

Olfactory volume measured in mm3.
*
Statistically significant difference (p < 0.005).

Fig. 3. Evaluation of CCCRC olfactory test scores, patient distribution (percentage). Normosmic: 6.00–7.00, mildly hyposmic: 5.00–5.75, moderately hyposmic: 4.00–4.75,
severely hyposmic: 2.00–3.75, anosmic: 0–1.75 (out of 7)

radiotherapy, upon completion of radiotherapy, and then at the
3rd, 6th, and 12th months after completion of radiotherapy: TDI
scores deteriorated significantly (p < 0.001) at the 12th month.
Further recovery or deterioration of olfactory function 1 year after
irradiation was left unanswered in this study.
The largest study with the longest duration of follow-up
reported has been published only in the Chinese language [20];
100 patients with nasopharyngeal carcinoma were followed for 36
months. The patients’ smell acuity decreased sharply 3 months
after therapy, but varying degrees of recovery were noted after
6 and 12 months. In general their olfactory acuity decreased
after RT and did not recover fully. A control group was missing in
this study.
Chemotherapy used in the NPC group in addition to
radiotherapy is mainly cisplatin. Although cited in some
subjective reports as a cause of altered olfactory perception, it
has been shown in the prospective current study that it has no
effect on the sense of smell [22]. Docetaxel has been shown to
exert neurotoxic effect on the olfactory epithelia of rodents; but
there are no clinical studies in the English literature citing its
effects on olfaction [23]. Therefore patients receiving docetaxel
were studied separately (Table 1): olfactory and olfactory bulb
volume evaluations revealed no significant difference in this
group.
It is well known that women have better olfactory function. The
control group consisted of a higher percentage of female patients;
therefore, olfactory analysis was carried out individually for each
gender. Olfactory function test for each gender separately was
similar to the results already given. Therefore we concluded that
superior olfactory function is not due to difference in gender
distribution.

5. Conclusion

This study was the first to examine the long-term side effects of
RT on olfactory dysfunction and olfactory bulb. Radiotherapy
Fig. 4. Comparison of mean olfactory bulb volumes (mm3). Significant difference following nasopharyngeal cancer results in diminished OB volume
was present in terms of mean OB volume (p < 0.05). and olfactory dysfunction in the long term. Diminished chemo-

Please cite this article in press as: Veyseller B, et al. Olfactory bulb volume and olfactory function after radiotherapy in patients with
nasopharyngeal cancer. Auris Nasus Larynx (2014), http://dx.doi.org/10.1016/j.anl.2014.02.004
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sensory olfactory dysfunction might be an aggravating factor of
quality of life in NPC patients.
Authors’ contributions
Bayram Veyseller: Idea, analysis and interpretation of data, and
writing the manuscript. Berke Ozucer: Patient follow-up, collect-
ing data, and writing the manuscript. Nazan Değirmenci: Patient
follow-up and collecting data. Defne Gürbüz: Radiological assess-
ment. Makbule Tambaş, Musa Altun: Patient follow-up and
oncological assessment. Fadullah Aksoy, Orhan Ozturan: Super-
visors.
Funding
Bezmialem Vakif University, Scientific Research Project Unit
Sponsorship.
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