Journal of the Egyptian Nat. Cancer Inst., Vol. 18, No.
2, June: 147-155, 2006
Treatment Results of Nasopharyngeal Carcinoma:
A 15-Year Single Institutional Experience
BIJAN KHADEMI, M.D.*; JALAL MAHMOODI, M.D.**; SHAPOUR OMIDVARI, M.D.** and
MOHAMMAD MOHAMMADIANPANAH, M.D.**
The Departments of Otolaryngology*, Khalili Hospital, Shiraz University of Medical Sciences, Shiraz, Iran and
Radiation Oncology**, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
ABSTRACT
Background: Nasopharyngeal Carcinoma (NPC) is
a common malignant neoplasm of the head and neck that
occurs most commonly in people in the South Eastern
Asia but its condition in Iran is not much clear.
Objective: In this retrospective study, we evaluated
the treatment characteristics determining the outcome in
patients with NPC.
Patients and Methods: In this retrospective study, we
reviewed the records of one hundred and seven patients
with biopsy proven diagnosis of NPC who were referred
to the radiation oncology department, Nemazee Hospital,
Shiraz University of Medical Sciences, Iran, during the
time period from January 1985 to December 2000. Eighty-
five patients (79.4%) received 60-70Gy radiation (1.8-
2Gy/fraction, one fraction per day, and 5 fractions per
week). Sixty-two patients (57.5%) received radiotherapy
combined with adjuvant chemotherapy which consisted
of cisplatin and 5-fluorouracil. Eighty-six patients (80.4%)
had WHO II-III histopathologic diagnosis. According to
the AJCC 1997 staging system, 4 (3.6%), 3 (2.7%), 33
(30.8%) and 67 (62%) patients were in stages I, II, III and
IV, respectively.
Results: With a median follow-up of 12 months, the
2-year overall and disease-free survival rates were 35%
and 21%, respectively.
According to the multivariate analysis for overall
survival, patients under 40 years had a better prognosis
(p=0.041). Node stage and stage of disease were significant
prognostic factors (p=0.0001). On multivariate analysis
for disease-free survival, age and node stage were signif-
icant prognostic factors. The patients who received more
than 60Gy radiation had a better prognosis (p=0.02),
however; sequential adjuvant chemotherapy had no impact
on survival and response (p=0.6).
Correspondence: Dr Mohammad Mohammadianpanah,
Department of Radiation Oncology, Shiraz University of
Medical Sciences, Shiraz 71345, Iran, mohpanah@sums.ac.ir
147
Conclusion: Our experience confirmed earlier reports
showing poor outcomes for locoregionally advanced
nasopharyngeal carcinomas. This study failed to demon-
strate improvement in the outcome regarding overall and
disease-free survival by adding sequential adjuvant che-
motherapy after radiotherapy for patients with advanced
NPC.
Key Words: Nasopharyngeal carcinoma (NPC) - Radio-
therapy - Chemotherapy.
INTRODUCTION
Among head and neck tumors, nasopharyn-
geal carcinoma (NPC) is a special entity in
which the location does not lend itself to curative
surgery. NPC is highly radiosensitive, and rad-
ical external beam radiotherapy is the mainstay
of treatment for this neoplasm and its regional
lymph node metastasis [1,2,3].
Despite aggressive radiotherapy, the 5-year
survival rate of the patients with locoregionally
advanced disease at presentation has approxi-
mated to 30-45% [4]. Over the past 2 decades,
attempts have been made to improve the results
of radiotherapy in the treatment of patients with
other head and neck cancers by incorporating
some forms of chemotherapy into the primary
treatments. In view of the well-documented
poor 5-year survival rate for locoregionally
advanced NPC, the use of combination chemo-
therapy plus radiotherapy in the primary treat-
ment has been investigated, for decreasing the
rate of distant metastasis and locoregional re-
lapse, as well as increasing disease free and
overall survival [2].
Several trials have sought to improve the
effect of radiotherapy by adding concurrent
148
chemotherapy followed by adjuvant chemother-
apy; however, they have not been in uniform
agreement [4,5].
The purpose of this retrospective study is
to assess treatment characteristics determining
the outcome in patients with NPC in Fars prov-
ince, South of Iran.
PATIENTS AND METHODS
This study included 107 biopsy-proven na-
sopharyngeal carcinoma patients treated from
January 1985 through December 2000. All the
patients had expected survival longer than 2
months and had received no prior treatment.
Pretreatment evaluation included a thorough
history, physical examination with direct na-
sopharyngoscopy, complete blood count, serum
chemistries, chest X-Ray and CT-scan as needed.
All the patients had peripheral absolute granu-
locyte count of 2000/L, platelet 100,000/L
and creatinine less than 1.5mg/dl before treat-
ment.
Radiation therapy:
External beam radiation therapy was deliv-
ered using Cobalt 60 unit, with daily fraction
of 1.8-2Gy, 5 fractions per week. The total dose
of radiation ranged from 60-70Gy. All patients
received the same dose, except 22 patients who
received less than 60Gy (with the same frac-
tionation) due to complications and/or loss to
follow-up. Initially, the base of skull, nasophar-
ynx, oropharynx and upper cervical lymph nodes
were treated with two lateral parallel opposed
fields; the lower cervical lymph nodes were
treated with a low anterior field. The spinal
cord was excluded from the radiation fields
after 46Gy. After 50Gy, radiotherapy was con-
tinued with reduced fields to primary tumors
up to 60-70Gy. Metastatic cervical lymph nodes
were boosted through a posteroanterior neck
field with a central block and a dose of 15-
20Gy.
Chemotherapy:
Forty-five (42.5%) patients were treated
with radiation alone, and sixty-two (57.5%)
patients with adjuvant chemotherapy in combi-
nation with radiation. The chemotherapy regi-
men consisted of cisplatin 80mg/m2 on day 1
and 5-fuorouracil 750mg/m2 on days 1-5. Most
patients received 2 courses of chemotherapy
before and 2 courses after finishing radiotherapy.
Treatment Results of Nasopharyngeal Carcinoma
Statistical analysis:
Overall survival was defined as the time
from diagnosis to death from any cause or last
follow-up. Disease free survival was defined
as the time from diagnosis to locoregional failure
or distant metastasis. Survival was calculated
according to the Kaplan-Meier method. For
comparison of cumulative survival rates, the
log-rank test was used and a p-value of 0.05 or
less was considered to be statistically significant.
Multivariate analysis was performed using the
Cox proportional hazards model.
RESULTS
The study population consisted of 107 pa-
tients (77 males, 30 females), with an age range
of 13-90 years, and median age of 49 years.
Follow-up ranged from 2-166 months (median
12 months).
The peak incidence was observed between
the fifth and sixth decade of life and the male
to female ratio was 2.57. Our results demon-
strated that patients under 40 years had better
prognosis with a median survival of 17 months
compared with 10 months for older patients
(p=0.041). Eighty-six patients (80.4%) were
identified to have non-keratinizing and undif-
ferentiated carcinoma (WHO II-III). Table (1)
shows the TNM classification of patients.
The complaints of patients with NPC are
related to location of the primary tumor and the
degree and direction of spread. Table (2) shows
the clinical features of the patients. Neck mass,
epistaxis and nasal obstruction were the most
frequent clinical manifestations, encountered
in 86%, 27% and 26% of the patients, respec-
tively.
Most of the patients developed some degree
of treatment related complications during and
after radiotherapy. The overall complication
rate ranges from 31% to 66%. Complication
rates increased in patients receiving concurrent
chemotherapy and in those who had coexisting
medical conditiond, such as diabetes mellitus.
Mucositis and sore throat were the most fre-
quently observed acute complication encoun-
tered in almost all patients. Xerostomia was the
most common and major late sequelae which
was followed by dental caries, otorrhea, tinnitus,
hearing loss, trismus and neck fibrosis in a
remarkable percentage of the patients.
Bijan Khademi, et al. 149

Distant metastasis has been observed in 26
of the patients (24.7%). The most common sites
of metastasis included bone (53.8%), lung
(23%), and brain (14%). Of patients with bone
metastasis, thoracolumbar vertebrae, pelvis,
femur and tibia were the most common sites of
bone involvement, in decreasing order. Prog-
nostic factors that appeared to influence the
response, overall survival and disease free sur-
vival included gender, age, histopathologic type,
tumor stage, node stage, stage group, total
radiation dose and chemotherapy; these were
assessed using univariate and multivariate anal-
ysis.
On univariate analysis for response, only
the dose of radiation was a significant prognostic
factor (OR = 5.37, 95% CI 1.88-5.38) (Table
3).
On multivariate analysis for overall survival,
age (with a median overall survival of 26 months
for patients under 40 and 14 months for older
patients), stage group, (with a median overall
survival of 17, 79, 14, and 14 months for stages
I, II, III and IV, respectively), and node stage
(with a median overall survival of 34, 23, 31,
and 17 months for node stages I, II, III and IV
respectively) were significant prognostic factors.
Adjuvant chemotherapy had no impact on sur-
vival and response with a median overall sur-
vival of 15 months for patients receiving adju-
vant chemotherapy and 13 months for patients
treated with radiotherapy alone (p=0.6). On
multivariate analysis for disease free survival,
age, node stage and total dose of radiation were
significant prognostic factors (p=0.041 and
p=0.02) (Table 4).
Overall survival and disease free survival
rates were 34% and 21%, respectively in 2
years, and 19% and 15%, respectively during
3 years. The median overall survival was 14
months (Fig. 1).

1.0 25
Female
Male
0.8 20
Patients number

0.6 15
Survival

0.4 10

0.2 5

0.0 0
21-30

31-40

41-50

71-80
51-60

61-70

81-90
11-20
0-10

0 8 16 24 32 40 48

Months
Age
Fig. (1): Overall and disease free survival at 48 months. Fig. (2): Age distribution of 107 patients with NPC.

Table (1): Distribution of Patients by 1997 AJCC Staging Table (2): Distribution of clinical features of patients.
Classification.

N Clinical features No. (%) Clinical features No. (%)

T Total
N0 N1 N2 N3
Epistaxis 29 (27%) Otalgia 15 (14%)
T1 4 12 2 3 21
T2 3 6 10 5 24 Nasal obstruction 28 (26%) Cranial nerve 11 (10%)
T3 1 14 10 15 40 Involvement
T4 5 2 6 9 22
Ear fullness and 18 (16.7%) Diplopia 9 (8%)
Total 13 34 28 32 107 hearing loss
150 Treatment Results of Nasopharyngeal Carcinoma

Table (3): Univariate and multivariate analysis for survival.

Locoregional control DFS

Factors N
p OR (95% CI) MS (months)

Sex: >0.05 0.39 (0.14-1.06)

Male 77 10
Female 30 17

Age: >0.05 1.22 (0.44-3.42)

40 years 31 17
>40 years 76 10

Histopathology: >0.05 0.98 (0.28-3.34)

WHO I 21 12
WHO II 62 12
WHO III 24 12

Tumor stage:
T1 21 >0.05 10
T2 24 >0.05 0.83 (0.12-5.33) 13
T3 40 >0.05 0.44 (0.08-2.06) 9
T4 22 1.06 (0.14-7.82) 12

Node stage:
N0 13 >0.05 14
N1 34 >0.05 0.60 (0.02-6.99) 9
N2 28 >0.05 0.29 (0.01-3.07) 12
N3 32 0.18 (0.01-1.74) 10

Stage group:
I 4 >0.05 14
II 3 >0.05 76
III 33 >0.05 2.42 (0.0-42.74) 11
IV 67 12

Radiation dose: <0.05 05.37 (1.88-5.38)

60Gy 22 11
>60Gy 85 12

Chemotherapy: >0.05 0.95 (0.36-2.50)

Given 62 12
Not given 45 12

DFS : Disease free survival.

N : Number of patients.
OR : Odds Ratio.
95% CI: 95% Confidence interval.
P : Probability value (univariate analysis).
MS : Median survival.
Bijan Khademi, et al. 151

Table (4): Univariate and multivariate analysis for survival.

OS DFS

MS MS
Factors N p p OR (95% CI) p p RR (95% CI)
(months) (months)

Sex: >0.05 0.28 (0.48-3.39) >0.05 0.14 (0.28-3.34)

Male 77 14 1.28 10 0.97
Female 30 19 (0.014-0.90) 17
Age: < 0.05 0.031 0.35 <0.05 0.041 (0.103-0.964)
40 years 31 26 17 0.31
>40 years 76 14 10
Histopathology: >0.05 0.3 (0.0987-2.042) >0.05 0.618 (0.286-8.239)
WHO I 21 27.7 0.449 12 1.534
WHO II 62 27.7 12
WHO III 24 16.7 12
Tumor stage:
T1 21 27.6 >0.05 0.721 0.672 10 >0.05 0.861 1.268
(0.075-5.989) (0.088-18.218)
T2 24 31.3 >0.05 0.291 0.364 13 >0.05 0.58 1.895
(0.0558-23.79) (0.197-18.182)
T3 40 24.4 >0.05 0.911 1.113 9 >0.05 0.196 3.375
(0.171-7.259) (0.0534-21.352)
T4 22 18.1 - 12
Node stage:
N0 13 33.6 <0.05 0.0001 0.0018 14 >0.05 0.988 -(0.534-21.352)
(0.0089-0.0039)
N1 34 22.8 <0.05 0.0001 0.004 9 <0.05 -(0.00025-0.00255)
(0.00249-0.0039)
N2 28 30.6 <0.05 0.0001 - 12 >0.05 0.531 0.594
(.166-3.031)
N3 32 17.4 - 10
Stage group:
I 4 17 <0.05 0.0001 0.0002 14 >0.05 0.998 (0.000112-0.000113)
(0.0005-0.0001) 0.00011
II 3 79 <0.05 0.0001 0.00012 76 >0.05 1.000 0.402
(0.000242-0.00065)
III 33 14 >0.05 0.882 0.802 11 >0.05 0.998 0.000065
(0.0435-14.78)
IV 67 14 12
Radiation dose: >0.05 0.867 (0251-5.60) <0.05 0.02 (0.015-0.392)
60Gy 22 14 1.137 11 0.078
>60Gy 85 17 12
Chemotherapy: >0.05 0.661 (.254-2.2382) >0.05 0.838 (0.291-4.571)
Given 62 15 0.778 12 1.154
Not given 45 13 12

n : Number of patients. DFS : Disease free survival. P: Probability value (univariate analysis) RR: Relative Risk
Os : Overall survival. 95% CI: 95% Confidence interval. P: Probability value (multivariate analysis) MS: Median survival.

DISCUSSION gradient from South Eastern Asia to Northern

Nasopharyngeal carcinoma (NPC) is a
unique type of head and neck cancer with a
remarkable racial and geographical distribution
worldwide [6,7]. It is uncommon in most coun-
tries of the world and displays a declining
America. This neoplasm has multifactorial risk
factors. Genetic, environmental, viral, dietary,
occupational and racial risks are the most com-
mon contributing factors [1,8,9]. NPC has varying
degrees of differentiation and frequently arises
in the pharyngeal recess, in particular, from the
152
fossa of Rosenmuller and Eustachian tube cush-
ions. Based on the degree of differentiation,
NPC is classified into 3 histopathologic types.
WHO type I includes typical keratinizing squa-
mous cell carcinomas, similar to other head and
neck cancers. Type II includes nonkeratinizing
carcinoma, while type III includes undifferen-
tiated carcinoma. WHO type III is the most
common [8]. Almost all adult nasopharyngeal
malignant tumors are carcinoma. In contrast,
in children only 20-50% of nasopharyngeal
malignancies are carcinoma [10]. In south-eastern
Asia, nasopharyngeal carcinoma mainly consists
of WHO type III undifferentiated carcinomas,
likely associated with Epstein-Barr virus ex-
pression. On the contrary, WHO type I histology
accounts for most nasopharyngeal carcinomas
in southern Europe, regularly dissociated from
Epstein-Barr virus (EBV) expression [6]. WHO
type I histology responds to treatment paradox-
ically, that is, this type of tumors does not
respond to radiation as well as WHO type III
histology [1]. The impact of histopathology on
the outcome is debatable [1,11]. In agreement
with the experience of Erkal et al., the current
study confirmed that the histopathologic type
does not predict the response and survival
(RR=0.449) [12]. However, other investigators
have reported improved response for WHO type
III histology and have observed comparable
survival for patients with WHO type III histol-
ogy [9].
This neoplasm is silent, and its clinical
symptoms are delayed. The most common pre-
senting symptom is a neck mass, followed by
nasal obstruction, epistaxis and increasing nasal
discharge, auditory symptoms such as tinnitus,
stuffiness, and hearing loss, and neurological
symptoms [8]. In the current study, neck mass,
nasal, aural and neurological symptoms were
the most common clinical presentation.
NPCs are invariably higher in men than
women and the male to female ratio is roughly
2-3 to 1. In our study, males were affected by
NPC more frequently than females (RR=1.28).
This finding is in agreement with other reports
[1,3,9,13,14]. Although the pattern of age distri-
bution of NPC varies in different parts of the
world, a bimodal age distribution in late ado-
lescence and in the 5th or 6th decade of life can
be observed [8]. In our current study, age-specific
distribution rates revealed distinct patterns
across different sexes. NPC incidence rises
Treatment Results of Nasopharyngeal Carcinoma
monotonically with age, among female patients,
as seen in most low-risk populations [8]. In male
patients, however, the incidence of NPC shows
a bimodal age distribution in the second and in
the 5th to 6th decades of life. The age distribution
of both sexes shows a peak incidence of NPC
in the 5th and 6th decades and a clear-cut decline
at older ages (Fig. 2).
The extent of the disease incorporated in
the TMN staging system, sex, age, histopatho-
logic type, and radiation dose are considered
as independent prognostic factors in patients
with NPC, among which the AJCC staging
system is the most important prognostic factor
[1,15,16].
The incidence of local relapse and distant
metastasis in the predominantly advanced dis-
ease is remarkable and the patients with locore-
gionally advanced disease (T3-T4-N2-N3) have
a worse prognosis than patients with early stage
disease (T1-2-No-1) [4,9-14,17,18]. Consequently
different strategies may be needed to improve
the treatment outcomes and as identified in the
present study, Sham and Choy as well as Teo
et al., have documented the nodal status to
determine survival [1,17].
Improved outcome for nasopharyngeal car-
cinoma relies on the delivery of higher radiation
dose, which is crucial for achieving complete
locoregional clearance [9,11]. Tange et al. and
Perez et al., have reported radiation dose to
predict local response, and survival [19,20].
In agreement with the experience of Erkal
et al., analysis of our data demonstrated that
radiation dose correlated with locoregional
control (OR=5.37) and the patients who have
received more than 60Gy had a better disease-
free survival (p=0.02) [12].
Definitive radiotherapy with or without che-
motherapy is currently the standard treatment
for nasopharyngeal carcinoma [6-8,21,22] . In
conventional radiotherapy (once daily, 5 frac-
tions per week, 1.8-2Gy per fraction) a tumor-
icidal dose of 65-75Gy is currently given to the
primary tumor and 65-70Gy to the involved
cervical lymph nodes. A dose of 50-60Gy is
considered for elective treatment of a node-
negative neck [8,23,24].
In 2-dimensional radiotherapy, the radiation
technique usually consists of parallel opposed
Bijan Khademi, et al.
lateral fields at the primary tumor and upper
neck. The lower neck nodes are separately
irradiated by a single anterior field with a central
block. A three-field combination technique
(parallel opposed lateral and anterior fields)
may be used in patients with anterior extension
of the primary tumor. However, there are major
limitations, in particular xerostomia and middle
and inner ear complications for delivering high-
dose radiation of 2-dimensional planning for
the nasopharyngeal carcinoma [8,25,26]. Xeros-
tomia is the most common radiation-related
toxicity with 2-dimensional radiotherapy. Xe-
rostomia contributes to the patients nutritional
deficiency, swallowing difficulty, weight loss,
poor oral and dental hygiene, altered taste sen-
sation, impaired speech function, and poor sleep
quality. Therefore, xerostomia is directly or
indirectly responsible for many patients com-
plaints which could lead to poor quality of life
and poor social activity [27,28].
External radiation dose more than 72Gy is
associated with significantly higher incidence
of hearing loss, trismus, and temporal lobe
necrosis [3,28]. These radiation-related compli-
cations can be overcome using 3D conformal
radiotherapy and intensity-modulated radiother-
apy. Using these modern radiotherapy tech-
niques, more critical structures next to the
nasopharynx, in particular parotid glands, brain,
optic nerve, and spinal cord can be spared.
Recent studies support that intensity modulated
radiotherapy yields equivalent or more locore-
gional control in comparison with conventional
radiotherapy [8,23,24,25,28,29]. Radiation-related
toxicity in the current study was similar to
previous studies [3,29].
NPC is a chemosensitive tumor and the role
of chemotherapy in the management of locally
advanced disease is promising and undergoing
a rapid evolution [6,31].
In an effort to improve response and survival
rate, some authors have used neoadjuvant che-
motherapy before starting radical radiotherapy
in locoregionally NPC [5]. Chemotherapy for
advanced-stage NPC currently consists of cis-
platin 100mg/m2 on day 1 and 5-Fluorouracil
1000mg/m 2 on days 1-5, repeated every 3
weeks. This chemotherapy regimen is usually
followed by concurrent chemoradiotherapy with
or without adjuvant chemotherapy. Later, tax-
anes and Gemcitabine were added to this regi-
153
men to improve response rate and survival in
advanced NPC [6,8,31]. Some reports failed to
demonstrate considerable survival benefit with
the addition of neoadjuvant chemotherapy in
locoregionally advanced nasopharyngeal carci-
noma [4,32,33]. Chua et al., have observed no
significant difference in 3-year overall survival
rates (78% vs. 71%, respectively p=0.57) and
in the pattern of failure in a prospective ran-
domized trial of induction chemotherapy fol-
lowed by radiotherapy vs. radiotherapy alone
for locoregionally advanced NPC [34]. However,
in inter group study 0099 and other several
recent studies, significant overall survival was
demonstrated by administering concurrent che-
motherapy and radiation therapy in locoregion-
ally advanced NPC [4].
Accordingly, concurrent chemoradiation
with or without adjuvant chemotherapy is cur-
rently the standard care for locoregionally ad-
vanced nasopharyngeal carcinoma, despite un-
clear its reproducibility and poor chemotherapy
compliance [9,35-41].
In univariate and multivariate analysis, we
did not observe any impact on locoregional
control and overall disease free survival rates
(p=0.66 RR=0.778).
Admittedly, there are some shortcomings in
the current study regarding low survival rate in
comparison with other reports. The low survival
rates in our current report may be related in
part to the more advanced disease stage in our
patients (more than 93% had stage III and IV
disease), remarkable percentage of patients
received suboptimal dose of radiation and che-
motherapy due to the low patient's compliance
to therapy, loss of follow-up and incompleteness
of the course of treatment. Considering the
points mentioned above and also our practice,
we believe that the real overall and disease-free
survival of our patients is higher than those
observed before.
Patients with NPC tend to have advanced
disease at the time of presentation. Locoregional
and systemic failures are high in these patients
and contribute to the poor survival. More effec-
tive chemotherapeutic regimens and other sys-
temic therapy are needed to decrease the rate
of locoregional and distant failure and improve
survival [41].
154
According to a remarkable high cure rate in
early-stage NPC, early detection and prompt
treatment is essential to improve survival. The
high frequencies of epigenetic alterations in
this neoplasm suggest the potential application
of novel inhibitors targeting DNA methylation
and histone acetylation. Early detection using
selective application of EBV DNA and epige-
netic markers in a serological screening protocol
is showing promising results [42]. The novel
treatment approaches including gene therapy
and immune therapy may brighten up the out-
come of NPC patients with poor prognosis [6-
8].
In conclusion, NPC is a unique type of head
and neck cancer and usually presents as a locally
advanced disease. The current study supports
that radiotherapy is the treatment of choice for
early stage of NPC and the chance of cure is
usually high. Combined concurrent chemorad-
iation is usually required to improve the outcome
of patients with locoregionally advanced NPC.
However, our experience failed to demonstrate
improvement in survival by adding sequential
adjuvant chemotherapy following radiotherapy
for patients with advanced NPC.
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