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.

Conclusion: Our experience confirmed earlier reports

showing poor outcomes for locoregionally advanced
nasopharyngeal carcinomas. This study failed to demonstrate improvement in the outcome regarding overall and
disease-free survival by adding sequential adjuvant chemotherapy after radiotherapy for patients with advanced
NPC.

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.

Key Words: Nasopharyngeal carcinoma (NPC) - Radiotherapy - Chemotherapy.

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. Eightyfive patients (79.4%) received 60-70Gy radiation (1.82Gy/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.

INTRODUCTION
Among head and neck tumors, nasopharyngeal carcinoma (NPC) is a special entity in
which the location does not lend itself to curative
surgery. NPC is highly radiosensitive, and radical 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 approximated 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 chemotherapy plus radiotherapy in the primary treatment has been investigated, for decreasing the
rate of distant metastasis and locoregional relapse, as well as increasing disease free and
overall survival [2].

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 significant 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

Several trials have sought to improve the

effect of radiotherapy by adding concurrent

147

148

Treatment Results of Nasopharyngeal Carcinoma

chemotherapy followed by adjuvant chemotherapy; 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 province, South of Iran.
PATIENTS AND METHODS
This study included 107 biopsy-proven nasopharyngeal 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 nasopharyngoscopy, complete blood count, serum
chemistries, chest X-Ray and CT-scan as needed.
All the patients had peripheral absolute granulocyte count of 2000/L, platelet 100,000/L
and creatinine less than 1.5mg/dl before treatment.
Radiation therapy:
External beam radiation therapy was delivered 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 fractionation) due to complications and/or loss to
follow-up. Initially, the base of skull, nasopharynx, 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 continued 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 1520Gy.
Chemotherapy:
Forty-five (42.5%) patients were treated
with radiation alone, and sixty-two (57.5%)
patients with adjuvant chemotherapy in combination with radiation. The chemotherapy regimen 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.

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 patients (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 demonstrated 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 undifferentiated 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, respectively.
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 frequently observed acute complication encountered 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. Prognostic factors that appeared to influence the
response, overall survival and disease free survival included gender, age, histopathologic type,
tumor stage, node stage, stage group, total
radiation dose and chemotherapy; these were
assessed using univariate and multivariate analysis.
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 survival and response with a median overall survival of 15 months for patients receiving adjuvant 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

0.8

20

Female

Patients number

0.6
0.4
0.2

15
10
5

0.0

81-90

Months

71-80

48

61-70

40

51-60

32

41-50

24

31-40

16

21-30

11-20

0
0

0-10

Survival

Male

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

Classification.

Table (2): Distribution of clinical features of patients.

Clinical features No. (%)

N
T

Clinical features No. (%)

Total

N0

N1

N2

N3

T1
T2
T3
T4

4
3
1
5

12
6
14
2

2
10
10
6

3
5
15
9

21
24
40
22

Total

13

34

28

32

107

Epistaxis

29 (27%)

Nasal obstruction 28 (26%)

Ear fullness and
hearing loss

Otalgia

15 (14%)

Cranial nerve 11 (10%)

Involvement

18 (16.7%) Diplopia

9 (8%)

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Treatment Results of Nasopharyngeal Carcinoma

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

Locoregional control
Factors

DFS

N
p

OR (95% CI)

>0.05

0.39 (0.14-1.06)

MS (months)

Sex:
Male
Female

77
30

Age:
40 years
>40 years

31
76

Histopathology:
WHO I
WHO II
WHO III

21
62
24

Tumor stage:
T1
T2
T3
T4

21
24
40
22

>0.05
>0.05
>0.05

0.83 (0.12-5.33)
0.44 (0.08-2.06)
1.06 (0.14-7.82)

10
13
9
12

Node stage:
N0
N1
N2
N3

13
34
28
32

>0.05
>0.05
>0.05

0.60 (0.02-6.99)
0.29 (0.01-3.07)
0.18 (0.01-1.74)

14
9
12
10

Stage group:
I
II
III
IV

4
3
33
67

>0.05
>0.05
>0.05

2.42 (0.0-42.74)

14
76
11
12

Radiation dose:
60Gy
>60Gy

<0.05
22
85

05.37 (1.88-5.38)

11
12

Chemotherapy:
Given
Not given

62
45

10
17
>0.05

17
10
>0.05

0.98 (0.28-3.34)
12
12
12

>0.05

DFS : Disease free survival.

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

1.22 (0.44-3.42)

0.95 (0.36-2.50)
12
12

Bijan Khademi, et al.

151

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

OS
MS
(months)

Factors

Sex:
Male
Female

77
30

14
19

Age:
40 years
>40 years

31
76

26
14

DFS
p

OR (95% CI)

>0.05

0.28

(0.48-3.39)
1.28
(0.014-0.90)

< 0.05 0.031

27.7
27.7
16.7

Tumor stage:
T1

21

27.6

>0.05

0.721

T2

24

31.3

>0.05

0.291

T3

40

24.4

>0.05

0.911

T4

22

18.1

13

33.6

<0.05

0.0001

N1

34

22.8

<0.05

0.0001

N2

28

30.6

<0.05

0.0001

N3

32

17.4

17

<0.05

II

79

<0.05

III

33

14

>0.05

IV

67

14

Radiation dose:
60Gy
22
>60Gy
85

14
17

Chemotherapy:
Given
Not given

15
13

Stage group:
I

>0.05

>0.05

>0.05
62
45

n : Number of patients.
Os : Overall survival.

0.35

0.3

(0.0987-2.042)
0.449

(0.28-3.34)
0.97

<0.05 0.041

(0.103-0.964)
0.31

>0.05 0.618

(0.286-8.239)
1.534

1.268
(0.088-18.218)
1.895
(0.197-18.182)
3.375
(0.0534-21.352)

0.672
(0.075-5.989)
0.364
(0.0558-23.79)
1.113
(0.171-7.259)
-

10

>0.05 0.861

13

>0.05 0.58

>0.05 0.196

0.0018
(0.0089-0.0039)
0.004
(0.00249-0.0039)
-

14

>0.05 0.988

<0.05

12

>0.05 0.531

10

0.0001

0.0002
(0.0005-0.0001)
0.0001
0.00012
(0.000242-0.00065)
0.882
0.802
(0.0435-14.78)

0.867

0.661

12
12
12

(0251-5.60)
1.137
(.254-2.2382)
0.778

DFS : Disease free survival.

95% CI: 95% Confidence interval.

DISCUSSION
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 countries of the world and displays a declining

12

14

RR (95% CI)

>0.05 0.14
10
17
17
10

Histopathology:
WHO I
21
WHO II
62
WHO III
24

Node stage:
N0

MS
(months)

-(0.534-21.352)
-(0.00025-0.00255)
0.594
(.166-3.031)

76

>0.05 0.998 (0.000112-0.000113)

0.00011
>0.05 1.000
0.402

11

>0.05 0.998

12

0.000065

<0.05 0.02

(0.015-0.392)
0.078

>0.05 0.838

(0.291-4.571)
1.154

11
12
12
12

P: Probability value (univariate analysis)

P: Probability value (multivariate analysis)

RR: Relative Risk

MS: Median survival.

gradient from South Eastern Asia to Northern

America. This neoplasm has multifactorial risk
factors. Genetic, environmental, viral, dietary,
occupational and racial risks are the most common 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 cushions. Based on the degree of differentiation,
NPC is classified into 3 histopathologic types.
WHO type I includes typical keratinizing squamous cell carcinomas, similar to other head and
neck cancers. Type II includes nonkeratinizing
carcinoma, while type III includes undifferentiated 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 expression. 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 paradoxically, 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 histology [9].
This neoplasm is silent, and its clinical
symptoms are delayed. The most common presenting 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 distribution of NPC varies in different parts of the
world, a bimodal age distribution in late adolescence 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, histopathologic 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 disease is remarkable and the patients with locoregionally 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 carcinoma 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 diseasefree survival (p=0.02) [12].
Definitive radiotherapy with or without chemotherapy is currently the standard treatment
for nasopharyngeal carcinoma [6-8,21,22] . In
conventional radiotherapy (once daily, 5 fractions per week, 1.8-2Gy per fraction) a tumoricidal 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 nodenegative 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 highdose radiation of 2-dimensional planning for
the nasopharyngeal carcinoma [8,25,26]. Xerostomia is the most common radiation-related
toxicity with 2-dimensional radiotherapy. Xerostomia contributes to the patients nutritional
deficiency, swallowing difficulty, weight loss,
poor oral and dental hygiene, altered taste sensation, impaired speech function, and poor sleep
quality. Therefore, xerostomia is directly or
indirectly responsible for many patients complaints 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 complications can be overcome using 3D conformal
radiotherapy and intensity-modulated radiotherapy. Using these modern radiotherapy techniques, 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 locoregional 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 chemotherapy before starting radical radiotherapy
in locoregionally NPC [5]. Chemotherapy for
advanced-stage NPC currently consists of cisplatin 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, taxanes 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 carcinoma [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 randomized trial of induction chemotherapy followed 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 chemotherapy and radiation therapy in locoregionally advanced NPC [4].
Accordingly, concurrent chemoradiation
with or without adjuvant chemotherapy is currently the standard care for locoregionally advanced nasopharyngeal carcinoma, despite unclear 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 chemotherapy 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 effective chemotherapeutic regimens and other systemic therapy are needed to decrease the rate
of locoregional and distant failure and improve
survival [41].

154

Treatment Results of Nasopharyngeal Carcinoma

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 epigenetic 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 outcome of NPC patients with poor prognosis [68].
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 chemoradiation 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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