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Original Article
Efficacy and safety of concurrent
chemoradiation with weekly cisplatin 
low-dose celecoxib in locally advanced
undifferentiated nasopharyngeal
carcinoma: A phase II–III clinical trial
ABSTRACT
Background: This is the first study that aimed to determine the efficacy and safety of concurrent chemoradiation with weekly cisplatin
± celecoxib 100 mg twice daily in locally advanced undifferentiated nasopharyngeal carcinoma.
Materials and Methods: Eligible patients had newly diagnosed locally advanced (T3–T4, and/or N2–N3, M0) undifferentiated
nasopharyngeal carcinoma, no prior therapy, Karnofsky performance status  70, and normal organ function. The patients were
assigned to receive 7 weeks concurrent chemoradiation (70 Gy) with weekly cisplatin 30 mg/m2 with either celecoxib 100 mg twice
daily, (study group, n = 26) or placebo (control group, n = 27) followed by adjuvant combined chemotherapy with cisplatin 70 mg/m2
on day 1 plus 5-fluorouracil 750 mg/m2/d with 8-h infusion on days 1–3, 3-weekly for 3 cycles.
Results: Overall clinical response rate was 100% in both groups. Complete and partial clinical response rates were 64% and 36% in
the study group and 44% and 56% in the control group, respectively (P > 0.25). The addition of celecoxib to concurrent chemoradiation
was associated with improved 2-year locoregional control rate from 84% to 100% (P = 0.039).
Conclusions: The addition of celecoxib 100 mg twice daily to concurrent chemoradiation improved 2-year locoregional control rate.
KEY WORDS: Celecoxib, chemotherapy, concurrent chemoradiation, cyclooxygenase-2 (COX-2) inhibitors, locally advanced
undifferentiated nasopharyngeal carcinoma, weekly cisplatin
INTRODUCTION
Nasopharyngeal carcinoma has unique features of
epidemiology, staging, and treatment compared to
other cancers of the head and neck. The majority
of patients with nasopharyngeal carcinoma present
at locally advanced stage. Radiation therapy (RT)
alone or combined chemoradiation is the current
cornerstone in the management of nasopharyngeal
carcinoma. [1,2] The poor prognosis of locally
advanced disease has led to increasing interests in
exploring the use of novel antineoplastic agents
in these patients. Cyclooxygenase-2 (COX-2) is
one interesting potential target for the treatment
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DOI: 10.4103/0973-1482.92013
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of nasopharyngeal carcinoma. COX-2 enzyme
overexpresses in many malignant tumors, as well
as nasopharyngeal carcinoma and is associated
with more aggressive tumor behavior and poor
prognosis. Several preclinical studies on selective
COX-2 inhibitors, such as celecoxib, have shown
that these agents have antitumor, antiangiogenesis,
and radiosensitizing effects.[3-14] In addition, there
are evidences that COX-2 inhibitors have been
associated with significant reduction in vascular
permeability and decrease in acute and chronic
inflammation.[15]
Celecoxib has been progressively used in clinical
studies for improving the response to therapy
in many cancers.[16-20] This is the first study that
aimed to determine the efficacy and safety of
concurrent chemoradiation with weekly cisplatin
± celecoxib 100 mg twice daily in locally
advanced undifferentiated nasopharyngeal
carcinoma.
Mohammad
Mohammadianpanah1,
Sasan RazmjouGhalaei2,
Amin Shafizad3,
Yaghoub AshouriTaziani1,
Bijan Khademi4,5,
Niloofar
Ahmadloo1,
Mansour Ansari1,
Shapour
Omidvari1,
Ahmad
Mosalaei1,5,
Mohammad Amin
Mosleh-Shirazi1
1
Department of
Radiation Oncology,
Namazi Hospital,
Shiraz University of
Medical Sciences,
Shiraz, 2Department of
Radiation Oncology,
Golestan Hospital,
Ahwaz University
of Medical Sciences,
Ahwaz, 3Department
of Radiation Oncology,
Hormaozgan
University of Medical
Sciences, Bandar
Abbass, 4Department
of Otolaryngology,
Head and Neck
Surgery, Khalili
Hospital, Shiraz
University of Medical
Sciences, Shiraz,
5
Cancer Research
Center, Shiraz
University of Medical
Sciences, Shiraz, Iran
For correspondence:
Dr. Mohammad
Mohammadianpanah,
Department of
Radiation Oncology,
Cancer Research
Center, Namazi
Hospital, Shiraz
University of Medical
Sciences, Shiraz
71936-11351, Iran.
E-mail: mohpanah@
gmail.com
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Mohamma-Dianpanah, et al.: Chemoradiation ± celecoxib in nasopharyngeal carcinoma
MATERIALS AND METHODS
This phase II–III study enrolled patients with newly diagnosed
locally advanced (T3–T4 and/or N2–N3, M0) undifferentiated
nasopharyngeal carcinoma. From January 2007 to November
2008, 53 patients with locally advanced undifferentiated
nasopharyngeal carcinoma were randomly assigned to
concurrent chemoradiation with weekly cisplatin (30 mg/m2)
plus either celecoxib 100 mg twice daily (study group, n = 26)
or placebo (control group, n = 27). The trial was approved by
the local university ethics committee in accordance with the
ethical standards laid down in the 1964 Declaration of Helsinki.
All the patients provided written informed consent prior
to their inclusion in the study. The diagnosis of the disease
was based on nasopharyngeal biopsy and a histopathologic
examination of the specimen. Eligible patients had to be
aged 15–80 years, Karnofsky performance score of ≥70
and have biopsy-proven, newly diagnosed locally advanced
undifferentiated nasopharyngeal carcinoma and with normal
or acceptable kidney, liver, cardiovascular, and bone marrow
functions. Exclusion criteria included prior treatment for
nasopharyngeal carcinoma, clinical and imaging evidence of
distant metastasis before or during the trial, inability to receive
celecoxib or chemotherapy for any reason, presence of severe
cardiovascular, kidney, liver, inflammatory bowel disease, or
coagulation disorders, and patients’ refusal to participate in
the trial or to sign on the consent form.
All the patients were initially treated with concurrent
chemoradiation with weekly cisplatin (30 mg/m2) from the
first day of RT, up to 7 cycles. They received a total dose of
70 Gy with 2 Gy daily fractions in 7 weeks with conventional
external beam RT using megavoltage telecobalt units or linear
accelerator photons. The primary site and upper cervical
lymph nodes were treated with two lateral parallel opposed
fields; the lower cervical lymph nodes were treated with
a separate en face anterior field with a central block. The
spinal cord was excluded from the radiation fields after 44
Gy. After 50 Gy, RT was continued to the primary tumor, using
reduced size fields, up to 70 Gy. The dose was calculated at
the central axis of the upper field. Metastatic cervical lymph
nodes were boosted through a direct electron field or anterior
and posterior neck fields with a central block and a dose of
15–20 Gy. Three patients were excluded due to early skeletal
metastasis (2 patients) or chemotherapy refusal (1 patient),
during the course of concurrent chemoradiation. After
completion of concurrent chemoradiation, all the patients
received adjuvant chemotherapy in an outpatient setting,
consisting of cisplatin 70 mg/m2 for day 1, and 5-fluorouracil
(5-FU) 750 mg/m2/day with 8-h infusion on days 1–3, which was
repeated every 3 weeks, up to 3 cycles. Antiemetic medication
including a selective 5-hydroxytryptamine-3 (5HT3) antagonist
and steroids was routinely prescribed intravenously for all
chemotherapy cycles. The patients in the study group received
celecoxib 100 mg twice a day from the first day of concurrent
chemoradiation until 3 weeks after the last cycle of adjuvant
chemotherapy (18th week). The patients in the control group
received placebo with the same schedule as the study group
[Figure 1]. Clinical response rates and safety were the primary
and secondary endpoints, respectively.
Before starting therapy, all the patients were asked about any
history of allergic reaction to nonsteroidal anti-inflammatory
drugs, celecoxib intolerance, uncontrolled hypertension,
gastrointestinal bleeding, gastrointestinal ulcer, hepatic and/
or renal dysfunction, and/or insufficiency. All the patients
were examined with special attention on the status of the
cervical lymph nodes regarding the location of the involved
nodes, and their sizes, consistency, and fixation. Location,
size, and extension of the primary tumor and the cervical
lymph nodes were assessed by magnetic resonance imaging
(MRI) and computed tomography (CT) scans. Stages were
assigned according to the 6th edition of the American Joint
Committee on Cancer (AJCC) TNM 2002 staging system. The
patients’ functional statuses were evaluated according to
the Karnofsky performance status. Chest radiograph and
laboratory tests, including complete blood count (CBC),
erythrocyte sedimentation rate (ESR), lactic dehydrogenase
(LDH), liver function tests (LFT), and renal function tests
(RFT) were obtained from all the patients. A whole body bone
scintigraphy was performed in symptomatic patients or those
with elevated alkaline phosphatase level. After completion
of concurrent chemoradiation, all the patients from both
groups were followed and evaluated during the rest of the
treatment every 3 weeks before every adjuvant chemotherapy
administration. At the end of intervention (18th week), new
evaluation, including CBC, ESR, LDH, LFT, RFT, and MRI and
CT scan of the primary site and neck were performed for all
the patients.
Figure 1: Study design
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Mohamma-Dianpanah, et al.: Chemoradiation ± celecoxib in nasopharyngeal carcinoma
The patients were followed weekly during the first 7 weeks
of treatment, before every concurrent cisplatin infusion. They
were examined every week and the changes of their lymph
nodes and Karnofsky performance statuses were evaluated.
Grades of mucositis and dermatitis were determined based on
the Radiation Therapy Oncology Group (RTOG) scoring criteria.
CBC, ESR, LDH, LFT, and RFT were checked weekly. The grades
of the hematologic toxicities were also determined based on
the RTOG scoring criteria. Complete response was defined as
complete (100%) clinical and radiologic disappearance of the
tumor. Partial response was defined as incomplete (less than
100% but more than 50%) clinical and radiologic shrinkage
of the tumor. Less than 50% clinical and radiologic shrinkage
of the tumor was considered as no response. Assessment of
clinical response rates was performed 18 weeks following the
first day of RT.
A minimum sample size required 24 patients in each arm to
ensure 80% power at the 5% significance level for detecting a
40% improvement in the clinical complete response rate from
30% to 70%. The survival durations were calculated from the
date of RT start till the events of treatment failure (locoregional
control), death from any reason (overall survival) or the last
follow-up. The significance of differences in survival was
evaluated using the log-rank test. The Chi-squared (2) test,
Fisher’s exact test, and Mann–Whitney test were used for
comparing the clinical response rates and the clinicopathologic
characteristics of the groups. Analysis for disease-free survival
and overall survival rates was performed using the Kaplan–
Meier method, and prognostic factors were compared using
the log-rank test. P values less than 0.05 were considered
significant.
RESULTS
After excluding 3 patients who developed skeletal metastases
or refused chemotherapy, 50 patients were evaluable (25
patients in each group). The mean age was 42 years (range
18–69 years) in the study group, and 44 years (range 18–65
years) in the control group. In each group, 15 patients (60%)
were men and 10 (40%) were women. Thirty-five patients (70%)
presented with stage III disease and 30% had stage IV disease.
The median dose of radiation was 70 Gy (range 60–70 Gy) in
both groups. In addition all the patients received a median 5
cycles of weekly cisplatin (range 4–7 cycles); and a median 3
cycles of adjuvant chemotherapy (range 2–3 cycles) [Table 1].
Overall clinical response rate was 100% in both groups.
Complete and partial clinical response rates were 64% and 36%
in the study group, and 44% and 56% in the control group,
respectively (P > 0.25).
Patients with partial response had suspected (7 in study
group and 10 in control group) or obvious (2 in study group
and 4 in control group) residual disease at primary site on
imaging. Those with obvious residual disease underwent
444
Table 1: Patients and treatment characteristics for
all 50 patients with locally advanced undifferentiated
nasopharyngeal carcinoma
Characteristics
No. of patients
Age range (years)
Median age (years)
Male/female ratio
Stage of disease
T3N1M0
T3N2M0
T3N3M0
T4N0M0
T4N1M0
T4N2M0
T4N3M0
Dose of radiotherapy (Gy)
Mean
Median
Range
No. of weekly cisplatin cycles
Mean
Median
Range
Study
group
25
18–69
42
1.5
Control
group
25
18–65
44
1.5
Total
50
18–69
43
1.5
6
10
1
2
0
5
1
8
11
0
1
1
3
1
14
21
1
3
1
8
2
67.24
70
60–70
67.92
70
60–70
67.55
70
60–70
5.04
5
4–7
4.76
5
4–7
4.89
5
4–7
direct nasopharyngoscopy for accurate clinical evaluation and
pathologic confirmation. Among these patients, pathologic
examination revealed viable residual disease in 2 patients
of the control group, and only necrosis and inflammation in
the remaining 4 patients. For patients with partial response
and suspected residual disease, a follow-up imaging (MRI
and CT scan) was performed 3 months later. All of the 17
patients had normal follow-up imaging without evidence of
abnormal finding that favors residual disease. Therefore, when
considering these results, the ultimate complete response rates
were increased from 64% to 100% in the study group, and
from 44% to 92% in the control group at the end of the 30th
week. During the follow-up period 12 patients experienced
recurrent disease (8 cases with isolated skeletal relapse and 4
cases with locoregional and skeletal failure). After a median
follow-up of 26 months (range 21–31 months) for surviving
patients, 38 patients are alive and without disease, 5 (2 of the
study group and 3 of the control group) are alive with disease
and 7 (3 of the study group and 4 of the control group) died
due to disease. We found a significant improvement in 2-year
locoregional control rate in the study group when compared
with the control group (100% vs. 84%, P = 0.039). However,
2-year overall survival was not significantly different by
treatment groups (88% vs. 84%, P = 0.698). In addition, there
was no significant association between the stage of disease
and complete response rate (P > 0.15).
All the patients well tolerated concurrent chemoradiation and
adjuvant combined chemotherapy regimen. Acute treatmentrelated toxicities were manageable in both the groups. The
patients in study group tolerated celecoxib well, and none
of them had significant complaint of side effects. Anorexia,
nausea, pharyngitis, fatigue, vomiting, xerostomia, and
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Mohamma-Dianpanah, et al.: Chemoradiation ± celecoxib in nasopharyngeal carcinoma
dermatitis were the most frequent treatment-related toxicities
in both groups. None of patients developed grade 4 toxicities,
and treatment-related death was not observed. One patient in
the study group developed profound hypokalemia (2.1 mmol/L)
2 weeks after the third cycles of adjuvant chemotherapy
(17th weeks). Another patient in the study group developed
lung abscess 4 weeks after the third cycles of adjuvant
chemotherapy (19th weeks). All the patients in both the
groups were managed well, with a similar rate of late sequelae.
Xerostomia, soft tissue fibrosis, otitis media, dental caries,
and hearing loss were the most frequent late complications
in both arms [Figure 2]. There was no significant difference
in terms of acute treatment-related toxicities between the 2
groups. Table 2 shows the frequency of acute treatment-related
toxicity rates of the 2 groups.
DISCUSSION
There are increasing evidences of the superiority of concurrent
chemoradiation compared to radiotherapy alone in patients
with locally advanced nasopharyngeal carcinoma. According
to these evidences, concurrent chemoradiation with cisplatin-
Figure 2: Relative late complication frequency in the study and control
arm
Table 2: Acute toxicity of concurrent chemoradiation and
adjuvant chemotherapy in 50 patients with locally advanced
undifferentiated nasopharyngeal carcinoma
Toxicity
Myelosuppression
Grade 1–2
Grade 3
Mucositis
Grade 1–2
Grade 3
Xerostomia
Grade 1–2
Grade 3–4
Dermatitis
Grade 1–2
Grade 3
Study group
Control
group
P value
22 (88%)
3 (12%)
19 (76%)
6 (24%)
0.46
7 (28%)
18 (72%)
4 (16%)
21 (84%)
0.49
25 (100)
—
25 (100)
—
1.0
22 (88%)
3 (12%)
25 (100)
—
0.23
based regimen with or without neoadjuvant or adjuvant
chemotherapy is currently considered the standard of care for
locoregionally advanced nasopharyngeal carcinoma. Despite
this improvement, outcome of patients with locally advanced
nasopharyngeal carcinoma remains poor.[1,2] Therefore, novel
antineoplastic agents need to receive more attention. One of
the most promising agents is COX-2 inhibitors, which are under
investigation for improving the response to radiotherapy
and chemotherapy. COX-2 inhibitors, such as celecoxib, may
have a role in the treatment of cancers via inhibiting cellular
proliferation and angiogenesis, decreasing distant metastases,
and inducing apoptosis.[3-14]
COX-2 enzyme overexpresses in many different tumors, and
its role in tumorigenesis, angiogenesis, transformation, and
metastasis has been shown in several studies.[3-14] Many studies
assessed the prophylactic role of COX-2 inhibitors in various
tumors, such as colon and breast cancer, and showed that
nonsteroidal anti-inflammatory drugs and COX-2 inhibitors
decrease the incidence of colon and breast cancer via inhibiting
cyclooxygenase-1 and -2 enzymes.[3,4] Lee et al. showed that
COX-2 enzyme was overexpressed in cultured cells of squamous
cell carcinoma of the head and neck, when compared with
normal cells. The authors concluded that COX-2 inhibitors
significantly decreased cell growth and increased apoptosis in
cultured cells.[5] This study and several others have shown that
COX-2 inhibitors may have chemopreventive and therapeutic
effects in squamous cell carcinoma of the head and neck.[5-9] In
another study, Soo et al. found celecoxib 400 mg twice daily for
14 days reduced microvessel density and induced changes in
gene expression in patients with newly diagnosed, untreated
nasopharyngeal carcinoma.[6]
In addition, several studies found that COX-2 inhibitors
significantly enhanced the response of tumor cells to
radiotherapy. The exact mechanism(s) responsible for the
antiproliferative effect of COX-2 inhibitors remains to be
defined; however, antiangiogenic effects of COX-2 inhibitors
seem to be mainly responsible for increasing the antitumor
effects of ionizing radiation.[10] Therefore, COX-2 inhibitors have
a potential role for improving response to radiotherapy.[10-14]
Several clinical trials studied the role of COX-2 inhibitors in
improving response to radiotherapy or chemotherapy in many
different cancers, such as head and neck and breast cancer.
Despite promising results in preclinical studies, most clinical
studies showed that COX-2 inhibitors have had no effect on
response or survival rates in patients.[3-6,8,9,13,14] In a phase I–II
trial at Princess Margaret Hospital, the toxicity and efficacy of
celecoxib in combination with definitive chemoradiation were
evaluated in 31 women with locally advanced cervical cancer.
All the patients received oral celecoxib 400 mg twice daily for
2 weeks before and during chemoradiation. They found acute
grade 3/4 hematologic and gastrointestinal toxicities were the
most frequent and were largely attributed to chemotherapy.
Twenty-five of 31 patients (81%) achieved complete response
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Mohamma-Dianpanah, et al.: Chemoradiation ± celecoxib in nasopharyngeal carcinoma
during the first year of follow-up. The authors concluded that
definitive chemoradiation in combination with celecoxib was
associated with acceptable acute toxicity, and higher than
expected late complications. They found the addition of celecoxib
to definitive chemoradiation did not improve tumor response.[16]
Another phase II trial studied response rate, toxicity, and
overall survival rates in patients with potentially resectable
esophageal cancer. Thirty-one patients received neoadjuvant
chemoradiation with cisplatin and 5-FU plus celecoxib 200 mg
twice daily on day 1 until surgery and then at 400 mg twice
daily until disease progression or unexpected toxicities, or for a
maximum of 5 years. The patients underwent esophagectomy
4–6 weeks after completion of chemoradiation. Most
patients experienced grade 3/4 toxicities, of which diarrhea,
neutropenia, nausea/vomiting, esophagitis, dehydration, and
stomatitis were most frequent. There were 7 treatment-related
deaths.[3] Of 22 patients who underwent esophagectomy,
5 had pathologic complete response (22%). The authors
concluded that the addition of celecoxib 400 mg twice daily to
chemoradiation was well tolerated, however, the pathologic
complete response rate of 22% in their study was similar to
that reported with the use of preoperative chemoradiation
alone in other trials.[17]
Recently, few studies evaluated the efficacy and safety of
concurrent chemoradiation with weekly cisplatin in patients
with nasopharyngeal carcinoma. These studies concluded
that this treatment approach is safe and effective for most
patients with nasopharyngeal carcinoma even in the elderly
patients.[21-24]
The present study is the first clinical trial evaluating the
efficacy and safety of low-dose (100 mg twice daily) celecoxib
with concurrent chemoradiation plus weekly cisplatin in
locally advanced undifferentiated nasopharyngeal carcinoma.
Consistent with the recent studies, this study confirmed the
safety and efficacy of this treatment for patients with locally
advanced undifferentiated nasopharyngeal carcinoma.[21-24] The
addition of celecoxib 100 mg twice daily did not change the
rates of overall survival or treatment-related acute toxicities,
however, it significantly improved locoregional control rate,
which is a promising point that should be evaluated in future
studies using higher doses of celecoxib. The incidence of
severe treatment-related toxicities was infrequent and most
patients well tolerated the treatment. In this study, 1 patient
developed severe hypokalemia, a complication of cisplatin-based
chemotherapy that was rarely reported in the literature.[25] The
rather high incidence of skeletal metastases in this study
may be attributable to the suboptimal or ineffective adjuvant
systemic chemotherapy and/or aggressive behavior of this
neoplasm. In any case, this highly suggests the need for a
more effective systemic treatment in these patients. The use
of more effective chemotherapeutic agents, such as taxanecontaining regimen, particularly in neoadjuvant setting, may
further improve locoregional control and survival in patients
446
with locally advanced undifferentiated nasopharyngeal
carcinoma.[24,26]
There is no evidence in phase I or phase II clinical trials defining
radiosensitizing dose for celecoxib. In recent few phase I
clinical trials an escalating dose (100–400 mg, twice daily) has
been used.[27,28] The rationale for this lower dose administration
of celecoxib was to evaluate the radiosensitizing effect of lower
dose of celecoxib, rather than antitumor and antiangiogenesis
effects. Most other studies, however, despite using higher
doses of celecoxib, failed to show any survival benefit for the
addition of celecoxib.[29-31]
CONCLUSIONS
Concurrent chemoradiation with weekly cisplatin followed by
adjuvant combined cisplatin-based chemotherapy is highly
effective in locally advanced undifferentiated nasopharyngeal
carcinoma. The addition of celecoxib 100 mg twice daily to
concurrent chemoradiation improved 2-year locoregional
control rate, however, its effect on the response rates,
treatment-related toxicities and overall survival was not
statistically significant.
ACKNOWLEDGMENT
This clinical trial was approved and supported by Shiraz University
of Medical Sciences as research number project 2664. In addition,
the study was registered on the clinical trials registration website of
Australia and New Zealand (ANZCTR) on 12 October 2008 (number:
ACTRN12608000449336).
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Cite this article as: Mohamma-Dianpanah M, Razmjou-Ghalaei S,
Shafizad A, Ashouri-Taziani Y, Khademi B, Ahmadloo N, et al. Efficacy
and safety of concurrent chemoradiation with weekly cisplatin ± low-dose
celecoxib in locally advanced undifferentiated nasopharyngeal carcinoma:
A phase II-III clinical trial. J Can Res Ther 2011;7:442-7.
Source of Support: Shiraz University of Medical Sciences as research
number project 2664, Conflict of Interest: The authors disclose any
commercial or other associations that might pose a conflict of interest in
connection with submitted manuscript.
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