IJC

International Journal of Cancer

Sequential chemoradiotherapy with gemcitabine and cisplatin

for locoregionally advanced nasopharyngeal carcinoma
Mo-Fa Gu1*, Li-Zhi Liu2*, Long-Jun He3, Wen-Xin Yuan2, Rong Zhang3, Guang-Yu Luo3, Guo-Liang Xu3, Hua-Man Zhang2,
Chao-Xian Yan3 and Jian-Jun Li3
1

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University,
Guangzhou, Peoples Republic of China
2
Imaging Diagnosis and Interventional Center, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou,
Peoples Republic of China
3
Department of Endoscopy, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou,
Peoples Republic of China

Key words: nasopharyngeal carcinoma, chemotherapy, gemcitabine,

radiotherapy
Abbreviations: Con-RT PF: cisplatin-based concurrent
chemoradiotherapy plus adjuvant PF chemotherapy; GEM:
gemcitabine; NPC: nasopharyngeal carcinoma; PF: cisplatin
uorouracil regimen; sGC-RT: sequential chemoradiotherapy with
cisplatingemcitabine regimen; sPF-RT, sequential
chemoradiotherapy with cisplatinuorouracil regimen
*M.-F.G. and L.-Z.L. contributed equally to this work.
Grant sponsor: Science and Technology Plan Projects of
Guangdong Province, Peoples Republic of China; Grant numbers:
2006B36002026, 2007B030700001, 2010B080701015; Grant sponsor:
Natural Science Foundation of Guangdong Province, China; Grant
number: 8151008901000216
DOI: 10.1002/ijc.27638
History: Received 3 Jan 2012; Accepted 3 May 2012; Online 18 May
2012
Correspondence to: Jian-Jun Li, Department of Endoscopy, State
Key Laboratory of Oncology in South China, Cancer Center, Sun
Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060,
Peoples Republic of China, Tel.: 86-20-87343383,
Fax: 86-20-87343392, E-mail: lijj@sysucc.org.cn

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Int. J. Cancer: 132, 215223 (2013) V

Nasopharyngeal carcinoma (NPC) is endemic in Southeast

Asia, especially in the southern provinces of China.1 Furthermore, between 63.3 and 68.1% of patients with NPC present
with Stage III or IV disease in southern China.2,3 Patients
with locoregionally conned advanced NPC have a worse
prognosis, with frequent local relapse and distant metastases.
In recent years, local tumor control for NPC has been greatly
improved by developments in radiotherapy (RT) techniques;
however, the incidence of distant metastases remains high,
and further research is needed to address this.4
NPC is known for its high rates of response to RT and
chemotherapy. The results from the Intergroup-0099 trial,
which compared concurrent chemoradiotherapy (Con-RT)
plus adjuvant chemotherapy with RT alone in patients to
Stages IIIIVB disease, suggest that the addition of chemotherapy to RT is benecial.5 However, a randomized trial in
endemic geographic areas showed that the Intergroup-0099
regimen only improved relapse-free survival and not overall
survival (OS) or distant metastasis-free survival (DMFS).6
Additionally, the Intergroup-0099 regimen resulted in signicantly increased toxicity rates.7 Therefore, an exploration of
new therapies and regimens that improve outcome and
decrease treatment-related toxicity in locoregionally conned
advanced NPC is needed.

Cancer Therapy

We investigated a new chemoradiotherapy (CRT) regimen for locoregionally advanced nasopharyngeal carcinoma (NPC). A total
of 240 patients were randomly assigned to three different CRT regimens: sequential CRT [1 cycle chemotherapy 1 Phase I
radiotherapy (RT) 1 1 cycle chemotherapy 1 Phase II RT 1 2 cycles chemotherapy] with a cisplatingemcitabine (GC) regimen
(800 mg/m2 gemcitabine on Days 1 and 8 and 20 mg/m2 cisplatin on Days 15, every 4 weeks) (sGC-RT); sequential
chemoradiotherapy with a cisplatinfluorouracil (PF) regimen (20 mg/m2 DDP and 500 mg/m2 5-FU on Days 15, every 4
weeks) (sPF-RT) and cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy (Con-RT 1 PF). The
complete response rate was higher in the sGC 1 RT group than in the other two groups (98.75% vs. 92.50%, p < 0.01). The
3-year overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates in the sGC-RT group
were significantly higher than those observed in the Con-RT group (OS, 95.0% vs. 76.3%, p < 0.001; DFS, 89.9% vs. 67.5%, p
< 0.001; DMFS, 92.5% vs. 76.0%, p 5 0.004) and in the sPF 1 RT group (OS, 95.0% vs. 73.6%, p < 0.001; DFS, 89.9% vs.
63.3%, p < 0.001; DMFS, 92.5% vs. 74.7%, p 5 0.002). There were no significant differences in 3-year OS, DFS and MFS
rates between the Con-RT and the sPF-RT groups. The GC-RT group experienced more hematologic toxicity, constipation and
rash; however, there were no differences in late RT toxicity between the groups. These results demonstrate that a sGC-RT
regimen is effective and well tolerated in patients with locoregionally advanced NPC.

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Sequential chemoradiotherapy with GC regimens for NPC

Cancer Therapy

Figure 1. Trial profile.

Gemcitabine is an analog of deoxycytidine, which inhibits

DNA synthesis. Encouraging efcacy results and tolerable
toxicity proles of gemcitabine-containing regimens have
been conrmed in metastatic and recurrent NPC.810 A clinical trial in patients with cisplatin-resistant metastatic and
recurrent NPC demonstrated that treatment with a gemcitabine and vinorelbine combination resulted in favorable toxicity proles and moderately high activity.11 To our knowledge,
only a few studies have examined the activity and toxicity of
gemcitabine-containing regimens in locoregionally advanced
NPC. Ou et al.12 analyzed a group of 40 patients with locally
advanced NPC who received cisplatingemcitabine (GC) chemoradiotherapy and reported favorable toxicity prole and
impressive antitumor activity. Recently, the same authors also
reported favorable 3-year survival rates in 54 patients treated
with a combination of GC chemotherapy and intensitymodulated RT (IMRT).13 However, compared to cisplatin
uorouracil (PF) chemoradiotherapy, the benets of the GC
regimen remain unclear.
A regimen involving sequential chemoradiotherapy and
GC (1 cycle GC Phase I RT 1 cycle GC Phase II RT
2 cycles GC arm) has been used at the Cancer Center of
Sun Yat-Sen University for patients with Stages IIIIVB disease. To determine the benets of a regimen involving sequential chemoradiotherapy and GC, we conducted a threearm randomized trial to compare three different chemoradiotherapy (CRT) regimens, in terms of efcacy and tolerability,
in patients with locoregionally advanced NPC. We selected
cisplatin-based Con-RT plus adjuvant PF chemotherapy and

a PF-based sequential chemoradiotherapy as the reference

arms.

Patients and Methods

Patients

Between August 2006 and July 2007, a total of 240 patients

with newly diagnosed, biopsy-proven, nonmetastatic Stages
IIIIVA-B NPC, according to the AJCC 6th Edition Criteria,
were eligible for enrollment into this randomized study. All
the patients were treated at the Cancer Center, Sun Yat-Sen
University, South China. Additional eligibility criteria
included a Karnofsky performance status of at least 80;
adequate renal function as demonstrated by a creatinine
clearance rate of at least 60 mL/min; a WBC
3.5  109
L1; a platelet count
100  109 L1 and a hemoglobin level

100 g/L. Exclusion criteria included the following: the presence of distant metastases; age
60 years or <16 years; pregnancy or lactating; a history of renal disease; unstable cardiac
disease requiring treatment and a history of previous RT in
the nasopharyngeal region or a history of previous chemotherapy. The study was performed with approval from the
institutional Ethics Committee, and each patient provided
written informed consent prior to any study-specic
procedure.
The cohort composed of 183 males and 57 female
patients, with a male to female ratio of 3.2 to 1. The median
age was 44.4 years (range, 1660 years). Histologically, all
patients had Type II or Type III disease, according to the
World Health Organization (WHO) criteria.
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Gu et al.

Number of patients
Characteristics

sGC RT

Con-RT

sPF RT

Age (years)

p value
0.883

<40

32

29

30

40

48

51

50

Male

62

61

63

Female

18

19

17

Gender

0.931

T-category1

0.966

T2

T3

68

68

69

T4

11

10

10

N-category1

0.757

N0

N1

41

44

40

N2

25

26

25

N3

11

11

III

62

66

60

IVA-B

18

14

20

Stage

0.503

According to the AJCC, 6th edition. Abbreviations: sGC-RT: sequential

chemoradiotherapy with cisplatingemcitabine regimen; sPF-RT:
sequential chemoradiotherapy with cisplatinfluorouracil regimen; ConRT PF: cisplatin-based concurrent chemoradiotherapy plus adjuvant
PF chemotherapy.

Pretreatment evaluation and study design

All patients completed a pretreatment evaluation that

included a full medical history, physical examination, hematology and biochemistry proles, MRI of the neck and nasopharynx, CT of chest and abdomen, abdominal ultrasonography and a whole body bone scan using single-photon
emission computed tomography.
Patients were randomly assigned into one of three treatment arms (Fig. 1). The randomization codes were produced
using a computerized random number generator. Participant
characteristics (including age, gender, T classication, N classication and stage groups) were well balanced between the
groups in this trial (Table 1).
Radiotherapy

All patients were treated with denitive intent radiation therapy using a two-phase technique. Details of the RT technique
used at the Cancer Center of Sun Yat-Sen University have
been previously reported.14 All patients were treated using 6
MV linear accelerators (Varian, Palo Alto, CA) and conventional fractionation (2 Gy per fraction). In Phase I RT, the
primary tumor and the upper neck were treated with two lateral opposing faciocervical portals in one volume to 38 Gy.
In the sequential chemoradiotherapy groups, there was a 2week break between Phases I and II RT, and one cycle of CT
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was administered 23 days after the end of Phase I RT. In

Phase II RT, the primary tumor and the upper neck were
treated with a shrinking eld technique using two laterally
opposed facial elds to limit irradiation of the spinal cord.
The posterior cervical lymphatics were then treated with electrons (912 MV). An anterior cervical eld was used to treat
the neck with a laryngeal block. All elds were treated once
daily, and the accumulated radiation doses were 70 Gy for
the primary tumor, 6062 Gy for involved areas of the neck
and 50 Gy for uninvolved areas.
Booster portal was performed using different radiation
energies, including megavoltage photons (6 MV or 8 MV)
and electrons (912 MV). An anterior facial electron eld
was added in patients with nasal or ethmoidal involvement.
The parapharyngeal boost technique, as described by
Tsao,15 was used in patients with bulky parapharyngeal disease. A booster dose (1014 Gy per ve to seven fractions)
was delivered to the skull base in patients with involvement
in that area and in those with intracranial extension. Any
palpable residual nodes after external RT were boosted to 70
Gy at the 90% isodose level with an electron eld.
The RT plan was designed according to pretreatment tumor imaging, and re-planning based on response to chemotherapy was not undertaken.
Chemotherapy

Patients in the sequential chemoradiotherapy with GC (sGCRT) group were scheduled to receive a total of four cycles of
chemotherapy, with the rst cycle administered before Phase
I RT, the second cycle 23 days after the end of Phase I RT
and the nal two cycles 710 days after the end of Phase II
RT. The chemotherapy regimen consisted of 800 mg/m2
gemcitabine on Days 1 and 8 and 20 mg/m2 cisplatin on
Days 15 every 4 weeks.
Patients in the sequential chemoradiotherapy with PF (sPFRT) group were scheduled to receive a total of four cycles of
chemotherapy, with the rst cycle administered before Phase I
RT, the second cycle 23 days after the end of Phase I RT and
the nal two cycles 710 days after the end of Phase II RT. The
chemotherapy regimen consisted of 20 mg/m2 DDP and 500
mg/m2 5-FU on Days 15 every 4 weeks.
In the cisplatin-based Con-RT plus adjuvant PF chemotherapy (Con-RT PF) group, concurrent chemotherapy
with cisplatin (40 mg/m2 on Day 1) was administered intravenously on a weekly basis for 7 weeks during the RT phase.
Two subsequent cycles of adjuvant chemotherapy, consisting
of a combination of cisplatin (80 mg/m2 intravenously) on
Day 1 and uorouracil (800 mg/m2 intravenously) on Days
15 as a 120-hr infusion, were administered 710 days after
the completion of RT.
Patient assessment and follow-up

Chemotherapy-related toxicity was evaluated according to the

WHO criteria.16 RT-related toxicities were graded according
to the European Organization for Research and Treatment of

Cancer Therapy

Table 1. Patient characteristics

218

Cancer Radiation guidelines.17 Response efcacy was based

on the Response Evaluation Criteria in Solid Tumors criteria,
which included complete remission, partial remission, stable
disease and progressive disease.18 A complete clinical
response required the disappearance of all clinical evidence of
disease. Any responses that were less than complete were
considered a failure to respond to treatment.
The nal responses to the treatments were assessed
between 2 and 3 months after completion of CRT. The
response assessment included physical examination, nasopharyngoscopy and biopsy and MRI scans of the nasopharynx and neck. The duration of follow-up was calculated as
the period from the day of assignment to groups to either
the day of death or the day of the last examination. Patients
were assessed every 3 months during the rst 2 years, and
then 6 monthly thereafter until death. All local recurrences
were diagnosed by beroptic endoscopy and biopsy and/or
MRI. Progressive bone erosion or soft-tissue swelling were
considered signs of local recurrence. Regional recurrences
were diagnosed by clinical examination of the neck, and
uncertain cases underwent a ne-needle aspiration or MRI.
Distant metastases were diagnosed by a combination of clinical symptoms, physical examination and imaging, including
chest X-ray, bone scan, MRI, CT and abdominal ultrasound.

Cancer Therapy

Statistical analyses

The following endpoints (time to the rst dening event)

were determined: OS, disease-free survival (DFS) and DMFS.
All events were assessed from the date of commencement of
treatment.
Statistical analyses were performed using the Statistical
Package for the Social Sciences (SPSS, Chicago, IL) version
12.0 software. The actuarial rates were calculated using the
KaplanMeier method, and the differences were compared
using the Log-Rank test. The hazard ratio (HR) and corresponding 95% condence interval (CI) on univariate analysis
were calculated using the Cox regression model. Multivariate
analyses with the Cox proportional hazards model were used
to test independent signicance by backward elimination of
insignicant explanatory variables. Host factors (age and sex)
were included as the covariables in all tests. Toxicity and
response rates were compared using the v2 test. Fishers exact
test was used when a small sample size existed. A two-tailed
p-value of less than 0.05 was considered statistically
signicant.

Results
Clinical response to chemoradiotherapy

All 240 patients completed the chemoradiotherapy regimens

and received nal treatment-response assessments. A complete response was observed in 226 patients. Ten of the 14
patients with a less than complete primary site response had
intracranial disease. The percentage of patients with a complete response was higher in the group receiving sGC-RT
than in the other two groups (98.8% vs. 91.90%, p 0.039),

Sequential chemoradiotherapy with GC regimens for NPC

and no signicant differences were observed between the

sPF-RT group and the cisplatin-based Con-RT plus adjuvant
PF group (92.5% vs. 91.3%, p 1.0).
Chemotherapy toxicity

The major side effects caused by the GC regimen are listed

in Table 3. The main grade 3/4 side effects were hematologic
toxicities, and there were no treatment-related mortalities.
The most common grade 3/4 hematologic side effect in the
sGC-RT group was thrombocytopenia (15.0%), followed by
leukopenia (12.5%), anemia (10.0%) and granulocytopenia
(5%). No neutropenic sepsis was reported, and no red blood
cell transfusions were required. Grade 3/4 nonhematological
toxicities occurred at a rate of 10.0% and included vomiting
and liver function damage. One patient in the sGC-RT group
developed a reactivation of hepatitis during adjuvant chemotherapy, but later recovered once treatment was discontinued.
The most common grade 1/2 nonhematological side effects
were constipation (97.5%), vomiting (20.0%) and skin rash
(35.0%).
All 240 patients were included in the analysis of side
effects. The major side effects encountered by the different
groups are listed in Table 2. Patients treated with the GC regimen suffered more hematologic side effects, constipation
and rash. In the sGC-RT group, 38 patients with thrombocytopenia received interleukin-11, whereas only six patients
required platelet transfusions. In the sPF-RT and Con-RT
PF groups, 8 and 10 patients, respectively, developed Grade 3
thrombocytopenia, and no Grade 4 thrombocytopenia was
reported. Leukopenia was also noted in all three arms, at
rates of 95.0, 80 and 83.8% for the sGC-RT, Con-RT PF
and sPF-RT groups, respectively. Most patients had Grades
12 leukopenia, and their white blood cell counts returned to
normal following nutritional support and cytokine therapy.
Higher rates of skin rash and constipation were also detected
in the sGC-RT group.
Radiotherapy toxicity

RT toxicities in all three arms are summarized in Table 3.

Levels of compliance with conventional RT were satisfactory
overall, and all patients completed the RT course according
to schedule. There were no treatment-related deaths in any
of the groups. Eighty-nine (37.1%) patients reported at least
one Grade 3 to Grade 4 acute RT side effect, the most common being mucositis. No patient had dysphagia or odynophagia to such an extent that a feeding tube was required.
Thirty-two (13.3%) patients reported at least one Grade 3 to
Grade 4 late RT side effect, the most common being tympanitis. There was no difference in the incidence of acute and
late RT side effects between the three arms.
Treatment outcomes

The median duration of follow-up was 37.5 months (range,

748 months). At the time of the last follow-up assessment,
194 (80.8%) patients were still alive, and 179 (74.6%) were
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Gu et al.

Table 2. Comparison of chemotherapy toxicity in the three groups

sGC RT

sPF RT

Con-RT

Grades 12

Grades 34

Grades 12

Grades 34

Grades 12

Grades 34

Anemia

26

32

12

20

11

Leukopenia

66

10

53

11

55

12

Thrombocytopenia

66

12

15

24

Vomiting

16

16

12

15

Renal function damage

Hepatic function damage

Diarrhea

Constipation

78

Skin rash

28

Abbreviations: sGC-RT: sequential chemoradiotherapy with cisplatingemcitabine regimen; sPF-RT: sequential chemoradiotherapy with cisplatin
fluorouracil regimen; Con-RT PF: cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy.

Table 3. Comparison of radiotherapy toxicity in the three groups

sGC RT

sPF RT

Con-RT

Grades 12

Grades 34

Grades 12

Grades 34

Grades 12

Grades 34

Mucositis

50

53

45

Dermatitis

63

53

56

Dysphagia

68

70

68

75

73

74

Acute toxicity

Late toxicity
Xerostomia
Skin fibrosis

26

23

20

Trismus

10

11

42

Hearing loss

42

39

41

Cranial neuropathy

free from disease. Fifteen patients developed a locoregional

recurrences, and 45 patients were found to have distant
metastases.
Patients in the sGC RT arm had signicantly better OS,
DFS and DMFS rates. The 3-year OS rates in the sGC RT
arm were signicantly better than those of the Con-RT
(95.0% vs. 76.3%, p < 0.001; HR 5.67, 95% CI 1.95
16.53) and sPF RT arms (95.0% vs. 73.6%, p < 0.001; HR
6.05, 95% CI 2.0717.62). There were no signicant differences between the 3-year OS rates of the Con-RT group
and the sPF RT group (76.3% vs. 73.6%, p 0.833; Fig.
2a). The 3-year DFS rates in the sGC RT arm were signicantly higher than those in the Con-RT (89.9% vs. 67.5%, p
< 0.001; HR 3.68, 95% CI 1.678.14) and sPF RT
arms (89.9% vs. 63.3%, p < 0.001; HR 3.92, 95% CI
1.788.63). There was no signicant difference between the
3-year DFS rates of the Con-RT group and the sPF RT
group (67.5% vs. 63.3%, p 0.818; Fig. 2b). The 3-year
DMFS rates of the sGC RT arm were signicantly higher
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than those of the Con-RT (92.5% vs. 76.0%, p 0.004; HR

3.48, 95% CI 1.398.72) and the sPF RT arms (92.5%
vs. 74.7%, p 0.002; HR 3.76, 95% CI 1.519.38).
There were no signicant differences between the 3-year
DMFS rates of the Con-RT group and the sPF RT group
(76.0% vs. 74.7%, p 0.809; Fig. 2c).
Multivariate analyses were performed to adjust for various
prognostic factors in all groups. The following parameters
were included in the Cox proportional hazards model by
backward elimination of insignicant explanatory variables:
age (
40 years vs. <40 years), gender, stage (III vs. IVA-B
disease) and treatment arms (sGC RT vs. Con-RT or sPF
RT). Both the treatment arm and the stage were signicant
predictive factors for OS, DFS and DMFS rates (Table 4).

Discussion
Treatment regimen design

Nasopharnygeal carcinoma is highly radiosensitive and

extremely responsive to chemotherapy. Recent results have

Cancer Therapy

Abbreviations: sGC-RT: sequential chemoradiotherapy with cisplatingemcitabine regimen; sPF-RT: sequential chemoradiotherapy with cisplatin
fluorouracil regimen; Con-RT PF: cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy.

Cancer Therapy

220

Figure 2. Patient data for the sGC RT arm shows significantly

better overall survival rates (a), disease-free survival rates (b) and
distant metastasis-free survival rates (c) than the Con-RT and sPF
RT arms.

clearly demonstrated that Con-RT ensures higher local and

regional control and improved survival rates for locally/
locoregionally advanced disease.6 However, distant metastases
remain a major concern, in terms of disease recurrence, and
are a key therapeutic challenge in the management of NPC.19
Thus, there is a need for the development of an optimal
combination of RT and chemotherapy that is appropriately

Sequential chemoradiotherapy with GC regimens for NPC

aggressive and reduces the incidence of distant metastases.

Gemcitabine (GEM, deoxidizing-2-22-hydrochloric acid deoxidizing cell double uorine nucleoside) is a new cytarabine
analog with antitumor activity. Its main action is to prevent
cell progression within the cell cycle. Treatment with GEM
plus cisplatin is a logical combination treatment, given their
nonoverlapping toxicities and synergistic cytotoxic activities,
which have been demonstrated in vitro.20 Retrospective and
Phase II data support the use of GEM alone or in combination with cisplatin for the treatment of metastatic NPC
because of the impressive response rates that result from
treatment with both drugs.810 Gemcitabine has also been
shown to be active in salvage therapy when cisplatin-containing combinations have failed.11
Considering these encouraging results with gemcitabinecontaining regimens in metastatic NPC, we explored combined GC-based chemotherapy and RT, in an attempt to
improve the outcome of locoregionally advanced NPC. A
Con-RT and continuous-course RT approach appears to be
the optimal treatment choice. However, GC-based chemoradiotherapy was associated with intolerable mucosal and
hematologic toxicity in our pilot test. When using a combination of induction chemotherapy followed by RT and
adjuvant chemotherapy, the interval time between induction chemotherapy and adjuvant chemotherapy may be too
long, which is not ideal in terms of decreasing the risk of
distant micrometastases. We designed this sequential chemoradiotherapy regime in an attempt to avoid excessive
toxicity, while at the same time taking advantage of the
potentially favorable synergism between combination chemotherapy and RT. Although it has been shown that continuous is superior to split-course RT, especially for Stages
III and IV patients and those with a split of 21 days or
more,21,22 the interval of the split was too long, and chemotherapy was not administered in the interval period in
these studies. In our trial, we found a statistically signicant difference in outcome between the Con-RT and sPFRT groups. This split RT technique has been used in
other published series.23 Considering the serious side
effects associated with concurrent gemcitabine-containing
chemoradiotherapy, a sequential regime may be an effective
alternative. Although the recommended dose of gemcitabine is 1,000 mg/m2 on Days 1 and 8 in each cycle, we
used a dose of 800 mg/m2 in our trial in an attempt to
reduce the potentially additive side effects of radiation
therapy and gemcitabine.
The current standard of care for locoregionally advanced
NPC is Con-RT with cisplatin-based regimens, which are
generally followed by adjuvant chemotherapy. Therefore, in
our trial, we selected a cisplatin-based Con-RT regimen plus
an adjuvant PF chemotherapy protocol as a reference arm.
To determine the impact of the sequential chemotherapy
combination in the experimental group, we designed a new
chemotherapy combination, which consisted of a PF-based
sequential chemoradiotherapy group as reference.
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Gu et al.

Table 4. Summary of multivariate analysis of prognostic factors for OS, DFS and DMFS rates
Endpoint
OS

DFS

DMFS

Variable

HR

95% CI for HR

sPF-RT vs. sGC-RT

1.79

6.00

2.0617.48

0.001

Con-RT PF vs. sGC-RT

1.79

6.01

2.0617.51

0.001

Stage1

1.11

3.02

1.685.45

0.000

sPF-RT vs. sGC-RT

1.38

3.97

1.808.74

0.001

Con-RT PF vs. sGC-RT

1.40

4.05

1.838.96

0.001

Stage1

1.41

4.11

2.486.81

0.000

sPF-RT vs. sGC-RT

1.31

3.69

1.489.20

0.005

Con-RT PF vs. sGC-RT

1.32

3.73

1.499.34

0.005

Stage1

1.21

3.35

1.866.06

0.000

Arms

p-value
0.003

Arms

0.001

Arms

0.012

Clinical response and outcome

Gemcitabine combined with cisplatin is an effective combination for the treatment of patients with locoregionally
advanced NPC. Ou and coworkers13 reported that 70.3% of
those with locally advanced NPC partially responded,
whereas 29.7% achieved a complete response after two cycles
of a GC regimen before RT. In two other retrospective studies, the overall response rates to the PF regimen, when used
as induction chemotherapy, were 88.6 and 91.2%, respectively. In our study, almost all patients achieved a complete
response to sGC-RT regimen. Compared to the PF group,
the GC group achieved a higher overall response rate.
In terms of long-term treatment outcomes, cisplatin therapy concurrent with RT, followed by adjuvant DDP and uorouracil, results in the elimination of cancer for most
patients, with 3-year DFS and OS rates of approximately 70
and 80%, respectively.5,24 Ou et al. reported improved outcome in patients with locally advanced NPC who had
received induction chemotherapy with two cycles of GC followed by RT. The 3-year locoregional progression-free, distant metastases-free, DFS and OS rates were impressive at
93.8, 94.5, 88.5 and 90.0%, respectively.12 However, in a further retrospective study25 that assessed outcome in patients
with Stage IVA-B NPC who were treated with three cycles of
PF or GC induction chemotherapy followed by accelerated
RT concurrently administered with two cycles of cisplatin, no
signicant difference was found between the two induction
regimens. In our exploratory randomized trial, the sGC
RT group achieved a signicant benet in outcome, as demonstrated by improved DFS, DMFS and OS rates compared
to the Con-RT and sPF RT groups.
There are a number of reasons why the use of gemcitabine may be associated with improved outcome. First, gemcitabine is active in single-agent chemotherapy,9 and the combination of gemcitabine and carboplatin achieves a high
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response rate in metastatic NPC.10 Thus, chemotherapy

treatment that contains both gemcitabine and carboplatin
demonstrates high activity in terms of micrometastases,
thereby reducing the rates of distant metastases rates and
improving long-term survival. Second, both gemcitabine and
cisplatin sensitize cancer cells to the effects of RT.26 Among
proliferating cells, cells in the G2 and M phases are the
most radiosensitive, and cells in the S phase are the most
radioresistant.27 When chemotherapy is administered after
RT, gemcitabine is incorporated into radioresistant S-phase
cells, many of which die by apoptosis, and cisplatin reacts
with cellular DNA to form intrastrand and interstrand crosslinks, causing inhibition of DNA replication and RNA transcription as well as activation of apoptosis. Tumor reoxygenation, or other changes in the tumor microenvironment,
can improve radioresponsiveness of tumor cells when second-phase RT is initiated.28 Chemotherapy between the two
phases of RT, and the synergistic effects of RT and chemotherapy, optimally treat the tumor. Third, gemcitabine has
potential anti-EBV activity and inhibits viral replication.29
Feng et al. demonstrated that gemcitabine (but not DDP or
5-uorouracil) induce lytic EBV infection in EBV-transformed B cells both in vitro and in vivo. They also reported
that gemcitabine activated transcription from the promoters
of the two viral immediate-early genes, BZLF1 and BRLF1,
in EBV-negative B cells.30 Finally, there is increasing evidence that gemcitabine enhances the antigenicity and immunogenicity of tumors by promoting adaptive immune
responses.31 Plate et al.32 discovered that gemcitabine therapy may decrease memory T cells and promote naive T-cell
activation, and the authors concluded that gemcitabine therapy is not immunosuppressive and may in fact enhance
response to specic vaccines or immunotherapy administered
to activate or support immune responses directed toward
driving effector immunity to cancer cells.

Cancer Therapy

According to the AJCC, 6th edition. Abbreviations: HR: hazard ratio; CI: confidence interval; OS: overall survival; DFS: disease-free survival; DMFS:
distant metastasis-free survival; sGC-RT: sequential chemoradiotherapy with cisplatingemcitabine regimen; sPF-RT: sequential chemoradiotherapy
with cisplatinfluorouracil regimen; Con-RT PF: cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy.

222

Sequential chemoradiotherapy with GC regimens for NPC

Comparison of toxicity

In our study, the main side effect of GC was bone marrow

suppression, most commonly thrombocytopenia. A mild
decrease in the platelet count does not generally require specic treatment, and the levels can be restored once chemotherapy is discontinued. Subcutaneous IL-11 3 mg every 2
weeks was administered to patients with Grades IIIII thrombocytopenia, and platelet levels were recovered thereafter. For
the minority of patients with Grade IV thrombocytopenia,
allogeneic platelet transfusions may be appropriate. The second most common side effect was neutropenia, which was
corrected by the administration of G-CSF or GM-CSF. We
noted that thrombocytopenia usually occurred during the
second chemotherapy treatment and before the appearance of
the leukopenia. Other side effects such as nausea, vomiting
and rash were mild. Patients appeared tolerant of the treatment regimens, and compliance was satisfactory. Thus, the
regimens could be administered repeatedly, and all patients
successfully completed four cycles of chemotherapy.
There was a signicantly higher incidence of mucositis in
the CRT arm. Lee et al.6 reported an overall incidence of
Grades 34 mucositis in 62% of patients treated with cisplatin-based Con-RT plus adjuvant PF chemotherapy. In our
study, there was no signicant difference in acute RT-related

toxicity between the three groups. Radiation therapy for NPC

often results in late radiation-induced toxicity, such as permanent xerostomia, hearing loss, skin brosis and trismus. In
our trial, all patients were treated using conventional techniques, and there was no difference in the incidence of late RT
toxicity between the three treatment arms.
Sequential chemotherapy (GC RT or PF RT) treatment options can be problematic, for example, they require
longer courses of treatment and are associated with more
blood-related side effects. Therefore, factors such as age and
physical tness levels need to be taken into account. The RT
method used in our study was conventional. Recently, Xiayun
et al.13 reported the use of a combination of GC chemotherapy and IMRT for locoregionally advanced NPC, with
encouraging outcomes. An understanding of how to combine
the GC program with IMRT, and how to improve outcome
in NPC, while at the same time reducing the toxicity of RT
and chemotherapy, needs further research.
This is the rst study to conrm that chemoradiotherapy
with a GC regimen is superior to the regimen of Con-RT
plus adjuvant PF chemotherapy, in terms of DMFS, DFS and
OS, in patients with advanced NPCs. However, patients
treated with sGC-RT regimen suffer more side effects, particularly hematologic toxicity, constipation and rash.

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