Chinese Journal of Cancer

Original Article

Neoadjuvant chemotherapy followed by concurrent

chemoradiation for locally advanced nasopharyngeal
carcinoma
Lin Kong1, YouWang Zhang1, ChaoSu Hu1, Ye Guo2
1

Department of Radiation Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, P. R. China

Department of Medical Oncology,

Fudan University, Shanghai Cancer Center, Shanghai 200032, P. R. China

Abstract Background and Objective:

Methods:

Results:

Conclusions:

Key words:

Correspondence to: Lin Kong Tel: +8602164175590 Fax: +8602164174774

Email:konglinj@[Link]
This paper was translated from Chinese into English by
and edited by Hope J. Lafferty on20100312.
Received: 20090911 Accepted: 20100118

[Link]

Medical Translation

Nasopharyngeal carcinoma (NPC) is prevalent in Southeast

Asia. Radiotherapy can control early stage NPC effectively.
However, for patients with locoregionally advanced NPC, which
has higher rates of locoregional relapse and distant metastasis,
radiotherapy alone can only achieve a 5year survival rate of
about 50% . As a result, to improve the treatment efficacy for
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Chinese Journal of Cancer

locoregionally advanced NPC, various phase III clinical trials on
treatment modalities combining radiotherapy and chemotherapy
have been launched since the 1990s, and concurrent
chemoradiation therapy (CCRT) was finally defined as the
standard treatment strategy for patients with locoregionally
advanced NPC [16]. To improve treatment outcomes further,
neoadjuvant chemotherapy combined with CCRT gradually
became the focus of clinical research. Many phase III clinical
trials from western countries have proved that compared with the
PF [ciplatin (DDP) + 5fluorouracil (5Fu)] chemotherapy
regimen, neoadjuvant chemotherapy adding taxanes to the PF
regimen (TPF regimen) could significantly improve treatment
outcomes [79] for patients with head and neck squamous cell
carcinoma. However, there have not been any reports on the
TPF regimen applied to Chinese patients. Hence in early 2007,
investigators at Fudan University Shanghai Cancer Center
carried out 2 prospective phase II clinical trials on patients with
locoregionally advanced stageIII and IV (AB) NPC, to evaluate
the efficacy and safety of neoadjuvant chemotherapy of the TPF
regimen combined with CCRT. This paper will give a preliminary
report on the toxicity and shortterm treatment outcomes of this
treatment modality.

Patients that met the following criteria were enrolled: (1) age
> 18 years and < 70 years (2) pathology proven to be World
Health Organization (WHO) type II/III NPC (3) stage III/IV (AB)
according to the 2002 American Joint Committee on Cancer
(AJCC) staging criteria (4) no distant metastasis (5) expected
lifespan of at least 6 months (6) Karnofsky Performance Scale
(KPS) score was more than 70 (7) Neutrophil count > 2 109/L
and platelet count > 100 109 /L before treatment (8) Bilirubin <
1.5 mg/dL, AST/ALT < 2 times the upper limits of normal, serum
creatinine < 1.5 mg/dL, creatinine clearance rate > 50 mL/min
before treatment and (9) informed consent was signed before
treatment. A total of 52 patients with stageIII NPC and 64
patients with stageIV(AB) were planned to be enrolled.
Exclusion criteria included: pathology types that were not
WHO II/III NPC distant metastasis discovered by clinical or
imaging examination previous radiotherapy to the head and neck
region previous surgery in the primary tumor site or neck, except
for diagnostic biopsy history of malignant tumors or
simultaneous multiple tumors, except for basal cell carcinoma of
the skin a positive pregnancy test result for women of
reproductive age accompanying disease or status influencing the
normal enrollment of patients or safety during the research
active mental disorders or other mental disorders that influenced
the patient s signature on the informed consent or
comprehensibility uncontrolled active infections and participation
in other clinical research at the same time.
Patients received radiotherapy by threedimensional
conformal (3DCRT) or intensity modulated radiotherapy (IMRT)
552

techniques. Gross tumor volume (GTV) referred to tumor extent

found in clinical and imaging examinations, including primary
tumor (GTVP) and metastatic lymph nodes (GTVN). To ensure
that the pterygomaxillary fossa and areas of lymph node
drainage of the upper neck (retropharyngeal lymph nodes and
levels II, III, and Va) were included, clinical target volume (CTV)
consisted of a certain margin surrounding the GTV, the whole
nasopharynx cavity, the anterior one to twothirds of the clivus
(when invaded, the whole clivus should be covered), the skull
base, the pterygoid plates, the parapharyngeal space, the inferior
sphenoid sinus (the whole sphenoid sinus should be covered for
stages T3 and T4), the posterior onequarter to onethird of the
nasal cavity and the maxillary sinus. Level Ib was at high risk in
patients with metastatic lymph nodes in level IIa, and any lymph
node drainage pathways containing metastatic lymph nodes were
at high risk. Lowrisk CTV referred to levels IV and Vb without
metastatic cervical lymph nodes.
In 3DCRT, highrisk GTVP, GTVN, and CTV were given a
radiation dose of 60 Gy/30 fractions, followed by 1014 Gy/57
fractions to GTVP and 610 Gy/35 fractions to GTVN. Due to
the shortage of machine resources, most of the patients
receiving IMRT used a simplified IMRT technique to shorten the
radiation time in each fraction, with prescription doses of 70 Gy,
66.5/68.25 Gy, and 61.25 Gy (in 35 fractions) for highrisk
GTVP, GTVN, and CTV, respectively. Part of the patients were
given boost irradiation doses of 46 Gy/23 fractions to the
residual focus in the nasopharynx or the neck. CTV at low risk
was radiated by 54 Gy/30 fractions in the anteriorposterior fields.
All patients received neoadjuvant chemotherapy before
radiotherapy with the TPF regimen [docetaxel 75 mg/m2, day 1
cisplatin 75 mg/m2, day 1 5Fu 500 mg/ m2day , continuous
intravenous infusion (CIV) for 120 h], every 3 weeks for 3 cycles.
Dose titration of the neoadjuvant chemotherapy was the
following. Complete blood count, liver function, and renal function
were tested before each chemotherapy course, and only patients
with a qualifying index (see enrollment criteria) could proceed
with the next chemotherapy course. Chemotherapy was
postponed in patients with hematologic index disqualification. The
dosage of docetaxel was decreased by 20% with constant
cisplatin and 5Fu dosages if a grade IV hematology adverse
event or febrile neutropenia emerged in the former course. All of
the dosages of docetaxel, cisplatin, and 5Fu were decreased by
20% if more than grade III mucositis or diarrhea happened in the
former course. Concurrent chemoradiotherapy would be given
after 3 courses of neoadjuvant chemotherapy as planned.
Concurrent chemotherapy consisted of weekly cisplatin (40
mg/m2) during radiotherapy, with a maximum of 7 courses. Dose
adjustments of concurrent chemotherapy went as follows.
Complete blood count and serum biochemistry were tested
before each course of chemotherapy, and only patients with a
qualifying index (see enrollment criteria) could proceed with next
course. Chemotherapy at the full dose would be delivered strictly
according to the treatment protocol, and no adjustment would be
allowed under any situation. The chemotherapy time could be
postponed if neutropil < 2 109/L or platelets < 100 109/L .
Chemotherapy could be suspended if the creatinine clearance
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Chinese Journal of Cancer

rate < 50 mL/min.
Shortterm treatment outcomes were evaluated according to
physical examinations and magnetic resonance imaging (MRI) of
the head and neck after neoadjuvant chemotherapy and 3
months after radiotherapy. According to the Response Evaluation
Criteria in Solid Tumors
(RECIST), shortterm treatment
outcomes were divided into complete remission (CR), partial
remission (PR), stable disease (SD), and progressive disease
(PD). Adverse events were evaluated according to the latest
version of the National Cancer Institute s Common Terminology
Criteria for Adverse Events (NCI CTCAE 3.0).
SPSS16.0 was used for statistical analysis. Descriptive
statistics were used in summarizing the safety analysis. Survival
rates were calculated with the KaplanMeier method. Each
observation index was calculated from the commencement date
of the cancer treatment.

This study analyzed 59 patients who were followed for 3

Response

NP
PR
69.5%
3.4%

CR
25.4%
96.6%

After neoadjuvant chemotherapy

3 months after CCRT

months. The median followup time was 14.3 months (3.124.6

months). The median age was 44 years (2169 years). The
study included 46 men (78% ) and 13 women (22% ). The
number of patients with stageIII and stageIV(AB) disease were
30 (50.8%) and 29 (49.2%), respectively.
The effectiveness of neoadjuvant chemotherapy to the
primary tumor and cervical lymph nodes were 94.9% (CR rate
was 25.4% ) and 100% (CR rate was 19.6% ), respectively.
Shortterm treatment outcomes were evaluated 3 months after
treatment, and the efficacy and the CR rate of the primary tumor
rose to 100% and 96.6% , respectively, with the CR rate of
cervical lymph nodes rising to 90.2% (Table 1). Treatment failure
was observed in 5 patients during followup, including 1 patient
with lymph node relapse alone, 2 patients with distant metastasis
alone, 1 patient with primary tumor and cervical lymph node
relapse, and 1 patient with cervical lymph node relapse and
distant metastasis. Two patients died. The rates of 1year overall
survival
(Figure 1), distant metastasisfree survival, and
locoregional relapsefree survival were 100% , 95.7% , and
97.7%, respectively.
All patients completed at least 2 courses neoadjuvant

CR+PR
94.9%
100%

CR
19.6%
90.2%

LN
PR
80.4%
9.8%

CR+PR
100%
100%

CCRT, concurrent chemoradiation therapy.

100.00
80.00
60.00
40.00
20.00
0

5.00

Figure 1

10.00

15.00

20.00

Time (month)

25.00

30.00

course and 2 in the third course. The median course of

concurrent chemotherapy was 5 (17 courses). The number of
patients who finished at least 5 or 4 courses of concurrent
chemotherapy totaled 39 (66.1% ) and 50 (84.7% ), respectively.
The incidence of severe bone marrow suppression and
gastrointestinal reactions during neoadjuvant chemotherapy was
55.9% and 16.9% , respectively. The incidence of severe bone
marrow suppression and gastrointestinal reaction during
concurrent chemotherapy was 11.9% and 23.7% , respectively,
while the incidence of severe radiation dermatitis, mucositis, and
xerostomia were 6.8% , 44.1% , and 27.1% , respectively. No
severe liver or renal function damage was observed. No
treatmentrelated deaths occurred. Treatmentrelated adverse
events are detailed in Table 2.

Overall survival rate of patients with NPC

chemotherapy, and 51 (86.4% ) patients completed 3 courses.

Chemotherapy dosage was decreased in 14 (23.7% ) patients
due to adverse events, including 12 patients in the second

[Link]

Satisfactory treatment outcomes for patients with early stage

NPC can be achieved by radiotherapy alone, with the 5year
survival of 90% for patients with stageI disease, and 70% for
patients with stageII disease. However, treatment results for
patients with locoregionally advanced NPC have been
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Chinese Journal of Cancer

Event
Leukopenia
Neutropenia
Neutropenic fever
Thrombocytopenia
Anemia
Nausea/vomiting
Diarrhea
Liver dysfunction
Kidney dysfunction
Mucositis
Skin reaction
Xerostomia

During neoadjuvant chemotherapy acute adverse events ratio (%)

Grade 1
20.3
10.2
0
5.1
37.3
33.9
16.9
23.7
3.4
5.1
0
0

Grade 2
27.1
22.0
0
0
6.8
37.3
13.6
3.4
0
5.1
0
0

Grade 3
30.5
22.0
18.6
0
1.7
16.9
1.7
0
0
1.7
0
0

unsatisfactory, with the 5year survival rate around 35% for

patients with stageIV (A B) disease (AJCC staging criteria,
1997)[1012]. NPC cells are sensitive to chemotherapy. As a result,
oncologists have tried to combine chemotherapy to improve
treatment outcomes for patients with locoregionally advanced
NPC. After years of research, CCRT has recently become the
standard treatment for patients with locoregionally advanced
NPC [16].
For NPC patients with advanced N stages, especially those
with metastatic lymph nodes in level IV, the risk of distant
metastasis after treatment is far higher than locoregional relapse.
Neoadjuvant chemotherapy is an effective way to control
subclinical metastatic foci, and may be of great help in reducing
the rate of distant metastasis, and hence improving overall
survival. In patients with local large tumors or tumors close to
critical normal tissue such as the brain stem, it is usually hard to
deliver radiotherapy directly, and delivering full doses of radiation
to tumors is always restricted by surrounding normal tissue. If
tumors could shrink after neoadjuvant chemotherapy, it would
benefit the design and delivery of radiotherapy.
However, compared to concurrent chemotherapy, phase III
clinical trials have failed to prove that radiotherapy combined with
neoadjuvant chemotherapy could improve the survival rate of
patients with NPC with locoregionally advanced disease
compared with radiotherapy alone[1315]. However, metaanalyses
have shown that combined neoadjuvant chemotherapy could
significantly reduce the risks of locoregional relapse (RR, 0.74
95% CI, 0.600.91
= 0.005) and distant metastasis (RR,
0.67 95% CI, 0.540.83 = 0.0003)[16]. Recently, Chua
.[17] conducted a pooled analysis for 2 randomized clinical trials
that were similarly designed on neoadjuvant chemotherapy for
patients with NPC. They collected data of 784 enrolled patients,
reconstructed the database, and updated the followup results.
The results showed that combined neoadjuvant chemotherapy
brought down the rates of locoregional relapse ( = 0.037) and
distant metastasis ( = 0.088), and significantly improved the
rates of 5year relapsefree survival (50.9% vs. 42.7% ,
=
0.014) and diseaseassociated survival (63.5% vs. 58.1% , =
0.029). Nevertheless, there was not any improvement in overall
554

Grade 4
8.5
30.5
1.7
0
0
0
0
0
0
0
0
0

During CCRT acute adverse events ratio (%)

Grade 1
22.0
37.3
0
11.9
42.2
28.8
0
3.4
8.5
11.9
44.0
22.0

Grade 2
54.2
25.4
0
5.1
35.6
42.4
0
0
0
44.1
49.2
49.2

Grade 3
8.5
1.7
0
6.8
1.7
22.0
0
0
0
37.3
6.8
27.1

Grade 4
0
0
0
0
0
1.7
0
0
0
6.8
0
0

survival, with 5year survival being 61.9% and 58.1%, and 7year
survival being 57.2% and 48% , respectively. Neoadjuvant
chemotherapy could reduce the risk of locoregional relapse and
distant metastasis, but this could not be converted to the
improvement of overall survival. Insufficient intensity and
effectiveness of the chemotherapy agents or insufficient intensity
of the local treatment might be the cause. As a result, changing
to neoadjuvant chemotherapy regimens based on taxanes
combined with CCRT might improve treatment outcomes.
Various phase III clinical trials on other head and neck squamous
cell carcinomas besides NPC have proven that TPF was
significantly better than traditional PF regimens[79].
In recent years, various phase II clinical trials have been
conducted with patients with locoregionally advanced NPC to
evaluate treatment efficacy of neoadjuvant chemotherapy
combined with CCRT. All of them showed encouraging results,
and the 3year survival rates reached more than 70%[1823]. The
phase II randomized clinical trial reported by Hui
.[23] from
Hong Kong was the most representative one. Sixtyfive patients
with NPC were enrolled on this clinical trial and were randomly
assigned to receive CCRT alone (the control group) or
neoadjuvant chemotherapy combined with CCRT (the study
group). Neoadjuvant chemotherapy with the TPF regimen was as
follows: docetaxel 75 mg/m2, day 1 cisplatin 75 mg/m2, day 1,
every 3 weeks for 2 cycles. The concurrent chemotherapy was
as follows: weekly cisplatin 40 mg/m2 concurrent with
radiotherapy. Statistical results indicated that the rate of 3year
survival was significantly higher in the study group compared with
the control group (94.1% vs. 67.7% ,
= 0.012). Our study
adopted TPF as the neoadjuvant chemotherapy regimen
combined with CCRT for patients with locoregionally advanced
NPC, and also achieved good shortterm treatment results. Its
longterm outcome still awaits further followup to be confirmed.
The most common adverse events during neoadjuvant
chemotherapy based on taxanes was neutropenia, and the
incidence of severe neutropenia was 37 % 97 % , whereas the
incidence of febrile neutropenia was only 5.2%12.0%[79,23]. Although
neoadjuvant chemotherapy with higher treatment intensities were
used, it seems that no significantly increased adverse events
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Chinese Journal of Cancer

were observed during CCRT. In the study by Hui
. [23],
incidence of adverse events such as severe neutropenia (15.3%
vs. 26.4%, = 0.30) and mucocitis (7.7% vs. 23.5%, = 0.11)
in the control and study groups were similar. In the present
study, patients showed good tolerance and compliance to the
TPF neoadjuvant chemotherapy combined with CCRT. All the
patients finished at least 2 courses of neoadjuvant
chemotherapy, including 51 (86.4% ) patients who completed 3
courses. All patients received radiotherapy as planned, and
66.1% and 84.7% completed at least 5 or 4 courses concurrent
chemotherapy, respectively. The incidence of severe neutropenia
and febrile neutropenia caused by the TPF regimen was 52.5%
and 20.3%, respectively, which was lower than those reported by
Vermorken and Posner [8,9]. This might due to the relatively lower
dose of 5Fu in our study. The incidence of severe neutropenia,
radiation dermatitis, and mucocitis was 1.7% , 6.8%, and 44.1% ,
respectively. No treatment related death occurred.
The results of our study indicated that TPF as a neoadjuvant
chemotherapy regimen combined with CCRT for patients with
locoregionally advanced NPC had tolerable adverse events, good
compliance, and satisfying shortterm treatment efficacy.
Confirming its longterm outcome awaits further followup. The
taxanebased TPF neoadjuvant chemotherapy regimen combined
with CCRT is worth further research in the patients with
locoregionally advanced NPC.

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