Seminar
Nasopharyngeal carcinoma
Lancet 2016; 387: 1012–24
Published Online
August 28, 2015
http://dx.doi.org/10.1016/
S0140-6736(15)00055-0
Division of Radiation Oncology,
National Cancer Centre
Singapore, Singapore
(M L K Chua FRCR,
J T S Wee FRCR); Duke-NUS,
Graduate Medical School,
Singapore (M L K Chua,
J T S Wee); and State Key
Laboratory of Oncology in
South China, Sir Y K Pao Centre
for Cancer, Department of
Clinical Oncology, Hong Kong
Cancer Institute, The Chinese
University of Hong Kong,
Hong Kong, China (E P Hui FRCP,
Prof A T C Chan FRCP)
Correspondence to:
Dr Melvin L K Chua, Division of
Radiation Oncology, National
Cancer Centre Singapore,
11 Hospital Drive,
Singapore 169610, Singapore
melvin.chua.l.k@nccs.com.sg
See Online for appendix
1012
Melvin L K Chua, Joseph T S Wee, Edwin P Hui, Anthony T C Chan
Epidemiological trends during the past decade suggest that although incidence of nasopharyngeal carcinoma is
gradually declining, even in endemic regions, mortality from the disease has fallen substantially. This finding is
probably a result of a combination of lifestyle modification, population screening coupled with better imaging,
advances in radiotherapy, and effective systemic agents. In particular, intensity-modulated radiotherapy has driven
the improvement in tumour control and reduction in toxic effects in survivors. Clinical use of Epstein-Barr virus
(EBV) as a surrogate biomarker in nasopharyngeal carcinoma continues to increase, with quantitative assessment
of circulating EBV DNA used for population screening, prognostication, and disease surveillance. Randomised
trials are investigating the role of EBV DNA in stratification of patients for treatment intensification and
deintensification. Among the exciting developments in nasopharyngeal carcinoma, vascular endothelial growth
factor inhibition and novel immunotherapies targeted at immune checkpoint and EBV-specific tumour antigens
offer promising alternatives to patients with metastatic disease.
Introduction demographic trends, men are two to three times more
Nasopharyngeal carcinoma is a cancer arising from the likely to develop the disease than are women, and peak
nasopharynx epithelium. Within the boundaries of the age of disease occurrence is between 50 and 60 years. In
nasopharynx, the tumour epicentre is frequently seen at view of the heterogeneous epidemiological patterns, it is
the fossa of Rosenmüller, from where the tumour possible that other factors, not limited to genetic
invades adjacent anatomical spaces or organs. Despite susceptibility, are implicated in the pathogenesis of
being of a similar cell or tissue lineage, distinct nasopharyngeal carcinoma.
differences exist between nasopharyngeal carcinoma and
other epithelial tumours in the head and neck region. Pathology and risk factors
Compared with other cancer types, nasopharyngeal Morphologically, an abundance of lymphoid cells is often
carcinoma is uncommon, albeit with a very unique pattern seen intermixed with transformed epithelial cells, but
of geographical distribution. Worldwide, 86 500 cases nasopharyngeal carcinoma is widely regarded to be
of nasopharyngeal carcinoma were reported in 2012, squamous in origin. Depending on the degree of
accounting for only 0·6% of all cancers diagnosed in that differentiation, nasopharyngeal carcinoma is categorised
year. 71% of new cases were in east and southeast parts of into three pathological subtypes on the basis of WHO
Asia, with south-central Asia, and north and east Africa criteria. Differentiated tumours with surface keratin are
accounting for the remainder (appendix).1 defined as type I, whereas types II and III refer to
Besides geographical variation, some ethnic groups non-keratinising differentiated and undifferentiated
also seem to have a predisposition for nasopharyngeal tumours, respectively. In 1991, types II and III were
carcinoma—eg, the Bidayuh in Borneo, Nagas in combined into a single category of non-keratinising
northern India, and Inuits in the Artic, in whom carcinoma. The use of the numerical categorisation was
age-standardised incidence is reportedly higher than subsequently dropped, and a third category, the basaloid
16 per 100 000 person-years in men.2 In terms of squamous carcinoma, was added (figure).3 Each of these
definitions is also closely related to geographical
Search strategy and selection criteria distribution and epidemiological factors. In regions
We searched the PubMed and MEDLINE databases for articles where nasopharyngeal carcinoma is endemic, non-
published in English from Jan 1, 2000, to Dec 31, 2014, with keratinising subtypes constitute most cases (>95%)4,5 and
the keywords “nasopharyngeal carcinoma”, “epidemiology”, are invariably associated with Epstein-Barr virus (EBV)
“pathology”, “genetics”, “Epstein-Barr virus”, “human infection, whereas type I disease is more common in
papilloma virus”, “staging”, “imaging”, “functional magnetic other parts of the world.
resonance imaging”, “positron emission tomography”, EBV infection is perhaps the most extensively studied
“radiotherapy”, “intensity-modulated radiotherapy”, aetiological factor for nasopharyngeal carcinoma. On the
“adaptive radiotherapy”, “chemotherapy”, “salvage therapy”, basis of in-situ hybridisation techniques to EBV-encoded
“immunotherapy”, “clinical trials”, and “meta-analysis”. RNAs, the virus is detected exclusively in all tumour cells
Priority was given to large contemporary clinical trials or but not in normal nasopharyngeal epithelium, suggesting
studies in human beings. Selected references were judged on that EBV activation is necessary in the pathogenesis of
relevance and mainly consisted of publications from the past nasopharyngeal carcinoma. This notion is further
5 years, but did not exclude widely referenced and highly supported by reports that similar techniques undertaken
regarded older seminal work. Abstracts of recent pertinent on preinvasive lesions identified the presence of EBV even
medical conferences were also included for latest updates. during the initial phases of malignant transformation.6,7
Yet, the inability to detect EBV in nasopharyngeal biopsy
www.thelancet.com Vol 387 March 5, 2016

samples from high-risk individuals suggests that other
factors are needed for the EBV-infected epithelial cell to
undergo malignant transformation. Recent work has
proposed that deregulation of cell-cycle checkpoint
through p16 inactivation and cyclin D1 overexpression
promotes maintenance of the viral genome, favouring
transition of low-grade dysplasia to higher grade lesions.8,9
Intrinsic genetic determinants such as 3p and 9p deletions
have also been suggested as mechanisms of susceptibility
to EBV infection and its downstream effects.10 Epigenetic
modifications that are associated with a tumorigenic
phenotype have been identified in EBV-infected epithelial
cells and were shown to persist even in the absence of the
virus (appendix).11
Another viral cause for nasopharyngeal carcinoma
perhaps more associated with the non-endemic form is
human papillomavirus (HPV). Limited evidence on viral
epidemiology is available for HPV and nasopharyngeal
carcinoma because the non-endemic form has a low
prevalence worldwide. Nonetheless, small-scale studies
have suggested that HPV might be a contributing factor
in keratinising and even non-keratinising nasopharyngeal
carcinoma in white people.12–16 These studies also suggest
that EBV and HPV infection are nearly always mutually
exclusive. Prognosis differed between EBV-associated
and HPV-associated nasopharyngeal carcinoma; patients
with HPV-associated tumours had poorer survival and
local control, whereas distant failures were more
common with EBV-associated tumours.16 Nevertheless,
patients with non-viral-associated nasopharyngeal
carcinoma (ie, HPV-negative, EBV-negative tumours)
had worse outcomes than patients with viral-associated
tumours (table 1). Such findings lend further support to
the notion that non-viral-related oncogenic signalling
contributes to a more aggressive tumour phenotype, but
the exact underlying mechanisms remain elusive.
Apart from viruses, there is also substantial interest in
genetic susceptibility as a determinant of risk for
nasopharyngeal carcinoma in endemic regions. Studies
have mainly been small-scale case-control comparisons
reporting associations of genes involved in immune
responses, DNA repair, and metabolic pathways.17,18
Nonetheless, with the advent of high-throughput
whole-genome sequencing, genome-wide association
studies of large cohorts of patients with nasopharyngeal
carcinoma and high-risk individuals have now identified
a susceptibility locus within the MHC region of
chromosome 6p21 that codes for the HLA genes (HLA-A,
HLA-B, HLA-C, HLA-DQ, HLA-DR, HLA-F).19–24 Other
non-HLA susceptibility loci that were also identified from
genome-wide association studies were GABBR1 (on
chromosome 6p21), HCG9 (6p21), TNFRSF19 (13q12),
MECOM (3q26), and CDKN2A and CDKN2B (9p21).19,20
Additionally, a systematic review of 83 related studies
further highlighted the relevance of a few other genes
involved in DNA repair (RAD51L1), cell-cycle checkpoint
regulation (MDM2, TP53), and cell adhesion and
www.thelancet.com Vol 387 March 5, 2016
Seminar
A B
C D
Figure: Light microscopic appearance of nasopharyngeal carcinoma
(A) Keratinising squamous cell carcinoma; haematoxylin and eosin (H&E) stain, magnification 200×. (B) Non-
keratinising carcinoma, differentiated subtype; H&E stain, magnification 400×. (C) Non-keratinising carcinoma,
undifferentiated subtype; H&E stain, magnification 400×. (D) Detection of Epstein-Barr virus-encoded small RNA
by in-situ hybridisation.
Epidemiology Overall survival Local control Distant
metastasis-
free survival
HPV-negative/EBV-positive Endemic regions Most superior Most superior Lowest
HPV-positive/EBV-negative Non-endemic regions Moderate Moderate Moderate
HPV-negative/EBV-negative Non-endemic regions Lowest Lowest Moderate
HPV=human papillomavirus. EBV=Epstein-Barr virus.
Table 1: Characteristics of the different types of viral-associated nasopharyngeal carcinoma
migration (MMP2).18 Among them, the DNA double-strand
break repair pathway has been validated in a cohort
of 2349 individuals from Hong Kong as a potential
determinant of nasopharyngeal carcinoma risk.25
Large-scale epidemiological studies have proposed
associations between several dietary and social practices
and an increased risk of nasopharyngeal carcinoma.
Most notably, a history of salted fish consumption has
been reported to be common in patients with
nasopharyngeal carcinoma.26 Specifically, N-nitrosamine
is believed to be the associated carcinogen, and long-term
exposure is associated with a two-fold increase in risk of
developing the disease. Other risk factors are
consumption of preserved foods, herbal teas, slow-cooked
soups, and alcohol, and smoking habits; however, such
links were often inconsistent between studies, and even
when present, were weaker than that seen for salted fish.
In a proof-of-concept study, exposure of cells to nicotine
in vitro promoted EBV replication and expression of its
lytic gene products.27
1013
 Seminar
Population screening in endemic areas
In view of the prevalence of nasopharyngeal carcinoma
in southern China, population screening presents an
attractive strategy for early diagnosis and, consequently,
better outcomes. Immunoserology (IgA antibodies
against EBV capsid antigen [VCA-IgA], early antigen
[EA-IgA], EBV nuclear antigen 1 [EBNA1-IgA], and
EBV-specific DNase antibodies) and EBV DNA-based
screening methods have been studied. From the early
studies consisting of case-control and prospective
testing, immunoseropositivity is estimated to be
predictive of nasopharyngeal carcinoma susceptibility
after a year, and detection sensitivity is enhanced when
combining a panel of markers (appendix).28
Nonetheless, false-positive rates of 2–18% have been
reported with serological testing alone.29 A promising
method to reduce false-positive rates could entail use of a
confirmatory non-invasive test after positive serology. In a
study that incorporated this strategy, the combination of
serum VCA-IgA antibody and circulating EBV DNA had
an overall sensitivity (defined as positive result of either
marker) of 99%, but EBV DNA accurately identified 75%
of false-positive VCA-IgA-detected cases.30 A large-scale
prospective screening study (NCT02063399) for
nasopharyngeal carcinoma with use of plasma EBV DNA
is in progress and plans to recruit almost 20 000 healthy
men aged between 40 and 60 years (appendix).
Symptoms and diagnosis
Clinical presentation of nasopharyngeal carcinoma is
correlated with the extent of primary and nodal disease.
Possible routes of primary tumour invasion are anterior
spread into the nasal cavity, pterygoid fossa, and maxillary
sinuses; lateral involvement beyond the pharyngobasilar
fascia into the parapharyngeal and infratemporal spaces;
and base of skull, clivus, and intracranial structures when
the disease extends posteriorly and superiorly. Hence,
depending on the anatomical structures affected, clinical
presentation varies accordingly, ranging from non-specific
symptoms of epistaxis, unilateral nasal obstruction, and
auditory complaints to cranial nerve palsies (cranial nerves
third, fifth, sixth, and 12th being most affected). Nodal
metastasis in the neck is a frequent clinical finding
in nasopharyngeal carcinoma, occurring in roughly
three-quarters of all patients. Retropharyngeal and level 2
neck nodes are typically the first and second echelons of
spread, respectively, and skipped metastasis does not
usually occur in the lower neck in the absence of disease at
the upper nodal stations.31
Nasendoscopy is routine in eliciting a tumour in the
nasopharynx. Biopsy samples are obtained for pathological
diagnosis, and in the rare instance when no tumour is
visible, blind or radiology-guided targeted biopsies, or
both, are done if the index of suspicion is high. Differential
diagnoses of a malignant tumour in the nasopharynx are
lymphoma, extramedullary plasmacytoma, melanoma,
rhabdomyosarcoma, and adenoid cystic carcinoma.
1014
Benign condition-like tuberculosis of the nasopharynx
could also present with a similar range of symptoms, and
ought to be considered in immunocompromised
individuals. Characteristic histological features constitute
the microscopic morphology of nasopharyngeal
carcinoma, but at times, distinguishing between the
undifferentiated subtype and lymphoma might be difficult.
In such instances, immunohistochemical markers specific
to individual tumour types (leucocyte common antigen,
lymphoma; S100, melanoma; MNF116, a pancytokeratin
marker) and in-situ hybridisation to EBV-encoded RNAs
can supplement haematoxylin and eosin staining. Other
useful investigations for confirming a diagnosis of naso-
pharyngeal carcinoma are quantitative assessments of
plasma immunoserology and EBV DNA.32,33
Staging and prognosis
Nasopharyngeal carcinoma is classified by the joint Union
for International Cancer Control TNM Classification of
Malignant Tumours and the American Joint Committee
on Cancer staging system. This classification system was
updated in 2009 and introduced several modifications
to the staging of primary and nodal disease for the
seventh edition (appendix).34
Besides tumour burden as reflected by the TNM stage
classification, other clinical and molecular prognostic
variables have also been proposed. A history of smoking,
low-penetrance allelic variation of DNA repair genes,
overexpression of serglycin and p53, chromatin
modification, ERBB-PI3K signalling, and raised plasma
EBV DNA are among some highlighted determinants of
prognosis.35–39 Notably, quantification of plasma EBV DNA
before treatment has been shown to independently predict
for odds of recurrence and survival, complementing the
TNM stage classification.40,41 Large cohort studies have
further qualified that strength of prognostication with
EBV DNA is enhanced when combined with other
unrelated biomarkers such as fibrinogen, plasma D-dimer,
and C-reactive protein.42–44
Imaging studies
Optimum imaging is crucial for staging and radiotherapy
planning of nasopharyngeal carcinoma. MRI provides
better resolution than CT in terms of assessing
parapharyngeal spaces, marrow infiltration of the skull
base, intracranial disease, and deep cervical nodes. The
advent of functional MRI adds a biological dimension.
Parameters of cellularity (diffusion) and perfusion have
been correlated to clinical stage of nasopharyngeal
carcinoma.45 Likewise, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)-
PET provides metabolic parameters (maximum
standardised uptake value and total lesion glycolysis) that
could be interpreted to represent tumour biology and
predict clinical outcomes.46,47 It is also sensitive and
accurate for the detection of nodal metastasis, but lacks
the soft-tissue resolution of MRI for assessment of
primary tumour.48,49
www.thelancet.com Vol 387 March 5, 2016

In terms of distant metastasis staging, several studies
have concluded that ¹⁸F-FDG-PET is substantially more
sensitive (70–80% vs about 30%) and accurate (>90% vs
83–88%) than conventional work-up consisting of chest
radiography, abdominal ultrasound, and skeletal
scintigraphy.50,51 In the assessment of bone metastasis,
also the most common site of distant spread, a direct
comparison between ¹⁸F-FDG-PET and skeletal
scintigraphy showed that ¹⁸F-FDG-PET is substantially
more sensitive with similar specificity. Thus, MRI and
¹⁸F-FDG-PET are recommended as the preferred
modalities for staging in patients with TNM stage III,
IVA, or IVB nasopharyngeal carcinoma, or raised plasma
EBV DNA load of 4000 copies per mL or more.52
Radiotherapy in the management of
nasopharyngeal carcinoma
Radiotherapy is the primary and only curative treatment
for nasopharyngeal carcinoma. In centres where modern
radiation technology is available, intensity-modulated
radiotherapy (IMRT) is the preferred method. Briefly,
this technique caters for delivery of tumoricidal doses to
gross tumour and subclinical disease, while minimising
doses to adjacent normal tissues. Such a technology is
particularly advantageous in nasopharyngeal carcinoma,
in view of the late toxic effects reported in patients
treated with crude two-dimensional (2D) radiotherapy
techniques (appendix).53
The recent improvement in disease control and survival
in patients with nasopharyngeal carcinoma is partly
attributable to IMRT. Early studies by independent
groups reported 3-year local control and survival rates of
80–90%, even for advanced stages.54,55 In a randomised
study by Peng and colleagues,56 IMRT contributed to an
absolute improvement in 5-year locoregional control of
7·7% compared with conventional 2D radiotherapy.
Additionally, a review of 1593 patients who were treated
at a single institution with progressive radiotherapy
techniques (2D radiotherapy, 3D radiotherapy, and
IMRT) over two decades (1994 to 2010) also showed
increased disease-specific and overall survival in
individuals who received IMRT (disease-specific survival:
85% with IMRT vs 81% with 3D radiotherapy vs 78% with
2D radiotherapy; overall survival: 80% with IMRT vs 73%
with 3D radiotherapy vs 71% with 2D radiotherapy;
appendix).57
The clinical yield of modifying fraction size (hyper-
fractionation) and overall treatment time (acceleration)
in patients with nasopharyngeal carcinoma is uncertain.
Early studies testing a hyperfractionated, twice-daily
regimen did not show a benefit in tumour control, and
even more concerning, reported increased incidences
of late effects compared with conventionally
fractionationated radiotherapy.58,59 Nonetheless, two other
prospective trials did suggest efficacy with altered
fractionation schedules. Pan and colleagues60 showed
that a hyperfractionated radiotherapy regimen resulted
www.thelancet.com Vol 387 March 5, 2016
Seminar
in absolute improvements of 11·7% in locoregional
control and 16·1% in overall survival at 5 years, without
incurring incremental late neurological toxic effects,
compared with conventionally fractionated radiotherapy.
The NPC-9902 trial compared an accelerated regimen of
six times a week with conventional fractionation, with or
without concurrent chemotherapy, in patients with
T3–4N0–1 nasopharyngeal carcinoma.61 Although
concurrent chemotherapy and accelerated fractionation
reduced the risk of treatment failure compared with
conventionally fractionated radiotherapy alone (hazard
ratio [HR] for failure-free survival 0·35, 95% CI
0·14–0·84), neither accelerated radiotherapy alone nor
the combination of chemotherapy plus conventional
radiotherapy improved outcomes compared with the
control group. Since concurrent chemoradiotherapy is
the established standard treatment of locally advanced
nasopharyngeal carcinoma, the findings of the NPC-9902
trial are certainly peculiar and the question remains
whether altered fractionation improves the therapeutic
ratio over and above combination chemotherapy. The
NPC-0501 trial was a study designed in part to address
this clinical conundrum.62 Preliminary results suggest
that accelerated radiotherapy fractionation provides no
therapeutic benefit in patients with advanced disease
receiving concurrent systemic treatment compared with
conventional fractionation (HR for progression-free
survival 1·13, 95% CI 0·82–1·54; appendix).
Chemotherapy in non-metastatic disease
The strategy of combining chemotherapy with radio-
therapy is another pivotal advancement in the treatment
of locally advanced nasopharyngeal carcinoma. Since the
publication of the seminal INT-0099 trial, several trials
have substantiated the benefits in disease control and
survival reported with chemoradiotherapy, henceforth
establishing this treatment as the standard of care in this
subgroup (table 2).63–71 Combination regimens varied
between studies, but for the most part, cisplatin was the
chemotherapy of choice. In terms of dosing schedules,
either 30–40 mg/m² once a week or 100 mg/m² every
3 weeks is accepted practice; however, these schedules
were never prospectively compared. Nonetheless, any
differences in radiosensitisation effects and toxic effects
profiles between dosing schedules are likely to be
negligible relative to the importance of cisplatin dose
intensity, for which 200 mg/m² is the threshold for
optimum efficacy.72–74 Other concurrent agents with similar
efficacy to cisplatin are uracil plus tegafur (a prodrug of
fluorouracil) and oxaliplatin.69,70 Overall, meta-analyses
examining the effects of chemoradiotherapy in
nasopharyngeal carcinoma have consistently generated
HR estimates of 0·64–0·79 for overall survival, 0·67–0·71
for distant metastasis-free survival, and 0·59–0·73 for
locoregional control in favour of chemoradiotherapy over
radiotherapy alone.75–77 For TNM stage II nasopharyngeal
carcinoma, Chen and colleagues71 reported a benefit in
1015
 Seminar

Chemotherapy Number Overall survival Progression-free survival Distant metastasis-free Locoregional control
of survival
patients
Chemotherapy HR (95% CI); Chemotherapy HR (95% CI); Chemotherapy HR (95% CI); Chemotherapy HR (95% CI);
vs radiotherapy p value vs radiotherapy p value vs radiotherapy p value vs radiotherapy p value
Concomitant and adjuvant chemotherapy
Al-Sarraf et al63 Concurrent cisplatin, 147 67% vs 37% NR; 58% vs 29% NR; NR NR NR NR
adjuvant cisplatin plus p=0·001 p<0·001
fluorouracil
Wee et al64 Concurrent cisplatin, 221 67% vs 49% 0·60 59% vs 46% 0·67 55% vs 45% NR; NR NR
adjuvant cisplatin plus (0·41–0·87); (0·46–0·97); p=0·0013
fluorouracil p=0·0077 p=0·032
Lee et al65 Concurrent cisplatin, 348 68% vs 64% 0·81 62% vs 53% 0·72 74% vs 68% 0·82 88% vs 78% 0·45
adjuvant cisplatin plus (0·58–1·13); (0·53–0·98); (0·56–1·21); (0·25–0·79);
fluorouracil p=0·22 p=0·035 p=0·32 p=0·005
Chen et al66 Concurrent cisplatin, 316 72% vs 62% 0·69 68% vs 57% 0·65 80% vs 71% 0·65 89% vs 85% 0·59
adjuvant cisplatin plus (0·48–0·99); (0·46–0·92); (0·42–1·02); (0·31–1·14);
fluorouracil p=0·043 p=0·015 p=0·058 p=0·112
Concomitant chemotherapy only
Lin et al67 Cisplatin plus fluorouracil 284 72% vs 54% NR; 72% vs 53% NR; 79% vs 70% NR; 90% vs 73% NR;
p=0·0022 p=0·0012 p=0·0577 p=0·0009
Chan et al68 Cisplatin 350 70% vs 59% 0·71 60% vs 52%* 0·74 62% vs 48%* 0·65 80% vs 50% 0·45
(0·5–1·0); (0·54–1·0); (0·37–1·2); (0·21–1·0);
p=0·049 p=0·06 p=0·15 p=0·051
Kwong et al69 Uracil plus tegafur 219 81% vs 73% NR; 68% vs 54% NR; 84% vs 71% NR; 78% vs 71% NR;
p=0·075 p=0·038 p=0·02 p=0·22
Wu et al70 Oxaliplatin 115 73% vs 60% 0·54 NR NR 75% vs 63% 0·52 78% vs 75% 0·61
(0·31–0·94); (0·29–0·94); (0·29–1·29);
p=0·028 p=0·027 p=0·190
Chen et al71† Cisplatin 230 95% vs 86% 0·30 88% vs 78% 0·45 95% vs 84% 0·27 93% vs 91% 0·61
(0·12–0·76); (0·23–0·88); (0·10–0·74); (0·25–1·51);
p=0·007 p=0·017 p=0·007 p=0·29

NR=not reported. *Approximate values. †Trial in patients with stage II nasopharyngeal carcinoma.

Table 2: Phase 3 trials of concomitant chemoradiotherapy versus radiotherapy alone (5-year results)

overall survival with chemoradiotherapy compared with
radiotherapy alone mainly through improvement in
distant failures. Nonetheless, because local control
remains excellent with radiotherapy alone in this
subgroup, some centres prefer to restrict
chemoradiotherapy to individuals with a presumed high
risk of distant metastasis (single or unilateral bulky
node[s] 4–6 cm or EBV DNA >4000 copies per mL).
Part of the current controversy around supportive
evidence for combination treatment relates to the roles
of induction and adjuvant chemotherapy. Regarding
adjuvant chemotherapy, it typically consisted of cisplatin
(20 mg/m² daily for 4 days) and fluorouracil (1 g/m²
daily for 4 days) given every 4 weeks for three cycles.
Trends seen in specific trials of adjuvant chemotherapy
showed that additional treatment after radiotherapy was
poorly tolerated, with 55–75% compliance at best.63–65,71
Compounding the clinical dilemma, several trials
designed specifically to investigate the benefits of
adjuvant treatment largely did not show a survival
advantage.69,78 These results contradict the findings of
other retrospective analyses that suggested an
improvement in survival and reduction of distant
metastasis when two or more cycles of adjuvant
chemotherapy were delivered.73,79 Notably, in the trial by
Chen and colleagues,78 despite selecting for patients
who were at risk of developing distant metastasis
(defined as clinical presentation of T3–4N1 or N2–3
disease), the results of preliminary analyses after a
median follow-up of 37·8 months suggested similar
clinical endpoints irrespective of treatment assignment
(2-year outcomes for chemoradiotherapy vs
chemoradiotherapy plus adjuvant chemotherapy,
failure-free survival 84% vs 86%; distant metastasis-free
survival 86% vs 88%; overall survival 92% vs 94%).
While we await long-term results, further evidence
regarding the effectiveness of adjuvant chemotherapy
can be inferred from published meta-analyses.
Independent pooled analyses of chemoradiotherapy
trials based on whether adjuvant chemotherapy was
incorporated in the test group suggested similar benefits
in overall survival with either approach compared with
radiotherapy (HR 0·66–0·80 for chemoradiotherapy;
0·64–0·83 for chemoradiotherapy with adjuvant).75–77
However, an updated network meta-analysis reported a
favourable trend for overall survival (HR 0·84, 95% CI
0·67–1·03) and distant failure-free survival (HR 0·90,
0·69–1·17), and a significant advantage in terms of

1016 www.thelancet.com Vol 387 March 5, 2016

 Seminar

Registry Control regimen Experimental regimen Sample Overall survival Progression-free survival
identifier (chemoradiotherapy (induction chemotherapy size
regimen) regimen)
Control vs HR (95% CI); Control vs HR (95% CI);
experimental p value experimental p value
Randomised phase 2 with results
Hui et al81 NCT00436293 Cisplatin 40 mg/m² × 8 Cisplatin 75 mg/m² on 68 67·7% vs 94·1% 0·24 59·5% vs 88·2% 0·49
day 1 every 3 weeks × 2; (0·078–0·73); (0·20–1·19);
docetaxel 75 mg/m² on p=0·012 p=0·12
day 1 every 3 weeks × 2
Fountzilas et al82 ACTRN Cisplatin 40 mg/m² × 8 Epirubicin 75 mg/m² on 141 71·8% vs 66·6% 0·95 63·5% vs 64·5% 1·40
12609000730202 day 1 every 3 weeks × 3; (0·48–1·89); (0·71–2·77);
paclitaxel 175 mg/m² on p=0·888 p=0·334
day 1 every 3 weeks × 3;
cisplatin 75 mg/m² on
day 1 every 3 weeks × 3
Phase 3 with results
Tan et al83 NCT00997906 Cisplatin 40 mg/m² × 8 Gemcitabine 1000 mg/m² 172 92·3% vs 94·3% 1·05 67·4% vs 74·9% 0·77
on days 1 and 8 every (0–2·19); (0·44–1·35);
3 weeks × 3; carboplatin p=0·494 p=0·362
AUC 2·5 m² on days 1 and
8 every 3 weeks × 3;
paclitaxel 70 mg/m² on
days 1 and 8 every
3 weeks × 3
Lee et al62 NCT00379262 Cisplatin 100 mg/m² × 3 Cisplatin 100 mg/m² on 321 83% vs 85% 0·76 75·0% vs 79·0% 0·82
plus adjuvant cisplatin day 1 every 3 weeks × 3; (706)* (0·48–1·19); (0·57–1·19);
80 mg/m² on day 1 fluorouracil 1000 mg/m² p=0·23 p=0·29
every 4 weeks × 3; for 120 h every 3 weeks × 3
fluorouracil
1000 mg/m² for 96 h
every 4 weeks × 3
Phase 3 completed
Ma et al NCT01245959 Cisplatin 100 mg/m² ×3 Docetaxel 60 mg/m² on 476 ·· ·· ·· ··
day 1 every 3 weeks × 3;
cisplatin 60 mg/m² on
day 1 every 3 weeks × 3;
fluorouracil 600 mg/m²
on days 1–5 every
3 weeks × 3
Hong et al NCT00201396 Cisplatin every week MEPFL (mitomycin, 480 ·· ·· ·· ··
epirubicin, cisplatin,
fluorouracil, leucovorin)
Daoud et al NCT00828386 Cisplatin 40 mg/m² × 7 Docetaxel 75 mg/m² on 83 ·· ·· ·· ··
day 1 every 3 weeks × 3;
cisplatin 75 mg/m² on
day 1 every 3 weeks × 3;
fluorouracil 750 mg/m²
on days 1–5 every
3 weeks × 3
Phase 3 in progress
Hong et al NCT00705627 Cisplatin 80 mg/m² × 3 Cisplatin 80 mg/m² on 400 ·· ·· ·· ··
day 1 every 3 weeks × 2;
fluorouracil 4000 mg/m²
for 120 h every 3 weeks × 2
Ma et al NCT01872962 Cisplatin 100 mg/m² × 3 Cisplatin 80 mg/m² on 476 ·· ·· ·· ··
day 1 every 3 weeks × 3;
gemcitabine 1000 mg/m²
on days 1 and 8 every
3 weeks × 3

NCT=ClinicalTrials.gov identifier. ACTRN=Australian New Zealand Clinical Trials Registry. AUC=area under the concentration–time curve. *321 patients in arms 1A and 2A; 706 patients in whole trial.

Table 3: Randomised trials of concurrent cisplatin chemoradiotherapy with or without induction chemotherapy (3-year results)

www.thelancet.com Vol 387 March 5, 2016 1017

 Seminar
locoregional failure-free survival (HR 0·67, 0·46–0·95)
with chemoradiotherapy followed by adjuvant
chemotherapy compared with chemoradiotherapy
alone.80 The probabilities for being ranked as the most
effective treatment for overall survival were 84% for
chemoradiotherapy followed by adjuvant chemotherapy
and 3% for chemoradiotherapy alone. None of the meta-
analyses included the latest trials from Singapore
(NCT00997906) and Guangzhou (NCT01245959), which
adopted chemoradiotherapy alone as the standard
treatment (table 3).
Induction chemotherapy was once thought to be a
potentially more feasible and effective strategy of
treatment intensification than adjuvant sequencing.
However, early phase 3 studies assessing various
combinations of induction chemotherapy before
radiotherapy alone have mostly been inconclusive.
Generally, despite suggestions of better disease control,
none of the studies actually reported an improvement
in overall survival, although a combined exploratory
analysis of the Asian Oceania Clinical Oncology
Association (AOCOA) and Guangzhou trials did later
report a benefit in survival and distant failures in patients
with T1–2N0–1 disease.84 Interest, however, was
subsequently renewed after promising reports of 2-year
and 3-year overall survival of 71–95% from smaller
phase 2 studies that used induction chemotherapy and
chemoradiotherapy.81,85–88 In a randomised phase 2
comparison of chemoradiotherapy (cisplatin) with or
without induction cisplatin and docetaxel, Hui and
colleagues81 reported that 3-year progression-free survival
and overall survival was 88% and 94% in the experimental
group compared with 60% and 68% in the control group,
respectively. By contrast with these findings, a series of
randomised trials have yet to reproduce these favourable
results (table 3). Fountzilas and colleagues82 tested an
induction regimen consisting of epirubicin, cisplatin, and
paclitaxel, and reported no difference in response rates,
progression-free survival, and overall survival when the
triplet combination was added to chemoradiotherapy. Tan
and colleagues83 recently reported a phase 3 study of
172 patients with advanced nasopharyngeal carcinoma
and reported that locoregional control, distant metastasis-
free survival, and overall survival did not differ between
groups with the addition of induction gemcitabine,
carboplatin, and paclitaxel to chemoradiotherapy. Finally,
the six-arm NPC-0501 study (a 2 × 3 factorial study of
concurrent cisplatin and conventional or accelerated
radiotherapy, in combination with induction cisplatin
plus capecitabine, or induction cisplatin plus fluorouracil,
or adjuvant cisplatin plus fluorouracil) showed that overall
chemotherapy tolerance was similar between patients
who received induction or adjuvant chemotherapy, and
variation in sequencing of cisplatin and fluorouracil did
not achieve a statistically significant improvement in
progression-free survival and overall survival.62 In
summary, the role of induction chemotherapy in the
1018
management of locally advanced nasopharyngeal
carcinoma remains investigational, and current evidence
precludes its routine use in patients planned for
chemoradiotherapy.
A better patient stratification for treatment
intensification and deintensification is clearly needed. A
subgroup analysis of the Taiwanese chemoradiotherapy
trial showed that chemoradiotherapy was beneficial in
patients without high-risk features such as N3 or T4N2
disease or bulky nodal metastases (at least one node
>4 cm), whereas patients harbouring any of these disease
characteristics had poorer outcomes with chemo-
radiotherapy.89 These findings might be preliminary, but
they highlight the importance of improvising patient
stratification beyond the TNM staging system. The
incorporation of prognostic biomarkers is a potential
strategy. Two phase 3 trials are underway, in which
patients are randomly assigned to adjuvant regimens of
differing intensities depending on whether EBV DNA is
detectable after chemoradiotherapy (NRG-HN001,
NCT02135042; NPC-0502, NCT00370890). Findings that
persistent EBV DNA detection is strongly associated
with a high likelihood of tumour recurrence and poor
prognosis lend support to both trials.40,41,90–92
Coincidentally, a retrospective analysis from Taiwan
showed that in a cohort of 85 patients who had persistent
EBV DNA titres after radiation, adjuvant tegafur and
uracil substantially reduced distant failure and improved
survival (appendix).93
Disease surveillance and toxic effects
Initial post-treatment assessment entails monitoring of
acute effects and tumour response. Common acute
radiotherapy-related effects include mucositis, dysphagia,
dermatitis, and xerostomia. Clinical symptoms typically
improve within weeks after treatment cessation, but in
instances of grade 3 or 4 reactions, these can persist,
leading to consequential late effects. Chemoradiotherapy
is invariably associated with higher incidences of
haematological and non-haematological acute toxic
effects compared with radiotherapy alone.94,95 Unlike its
benefits in reducing late effects, IMRT seems to have a
limited role in mitigating acute toxic effects.
Pharmacological interventions for acute xerostomia and
mucositis are mostly ineffective, although studies have
suggested effective relief of mucositis with palifermin
(recombinant human keratinocyte growth factor) and
doxepin rinse (tricyclic antidepressant).96–98
Comprehensive assessment of tumour response
includes clinical examination, nasendoscopy with or
without biopsy, EBV DNA titre measurement, and
radiological imaging.99 Nasendoscopy is restricted to
assessing superficial lesions and a positive biopsy
sample 10 weeks after treatment has been shown to
probably represent persistent residual disease.100 For
deeper lesions within the skull base, radiological
assessment is necessary, but it might pose a challenge
www.thelancet.com Vol 387 March 5, 2016

when differentiating between post-radiotherapy changes
and residual tumour. In this regard, ¹⁸F-FDG-PET is the
most sensitive and specific method compared with CT
and MRI.101,102 Nonetheless, diffusion and perfusion
characteristics derived on MRI have the potential for
assessing early treatment response, residual disease,
and post-treatment fibrosis.103–105
Surveillance for late effects is an important
component in the follow-up of nasopharyngeal
carcinoma survivors. These effects include neurological
symptoms, such as temporal lobe injury, cranial
neuropathies, Lhermitte’s syndrome, and brachial
plexopathy, as well as non-neurological effects, such as
auditory and visual complications, soft-tissue fibrosis,
feeding difficulties, xerostomia, and endocrinopathies
related to thyroid and pituitary dysfunction. An excess
incidence of carotid artery stenosis probably pertaining
to irradiation of the neck has also been reported in
some series.106,107
Circulating cell-free EBV DNA
In addition to its role as a prognostic biomarker in
nasopharyngeal carcinoma, the clinical use of plasma
cell-free EBV DNA extends to screening and surveillance
of the disease. Quantitative response of plasma EBV
DNA to treatment has been investigated for surveillance,
prognostic risk assessment, and, possibly, treatment
stratification. Several reports have now confirmed that
persistent EBV DNA detection after definitive
radiotherapy is associated with an increased likelihood
of tumour recurrence and adverse prognosis.40,41,90,91
Leung and colleagues92 presented evidence that a
biomarker response elicited as early as midway (4 weeks)
into treatment was significantly predictive of distant
relapses (HR for detectable EBV DNA 12·02, 95% CI
2·78–51·93) and poorer overall survival (HR 3·29,
1·37–7·90). Additionally, EBV DNA can be introduced
as a surveillance method for local and distant relapses,
complementing conventional imaging.99 The sensitivity
of this assay in early detection of failures, particularly
distant metastasis, offers the potential for aggressive
salvage therapies in low-burden disease. Finally, the use
of EBV DNA for personalising cancer therapies is
being examined. An example would be the ongoing
NRG-HN001 trial, in which patients are randomly
assigned to adjuvant or no adjuvant chemotherapy if
EBV DNA is absent, or assigned to cisplatin plus
fluorouracil or gemcitabine plus paclitaxel if EBV DNA
is detectable. In an exploratory analysis of the induction
chemotherapy trial from Singapore (table 3), no
advantage with additional chemotherapy was seen in an
unselected cohort of patients with locally advanced
nasopharyngeal carcinoma; however, it was suggested
that individuals with baseline EBV DNA titres of more
than 6000 copies per mL might benefit, perhaps hinting
a role for EBV DNA in stratification of patients a priori
to treatment intensification.108–110
www.thelancet.com Vol 387 March 5, 2016
Seminar
Management of residual or recurrent disease
Local recurrences in the nasopharynx can be salvaged
with either surgery or radiotherapy. In principle, small
rT1–2 tumours are amenable to surgery, brachytherapy,
or stereotactic radiosurgery, whereas rT3–4 lesions are
best treated with external beam, preferably IMRT.
Generally, tumours that recur within a year are deemed
radioresistant, and surgery is recommended if resection
with adequate margins is feasible. In all cases, rightful
caution has to be accorded to repeat irradiation given
the risk of fatal late effects. Reports of patients who
were salvaged with IMRT attributed half of all mortality
to late effects.111,112 Other negative prognostic
determinants are age older than 50 years, rT3–4,
tumour volume more than 30 cm³, and synchronous
nodal recurrence (appendix).
Isolated neck failure occurs in less than 10% of patients
with contemporary treatment.113 In the unlikely event of
occurrence, surgical neck dissection is the preferred
choice for salvage, and is effective even for deep
retropharyngeal nodal metastasis.114
Management of distant metastasis
Treatment of patients with metastatic nasopharyngeal
carcinoma (stage IVC) has evolved, with a shift towards
personalised treatment for this group of patients.115
Foremost, it is acknowledged that outcomes of patients
with metastatic nasopharyngeal carcinoma are hetero-
geneous and long-term survivorship is possible.
Stratification for these individuals can be done on the
basis of clinical characteristics such as lung alone
metastasis, oligometastasis, metachronous relapse, and
the absence of liver metastasis.116,117 Incorporation of
markers such as haemoglobin and lactate dehydrogenase
could also augment current prognostic models.118,119
In patients with such favourable features, there is
progressively a strong advocacy for a curative approach
involving radical chemoradiotherapy to the primary
tumour and ablative treatment to the oligometastasis.120,121
Platinum-containing doublet regimens continue to
feature as the standard first-line systemic treatment.
Cisplatin and fluorouracil have been the conventional
choices, achieving response rates of 70–80%.
Gemcitabine, capecitabine, paclitaxel, and docetaxel have
also been combined with cisplatin and yielded similar
responses. Intensification through triplet regimens has
not been more effective at the expense of substantial
toxic effects.122 These findings concur with those from a
single-institution retrospective review, which reported
that progression-free survival and overall survival were
similar irrespective of doublet or triplet platinum-
containing regimens.123 Docetaxel, capecitabine, and
gemcitabine monotherapy are suitable second-line
therapies in platinum-resistant disease, with reported
response rates of 30–40%.124–126 Doublet combinations
(gemcitabine plus vinorelbine, cisplatin plus pemetrexed)
have been investigated in this setting, but response rates
1019
 Seminar
and time to disease progression with these regimens are
no better than those obtained with monotherapy.127,128
Molecular-targeted therapies
Inhibition of epidermal growth factor receptor (EGFR) or
vascular endothelial growth factor (VEGF) has shown
clinical efficacy in patients with platinum-refractory
disease. In a phase 2 study of cetuximab (monoclonal
antibody against EGFR) in heavily pretreated patients
with stage IVC nasopharyngeal carcinoma, measurable
responses were recorded in 12% of individuals, with 48%
showing stable disease.129 Likewise, sunitinib (multiple
receptor tyrosine kinase inhibitor not limited to VEGF
receptor) had preclinical anti-angiogenic activity and
modest clinical efficacy in a heavily pretreated cohort of
patients with nasopharyngeal carcinoma.130,131 Other
agents targeted at VEGF that have shown potency in
preclinical models and have transitioned into phase 2
testing are pazopanib, famitinib, and axitinib. These
novel therapies yielded impressive disease control of
longer than 3 months in 30–70% of patients who had
received at least two lines of systemic agents.132–134
Panel: Controversies in management of nasopharyngeal
carcinoma and outstanding research questions
Management
• Should UICC/AJCC 7th edition stage II nasopharyngeal
carcinoma be managed by radiotherapy alone or
concurrent chemoradiotherapy?
• Should UICC/AJCC 7th edition stage III, IVA, or IVB
nasopharyngeal carcinoma be managed by concurrent
chemoradiotherapy alone or chemoradiotherapy plus
adjuvant or induction chemotherapy?
Outstanding research questions
• Is early (neonatal) or late EBV infection implicated in the
carcinogenic cascade?
• Who should be screened for nasopharyngeal carcinoma,
and how and at what age should this be done?
• What biological mechanisms underlie the “upward”
(T3–4N0–1) versus “downward” (T1–2N3) variants of
endemic nasopharyngeal carcinoma?
• What is the best possible concurrent chemotherapy
regimen, fluorouracil (analogue) or cisplatin (analogue)?
• Which patients with metastatic nasopharyngeal
carcinoma should receive definitive radiotherapy or
chemoradiotherapy?
• In metastatic nasopharyngeal carcinoma, what is the role
for metastasectomy or stereotactic ablative radiotherapy
in oligometastatic disease?
• What is the emerging role of immunotherapy in
nasopharyngeal carcinoma?
• What are the ways to exploit EBV DNA as a biomarker for
personalised treatment in nasopharyngeal carcinoma?
UICC=Union for International Cancer Control. AJCC=American Joint Committee on
Cancer. EBV=Epstein-Barr virus.
1020
A pertinent concern with VEGF inhibition relates to the
increased risk of bleeding. Thus, it is suggested that
patients who have disease recurrence within a previously
irradiated field or invading major vascular structure
should be excluded from trials of VEGF inhibitors.131,135
Immunotherapy
The consistent presence of EBV in nasopharyngeal
carcinoma cells opens up the possibility of exploiting the
immune T-cell system to target such cells through
recognition of expressed viral antigens (EBNA1, latent
membrane protein 1 [LMP1], and LMP2). Adoptive
transfer of LMP2-specific cytotoxic T lymphocytes and
dendritic cell-based vaccines to LMP2 epitopes are
examples of immunotherapies that have shown clinical
efficacy in heavily pretreated patients with
nasopharyngeal carcinoma.136–138 AdE1-LMPpoly is an
adenovirus vector-based polysaccharide vaccine that
encodes for the antigenic epitopes of EBNA1, LMP1, and
LMP2, and early clinical testing in patients with
recurrent or metastatic nasopharyngeal carcinoma has
shown high potency in rapid expansion of autologous
T cells.139 The NATELLA study is another phase 1 trial
investigating LMP1-specific and LMP2-specific cytotoxic
T lymphocytes in relapsed or refractory disease
(NCT00516087). MVA-EL is another promising
immunotherapeutic developed with the modified
vaccinia ankara (MVA) vector to encode a functionally
inactive fusion protein of full-length LMP2 and the
C-terminal half of EBNA1.140 A phase 1 dose escalation
trial of this vaccine showed substantial amplification of
EBNA1-specific or LMP2-specific T lymphocytes, or
both, with vaccination, and a dose response was noted
within the cohort.141 Similar findings were reported when
the study was coanalysed with a parallel UK trial.142 This
vaccine has since ascended into phase 2 testing as an
adjunct in patients who have residual EBV DNA load
after conventional therapy (NCT01094405).
Programmed death ligand 1 (PD-L1) expression is also
a characteristic feature of EBV-associated malignancies.143
A phase 2 multicentre clinical trial testing nivolumab
(anti-PD1) in recurrent or metastatic nasopharyngeal
carcinoma is in progress. If the study is positive, it will
support the strategy to combine non-antigen-specific
immune checkpoint inhibitors with immunogenic
vaccination against tumour-specific antigens, which
could be the standard treatment for metastatic
nasopharyngeal carcinoma in the future.
Conclusions and future directions
Epidemiological studies undertaken over the past few
decades continue to reveal a gradual but progressive
decline in the incidence of nasopharyngeal carcinoma,
and a substantial reduction in mortality.144,145 These trends
are probably a result of enhanced understanding in the
pathogenesis and risk factors of the disease, and the
biological mechanisms underlying the prognostic risk
www.thelancet.com Vol 387 March 5, 2016

stratification. Advances in treatment on all fronts
(radiotherapy and chemotherapy) also had a huge effect
on the improvement of clinical outcomes, resulting in
long-term survival in patients with nasopharyngeal
carcinoma. However, a few controversies with respect to
management remain unresolved in view of the
conflicting published evidence (panel), but hopefully
studies in progress will provide the necessary
conclusions. The next decade of research in
nasopharyngeal carcinoma will focus on refining existing
screening and treatment strategies, and the development
of novel therapeutics for patients with treatment-
refractory recurrent disease (panel).
Contributors
MLKC, JTSW, and ATCC were involved in conception of the manuscript.
MLKC, JTSW, EPH, and ATCC wrote and reviewed the original
manuscript. MLKC and JTSW revised the manuscript. MLKC, JTSW,
EPH, and ATCC approved the final manuscript.
Declaration of interests
ATCC has received clinical research funding from Bristol-Myers Squibb,
Boehringer Ingelheim, and Pfizer Oncology, outside the submitted
work. All other authors declare no competing interests.
Acknowledgments
We would like to thank Jacqueline Hwang, Department of Pathology,
Singapore General Hospital, Singapore, for providing the
photomicrographs in the figure.
References
1 Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0,
Cancer incidence and mortality worldwide: IARC CancerBase
No. 11. http://globocan.iarc.fr/Default.aspx (accessed Aug 25, 2015).
2 Wee JT, Ha TC, Loong SL, et al. Is nasopharyngeal cancer really a
“Cantonese cancer”? Chin J Cancer 2010; 29: 517–26.
3 Chan JKC, Bray F, McCarron P, et al. Nasopharyngeal carcinoma.
In: Barnes L, Eveson JW, Reichart P, et al, eds. WHO classification
of tumours. Pathology and genetics of head and neck tumours.
Lyon: IARC Press, 2005: 85–97.
4 Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;
365: 2041–54.
5 Nicholls JM. Nasopharyngeal carcinoma: classification and
histological appearances. Adv Anat Path 1997; 4: 71–84.
6 Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N.
Clonal proliferations of cells infected with Epstein-Barr virus in
preinvasive lesions related to nasopharyngeal carcinoma.
N Engl J Med 1995; 333: 693–98.
7 Chan AS, To KF, Lo KW, et al. High frequency of chromosome 3p
deletion in histologically normal nasopharyngeal epithelia from
southern Chinese. Cancer Res 2000; 60: 5365–70.
8 Lo KW, Chung GT, To KF. Deciphering the molecular genetic basis
of NPC through molecular, cytogenetic, and epigenetic approaches.
Semin Cancer Biol 2012; 22: 79–86.
9 Tsang CM, Yip YL, Lo KW, et al. Cyclin D1 overexpression supports
stable EBV infection in nasopharyngeal epithelial cells.
Proc Natl Acad Sci USA 2012; 109: E3473–82.
10 Young LS, Rickinson AB. Epstein-Barr virus: 40 years on.
Nat Rev Cancer 2004; 4: 757–68.
11 Birdwell CE, Queen KJ, Kilgore PC, et al. Genome-wide DNA
methylation as an epigenetic consequence of Epstein-Barr virus
infection of immortalized keratinocytes. J Virol 2014; 88: 11442–58.
12 Maxwell JH, Kumar B, Feng FY, et al. HPV-positive/p16-positive/
EBV-negative nasopharyngeal carcinoma in white North Americans.
Head Neck 2010; 32: 562–67.
13 Chan YH, Lo CM, Lau HY, Lam TH. Vertically transmitted
nasopharyngeal infection of the human papillomavirus: does it play
an aetiological role in nasopharyngeal cancer? Oral Oncol 2014;
50: 326–29.
14 Dogan S, Hedberg ML, Ferris RL, et al. Human papillomavirus and
Epstein-Barr virus in nasopharyngeal carcinoma in a low-incidence
population. Head Neck 2014; 36: 511–16.
www.thelancet.com Vol 387 March 5, 2016
Seminar
15 Lin Z, Khong B, Kwok S, et al. Human papillomavirus 16 detected
in nasopharyngeal carcinomas in white Americans but not in
endemic Southern Chinese patients. Head Neck 2014; 36: 709–14.
16 Stenmark MH, McHugh JB, Schipper M, et al. Nonendemic
HPV-positive nasopharyngeal carcinoma: association with poor
prognosis. Int J Radiat Oncol Biol Phys 2014; 88: 580–88.
17 Bei JX, Jia WH, Zeng YX. Familial and large-scale case-control
studies identify genes associated with nasopharyngeal carcinoma.
Semin Cancer Biol 2012; 22: 96–106.
18 Hildesheim A, Wang CP. Genetic predisposition factors and
nasopharyngeal carcinoma risk: a review of epidemiological
association studies, 2000–2011: Rosetta Stone for NPC: genetics,
viral infection, and other environmental factors. Semin Cancer Biol
2012; 22: 107–16.
19 Tse KP, Su WH, Chang KP, et al. Genome-wide association study
reveals multiple nasopharyngeal carcinoma-associated loci within
the HLA region at chromosome 6p21.3. Am J Hum Genet 2009;
85: 194–203.
20 Bei JX, Li Y, Jia WH, et al. A genome-wide association study of
nasopharyngeal carcinoma identifies three new susceptibility loci.
Nat Genet 2010; 42: 599–603.
21 Zhao M, Cai H, Li X, et al. Further evidence for the existence of
major susceptibility of nasopharyngeal carcinoma in the region
near HLA-A locus in Southern Chinese. J Transl Med 2012; 10: 57.
22 Tang M, Lautenberger JA, Gao X, et al. The principal genetic
determinants for nasopharyngeal carcinoma in China involve the
HLA class I antigen recognition groove. PLoS Genet 2012;
8: e1003103.
23 Hsu WL, Tse KP, Liang S, et al. Evaluation of human leukocyte
antigen-A (HLA-A), other non-HLA markers on chromosome
6p21 and risk of nasopharyngeal carcinoma. PLoS One 2012;
7: e42767.
24 Chin YM, Mushiroda T, Takahashi A, et al, and the Malaysian NPC
Study Group. HLA-A SNPs and amino acid variants are associated
with nasopharyngeal carcinoma in Malaysian Chinese. Int J Cancer
2015; 136: 678–87.
25 Yee Ko JM, Dai W, Wun Wong EH, et al. Multigene pathway-based
analyses identify nasopharyngeal carcinoma risk associations for
cumulative adverse effects of TERT-CLPTM1L and DNA
double-strand breaks repair. Int J Cancer 2014; 135: 1634–45.
26 Guo X, Johnson RC, Deng H, et al. Evaluation of nonviral risk
factors for nasopharyngeal carcinoma in a high-risk population of
southern China. Int J Cancer 2009; 124: 2942–47.
27 Xu FH, Xiong D, Xu YF, et al. An epidemiological and molecular
study of the relationship between smoking, risk of nasopharyngeal
carcinoma, and Epstein-Barr virus activation. J Natl Cancer Inst;
104: 1396–410.
28 Yu KJ, Hsu WL, Pfeiffer RM, et al. Prognostic utility of anti-EBV
antibody testing for defining NPC risk among individuals from
high-risk NPC families. Clin Cancer Res 2011; 17: 1906–14.
29 Cao SM, Liu Z, Jia WH, et al. Fluctuations of Epstein-Barr virus
serological antibodies and risk for nasopharyngeal carcinoma:
a prospective screening study with a 20-year follow-up. PLoS One
2011; 6: e19100.
30 Leung SF, Tam JS, Chan AT, et al. Improved accuracy of detection
of nasopharyngeal carcinoma by combined application of
circulating Epstein-Barr virus DNA and anti-Epstein-Barr viral
capsid antigen IgA antibody. Clin Chem 2004; 50: 339–45.
31 Tang L, Mao Y, Liu L, et al. The volume to be irradiated during
selective neck irradiation in nasopharyngeal carcinoma: analysis of
the spread patterns in lymph nodes by magnetic resonance
imaging. Cancer 2009; 115: 680–88.
32 Lo YM, Chan LY, Lo KW, et al. Quantitative analysis of cell-free
Epstein-Barr virus DNA in plasma of patients with nasopharyngeal
carcinoma. Cancer Res 1999; 59: 1188–91.
33 Shao JY, Li YH, Gao HY, et al. Comparison of plasma Epstein-Barr
virus (EBV) DNA levels and serum EBV immunoglobulin A/virus
capsid antigen antibody titers in patients with nasopharyngeal
carcinoma. Cancer 2004; 100: 1162–70.
34 Sobin LH, Gospodarowicz M, Wittekind C. 2010. Pharynx. TNM
Online 2010; 30–38.
35 Guo SS, Huang PY, Chen QY, et al. The impact of smoking on the
clinical outcome of locoregionally advanced nasopharyngeal
carcinoma after chemoradiotherapy. Radiat Oncol 2014; 9: 246.
1021
 Seminar
36 Jin H, Xie X, Wang H, et al. ERCC1 Cys8092Ala and XRCC1
Arg399Gln polymorphisms predict progression-free survival after
curative radiotherapy for nasopharyngeal carcinoma. PLoS One
2014; 9: e101256.
37 Chia CS, Ong WS, Li XJ, et al. Serglycin expression: an independent
marker of distant metastases in nasopharyngeal carcinoma.
Head Neck 2014; published online July 3. DOI:10.1002/hed.23841.
38 Lin DC, Meng X, Hazawa M, et al. The genomic landscape of
nasopharyngeal carcinoma. Nat Genet 2014; 46: 866–71.
39 Zhang P, Wu SK, Wang Y, et al. p53, MDM2, eIF4E and EGFR
expression in nasopharyngeal carcinoma and their correlation with
clinicopathological characteristics and prognosis: a retrospective
study. Oncol Lett 2015; 9: 113–18.
40 Lo YM, Chan LY, Chan AT, et al. Quantitative and temporal
correlation between circulating cell-free Epstein-Barr virus DNA
and tumor recurrence in nasopharyngeal carcinoma. Cancer Res
1999; 59: 5452–55.
41 Wang WY, Twu CW, Chen HH, et al. Long-term survival analysis of
nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA
levels. Cancer 2013; 119: 963–70.
42 Tang LQ, Chen QY, Guo SS, et al. The impact of plasma Epstein-Barr
virus DNA and fibrinogen on nasopharyngeal carcinoma prognosis:
an observational study. Br J Cancer 2014; 111: 1102–11.
43 Chen WH, Tang LQ, Wang FW, et al. Elevated levels of plasma
D-dimer predict a worse outcome in patients with nasopharyngeal
carcinoma. BMC Cancer 2014; 14: 583.
44 Tang LQ, Li CF, Chen QY, et al. High-sensitivity C-reactive protein
complements plasma Epstein-Barr virus deoxyribonucleic acid
prognostication in nasopharyngeal carcinoma: a large-scale
retrospective and prospective cohort study.
Int J Radiat Oncol Biol Phys 2015; 91: 325–36.
45 Lai V, Li X, Lee VH, et al. Nasopharyngeal carcinoma: comparison
of diffusion and perfusion characteristics between different tumour
stages using intravoxel incoherent motion MR imaging. Eur Radiol
2014; 24: 176–83.
46 Chang KP, Tsang NM, Liao CT, et al. Prognostic significance of
¹⁸F-FDG PET parameters and plasma Epstein-Barr virus DNA load
in patients with nasopharyngeal carcinoma. J Nucl Med 2012;
53: 21–28.
47 Yang Z, Shi Q, Zhang Y, et al. Pretreatment (18) F-FDG uptake
heterogeneity can predict survival in patients with locally advanced
nasopharyngeal carcinoma—a retrospective study. Radiat Oncol
2015; 10: 4.
48 Lim TC, Chua ML, Chia GS, et al. Comparison of MRI, CT and
¹⁸F-FDG-PET/CT for the detection of intracranial disease extension
in nasopharyngeal carcinoma. Head Neck Oncol 2012; 4: 49.
49 Vellayappan BA, Soon YY, Earnest A, et al. Accuracy of
(18)F-flurodeoxyglucose-positron emission tomography/computed
tomography in the staging of newly diagnosed nasopharyngeal
carcinoma: a systematic review and meta-analysis. Radiol Oncol
2014; 48: 331–38.
50 Chua ML, Ong SC, Wee JT, et al. Comparison of 4 modalities for
distant metastasis staging in endemic nasopharyngeal carcinoma.
Head Neck 2009; 31: 346–54.
51 Chang MC, Chen JH, Liang JA, et al. Accuracy of whole-body
FDG-PET and FDG-PET/CT in M staging of nasopharyngeal
carcinoma: a systematic review and meta-analysis. Eur J Radiol
2013; 82: 366–73.
52 Tang LQ, Chen QY, Fan W, et al. Prospective study of tailoring
whole-body dual-modality [18F]fluorodeoxyglucose positron emission
tomography/computed tomography with plasma Epstein-Barr virus
DNA for detecting distant metastasis in endemic nasopharyngeal
carcinoma at initial staging. J Clin Oncol 2013; 31: 2861–69.
53 Tuan JK, Ha TC, Ong WS, et al. Late toxicities after conventional
radiation therapy alone for nasopharyngeal carcinoma.
Radiother Oncol 2012; 104: 305–11.
54 Lee N, Harris J, Garden AS, et al. Intensity-modulated radiation
therapy with or without chemotherapy for nasopharyngeal
carcinoma: radiation therapy oncology group phase II trial 0225.
J Clin Oncol 2009; 27: 3684–90.
55 Tham IW, Hee SW, Yeo RM, et al. Treatment of nasopharyngeal
carcinoma using intensity-modulated radiotherapy-the National
Cancer Centre Singapore experience. Int J Radiat Oncol Biol Phys
2009; 75: 1481–86.
1022
56 Peng G, Wang T, Yang KY, et al. A prospective, randomized study
comparing outcomes and toxicities of intensity-modulated
radiotherapy vs. conventional two-dimensional radiotherapy for the
treatment of nasopharyngeal carcinoma. Radiother Oncol 2012;
104: 286–93.
57 Lee AW, Ng WT, Chan LL, et al. Evolution of treatment for
nasopharyngeal cancer—success and setback in the intensity-
modulated radiotherapy era. Radiother Oncol 2014; 110: 377–84.
58 Teo PM, Leung SF, Chan AT, et al. Final report of a randomized trial
on altered-fractionated radiotherapy in nasopharyngeal carcinoma
prematurely terminated by significant increase in neurologic
complications. Int J Radiat Oncol Biol Phys 2000; 48: 1311–22.
59 Daoud J, Toumi N, Siala W, et al. Results of a prospective
randomised trial comparing conventional radiotherapy to split
course bifractionated radiation therapy in patients with
nasopharyngeal carcinoma. Radiother Oncol 2007; 85: 17–23.
60 Pan ZQ, He XY, Guo XM, et al. A phase III study of late course
accelerated hyperfractionated radiotherapy versus conventionally
fractionated radiotherapy in patients with nasopharyngeal
carcinoma. Am J Clin Oncol 2012; 35: 600–05.
61 Lee AW, Tung SY, Chan AT, et al. A randomized trial on addition of
concurrent-adjuvant chemotherapy and/or accelerated fractionation
for locally-advanced nasopharyngeal carcinoma. Radiother Oncol
2011; 98: 15–22.
62 Lee AW, Ngan RK, Tung SY, et al. Preliminary results of trial
NPC-0501 evaluating the therapeutic gain by changing from
concurrent-adjuvant to induction-concurrent chemoradiotherapy,
changing from fluorouracil to capecitabine, and changing from
conventional to accelerated radiotherapy fractionation in patients
with locoregionally advanced nasopharyngeal carcinoma. Cancer
2015; 121: 1328–38.
63 Al-Sarraf M, LeBlanc M, Giri PG, et al. Superiority of five year
survival with chemo-radiotherapy (CT-RT) vs radiotherapy in
patients with locally advanced nasopharyngeal cancer (NPC),
Intergroup (0099) (SWOG 8892, RTOG 8817, ECOG 2388) phase III
study: final report. 37th Annual Meeting of the American Society of
Clinical Oncology; San Francisco, CA, USA; May 12–15, 2001.
Abstract 905.
64 Wee J, Tan EH, Tai BC, et al. Randomized trial of radiotherapy versus
concurrent chemoradiotherapy followed by adjuvant chemotherapy
in patients with American Joint Committee on Cancer/International
Union against cancer stage III and IV nasopharyngeal cancer of the
endemic variety. J Clin Oncol 2005; 23: 6730–38.
65 Lee AW, Tung SY, Chua DT, et al. Randomized trial of radiotherapy
plus concurrent-adjuvant chemotherapy vs radiotherapy alone for
regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst
2010; 102: 1188–98.
66 Chen Y, Sun Y, Liang SB, et al. Progress report of a randomized trial
comparing long-term survival and late toxicity of concurrent
chemoradiotherapy with adjuvant chemotherapy versus radiotherapy
alone in patients with stage III to IVB nasopharyngeal carcinoma
from endemic regions of China. Cancer 2013; 119: 2230–38.
67 Lin JC, Jan JS, Hsu CY, et al. Phase III study of concurrent
chemoradiotherapy versus radiotherapy alone for advanced
nasopharyngeal carcinoma: positive effect on overall and
progression-free survival. J Clin Oncol 2003; 21: 631–37.
68 Chan AT, Leung SF, Ngan RK, et al. Overall survival after
concurrent cisplatin-radiotherapy compared with radiotherapy
alone in locoregionally advanced nasopharyngeal carcinoma.
J Natl Cancer Inst 2005; 97: 536–39.
69 Kwong DL, Sham JT, Au GK. Five-year update on a randomized
factorial study on concurrent and adjuvant chemotherapy for
advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys
2006; 66 (suppl): S15–16.
70 Wu X, Huang PY, Peng PJ, et al. Long-term follow-up of a phase III
study comparing radiotherapy with or without weekly oxaliplatin for
locoregionally advanced nasopharyngeal carcinoma. Ann Oncol
2013; 24: 2131–36.
71 Chen QY, Wen YF, Guo L, et al. Concurrent chemoradiotherapy vs
radiotherapy alone in stage II nasopharyngeal carcinoma: phase III
randomized trial. J Natl Cancer Inst 2011; 103: 1761–70.
72 Tao CJ, Lin L, Zhou GQ, et al. Comparison of long-term survival
and toxicity of cisplatin delivered weekly versus every three weeks
concurrently with intensity-modulated radiotherapy in
nasopharyngeal carcinoma. PLoS One 2014; 9: e110765.
www.thelancet.com Vol 387 March 5, 2016

73 Lee AW, Tung SY, Ngan RK, et al. Factors contributing to the efficacy
of concurrent-adjuvant chemotherapy for locoregionally advanced
nasopharyngeal carcinoma: combined analyses of NPC-9901 and
NPC-9902 Trials. Eur J Cancer 2011; 47: 656–66.
74 Loong HH, Ma BB, Leung SF, et al. Prognostic significance of the
total dose of cisplatin administered during concurrent
chemoradiotherapy in patients with locoregionally advanced
nasopharyngeal carcinoma. Radiother Oncol 2012; 104: 300–04.
75 Zhang L, Zhao C, Ghimire B, et al. The role of concurrent
chemoradiotherapy in the treatment of locoregionally advanced
nasopharyngeal carcinoma among endemic population: a meta-analysis
of the phase III randomized trials. BMC Cancer 2010; 10: 558.
76 Chen YP, Wang ZX, Chen L, et al. A Bayesian network
meta-analysis comparing concurrent chemoradiotherapy followed
by adjuvant chemotherapy, concurrent chemoradiotherapy alone
and radiotherapy alone in patients with locoregionally advanced
nasopharyngeal carcinoma. Ann Oncol 2015; 26: 205–11.
77 Blanchard P, Lee A, Marguet S, et al, and the MAC-NPC Collaborative
Group. Chemotherapy and radiotherapy in nasopharyngeal
carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol
2015; 16: 645–55.
78 Chen L, Hu CS, Chen XZ, et al. Concurrent chemoradiotherapy
plus adjuvant chemotherapy versus concurrent chemoradiotherapy
alone in patients with locoregionally advanced nasopharyngeal
carcinoma: a phase 3 multicentre randomised controlled trial.
Lancet Oncol 2012; 13: 163–71.
79 Lin CC, Chen TT, Lin CY, et al. Prognostic analysis of adjuvant
chemotherapy in patients with nasopharyngeal carcinoma.
Future Oncol 2013; 9: 1469–76.
80 Blanchard P, Lee A, Leclercq J, et al, and the MAC-NPC
Collaborative Group. What is the best treatment in nasopharyngeal
carcinoma? An individual patient data network meta-analysis.
Radiother Oncol 2015; 114 (suppl 1): 6–7.
81 Hui EP, Ma BB, Leung SF, et al. Randomized phase II trial of
concurrent cisplatin-radiotherapy with or without neoadjuvant
docetaxel and cisplatin in advanced nasopharyngeal carcinoma.
J Clin Oncol 2009; 27: 242–49.
82 Fountzilas G, Ciuleanu E, Bobos M, et al. Induction chemotherapy
followed by concomitant radiotherapy and weekly cisplatin versus
the same concomitant chemoradiotherapy in patients with
nasopharyngeal carcinoma: a randomized phase II study conducted
by the Hellenic Cooperative Oncology Group (HeCOG) with
biomarker evaluation. Ann Oncol 2012; 23: 427–35.
83 Tan T, Lim WT, Fong KW, et al. Concurrent chemo-radiation with or
without induction gemcitabine, Carboplatin, and Paclitaxel:
a randomized, phase 2/3 trial in locally advanced nasopharyngeal
carcinoma. Int J Radiat Oncol Biol Phys 2015; 91: 952–60.
84 Chua DT, Ma J, Sham JS, et al. Improvement of survival after
addition of induction chemotherapy to radiotherapy in patients with
early-stage nasopharyngeal carcinoma: subgroup analysis of
two phase III trials. Int J Radiat Oncol Biol Phys 2006; 65: 1300–06.
85 Chan AT, Ma BB, Lo YM, et al. Phase II study of neoadjuvant
carboplatin and paclitaxel followed by radiotherapy and concurrent
cisplatin in patients with locoregionally advanced nasopharyngeal
carcinoma: therapeutic monitoring with plasma Epstein-Barr virus
DNA. J Clin Oncol 2004; 22: 3053–60.
86 Lee AW, Yau TK, Wong DH, et al. Treatment of stage IV(A-B)
nasopharyngeal carcinoma by induction-concurrent
chemoradiotherapy and accelerated fractionation.
Int J Radiat Oncol Biol Phys 2005; 63: 1331–38.
87 Lim AM, Corry J, Collins M, et al. A phase II study of induction
carboplatin and gemcitabine followed by chemoradiotherapy for the
treatment of locally advanced nasopharyngeal carcinoma.
Oral Oncol 2013; 49: 468–74.
88 Kong L, Hu C, Niu X, et al. Neoadjuvant chemotherapy followed by
concurrent chemoradiation for locoregionally advanced
nasopharyngeal carcinoma: interim results from 2 prospective
phase 2 clinical trials. Cancer 2013; 119: 4111–18.
89 Lin JC, Liang WM, Jan JS, et al. Another way to estimate outcome
of advanced nasopharyngeal carcinoma—is concurrent
chemoradiotherapy adequate? Int J Radiat Oncol Biol Phys 2004;
60: 156–64.
90 Le QT, Jones CD, Yau TK, et al. A comparison study of different
PCR assays in measuring circulating plasma Epstein-Barr virus
DNA levels in patients with nasopharyngeal carcinoma.
Clin Cancer Res 2005; 11: 5700–07.
www.thelancet.com Vol 387 March 5, 2016
Seminar
91 Lin JC, Wang WY, Liang WM, et al. Long-term prognostic effects of
plasma Epstein-Barr virus DNA by minor groove binder-probe
real-time quantitative PCR on nasopharyngeal carcinoma patients
receiving concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys
2007; 68: 1342–48.
92 Leung SF, Chan KC, Ma BB, et al. Plasma Epstein-Barr viral DNA
load at midpoint of radiotherapy course predicts outcome in
advanced-stage nasopharyngeal carcinoma. Ann Oncol 2014;
25: 1204–08.
93 Twu CW, Wang WY, Chen CC, et al. Metronomic adjuvant
chemotherapy improves treatment outcome in nasopharyngeal
carcinoma patients with postradiation persistently detectable plasma
Epstein-Barr virus deoxyribonucleic acid. Int J Radiat Oncol Biol Phys
2014; 89: 21–29.
94 Zhang AM, Fan Y, Wang XX, et al. Increased treatment-related
mortality with additional cisplatin-based chemotherapy in patients
with nasopharyngeal carcinoma treated with standard radiotherapy.
Radiother Oncol 2012; 104: 279–85.
95 Sun X, Su S, Chen C, et al. Long-term outcomes of intensity-
modulated radiotherapy for 868 patients with nasopharyngeal
carcinoma: an analysis of survival and treatment toxicities.
Radiother Oncol 2014; 110: 398–403.
96 Le QT, Kim HE, Schneider CJ, et al. Palifermin reduces severe
mucositis in definitive chemoradiotherapy of locally advanced head
and neck cancer: a randomized, placebo-controlled study.
J Clin Oncol 2011; 29: 2808–14.
97 Henke M, Alfonsi M, Foa P, et al. Palifermin decreases severe oral
mucositis of patients undergoing postoperative radiochemotherapy
for head and neck cancer: a randomized, placebo-controlled trial.
J Clin Oncol 2011; 29: 2815–20.
98 Leenstra JL, Miller RC, Qin R, et al. Doxepin rinse versus placebo in
the treatment of acute oral mucositis pain in patients receiving
head and neck radiotherapy with or without chemotherapy:
a phase III, randomized, double-blind trial (NCCTG-N09C6
[Alliance]). J Clin Oncol 2014; 32: 1571–77.
99 Hong RL, Lin CY, Ting LL, et al. Comparison of clinical and
molecular surveillance in patients with advanced nasopharyngeal
carcinoma after primary therapy: the potential role of quantitative
analysis of circulating Epstein-Barr virus DNA. Cancer 2004;
100: 1429–37.
100 Kwong DL, Nicholls J, Wei WI, et al. The time course of histologic
remission after treatment of patients with nasopharyngeal
carcinoma. Cancer 1999; 85: 1446–53.
101 Yen RF, Hung RL, Pan MH, et al. 18-fluoro-2-deoxyglucose positron
emission tomography in detecting residual/recurrent
nasopharyngeal carcinomas and comparison with magnetic
resonance imaging. Cancer 2003; 98: 283–87.
102 Liu T, Xu W, Yan WL, et al. FDG-PET, CT, MRI for diagnosis of
local residual or recurrent nasopharyngeal carcinoma, which
one is the best? A systematic review. Radiother Oncol 2007;
85: 327–35.
103 Chen Y, Liu X, Zheng D, et al. Diffusion-weighted magnetic
resonance imaging for early response assessment of
chemoradiotherapy in patients with nasopharyngeal carcinoma.
Magn Reson Imaging 2014; 32: 630–37.
104 Hong J, Yao Y, Zhang Y, et al. Value of magnetic resonance
diffusion-weighted imaging for the prediction of radiosensitivity in
nasopharyngeal carcinoma. Otolaryngol Head Neck Surg 2013;
149: 707–13.
105 Lai V, Li X, Lee VH, et al. Intravoxel incoherent motion MR
imaging: comparison of diffusion and perfusion characteristics
between nasopharyngeal carcinoma and post-chemoradiation
fibrosis. Eur Radiol 2013; 23: 2793–801.
106 Lam WW, Yuen HY, Wong KS, et al. Clinically underdetected
asymptomatic and symptomatic carotid stenosis as a late
complication of radiotherapy in Chinese nasopharyngeal carcinoma
patients. Head Neck 2001; 23: 780–84.
107 Li CS, Schminke U, Tan TY. Extracranial carotid artery disease in
nasopharyngeal carcinoma patients with post-irradiation ischemic
stroke. Clin Neurol Neurosurg 2010; 112: 682–86.
108 Chua M, Whee Sze O, Wee J, et al. Plasma EBV DNA as a predictive
biomarker in patients with endemic nasopharyngeal carcinoma
treated with induction chemotherapy and concurrent chemoradiation
therapy. Int J Radiat Oncol Biol Phys 2014; 90: S120–21.
1023
 Seminar
109 Hui EP, Ma BB, Chan KC, et al. Clinical utility of plasma
Epstein-Barr virus DNA and ERCC1 single nucleotide polymorphism
in nasopharyngeal carcinoma. Cancer 2015; published online May 6.
DOI:10.1002/cncr.29413.
110 Hara W, Le QT. Individualizing treatment for patients with
nasopharyngeal cancer. Cancer 2015; published online May 6.
DOI:10.1002/cncr.29418.
111 Han F, Zhao C, Huang SM, et al. Long-term outcomes and
prognostic factors of re-irradiation for locally recurrent
nasopharyngeal carcinoma using intensity-modulated radiotherapy.
Clin Oncol (R Coll Radiol) 2012; 24: 569–76.
112 Tian YM, Tian YH, Zeng L, et al. Prognostic model for survival of
local recurrent nasopharyngeal carcinoma with intensity-modulated
radiotherapy. Br J Cancer 2014; 110: 297–303.
113 Zeng L, Sun XM, Chen CY, et al. Comparative study on prophylactic
irradiation to the whole neck and to the upper neck for patients
with neck lymph node-negative nasopharyngeal carcinoma.
Head Neck 2014; 36: 687–93.
114 Chan JY, Chow VL, Wong ST, Wei WI. Surgical salvage for recurrent
retropharyngeal lymph node metastasis in nasopharyngeal
carcinoma. Head Neck 2013; 35: 1726–31.
115 Chan OS, Ngan RK. Individualized treatment in stage IVC
nasopharyngeal carcinoma. Oral Oncol 2014; 50: 791–97.
116 Hui EP, Leung SF, Au JS, et al. Lung metastasis alone in
nasopharyngeal carcinoma: a relatively favorable prognostic group.
A study by the Hong Kong Nasopharyngeal Carcinoma Study
Group. Cancer 2004; 101: 300–06.
117 Pan CC, Lu J, Yu JR, et al. Challenges in the modification of the
M1 stage of the TNM staging system for nasopharyngeal carcinoma:
a study of 1027 cases and review of the literature. Exp Ther Med
2012; 4: 334–38.
118 Jin Y, Cai XY, Cai YC, et al. To build a prognostic score model
containing indispensible tumour markers for metastatic
nasopharyngeal carcinoma in an epidemic area. Eur J Cancer 2012;
48: 882–88.
119 Jin Y, Ye X, Shao L, et al. Serum lactic dehydrogenase strongly
predicts survival in metastatic nasopharyngeal carcinoma treated
with palliative chemotherapy. Eur J Cancer 2013; 49: 1619–26.
120 Pan CC, Wu PH, Yu JR, et al. Comparative survival analysis in
patients with pulmonary metastases from nasopharyngeal
carcinoma treated with radiofrequency ablation. Eur J Radiol 2012;
81: e473–77.
121 Zeng L, Tian YM, Huang Y, et al. Retrospective analysis of
234 nasopharyngeal carcinoma patients with distant metastasis at
initial diagnosis: therapeutic approaches and prognostic factors.
PLoS One 2014; 9: e108070.
122 Leong SS, Wee J, Tay MH, et al. Paclitaxel, carboplatin, and
gemcitabine in metastatic nasopharyngeal carcinoma: a phase II
trial using a triplet combination. Cancer 2005; 103: 569–75.
123 Jin Y, Shi YX, Cai XY, et al. Comparison of five cisplatin-based
regimens frequently used as the first-line protocols in metastatic
nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2012;
138: 1717–25.
124 Foo KF, Tan EH, Leong SS, et al. Gemcitabine in metastatic
nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol
2002; 13: 150–56.
125 Chua DT, Sham JS, Au GK. A phase II study of capecitabine in
patients with recurrent and metastatic nasopharyngeal carcinoma
pretreated with platinum-based chemotherapy. Oral Oncol 2003;
39: 361–66.
126 Ngeow J, Lim WT, Leong SS, et al. Docetaxel is effective in heavily
pretreated patients with disseminated nasopharyngeal carcinoma.
Ann Oncol 2011; 22: 718–22.
127 Chen C, Wang FH, Wang ZQ, et al. Salvage gemcitabine-
vinorelbine chemotherapy in patients with metastatic
nasopharyngeal carcinoma pretreated with platinum-based
chemotherapy. Oral Oncol 2012; 48: 1146–51.
1024
128 Yau TK, Shum T, Lee AW, et al. A phase II study of pemetrexed
combined with cisplatin in patients with recurrent or metastatic
nanopharyngeal carcinoma. Oral Oncol 2012; 48: 441–44.
129 Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of
cetuximab in combination with carboplatin in patients with
recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol
2005; 23: 3568–76.
130 Hui EP, Lui VW, Wong CS, et al. Preclinical evaluation of sunitinib
as single agent or in combination with chemotherapy in
nasopharyngeal carcinoma. Invest New Drugs 2011; 29: 1123–31.
131 Hui EP, Ma BB, King AD, et al. Hemorrhagic complications in a
phase II study of sunitinib in patients of nasopharyngeal carcinoma
who has previously received high-dose radiation. Ann Oncol 2011;
22: 1280–87.
132 Lim WT, Ng QS, Ivy P, et al. A phase II study of pazopanib in Asian
patients with recurrent/metastatic nasopharyngeal carcinoma.
Clin Cancer Res 2011; 17: 5481–89.
133 Huang Y, Zhang L, Pan JJ, et al. A phase II, multicenter, open-label,
single-arm trial of famitinib in patients with advanced recurrent
and/or metastatic nasopharyngeal carcinoma (NPC) after
two previous treatment regimens. 2013 ASCO Annual Meeting;
Chicago, IL, USA; May 31–June 4, 2013. Abstract 6026.
134 Hui EP, Lui WY, Hui WC, et al. Preclinical activity of axitinib and its
associated change of serum biomarkers in nasopharyngeal
carcinoma. Cancer Res 2012; 72: 1373.
135 Soria JC, Deutsch E. Hemorrhage caused by antiangiogenic therapy
within previously irradiated areas: expected consequence of tumor
shrinkage or a warning for antiangiogenic agents combined to
radiotherapy? Ann Oncol 2011; 22: 1247–49.
136 Louis CU, Straathof K, Bollard CM, et al. Adoptive transfer of
EBV-specific T cells results in sustained clinical responses in
patients with locoregional nasopharyngeal carcinoma. J Immunother
2010; 33: 983–90.
137 Chia WK, Wang WW, Teo M, et al. A phase II study evaluating the
safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced
dendritic cell vaccine in patients with advanced metastatic
nasopharyngeal carcinoma. Ann Oncol 2012; 23: 997–1005.
138 Chia WK, Teo M, Wang WW, et al. Adoptive T-cell transfer and
chemotherapy in the first-line treatment of metastatic and/or locally
recurrent nasopharyngeal carcinoma. Mol Ther 2014; 22: 132–39.
139 Smith C, Tsang J, Beagley L, et al. Effective treatment of metastatic
forms of Epstein-Barr virus-associated nasopharyngeal carcinoma
with a novel adenovirus-based adoptive immunotherapy. Cancer Res
2012; 72: 1116–25.
140 Taylor GS, Haigh TA, Gudgeon NH, et al. Dual stimulation of
Epstein-Barr virus (EBV)-specific CD4+- and CD8+-T-cell
responses by a chimeric antigen construct: potential therapeutic
vaccine for EBV-positive nasopharyngeal carcinoma. J Virol 2004;
78: 768–78.
141 Hui EP, Taylor GS, Jia H, et al. Phase I trial of recombinant
modified vaccinia ankara encoding Epstein-Barr viral tumor
antigens in nasopharyngeal carcinoma patients. Cancer Res 2013;
73: 1676–88.
142 Taylor GS, Jia H, Harrington K, et al. A recombinant modified
vaccinia ankara vaccine encoding Epstein-Barr virus (EBV) target
antigens: a phase I trial in UK patients with EBV-positive cancer.
Clin Cancer Res 2014; 20: 5009–22.
143 Fang W, Zhang J, Hong S, et al. EBV-driven LMP1 and IFN-γ
up-regulate PD-L1 in nasopharyngeal carcinoma: implications for
oncotargeted therapy. Oncotarget 2014; 5: 12189–202.
144 Lee AW, Foo W, Mang O, et al. Changing epidemiology of
nasopharyngeal carcinoma in Hong Kong over a 20-year period
(1980–99): an encouraging reduction in both incidence and
mortality. Int J Cancer 2003; 103: 680–85.
145 Cao SM, Simons MJ, Qian CN. The prevalence and prevention of
nasopharyngeal carcinoma in China. Chin J Cancer 2011; 30: 114–19.
www.thelancet.com Vol 387 March 5, 2016