Seminar
Nasopharyngeal carcinoma
Lancet 2019; 394: 64–80
Published Online
June 6, 2019
http://dx.doi.org/10.1016/
S0140-6736(19)30956-0
*Joint senior authors
Department of Radiation
Oncology, Sun Yat-sen
University Cancer Center, State
Key Laboratory of Oncology in
South China, Collaborative
Innovation Center for Cancer
Medicine, Guangdong Key
Laboratory of Nasopharyngeal
Carcinoma Diagnosis and
Therapy, Guangzhou, People’s
Republic of China (Y-P Chen MD;
Prof Y Sun MD, Prof Jun Ma MD);
Partner State Key Laboratory of
Oncology in South China,
Sir Y K Pao Centre for Cancer,
Department of Clinical
Oncology, Hong Kong Cancer
Institute and Prince of Wales
Hospital, The Chinese
University of Hong Kong,
Hong Kong, China
(A T C Chan MD); Department of
Radiation Oncology, Stanford
University, Stanford, CA, USA
(Q-T Le MD); and Department
of Radiation Oncology,
Gustave-Roussy; Centre for
Research in Epidemiology and
Population Health, INSERM
U1018, Paris-Saclay University,
Villejuif, France
(Prof P Blanchard MD)
Correspondence to:
Prof Jun Ma, Department of
Radiation Oncology, Sun Yat-sen
University Cancer Center, State
Key Laboratory of Oncology in
South China, Collaborative
Innovation Center for Cancer
Medicine, Guangdong Key
Laboratory of Nasopharyngeal
Carcinoma Diagnosis and
Therapy, 510060, China
majun2@mail.sysu.edu.cn
See Online for appendix
64 www.thelancet.com Vol 394 July 6, 2019
Yu-Pei Chen, Anthony T C Chan, Quynh-Thu Le, Pierre Blanchard, Ying Sun*, Jun Ma*
Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east
and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually
but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and
environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening,
advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular,
plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment
response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-
modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have
contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics,
immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent
a promising future direction in nasopharyngeal carcinoma.
Introduction past decades, nasopharyngeal carcinoma incidence has
Nasopharyngeal carcinoma is an epithelial carcinoma declined gradually worldwide: substantial reductions have
arising from the nasopharyngeal mucosal lining. In been observed in south and east Asia, north America,
the nasopharynx, the tumour is often observed at and the Nordic countries, with average annual changes of
the pharyngeal recess (fossa of Rosenmüller). Despite about –1% to –5%.3,4 In endemic regions, for example,
originating from similar cell or tissue lineages, naso­ the incidence rate has steadily decreased since the 1980s
pharyngeal carcinoma and other epithelial head and neck in Hong Kong, with a total decrease of about 30% over a
tumours are distinctly different. 20-year period;5 urban Guangzhou has shown average
In comparison with other cancers, nasopharyngeal annual changes of about –3% for men and –5% for
carcinoma is relatively uncommon. According to the women in the 2000–11 period.6 Lifestyle and environmental
International Agency for Research on Cancer, in 2018, changes may well be the contributory factors.
there were about 129 000 new cases of nasopharyngeal Nasopharyngeal carcinoma incidence is higher in
carcinoma, accounting for only 0·7% of all cancers males than in females, with a ratio of about 2·5 in
diagnosed in 2018.1,2 Nevertheless, its geographical global China in 2015.7 It is noteworthy that the high incidence
distribution is extremely unbalanced; >70% of new cases in people from southern China remains even after they
are in east and southeast Asia, with an age-standardised immigrate to non-endemic areas, but reduced incidence
rate (world) of 3·0 per 100 000 in China to 0·4 per 100 000 in has been observed in second-generation migrants.
populations that are mainly white (figure 1).1,2 Over the There is also a trend towards decreasing incidence the
farther the population has immigrated.8 These findings
suggest that a combination of genetic, ethnic, and
Search strategy and selection criteria environmental factors might affect nasopharyngeal
carcinoma pathogenesis.
We did an extensive search of MEDLINE and PubMed for
English-language articles published between Jan 1, 1990,
and Jan 31, 2019. The Cochrane Library was also searched for Pathology and risk factors
reviews that had been published between 1990 and 2018. According to the World Health Organization, there are
three pathological subtypes of nasopharyngeal carcinoma:
The search terms included: “nasopharyngeal carcinoma”,
“nasopharynx cancer”, “epidemiology”, “pathology”, keratinising squamous, non-keratinising, and basaloid
“genetics”, “Epstein-Barr virus”, “staging”, “imaging”, squamous. Non-keratinising nasopharyngeal carcinoma
“positron emission tomography”, “radiotherapy”, can be divided into differentiated and undifferentiated
“chemotherapy”, “combined treatment modality”, tumours (appendix p 22).9 The keratinising subtype
“salvage therapy”, “immunotherapy”, “clinical trials”, accounts for less than 20% of cases worldwide, and is
and “meta-analysis”. The search included reports on human relatively rare in endemic areas such as southern China;
studies. We prioritised large, current clinical trials or studies the non-­keratinising subtype constitutes most cases in
for selection. The abstracts of recent pertinent conferences endemic areas (>95%) and is predominantly associated
were also included for the most recent updates. with Epstein-Barr virus (EBV) infection.9–11
We evaluated the relevance of the references that had been The remarkable geographical distribution of naso­
selected, which comprised mainly articles that had been pharyngeal carcinoma incidence has spurred studies
published in the last 5 years; we did not exclude older, on its risk factors, and it is suggested that multiple factors,
original studies that have been referenced widely and are including EBV infection, host genetics, and environmental
greatly respected. factors are contributors in the devel­ opment of naso­
pharyngeal carcinoma. Linkage and association studies
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ASR (world) per 100 000

≥1·5
0·82 to <1·5
0·50 to <0·82
0·39 to <0·50
0·28 to <0·39
0·19 to <0·28
<0·19
Not applicable
No data

Others 28 200 (21·8%)

USA 2216 (1·7%)

Thailand 2200 (1·7%)

Philippines 2913 (2·3%) China 60 558 (47·7%)
Mediterranean countries* 3792 (2·9%)

India 5086 (4·0%)

Vietnam 6212 (4·9%)

Indonesia 17 992 (14·2%)

Figure 1: Worldwide distribution of nasopharyngeal carcinoma in 2018

(A) Estimated age-standardised incidence rates (ARS; world). (B) Pie chart presents the distribution of the estimated number of new cases for the seven countries in
which nasopharyngeal carcinoma is most commonly reported. Source: Globocan 2018.1,2 ARS=age-standardised rates. *Mediterranean countries include Morocco,
Algeria, Tunisia, Libya, Lebanon, Israel, Turkey, and Greece.

have identified that genetic susceptibility genes increase
nasopharyngeal carcinoma risk. HLA genes residing at
the MHC region on chromosome 6p21 have been widely
recognised as major risk loci conferring nasopharyngeal
carcinoma risk.12,13 Genome-wide association studies have
also reported other loci outside the MHC (eg—TNFRSF19
on 13q12, MECOM on 3q26, CDKN2A/2B on 9p21,
CLPTM1L/TERT on 5p15l; appendix).14–18 A recent study
showed that pathogenic heterozygous germline variants
of MST1R, which encodes a macrophage-stimulating 1 cell
surface receptor and is key in host defence against viral
infection, is strongly associated with early-age onset (age
≤20 years) of nasopharyngeal carcinoma,19 which may aid
population screening.
Several recent studies exploring the molecular
landscape of nasopharyngeal carcinoma have identified
crucial genomic changes that stimulate the development
and progression of disease: multiple loss-of-function
mutations in the NF-kB–negative regulators, recurrent
genetic lesions including loss of the CDKN2A/CDKN2B
locus, CCND1 amplification, TP53 mutation, and muta­
tions in the PI3K/MAPK signalling pathways, chromatin
modification, and DNA repair (appendix p 13).20–23 In
addition, although the EBV oncoprotein latent membrane
protein 1 (LMP1) constitutively activates NF-κB signalling,
Li and colleagues22 identified mutual exclusivity among
LMP1 overexpression and NF-κB pathway aberrations,
suggesting that both somatic and virus-mediated addic­
tion to NF-κB signalling contributed to pathogenesis of
nasopharyngeal carcinoma. Appendix pp 23–24 depicts
the pathway of significant signalling and transcription
factor alterations according to somatic variants identified
in the above mentioned studies.20–23
Besides host genetics, EBV infection is perhaps the
most common causal agent of nasopharyngeal carcinoma
(figure 2; appendix). Other potential risk factors identified
by epidemiological studies include family history of
nasopharyngeal carcinoma (appendix p 25), active and

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Tumour progression
Tumour formation
Clonal expansion of
EBV-infection cells

Latency II Chemotherapy
LMP1+ and Local recurrence
LMP1– radiotherapy
Normal Precancerous lesions
nasopharyngeal
epithelium Activation of telomerase Inflammation Global
↑Cyclin D1 hyper-methylation
Loss of chr.3p and 9p (inactivation
↓p16, RASSF1A
of RASS1A and CDKN2A) Somatic gene
EBV latent infection alterations in
NFκB pathways
Mutations in
MHC class I
genes
Mutations in P13K/MAPK
and chromatin Distant metastasis
remodelling pathways TP53, RAS or
LMP1 BART-miRNAs other mutations
Invasion and metastasis Potentiate tumour growth
Activate oncogenic signalling pathways Escape immune attack
Anti-apoptosis Anti-apoptosis
Inhibit differentiation of squamous cells EBERs
LMP2 Induce IGF-1 Driver mutations
Promote cell survival Anti-apoptosis
Maintain cell stemness BARF1 EBV
Epithelial–mesenchymal transition Promote cell growth
EBNA1 Tumour cell
Promote cell growth
Maintain EBV episome
Carcinogens
Damage DNA

Figure 2: Theory of the roles of Epstein-Barr virus (EBV) infection and genomic changes in the development of nasopharyngeal carcinoma*
Persistent EBV infection and progressive genomic changes promote clonal evolution of nasopharyngeal carcinoma. Persistent EBV infection in genetically mutated
epithelial cells and the proliferation of infected cells are considered the prerequisites for initiating tumorigenic transformation. Chronic exposure of the nasopharyngeal
mucosa to environmental carcinogens increases DNA damage and leads to somatic genetic changes in the epithelial cells. The activation of telomerase activity on
chromosomes 3p and 9p (chr.3p & 9p) and the accumulation of driving events such as inactivation of the tumour suppressor genes RASSF1A and CDKN2A promote the
immortalisation of histologically normal and/or dysplastic cells, genomic instability, and EBV infection. Furthermore, p16 inactivation and cyclin D1 pathway activation
may contribute to undifferentiated nasopharyngeal epithelial cells, supporting EBV infection. The expression of type II EBV latency gene products, such as LMP1, LMP2,
EBNA1, BART miRNAs, EBERs, and BARF1, alters multiple cellular pathways, promotes cell proliferation, regulates the host microenvironment, and thereby promotes
the clonal expansion of EBV-infected pre-invasive nasopharyngeal epithelial cells. Importantly, EBV facilitates global hypermethylation, consequently inactivating a
variety of cancer-related genes. Moreover, during tumour development, acquired mutations of several negative regulatory factors in the NF-κB signalling pathway alter
the activity of various cancer-related genes. All these conditions enhance tumour heterogeneity. In nasopharyngeal carcinoma progression, the loss of LMP1 may be
associated with the acquisition of additional genetic changes during tumour progression, which compensate for LMP1 function. Further genetic alterations are
acquired during tumour progression. In advanced stages, mutations in the MHC class I genes and in the PI3K/MAPK and chromatin remodelling pathways, and somatic
mutations of TP53, RAS, and other genes may be the driving force of local recurrence and distant metastasis of nasopharyngeal carcinoma cells after conventional
treatment. EBV=Epstein-Barr virus. *The theory was proposed by Kwok-Wai Lo (Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong,
Hong Kong, China), and the figure was modified with his permission.

passive tobacco smoking, consumption of preserved nasopharyngeal carcinoma screening in asymptomatic

foods and alcohol, and oral hygiene.24–28
Population screening
Effective population screening could improve treatment
outcomes by identifying early-stage disease in patients,
and presents an attractive strategy considering the strained
medical resources in endemic areas such as southern
China. Although anti-EBV IgA antibody (eg—early antigen
[EA-IgA], anti–EBV capsid antigen [VCA-IgA], anti–EBV
nuclear antigen 1 [EBNA1-IgA]) serological testing is com­
monly used to detect incident nasopharyngeal carcinoma,
the low sensitivities and specificities impede their use in
participants.29
Encouragingly, a recent prospective screening study
involving more than 20 000 participants30 showed that
plasma EBV DNA detection was useful for nasopharyn­
geal carcinoma screening, with 97·1% sensi­tivity and
98·6% specificity. Nasopharyngeal carcinoma was
detected significantly earlier, with a higher proportion of
stage I–II disease than in a historical cohort (71% vs
20%), and the outcomes were also better compared with
a historical cohort (3-year progression-free survival
hazard ratio [HR]: 0·10 [95% CI 0·05–0·18]).30 Plasma
EBV DNA population screening represents a very

66 www.thelancet.com Vol 394 July 6, 2019

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Seventh edition Eighth edition

Primary tumour (T)
TX Primary tumour cannot be assessed Primary tumour cannot be assessed
T0 ·· No tumour identified, but there is EBV-positive cervical node(s)
involvement
T1 Nasopharynx, oropharynx, or nasal cavity without Nasopharynx, oropharynx, or nasal cavity without parapharyngeal
parapharyngeal extension extension
T2 Parapharyngeal extension Parapharyngeal extension, adjacent soft tissue involvement
(medial pterygoid, lateral pterygoid, prevertebral muscles)
T3 Bony structures of skull base and/or paranasal sinuses Bony structures (skull base, cervical vertebra) and/or paranasal
sinuses
T4 Intracranial, cranial nerves, hypopharynx, orbit, Intracranial extension, cranial nerve, hypopharynx, orbit, extensive
infratemporal fossa or masticator space soft tissue involvement (beyond the lateral surface of the lateral
pterygoid muscle, parotid gland)
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis No regional lymph node metastasis
N1 Unilateral cervical, unilateral, or bilateral retropharyngeal Unilateral cervical, unilateral, or bilateral retropharyngeal lymph
lymph nodes, above the supraclavicular fossa; ≤6 cm nodes, above the caudal border of cricoid cartilage; ≤6 cm
N2 Bilateral metastasis in lymph node(s), ≤6 cm in greatest Bilateral metastasis in lymph node(s), ≤6 cm in greatest dimension,
dimension, above the supraclavicular fossa above the caudal border of cricoid cartilage
N3a >6 cm in dimension >6 cm and/or below caudal border of cricoid cartilage (regardless of
laterality)
N3b Supraclavicular fossa ··
Distant metastasis (M)
M0 No distant metastasis No distant metastasis
M1 Distant metastasis Distant metastasis
Stage group
I T1 N0 M0 T1 N0 M0
II T2 N0–1 M0, T1 N1 M0, T2 N0–1 M0, T0–1 N1 M0
III T1–3 N2 M0, T3 N0–1 M0 T3 N0–2 M0, T0–2 N2 M0
IVA T4 N0–2 M0 T4 or N3 M0
IVB Any T, N3 M0 Any T, any N, M1
IVC Any T, any N, M1 ··
EBV=Epstein-Barr virus. UICC/AJCC=International Union Against Cancer/American Joint Committee on Cancer. T category: T0 is added for EBV-positive cervical node(s)
involvement despite unidentified primary tumour. Involvement of medial pterygoid, lateral pterygoid, and prevertebral muscles is now staged as T2. In T4, the original
“infratemporal fossa or masticator space” has been replaced by specific description of soft tissue involvement to avoid potential ambiguity. N category: the previous N3b
criterion of “supraclavicular fossa” has been changed to “below caudal border of cricoid cartilage”. N3a and N3b have been merged into a single N3. Stage group: the previous
stages IVA and IVB have been merged into IVA. The previous IVC has been upstaged to IVB.

Table 1: Comparison of the 7th and 8th editions of the UICC/AJCC staging system for nasopharyngeal carcinoma

promising approach for detecting early-stage naso­
pharyngeal carcinoma (appendix).
Symptoms and diagnosis
The clinical symptoms and signs of nasopharyngeal
carcinoma correlate with the involved anatomical
regions, and comprehensive head and neck evaluation
is indicated in patients with presumed diagnosis of
nasopharyngeal carcinoma (see appendix for more
detail).
Staging and prognosis
Nasopharyngeal carcinoma is classified according to the
International Union Against Cancer/American Joint
Committee on Cancer (UICC/AJCC) TNM (tumour-node-
metastasis) staging system. This system was updated to
the 8th edition in 2016 (from the 7th edition in 2009),
where primary and nodal disease classification, and the
stage groups were further refined (table 1).31,32
As the current anatomy-based staging system is
insufficient for predicting prognosis or treatment
benefits, many studies have assessed whether incor­
porating other clinical factors and molecular biomarkers
into the system would better predict survival. A recent
study33 proposed a nomogram combining pre-treatment
plasma EBV DNA and clinicopathological variables, and
found that it resulted in more accurate prognostic
prediction for patients with nasopharyngeal carcinoma.
Other biomarkers such as DNA methylation, miRNAs,
and mRNAs also have demonstrated their prognostic
value and potential clinical applications in nasopharyngeal
carcinoma. A six–hypermethylated gene panel34 and a

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five-miRNA signature35 have been associated with survival
in nasopharyngeal carcinoma. A gene expression–based
signature was recently proposed as a reliable prognostic
tool for distant metastasis in nasopharyngeal carcinoma,
and might be able to predict which patients might
benefit from concurrent chemotherapy as well.36 With
the advances in immunotherapy, the prognostic value
of programmed death-1 or programmed death-1 ligand
(PD-1/PD-L1) expression in nasopharyngeal carcinoma
has been explored despite inconsistent conclusions,37–41
possibly due to different immune microenvironment
statuses. High intratumoral and stromal tumour-
infiltrating lymphocytes (TILs) have been associated with
favourable outcomes.42 These immune-related prognostic
biomarkers may also reflect immunological heterogeneity
and guide future immunotherapy.
Notably, the addition of pre-treatment plasma EBV DNA
to the 8th edition greatly improved its prognostic
performance.43–45 Future revisions of the TNM staging
system adapted to incorporate plasma EBV DNA represent
a promising strategy. Beyond pre-treatment EBV DNA,
unfavourable EBV DNA response after induction chemo­
therapy, midcourse of radiotherapy, or post-treatment is
also adverse prognosticators for clinical outcomes.46–48
These observations present the possibility of incorporating
EBV DNA for risk-stratified treatment adaptation, based
on liquid biopsy of biomarker response. Well conducted
studies with regular longitudinal EBV DNA measurements
during and after treatment are warranted to further assess
the role of EBV DNA in treatment modification during
active therapy and in tumour surveillance after therapy
has been completed. However, although EBV DNA has
been established as a robust prognostic marker in naso­
pharyngeal carcinoma, there is comparatively large
interlaboratory variability, even for the same assay using
identical procedures without harmonisation.49 Accordingly,
assay standard­ isation is necessary for measuring this
biomarker in prospective studies that involve more than
one par­ticipating laboratory. Notably, Le and colleagues49
have shown that harmonisation is feasible, and have
established a standardised assay that is being used in an
international biomarker-driven clinical trial. In addition to
the tech­nical aspects, other challenges in plasma EBV
DNA measurements include the variable number of viral
episomes within each nasopharyngeal carcinoma cell and
the variable number of repeats (5–11 repeats) of the
BamHI W region, which is the target sequence of the
harmonised assay but which can vary in different viral
isolates. In 2016, at a National Cancer Institute EBV
testing harmonisation workshop for nasopharyngeal
carcinoma, nasopharyngeal carcinoma and laboratory
medicine experts spoke on the limitations of the current
quantitation assays and discussed approaches for
improving harmonised assays in the future.50 They made
key suggestions to guide assay harmonisation and
validation efforts in the future; one of which was focusing
on an assay that would target two EBV sequences in
68 www.thelancet.com Vol 394 July 6, 2019
parallel: a single-copy sequence for comparing between
patients, and a multicopy sequence for enhancing
the assay sensitivity. Considerations were also made
for adapting new technologies such as next-generation
sequencing or digital PCR to improve the assay quanti­
tation. At least two laboratories are currently working to
optimise the assay, which, once validated, can substantially
improve the staging system and promote daily use of this
biomarker in the clinic.
Imaging studies
MRI, CT, and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)-PET/CT
are currently the most commonly used imaging
modalities for nasopharyngeal carcinoma staging and
radiotherapy. With high soft-tissue resolution, MRI is
better for evaluating primary tumour extension and
retropharyngeal lymph node metastasis than CT, while
they share similar accuracy in detecting cervical lymph
node metastasis (appendix p 27).51,52 ¹⁸F-FDG-PET/CT
performs better than conventional work-up (eg—chest
radiography, abdominal ultrasound, skeletal scintigraphy)
for diagnosing distant metastasis, and is also relatively
more sensitive and accurate for detecting small cervical
lymph node metastases and local residual, recurrent
disease, or both.52–55 Therefore, MRI and ¹⁸F-FDG-PET/CT
might be preferred for staging in patients with high
risk of distant metastasis. Recently, the clinical utility
of simultaneous whole-body ¹⁸F-FDG-PET/MRI was
assessed for staging primary nasopharyngeal carcinoma,
and showed more accuracy than separate MRI and
PET/CT, and could serve as a single-step staging modal­
ity.56 Because ¹⁸F-FDG-PET/CT also provides metabolic
parameters, it could represent tumour biology and predict
treatment outcomes. It has been proposed that the
metabolic indexes of PET/CT performed before and
during radiotherapy are useful prognostic factors for
predicting patients with high-risk of regional or distant
metastatic failure.57 Combining ¹⁸F-FDG-PET derived
parameters and EBV DNA stratifies patients with
nasopharyngeal carcinoma into different risk subgroups
better than the conventional TNM system.58
The emerging radiomics methods aim to convert
medical images into high-dimensional, quantitative
imaging features to improve oncological decision support
economically and non-invasively,59 and a multi­parametric
MRI-based radiomics nomogram has been proposed
to provide improved prognostic ability in advanced
nasopharyngeal carcinoma, suggesting that this may be a
promising field.60
Radiotherapy
Nasopharyngeal carcinoma is highly sensitive to ionising
radiation; radiotherapy is the mainstay treatment modality
for non-metastatic disease. Over time, photon-based radio­
therapy techniques have progressed from con­ ventional
two-dimensional (2D) radiotherapy to 3D conformal radio­
therapy and then to intensity-modulated radiotherapy

(IMRT). Locoregional control and survival have been
enhanced by the parallel improved dosimetric properties,
and toxicity has been reduced.61–65 Currently, IMRT is
the most widely used technique (appendix p 28). It has
reduced the 5-year occurrence rates of locoregional failure
for newly diagnosed and non-metastatic naso­pharyngeal
carcinoma to 7·4%.66 In a meta-analysis reviewing
3570 participants, IMRT was significantly associated with
better 5-year locoregional control (odds ratio 1·94 [95% CI
1·53–2·46]) and overall survival (1·51 [1·23–1·87]) com­
pared with 2D or 3D radiotherapy, along with signifi­cant
reduction of radiation-induced toxicities such as temporal
lobe neuropathy, late xerostomia, and trismus.64
While IMRT is the current preferred method, there is
great interest in using proton or carbon ion radiother­apy
for treating nasopharyngeal carcinoma to improve
the therapeutic ratio even further. In view of the
characteristic steep proton or carbon ion dose fall-off,
these techniques enable a high therapeutic radiation dose
to be delivered to the tumour region; the exit dose is
minimal, therefore more normal tissues are spared.67,68
Compared with IMRT, intensity-modulated proton
therapy (IMPT) has dosimetric advantages in naso­
pharyngeal carcinoma, with less radiation to normal
structures.67 In a small study of ten patients treated with
IMPT with short follow-up, the radiation dose to normal
structures was decreased, with 2-year locoregional control
and overall survival rates of 100% and 88·9%, respec­
tively;67 further large-scaled studies with long-term
follow-up data are warrant. Hu and colleagues69 showed
that intensity-modulated carbon ion therapy (IMCT)
resulted in 98·1% 1-year overall survival, 86·6% local
recurrence–free survival, and 97·9% re­gional recurrence–
free survival for 75 patients with locoregionally recur­
rent nasopharyngeal carcinoma. Despite the infrequent
severe toxicities reported in that study, it should be noted
that seven patients (9·3%) developed mucosal necrosis
(including one fatal haemorrhage);69 future studies are
needed to provide more information on the application of
IMCT in nasopharyngeal carcinoma.
Despite the radiotherapy technique improvements,
successful radiotherapy of nasopharyngeal carcinoma
hinges on precise delineation and exact dose delivery to
the gross tumour volume (GTV), clinical target volumes
(CTV), and organs at risk (OARs). International
consensus guidelines have been suggested for delineating
the CTV and OARs to guarantee peak target coverage and
to lessen adverse effects (appendix pp 14–18),70,71 providing
useful references for nasopharyngeal carcinoma radiation
management (appendix). Nevertheless, inter-observer
variability remains high even with these contouring
guidelines,72 prompting efforts to improve delineation.
Therefore, deep learning algorithms, especially con­
volutional neural networks, have recently been
investigated for automating primary GTV delineation,
aiming to improve contouring accuracy, consistency, and
efficiency (appendix p 29).73
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Chemotherapy in non-metastatic
nasopharyngeal carcinoma
While early-stage nasopharyngeal carcinoma is treated
with only radiotherapy as the main curative treatment,
locoregionally advanced disease requires more than
radiotherapy. Chemotherapy combined with radiotherapy
is a crucial development for treating locoregionally
advanced disease. At present, the National Comprehensive
Cancer Network (NCCN) Guidelines recommend both
concurrent chemoradiotherapy with adjuvant chemo­
therapy or induction chemotherapy followed by con­
current chemoradiation as level 2A evidence, and
concurrent chemoradiotherapy alone as level 2B evidence
for stage II–IVA nasopharyngeal carcinoma.74
Concurrent chemoradiotherapy
A number of trials have demonstrated the survival benefit
of concurrent chemoradiotherapy with or without
adjuvant chemotherapy versus radiotherapy alone in
locoregionally advanced nasopharyngeal carcinoma
(appendix pp 19–20).75–83 Recently, a meta-analysis has
shown that the most significant benefits of chemotherapy
on overall survival are seen with either concurrent plus
adjuvant chemotherapy (HR 0·65 [95% CI 0·56–0·76]) or
concurrent chemotherapy (0·80 [0·70–0·93]); by contrast,
there was no significant benefit following treatment with
only adjuvant chemotherapy (0·87 [0·68–1·12]) or only
induction chemotherapy (0·96 [0·80–1·16]).84 However,
whether adjuvant chemotherapy after concurrent chemo­
radio­therapy can confer further survival benefits remains
controversial. Notably, the preliminary results of a phase 3
trial85 showed no significant improvements when
adjuvant chemotherapy was added to concurrent chemo­
radiotherapy versus concurrent chemoradiotherapy alone
for all outcome parameters (2-year failure-free survival,
86% vs 84%; overall survival, 94% vs 92%; distant
metastasis–free survival, 88% vs 86%; locoregional
failure–free survival 98% vs 95%), and the long-term
results confirmed these findings (appendix p 20).86
Therefore, concurrent chemoradiotherapy is deemed the
mainstay treatment in locoregionally advanced disease.
Concurrent chemotherapy regimens vary between
studies: cisplatin is commonly the first choice; dosing
schedules of 40 mg/m² once a week or 80–100 mg/m²
every 3 weeks are acceptable in clinical practice.
Nonetheless, the differences in radiosensitivity and
toxicity profiles between different dosing schedules may
be neglected compared to the importance of dose
intensity, where cumulative 200 mg/m² cisplatin may be
the threshold for optimal efficacy without induction
chemotherapy,87–89 and 160 mg/m² cisplatin when
receiving additional induction chemotherapy.90 Other
alternative concurrent agents include uracil plus tegafur,
oxaliplatin, and nedaplatin (appendix pp 19–20).77,78,91
In the conventional 2D radiotherapy era, Chen and
colleagues92 reported significant improvements in survival
by concurrent chemoradiotherapy as compared to only
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radiotherapy for clinical stage II disease (appendix p 19).
However, as IMRT has become a routine choice, many
retrospective studies have proposed that radiotherapy
alone may be sufficient for treating stage II nasopharyngeal
carcinoma.93 The results of an ongoing phase 3 clinical
trial (NCT02633202) comparing radiotherapy alone
against concurrent chemoradiotherapy in stage II and
T3N0M0 disease might provide more evidence.
Adjuvant chemotherapy
Typically, adjuvant chemotherapy consists of cisplatin
(80–100 mg/m²) and fluorouracil (800–1000 mg/m² every
day for 4–5 days) every 4 weeks over three cycles (appendix).
As mentioned above, adjuvant chemotherapy alone cannot
improve survival, and additional adjuvant chemotherapy
following concurrent chemoradiotherapy may not yield
further benefits in locoregionally advanced disease. A
phase 3 trial48 compared adjuvant chemo­therapy against
observation for patients with high risk, in which
104 patients identified based on detectable EBV DNA in
the plasma after completing radiotherapy or chemo­
radiotherapy were randomly assigned to observation, or
six-cycle adjuvant cisplatin and gemcitabine chemotherapy.
This novel study represents the first biomarker-driven
randomised trial in nasopharyngeal carcinoma. However,
despite using EBV DNA in the plasma to identify adjuvant
chemotherapy patients with higher relapse risk, and using
gemcitabine and cisplatin, which is more successful
than cisplatin and fluorouracil in metastatic disease,94
the authors did not observe improved 5-year relapse-
free survival (adjuvant chemotherapy vs obser­vation:
49% vs 55%; HR 1·09 [95% CI 0·63–1·89]) or overall
survival (64% vs 68%; 1·09 [0·56–2·11]). The ongoing
NRG-HN001 trial (NCT02135042) also uses post-
radiotherapy plasma EBV DNA to establish whether
adjuvant gemcitabine and paclitaxel is better than cisplatin
and fluorouracil for patients with detectable EBV DNA in
the plasma, and whether adjuvant cisplatin and fluorouracil
can be omitted in patients with undetectable plasma EBV
DNA; it might provide more evidence for biomarker-
guided use of conventional adjuvant chemotherapy.
One potential reason for the poor efficacy of adjuvant
chemotherapy may be the poor tolerance of conventional
chemotherapy regimens (cisplatin and fluorouracil/
gemcitabine) in the first 6 months after radiotherapy
completion, with 50–76% compliance at best.79–83,85,94
Metronomic use of oral chemotherapy agents such as
capecitabine or uracil plus tegafur as adjuvant chemo­
therapy may be an alternative choice after concurrent
chemoradiotherapy. Metronomic chemotherapy describes
the close, regular administration of chemotherapy drugs at
less toxic doses over prolonged periods, with the advantages
of good compliance, low toxicities, and convenience.95 The
mechanisms of metronomic chemotherapy include anti-
angiogenic effects, induction of tumour dormancy, and
activation of immunity.95,96 Two retrospective analyses
showed that 12-month metronomic adjuvant uracil plus
70 www.thelancet.com Vol 394 July 6, 2019
tegafur substantially reduced distant failure and improved
survival in high-risk patients.97,98 In an ongoing phase 3
multicentre trial, patients with high-risk locoregionally
advanced nasopharyngeal carcinoma (stage III–IVA,
excluding T3–4N0 and T3N1 disease) have been randomly
assigned to a metronomic adjuvant regimen of single-
agent capecitabine (1300 mg/m² daily for 1 year) or
observation after concurrent chemoradiotherapy with or
without induction chemotherapy (NCT02958111); the
results are highly anticipated.
Induction chemotherapy
Compared with adjuvant sequencing, induction chemo­
therapy is better tolerated and eradicates micrometastases
earlier; therefore, induction chemotherapy followed by
concurrent chemoradiotherapy may represent a prom­
ising treatment strategy for nasopharyngeal carcinoma
in the IMRT era.99,100 However, randomised trials showed
inconsistent results regarding the efficacy of additional
induction chemotherapy,101–105 probably due to insufficient
sample size or different induction regimens (table 2).
Recently, two large-scale multicentre phase 3 trials from
Guangzhou have been reported: induction docetaxel,
cisplatin, and fluorouracil106,107 significantly improved
5-year overall survival (HR 0·65 [95% CI 0·43–0·98]),
failure-free survival (0·65 [0·43–0·98]), and distant failure-
free survival (0·60 [0·38–0·95]) in locoregionally advanced
nasopharyngeal carcinoma (excluding N0 disease) when
added to concurrent chemoradiotherapy; induction
cisplatin and fluorouracil108 significantly improved 3-year
disease-free survival (0·67 [0·47–0·95]; table 2). A small
phase 3 trial from Tunisia and France showed that
induction docetaxel, cisplatin, and fluorouracil signifi­
cantly improved 3-year progression-free survival (HR 0·44
[95% CI 0·20–0·97]), with a marginally significant effect
on overall survival (0·40 [0·15–1·04]),109 confirming the
efficacy of this triplet regimen. Another phase 3 trial from
Taiwan observed improved 5-year disease-free survival
(HR 0·74 [95% CI 0·57–0·97]) by adding induction
mitomycin, epirubicin, cisplatin, fluorouracil, and
leucovorin, although overall survival was not improved.110
Considering the controversial results, pooled analysis of
individual patient information from four randomised
trials from endemic areas was performed: induction
chemotherapy additional to concurrent chemoradiotherapy
significantly improved overall survival (HR 0·75 [95% CI
0·57–0·99]; 6% absolute benefit at 5 years) with the
survival benefit mainly associated with improved distant
control (0·68 [95% CI 0·51–0·90]; 7% absolute reduction
in distant failure rate at 5 years).111 To summarise eisting
studies, the 2018 NCCN Guidelines upgraded the evidence
for induction chemotherapy plus concurrent chemo­
radiotherapy from level 3 to level 2A, which is equal to that
of concurrent chemoradiotherapy plus adjuvant chemo­
therapy.74 In summary, induction chemotherapy plays an
increasingly important role in managing locoregionally
advanced nasopharyngeal carcinoma in the IMRT era,
 Seminar

Experimental chemotherapy Control chemotherapy Inclusion Sample Overall survival Progression-free survival
period size
Experimental vs HR (95% CI); Experimental vs HR (95% CI);
control (n-year p value control (n-year p value
results) results)
Induction chemotherapy plus concurrent chemoradiotherapy vs concurrent chemoradiotherapy alone
Hui et al101 Induction: docetaxel 75 mg/m² d1; cisplatin Concurrent: cisplatin 2002–04 68 94% vs 68% (3) 0·24 88% vs 60% (3) 0·49
(Phase 2) 75 mg/m² d1; q3wks × 2; concurrent: cisplatin 40 mg/m² d1; q1wk × 8 (0·08–0·73); (0·20–1·19);
40 mg/m² d1; q1wk × 8 p=0·012 p=0·12
Fountzilas et al102 Induction: cisplatin 75 mg/m² d1; epirubicin Concurrent: cisplatin 2003–08 141 70% vs 59% (3) 0·95 65% vs 64% (3) 1·40
(Phase 2) 75 mg/m2 d1; paclitaxel 175 mg/m² d1; 40 mg/m2 d1; q1wk × 8 (0·48–1·89); (0·71–2·77);
q3wks × 3; concurrent: cisplatin 40 mg/m² p=0·89 p=0·38
d1; q1wk × 8
Tan et al103 Induction: gemcitabine 1000 mg/m² d1, d8; Concurrent: cisplatin 2004–12 172 94% vs 92% (3) 1·05 (0–2·19); 75% vs 67% (3) 0·77
(Phase 3) carboplatin AUC=2·5 d1, d8; paclitaxel 40 mg/m² d1; q1wk × 8 p=0·49 (0·44–1·35);
70 mg/m² d1, d8; q3wks × 3; concurrent: p=0·36
cisplatin 40 mg/m² d1; q1wk × 8
Sun et al106,107 Induction: docetaxel 60 mg/m² d1; cisplatin Concurrent: cisplatin 2011–13 480 86% vs 78% (5) 0·65 77% vs 66% (5) 0·65
(Phase 3) 60 mg/m² d1; fluorouracil 600 mg/m² d1-5; 100 mg/m² d1; q3wks × 3 (0·43–0·98); (0·43–0·98);
q3wks × 3; concurrent: cisplatin 100 mg/m² p=0·042 p=0·019
d1; q3wks × 3
Cao et al108 Induction: cisplatin 80 mg/m² d1; Concurrent: cisplatin 2008–15 476 88% vs 89% (3) NR; p=0·82 82% vs 74% (3) 0·67
(Phase 3) fluorouracil 800 mg/m² d1-5; q3wks × 2; 80 mg/m2 d1; q3wks × 3 (0·47–0·95);
concurrent: cisplatin 80 mg/m² d1; q3wks × 3 p=0·028
Frikha et al109 Induction: docetaxel 75 mg/m² d1; cisplatin Concurrent: cisplatin 2009–12 83 86% vs 69% (3) 0·40 74% vs 57% (3) 0·44
(Phase 3) 75 mg/m² d1; fluorouracil 750 mg/m² d1-5; 40 mg/m² d1; q1wk × 7 (0·15–1·04); (0·20–0·97);
q3wks × 3; concurrent: cisplatin 40 mg/m² p=0·059 p=0·042
d1; q1wk × 7
Hong et al110 Induction: mitomycin 8 mg/m² d1; Concurrent: cisplatin 2003–09 479 72% vs 68% (5) 0·92 61% vs 50% (5) 0·74
(Phase 3) epirubicin 60 mg/m² d1; cisplatin 60 mg/m² 30 mg/m² d1; q1wk (0·67–1·27); (0·57–0·97);
d1; fluorouracil 450 mg/m² d8; leucovorin p=0·62 p=0·026
30 mg/m² d8; concurrent: cisplatin
30 mg/m² d1; q1wk
Others
Huang et al104 Induction: fluorouracil 750 mg/m² d1-5; Induction: fluorouracil 750 2002–05 400 50% vs 49% (10) 0·95 48% vs 48% (10) 1·01
(Phase 3) carboplatin AUC=6 d1; q3wks × 2; mg/m² d1-5; carboplatin (0·72–1·26); (0·77–1·33);
concurrent: carboplatin AUC=6 d7; q3wks × 3 AUC=6 d1; q3wks × 2 p=0·71 p=0·94
Lee et al105 Induction: cisplatin 100 mg/m² d1; Concurrent: cisplatin 2006–12 390 88% vs 83% (3) NR; p=0·12 80% vs 75% (3) NR; p=0·073
(Phase 3) fluorouracil 1000 mg/m² d1-5; or cisplatin 100 mg/m² d1; q3wks × 2/3; (706)*
100 mg/m² d1; capecitabine 2000 mg/m² adjuvant: cisplatin
d1-14; q3wks × 3; concurrent: cisplatin 80 mg/m² d1; fluorouracil
100 mg/m² d1; q3wks × 2/3 1000 mg/m² d1-4,
q4wks × 3
(Table 2 continues on next page)

which helps further improve distant control and sub­
sequently survival; patients with high risk of distant
metastasis may benefit from additional induction chemo­
therapy over concurrent chemoradiotherapy alone.
However, the ideal intensity for induction chemo­ ­ quality of life and convenience (ChiCTR-TRC-13003285,
therapy has not been established. The high-intensity
docetaxel plus cisplatin plus fluorouracil regimen appears
to confer more benefits than the docetaxel plus cisplatin
or cisplatin plus fluorouracil combinations,101,106–108 but
statis­
tically significant survival differences between
induction regimens were not detected by pooled analysis.111
Future prospective trials should be performed to identify
the ideal induction chemotherapy regimens and cycles.
The gemcitabine and cisplatin regimen has demon­
strated its superiority in metastatic nasopharyngeal
carcinoma,94 and is being tested as an induction regimen
in a phase 3 trial (NCT01872962), with the results being
greatly anticipated. Replacing cisplatin with lobaplatin
or nedaplatin, or fluorouracil with capecitabine during
induction and concurrent phases may help maintain non-
inferior efficacy with reduced toxicities and improved
NCT03503136; table 2). Furthermore, effective biomark­ers
predicting ideal candidates for induction chemo­therapy
remain investigational. Pre-treatment EBV DNA or
relevant genomic signatures may help identify patients
most likely to benefit from induction chemotherapy; EBV
DNA surveillance during induction chemotherapy may
also provide real-time information on tumour response
for therapeutic adaptation.
Disease surveillance and toxic effects
Local, regional, and/or distant failure can occur in non-
metastatic disease despite aggressive treatment. High-dose

www.thelancet.com Vol 394 July 6, 2019 71

 Seminar

Experimental chemotherapy Control chemotherapy Inclusion Sample Overall survival Progression-free survival
period size
Experimental vs HR (95% CI); Experimental vs HR (95% CI);
control (n-year p value control (n-year p value
results) results)
(Continued from previous page)
Phase 3 trials in progress
Ma et al Induction: gemcitabine 1000 mg/m² d1, d8; Concurrent: cisplatin 2013–16 480 ·· ·· ·· ··
(NCT01872962) cisplatin 80 mg/m² d1; q3wks × 3; 100 mg/m2 d1; q3wks × 3
concurrent: cisplatin 100 mg/m² d1;
q3wks × 3
Guo et al (ChiCTR- Induction: lobaplatin 30 mg/m2 d1; Induction: cisplatin 2013–16 494 ·· ·· ·· ··
TRC­13003285) fluorouracil 800 mg/m2 d1–5; q3wks × 2; 100 mg/m² d1; fluorouracil
concurrent: lobaplatin 30 mg/m2 d1; 800 mg/m² d1-5;
q3wks × 2 q3wks × 2; Concurrent:
cisplatin 100 mg/m² d1;
q3wks × 2
Mai et al Induction: paclitaxel liposome 135 mg/m2 Concurrent: cisplatin 2017– 322 ·· ·· ·· ··
(NCT03306121) d1; cisplatin 25 mg/m2 d1–3; fluorouracil 100 mg/m² d1; q3wks × 3; ongoing
750 mg/m2 d1–5; q3wks × 3; concurrent: Adjuvant: cisplatin
cisplatin 100 mg/m2 d1; q3wks × 3 80 mg/m² d1; fluorouracil
1000 mg/m² d1–4,
q4wks × 3
Ma et al Group A: Induction: docetaxel 60 mg/m² d1; ·· 2018– 632 ·· ·· ·· ··
(NCT03503136) cisplatin 60 mg/m² d1; fluorouracil ongoing
600 mg/m² d1–5; q3wks × 3; concurrent:
cisplatin 100 mg/m² d1; q3wks × 2; Group B:
Induction: docetaxel 60 mg/m² d1;
nedaplatin 60 mg/m² d1; fluorouracil
600 mg/m² d1–5; q3wks × 3; concurrent:
nedaplatin 100 mg/m² d1; q3wks × 2;
Group C: Induction: docetaxel 60 mg/m² d1;
cisplatin 60 mg/m² d1; capecitabine
1250 mg/m2 d1–14; q3wks × 3; concurrent:
cisplatin 100 mg/m² d1; q3wks × 2; Group D:
Induction: docetaxel 60 mg/m2 d1;
nedaplatin 60 mg/m² d1; capecitabine
1250 mg/m² d1–14; q3wks × 3; concurrent:
nedaplatin 100 mg/m² d1; q3wks × 2
AUC=area under the concentration–time curve. ChiCTR=Chinese Clinical Trial Register. HR=hazard ratio. NCT=ClinicalTrials.gov identifier. NR=not reported. q1/3/4wks=every 1/3/4 weeks. *390 patients in
conventional fractionation radiotherapy arms; 706 patients in the whole trial.

Table 2: Randomised trials evaluating induction chemotherapy plus concurrent chemoradiotherapy

radiation or chemoradiotherapy inevitably induces acute
and late toxicities, and the latter can emerge months or
even years after treatment completion. These issues
highlight the importance of close follow-up.
12 weeks after the completion of radiotherapy or
chemoradiotherapy is widely considered the appropriate
timepoint for initial assessment of residual disease, as by
then, treatment-induced inflammation would have largely
resolved, most tumours would have regressed, and delayed
tumour regression within this timepoint (12 weeks)
would not affect overall local control.112,113 Comprehensive
response assessment includes thorough history and
physical examination, nasopharyngoscopy with or without
biopsy, plasma EBV DNA, and radiological imaging. It
represents a challenge for distinguishing residual tumours
from post radiation changes. Although MRI is superior to
CT for diagnosing local residual/recurrent nasopharyn­
geal carcinoma, both modalities have unsatisfactorily low
accuracy.111,112 Here, ¹⁸F-FDG-PET/CT can add additional
value to the diagnosis, as it is more accurate in
distinguishing residual or recurrent disease from fibrosis
or scar tissue post radiotherapy, and combined MR and
¹⁸F-FDG-PET/CT is more accurate for tumour restaging
than either modality independently.55,114 Plasma EBV DNA
could also be used as a complementary surveillance
method to conventional imaging for monitoring failure,
particularly distant metastasis.115,116 A prospective, multi­
centre trial has confirmed that post-radiotherapy plasma
EBV DNA levels correlate significantly with the
corresponding hazards of locoregional failure, distant
metastasis, and death in nasopharyngeal carcinoma
(appendix p 21).48
The most commonly observed acute radiotherapy-
related toxicities in IMRT for nasopharyngeal carcinoma
include mucositis, dermatitis, xerostomia, and dysphagia
(appendix p 30). Adding chemotherapy to radiotherapy
invariably increases haematological and non-haemato­
logical acute toxicity incidence. Although pharmacological

72 www.thelancet.com Vol 394 July 6, 2019


interventions for acute mucositis and xerostomia are often
ineffective, clinical symptoms generally improve within
weeks after treatment cessation. Sometimes, grade 3 or
4 reactions can persist and lead to consequential late
effects. Surveillance and prompt management of late
toxicities are important for survivors’ long-term wellbeing.
Common late toxicities include xerostomia, sensorineural
hearing loss, osteoradionecrosis, trismus, CNS abnor­
malities (eg, temporal lobe injury), and hormonal dys­
function (eg, hypothyroidism; appendix p 30).
Managing residual or recurrent disease
In the IMRT era, around 10% of patients have residual
disease or develop recurrent disease at the primary
and/or regional site.66,117 It is widely acknowledged that
neck dissection is the primary choice for patients with
isolated regional failure; the 5-year overall survival rate
is 41%.118 Radiotherapy or surgery can salvage local
nasopharyngeal failure. Commonly, tumours that recur
within 1 year are considered radioresistant; surgery is
recommended if they are resectable. Recently, a
prognostic model119 was developed for stratifying
radioresistant nasopharyngeal carcinoma, where low-
risk patients are ideal candidates for curative repeat
IMRT. In addition, as previously mentioned, IMCT
could be a promising salvage treatment for recurrent
nasopharyngeal carcinoma, considering its physical/
biological advantages over IMRT.69 Nonetheless, repeat
irradiation should be approached with caution in all
cases, as there is a high risk of fatal late effects, with
a recent meta-analysis reporting 33% grade 5 toxicity
following repeat IMRT.120 In summary, aggressive treat­
ment including surgery or re-irradiation may be better
for improving the chances of long-term survival in the
management of recurrent nasopharyngeal carcinoma,
while chemotherapy may be better for residual/
recurrent disease that is neither resectable nor suitable
for re-irradiation, or for high-risk patients with poor
prognosis.121
Given the deep location and complex adjacency of the
nasopharynx, salvage surgery of local failure can be
challenging, with potentially severe morbidities. Although
various open approaches such as the transmaxillary
approach have been devised for nasopharyngectomy,122
where the 5-year disease-free survival rate can reach 57%,
>40% of patients experience complications such as facial
numbness, trismus, and palatal fistula.123 To avoid the
grave complications of open surgery, Chen and colleagues
developed an endoscopic nasopharyngectomy technique
that allowed en-bloc tumour resection similar to open
surgery; they further adapted a modified pedicle nasal
septum and floor mucosa flap to resurface the
nasopharyngeal defect that is very difficult to heal due to
the prior radiation.124,125 A new surgical staging system of
recurrent nasopharyngeal carcinoma has also been
proposed to help determine whether the disease is
resectable.126
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Seminar
Management of metastatic disease
Patients with metastatic nasopharyngeal carcinoma (stage
IVB) are heterogeneous groups with different outcomes;
in some cases, long-term survivorship is possible. For
example, in synchronous metastases, which are present in
approximately 10% of newly diagnosed patients, prognosis
is closely related with the anatomic degree of metastasis
lesions; palliative chemotherapy can lead to median
overall survival of approximately 10–15 months, which can
be greatly increased if the patient is suitable for com­bined
therapy such as locoregional radiotherapy and local
therapy of metastatic lesions.127–131 Therefore, individualised
treatment for metastatic nasopharyngeal carcinoma is
necessary. The risk stratification for metastatic naso­
pharyngeal carcinoma can be performed based on clinical
features such as metastasis status (e.g. oligo­metastases,
metachronous metastasis, lung or liver solitary metas­
tasis, multiple liver metastases), or the incorporation of
prognostic markers (eg—haemoglobin, lactate dehy­
drogenase, C-reactive protein or albumin).130,132–136
In prognostic groups with such favourable features, a
curative tactic that involves the primary tumour receiving
radical chemoradiotherapy and oligometastases under­
going ablative treatment may be optimal. In terms of
systemic treatment, the platinum-containing doublet of
cisplatin plus fluorouracil has been the first-line therapy
for recurring or metastatic disease for decades,
with 40–65% response rates.137–139 Nonetheless, whether
cisplatin plus fluorouracil represents the most efficacious
treatment strategy has always been contentious, as it has
never been directly compared with other regimens in
randomised trials.140 In the landmark GEM20110714 trial,141
Zhang and colleagues presented for the first time a
randomised phase 3 trial of two competing combinations
containing platinum: gemcitabine  plus cisplatin versus
fluorouracil plus cisplatin, in patients with recurrent or
metastatic disease. Inspiringly, a significantly higher
proportion of patients in the gemcitabine group achieved
an objective response than in the fluorouracil group
(64% vs 42%; p<0·0001). Compared with fluorouracil plus
cisplatin, gemcitabine plus cisplatin also significantly
improved progression-free survival (median: 7·0 vs
5·6 months; HR 0·55 [95% CI 0·44–0·68]) and overall
survival (median: 29·1 vs 20·9 months; 0·62 [0·45–0·84]).
That study establishes gemcitabine plus cisplatin as a
new standard first-line treatment option for recurrent or
metastatic nasopharyngeal carcinoma.
The progress of molecular-targeted therapies in
nasopharyngeal carcinoma is lagging (appendix), and
more large-scale randomised studies are warranted
to assess the value of targeted drugs in nasopharyn­
geal carcinoma. Encouragingly, immune checkpoint
therapies have achieved great progress in recurrent or
metastatic nasopharyngeal carcinoma, and represent
a promising approach towards improving clinical
outcomes, which will be discussed in the following
section.
 Seminar

Immunotherapy for nasopharyngeal carcinoma checkpoint blockades. EBV-directed vaccination exploits

Tumour immunotherapy may represent a promising T-cell activation to target nasopharyngeal cancer cells by
therapeutic approach in nasopharyngeal carcinoma, recognising expressed viral antigens (eg—EBNA1, LMP1,
where the primary strategies include EBV-directed LMP2). For example, vaccination against LMP2 epitopes
vaccination, adoptive T-cell therapy, and immune with dendritic cells or peptides, or adoptive transfer of

Key eligibility criteria Experimental regimen Control regimen Sample Objective Overall survival Progression-free
size response survival
Median 1-year Median 1-year
(months) rate (months) rate
Trials with results
Hsu et al142 Recurrent or metastatic disease; Pembrolizumab 10 mg/kg every ·· 27 26% 16·5 63% 6·5 33%
(phase 1) failure on previous standard 2 weeks up to 2 years or until
therapy; PD-L1 expression in 1% disease progression or unacceptable
or more of tumour cells or toxicity
tumour-infiltrating lymphocytes
Ma et al143 Recurrent or metastatic disease; Nivolumab 3 mg/kg every 2 weeks ·· 44 20% 17·1 59% 2·8 19%
(phase 2) failure on at least one previous on a 4-week cycle until disease
line of platinum-based progression
chemotherapy
Fang et al144 Recurrent or metastatic disease; Camrelizumab at escalating doses ·· 93 34% NR NR 5·6 27%
(phase 1) failure on at least one previous of 1 mg/kg, 3 mg/kg, and 10 mg/kg,
line of platinum-based and a bridging dose of 200 mg
chemotherapy per dose once every 2 weeks until
unacceptable toxicity
Fang et al144 Recurrent or metastatic disease; Camrelizumab 200 mg (day 1), ·· 23 91% NR NR NR 61%
(phase 1) treatment-naive patient gemcitabine 1 g/m² (days 1 and 8),
and cisplatin 80 mg/m² (day 1)
every 3 weeks for six cycles,
followed by camrelizumab 200 mg
maintenance once every 3 weeks
Phase 3 trials in progress
Merck Sharp & Recurrent or metastatic disease; Pembrolizumab 200 mg every Capecitabine 2000 mg/m² 230 ·· ·· ·· ·· ··
Dohme Corp failure on at least one previous 3 weeks on a 3-week cycle until d1-14 of each 3-week cycle or
(NCT02611960) line of platinum-based disease progression or unacceptable gemcitabine 1250 mg/m² d1,
chemotherapy toxicity or a maximum of up to d8; of each 3-week cycle or
35 cycles docetaxel 75 mg/m² d1 of each
3-week cycle until disease
progression or unacceptable
toxicity
Xu et al Recurrent or metastatic disease; JS001 combined with gemcitabine Placebo combined with 280 ·· ·· ·· ·· ··
(NCT03581786) treatment-naive patient and cisplatin given every 3 weeks in gemcitabine and cisplatin
3-week cycles given every 3 weeks in 3-week
cycles
Zhang et al Recurrent or metastatic disease; Camrelizumab 200 mg (day 1), Placebo combined with 250 ·· ·· ·· ·· ··
(NCT03707509) treatment-naive patient gemcitabine 1 g/m² (days 1 and 8), gemcitabine 1 g/m² (days 1
and cisplatin 80 mg/m² (day 1) and 8), and cisplatin 80 mg/m²
every 3 weeks for six cycles (day 1) every 3 weeks for
six cycles
Ma et al Stage III-IVA disease (except Adjuvant: camrelizumab 3 mg/kg Observation 400 ·· ·· ·· ·· ··
(NCT03427827) T3-4N0 and T3N1); completed (≤200 mg) d1; q4wks × 12
induction chemotherapy of
gemcitabine and cisplatin
followed by concurrent
cisplatin-radiotherapy;
4-6 weeks after chemoradiation
Ma et al Stage III-IVA disease (except Induction: gemcitabine Induction: gemcitabine 420 ·· ·· ·· ·· ··
(NCT03700476) T3–4N0 and T3N1) 1000 mg/m² d1, d8; cisplatin 1000 mg/m² d1, d8; cisplatin
80 mg/m² d1; sintilimab 200 mg 80 mg/m² d1; q3wks × 3;
d1; q3wks × 3; concurrent: cisplatin Concurrent: cisplatin
100 mg/m² d1; q3wks × 2; sintilimab 100 mg/m² d1; q3wks × 2
200 mg d1; q3wks × 3
NCT=ClinicalTrials.gov identifier. NR=not reported. PD-L1=programmed death-ligand 1. q3/4wks=every 3/4 weeks.

Table 3: Clinical trials evaluating immune checkpoint inhibitors in nasopharyngeal carcinoma

74 www.thelancet.com Vol 394 July 6, 2019


cytotoxic T lymphocytes or TILs have shown potential
clinical efficacy in advanced nasopharyngeal carcinoma
(appendix).
Recently, immune checkpoint blockade therapies have
achieved breakthroughs in tumour immnuotherapy.
Nasopharyngeal carcinoma tumours are characterised
by high PD-L1 expression (up to 90% of tumour cells)
and abundant infiltration of non-malignant lymphocytes
(about 50% of samples with >70% stromal TILs or
>10% intratumoral TILs; appendix),37–42 which renders
patients potentially suitable for immune checkpoint
blockade therapies. Several important single-arm trials
evaluating anti–PD-1 monoclonal antibodies in recur­
rent or metastatic nasopharyngeal carcinoma have been
reported, where PD-1 inhibitors showed promising
clinical activity (table 3).142–144 In a phase 1 trial of 27 pa­­
tients with unresectable or metastatic nasopharyngeal
carcinoma that had failed prior standard therapy and had
PD-L1 expression in ≥1% of tumour cells or TILs,
pembrolizumab treatment resulted in 26% objective
response, 63% 1-year overall survival, and 33% 1-year
progression-free sur­vival.142 In another phase 2 trial
evaluating nivolumab in 44 patients with multiply pre-
treated recurrent or metastatic nasopharyngeal carci­
noma, the objective response rate was 20%, with
59% 1-year overall survival and 19% 1-year progression-
free survival.143 Recently, Fang and colleagues144 reported
on two phase 1 trials, where camrelizumab (anti–PD-1
monoclonal antibody) was used as (1) monotherapy
for 93 patients with multiply pre-treated recurrent
or metastatic disease, and (2) in combination with
gemcitabine plus  cisplatin for 23 patients with treatment-
naïve recurrent or metastatic disease. In the monother­
apy trial, there was 34% objective response rate and
27% 1-year progression-free survival. In the combination
trial, the objective response rate was 91% and the
1-year progression-free survival rate was 61%. As
anti-PD-1 antibodies have promising anti-tumour activity
and predictable safety profile, several randomised
phase 3 trials for nasopharyngeal carcinoma are ongoing
(table 3). For recurrent or metastatic disease, the
KEYNOTE-122 trial (NCT02611960) aims to evaluate
pembrolizumab monotherapy against standard chemo­
therapy in previously treated patients, while another
two trials (NCT03581786 and NCT03707509) are further
assessing anti–PD-1 antibody combined with gemcitabine
and cisplatin versus gemcitabine and cisplatin for
treatment-naive patients. These studies’ final results will
show whether anti–PD-1 antibody is preferred for
salvaging chemotherapy failure or whether the combined
method is more suitable as a first-line standard of care for
appro­priate patients. Two phase 3 trials (NCT03427827
and NCT03700476) investigating adjuvant camrelizumab
or induction and concurrent sintilimab (anti-PD-1
antibody) in locoregionally advanced nasopharyngeal
carcinoma will test the value of adding anti-PD-1 therapy
to standard treatment in the curative setting.
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Seminar
Panel: Research questions on nasopharyngeal carcinoma that remain to be answered
• What biological mechanisms underlie the progress of Epsten-Barr virus (EBV)
infection and the development of nasopharyngeal carcinoma?
• What are the progressive genomic changes during nasopharyngeal carcinoma
development, progression, and recurrence?
• Which population should be screened for nasopharyngeal carcinoma, and how and at
what age and interval should this be done?
• How can plasma EBV DNA be incorporated into the current staging system?
• How can longitudinal plasma EBV DNA surveillance during treatment be applied for
risk-stratified therapeutic adaptation?
• How can biomarkers for predicting treatment response (eg, induction chemotherapy,
adjuvant chemotherapy, immunotherapy) and prognosis be developed and
validated?
• How can reliable radiomics models for improving decision support in nasopharyngeal
carcinoma be developed?
• How can artificial intelligence automation for nasopharyngeal carcinoma treatment
decision (radiotherapy planning, chemotherapy timing and regimens) be applied?
• What is the emerging role of IMPT and IMCT in nasopharyngeal carcinoma?
• What is the best possible way to administer concurrent cisplatin, tri-weekly or
weekly?
• Should stage II or T3N0M0 nasopharyngeal carcinoma be managed by radiotherapy
alone or concurrent chemoradiotherapy?
• Could lobaplatin or nedaplatin replace cisplatin, or could capecitabine replace
fluorouracil?
• What is the value of metronomic adjuvant chemotherapy (eg, low-dose oral
fluorouracil such as capecitabine) in locoregionally advanced nasopharyngeal
carcinoma?
• Which patients with residual or recurrent nasopharyngeal carcinoma should receive
surgery or radiotherapy?
• Which patients with metastatic nasopharyngeal carcinoma should receive definitive
radiotherapy or chemoradiotherapy?
• What is the role of metastasectomy or stereotactic ablative radiotherapy in
oligometastatic nasopharyngeal carcinoma?
• How can immunotherapy, especially immune checkpoint blockade, be incorporated
into the current treatment paradigm of nasopharyngeal carcinoma?
• How can patients that could benefit from immunotherapy be identified?
One future challenge is that PD-1 inhibition benefits
only a subset of patients. Identifying biomarkers
associated with treatment response would allow appro­
priate immunotherapy tailoring for different patient
subgroups. Unfortunately, no strong evidence currently
supports the correlation between response rate to anti-
PD-1 monoclonal antibodies and known biomarkers such
as PD-L1 expression in tumour or immune cells, HLA-A
and HLA-B expression, pre-treatment or post-treatment
EBV DNA levels, plasma EBV DNA clearance, and
tumour mutational burden in advanced nasopharyngeal
carcinoma.143,144 Nonetheless, these exploratory biomarker
analyses were insufficiently powered, and future large-
scale studies are warranted to identify and validate
potential therapeutic biomarkers (eg, TIL level, immune
gene signatures, immune molecular subgroups)145–151
associated with nasopharyngeal carcinoma treatment
response or resistance.
 Seminar
Apart from biomarker identification, a bigger patient
group might require an immuno-oncology cocktail.
Fang and colleagues144 reported on camrelizumab mono­
therapy in eight patients who had received ipilimumab
previously; they had a significantly higher response to
the consequent camrelizumab compared to patients
without prior ipilimumab (75% vs 30%). These results
suggest that dual immune checkpoint inhibition, such as
combination or sequential therapy with antibodies
against PD-1, CTLA-4, and other immune checkpoint
agents may further improve clinical activity.
Conclusions and future directions
Nasopharyngeal carcinoma incidence has declined
gradually but progressively, accompanied by substantially
reduced mortality, which is likely due to lifestyle and
environmental changes, enhanced understanding of the
pathogenesis and risk factors, population screening,
advancements in diagnostic techniques, and individualised
comprehensive chemoradiotherapy strategies. However,
considering the current lack of reliable evidence, several
questions on nasopharyngeal carcinoma pathogenesis and
clinical management remain to be addressed (panel). The
next decade of nasopharyngeal carcinoma research will
focus on exploring the biological mechanisms underlying
its pathogenesis, refining screening and staging strategies,
identifying biomarkers related to prognostic risk strati­
fication and treatment benefits gained, optimising
treatment strategies for the different patient subgroups,
and developing novel therapeutics. Hopefully, ongoing
studies will identify the needed knowledge, tools, and
therapies for advancing the management of naso­
pharyngeal carcinoma to the next level.
Contributors
YPC, YS, and JM were involved in the conception of the manuscript.
YPC, ATCC, QTL, PB, YS, and JM wrote and reviewed the original
manuscript. YPC, ATCC, QTL, PB, YS, and JM revised the manuscript.
YPC, ATCC, QTL, PB, YS, and JM 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.
PB has received funding from Astellas Pharma, Merck-Serono,
and Amgen outside the submitted work. All other authors declare no
competing interests.
Acknowledgments
We would like to thank Melvin L K Chua (Division of Radiation Oncology,
National Cancer Centre Singapore; Oncology Academic Clinical
Programme, Duke-NUS Medical School, Singapore) for his helpful
comments on this study. We thank Ming-Yuan Chen (Department of
Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center,
Guangzhou, China) for assisting with the writing of Management of
Residual or Recurrent Disease section. We thank Kwok-Wai Lo
(Department of Anatomical & Cellular Pathology, The Chinese University
of Hong Kong, Hong Kong, China) for providing materials and
comments on the plotting of figure 2. We thank Mu-Sheng Zeng,
Wei-Hua Jia, and Jin-Xin Bei (State Key Laboratory of Oncology in
South China, Sun Yat-sen University Cancer Center, Guangzhou, China)
for their comments on the Pathology and Risk Factors section. We thank
Zi-Qi Zheng and Wei-Jie Luo (Department of Radiation Oncology,
Sun Yat-sen University Cancer Center, Guangzhou, China) for assistance
with figure plotting. We thank Ling-Long Tang, Li Lin, Jia-Wei Lv,
Yuan Zhang, and Ya-Qin Wang (Department of Radiation Oncology,
76 www.thelancet.com Vol 394 July 6, 2019
Sun Yat-sen University Cancer Center, Guangzhou, China) for assistance
with providing the figure materials.
References
1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.
Global cancer statistics 2018: GLOBOCAN estimates of incidence
and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J Clin 2018; 68: 394–424.
2 Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory:
cancer today. Lyon, France: International Agency for Research on
Cancer 2018. https://gco.iarc.fr/today (accessed Dec 28, 2018).
3 Tang LL, Chen WQ, Xue WQ, et al. Global trends in incidence and
mortality of nasopharyngeal carcinoma. Cancer Lett 2016; 374: 22–30.
4 Wei KR, Zheng RS, Zhang SW, Liang ZH, Li ZM, Chen WQ.
Nasopharyngeal carcinoma incidence and mortality in China, 2013.
Chin J Cancer 2017; 36: 90.
5 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: 680–5.
6 Li K, Lin GZ, Shen JC, Zhou Q. Time trends of nasopharyngeal
carcinoma in urban Guangzhou over a 12-year period (2000–2011):
declines in both incidence and mortality. Asian Pac J Cancer Prev
2014; 15: 9899–903.
7 Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015.
CA Cancer J Clin 2016; 66: 115–32.
8 Yu WM, Hussain SS. Incidence of nasopharyngeal carcinoma in
Chinese immigrants, compared with Chinese in China and
South East Asia: review. J Laryngol Otol 2009; 123: 1067–74.
9 Wang HY, Chang YL, To KF, et al. A new prognostic histopathologic
classification of nasopharyngeal carcinoma. Chin J Cancer 2016;
35: 41.
10 Pathmanathan R, Prasad U, Chandrika G, Sadler R, Flynn K,
Raab-Traub N. Undifferentiated, nonkeratinizing, and squamous
cell carcinoma of the nasopharynx. Variants of Epstein-Barr
virus-infected neoplasia. Am J Pathol 1995; 146: 1355–67.
11 Young LS, Dawson CW. Epstein-Barr virus and nasopharyngeal
carcinoma. Chin J Cancer 2014; 33: 581–90.
12 Chua MLK, Wee JTS, Hui EP, Chan ATC. Nasopharyngeal
carcinoma. Lancet 2016; 387: 1012–24.
13 Bei JX, Zuo XY, Liu WS, Guo YM, Zeng YX. Genetic susceptibility
to the endemic form of NPC. Chin Clin Oncol 2016; 5: 15.
14 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.
15 Fachiroh J, Sangrajrang S, Johansson M, et al. Tobacco consumption
and genetic susceptibility to nasopharyngeal carcinoma (NPC) in
Thailand. Cancer Causes Control 2012; 23: 1995–2002.
16 Ng CC, Yew PY, Puah SM, et al. A genome-wide association study
identifies ITGA9 conferring risk of nasopharyngeal carcinoma.
J Hum Genet 2009; 54: 392–97.
17 Bei JX, Su WH, Ng CC, et al. A GWAS meta-analysis and replication
study identifies a novel locus within CLPTM1L/TERT associated
with nasopharyngeal carcinoma in individuals of Chinese ancestry.
Cancer Epidemiol Biomarkers Prev 2016; 25: 188–92.
18 Cui Q, Feng QS, Mo HY, et al. An extended genome-wide
association study identifies novel susceptibility loci for
nasopharyngeal carcinoma. Hum Mol Genet 2016; 25: 3626–34.
19 Dai W, Zheng H, Cheung AK, et al. Whole-exome sequencing
identifies MST1R as a genetic susceptibility gene in
nasopharyngeal carcinoma. Proc Natl Acad Sci USA 2016;
113: 3317–22.
20 Lin DC, Meng X, Hazawa M, et al. The genomic landscape of
nasopharyngeal carcinoma. Nat Genet 2014; 46: 866–71.
21 Zheng H, Dai W, Cheung AK, et al. Whole-exome sequencing
identifies multiple loss-of-function mutations of NF-kappaB
pathway regulators in nasopharyngeal carcinoma.
Proc Natl Acad Sci USA 2016; 113: 11283–88.
22 Li YY, Chung GT, Lui VW, et al. Exome and genome sequencing of
nasopharynx cancer identifies NF-kappaB pathway activating
mutations. Nature Commun 2017; 8: 14121.
23 Zhang L, MacIsaac KD, Zhou T, et al. Genomic analysis of
nasopharyngeal carcinoma reveals TIME-based subtypes.
Mol Cancer Res 2017; 15: 1722–32.

24 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.
25 Tsao SW, Yip YL, Tsang CM, et al. Etiological factors of
nasopharyngeal carcinoma. Oral Oncol 2014; 50: 330–8.
26 Liu Z, Chang ET, Liu Q, et al. Oral hygiene and risk of
nasopharyngeal carcinoma—a population-based case-control study
in China. Cancer Epidemiol Biomarkers Prev 2016; 25: 1201–7.
27 Liu Z, Chang ET, Liu Q, et al. Quantification of familial risk of
nasopharyngeal carcinoma in a high-incidence area. Cancer 2017;
123: 2716–25.
28 Chang ET, Liu Z, Hildesheim A, et al. active and passive smoking
and risk of nasopharyngeal carcinoma: a population-based
case-control study in southern China. Am J Epidemiol 2017;
185: 1272–80.
29 Coghill AE, Hsu WL, Pfeiffer RM, et al. Epstein-Barr virus serology
as a potential screening marker for nasopharyngeal carcinoma
among high-risk individuals from multiplex families in Taiwan.
Cancer Epidemiol BiomarkersPrev 2014; 23: 1213–19.
30 Chan KCA, Woo JKS, King A, et al. Analysis of plasma Epstein-Barr
virus DNA to Screen for Nasopharyngeal Cancer. New Engl J Med
2017; 377: 513–22.
31 Amin MB, American Joint Committee on Cancer. AJCC cancer
staging manual. 8th ed. New York: Springer; 2017.
32 Tang LL, Chen YP, Mao YP, et al. Validation of the 8th edition of
the uicc/ajcc staging system for nasopharyngeal carcinoma from
endemic areas in the intensity-modulated radiotherapy era.
J Natl Compr Canc Netw 2017; 15: 913–9.
33 Tang LQ, Li CF, Li J, et al. Establishment and validation of
prognostic nomograms for endemic nasopharyngeal carcinoma.
J Natl Cancer Inst 2016; 108(1).
34 Jiang W, Liu N, Chen XZ, et al. Genome-wide identification of a
methylation gene panel as a prognostic biomarker in
nasopharyngeal carcinoma. Mol Cancer Ther 2015; 14: 2864–73.
35 Liu N, Chen NY, Cui RX, et al. Prognostic value of a microRNA
signature in nasopharyngeal carcinoma: a microRNA expression
analysis. Lancet Oncol 2012; 13: 633–41.
36 Tang XR, Li YQ, Liang SB, et al. Development and validation of
a gene expression-based signature to predict distant metastasis
in locoregionally advanced nasopharyngeal carcinoma:
a retrospective, multicentre, cohort study. Lancet Oncol 2018;
19: 382–93.
37 Fang W, Zhang J, Hong S, et al. EBV-driven LMP1 and
IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma:
implications for oncotargeted therapy. Oncotarget 2014;
5: 12189–202.
38 Lee VH, Lo AW, Leung CY, et al. Correlation of PD-L1 expression of
tumor cells with survival outcomes after radical intensity-modulated
radiation therapy for non-metastatic nasopharyngeal carcinoma.
PLoS One 2016; 11: e0157969.
39 Zhu Q, Cai MY, Chen CL, et al. Tumor cells PD-L1 expression as a
favorable prognosis factor in nasopharyngeal carcinoma patients
with pre-existing intratumor-infiltrating lymphocytes.
Oncoimmunology 2017; 6: e1312240.
40 Larbcharoensub N, Mahaprom K, Jiarpinitnun C, et al.
Characterization of PD-L1 and PD-1 expression and CD8+
tumor-infiltrating lymphocyte in Epstein-Barr virus-associated
nasopharyngeal carcinoma. Am J Clin Oncol 2018; 41: 1204–10.
41 Ono T, Azuma K, Kawahara A, et al. Prognostic stratification of
patients with nasopharyngeal carcinoma based on tumor immune
microenvironment. Head Neck 2018; 40: 2007–19.
42 Wang YQ, Chen YP, Zhang Y, et al. Prognostic significance of
tumor-infiltrating lymphocytes in nondisseminated
nasopharyngeal carcinoma: a large-scale cohort study. Int J Cancer
2018; 142: 2558–66.
43 Xu C, Chen YP, Liu X, et al. Establishing and applying nomograms
based on the 8th edition of the UICC/AJCC staging system to select
patients with nasopharyngeal carcinoma who benefit from
induction chemotherapy plus concurrent chemoradiotherapy.
Oral Oncol 2017; 69: 99–107.
44 Lee VH, Kwong DL, Leung TW, et al. The addition of pretreatment
plasma Epstein-Barr virus DNA into the eighth edition of
nasopharyngeal cancer TNM stage classification. Int J Cancer 2019;
144: 1713–22.
www.thelancet.com Vol 394 July 6, 2019 77
Seminar
45 Guo R, Tang LL, Mao YP, et al. Proposed modifications and
incorporation of plasma Epstein-Barr virus DNA improve the
TNM staging system for Epstein-Barr virus-related nasopharyngeal
carcinoma. Cancer 2019; 125: 79–89.
46 Liu LT, Tang LQ, Chen QY, et al. The prognostic value of plasma
epstein-barr viral dna and tumor response to neoadjuvant
chemotherapy in advanced-stage nasopharyngeal carcinoma.
Int J Radiat Oncol Biol Phys 2015; 93: 862–69.
47 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.
48 Chan ATC, Hui EP, Ngan RKC, et al. Analysis of plasma
Epstein-Barr virus DNA in nasopharyngeal cancer after
chemoradiation to identify high-risk patients for adjuvant
chemotherapy: a randomized controlled trial. J Clin Oncol 2018;
JCO2018777847.
49 Le QT, Zhang Q, Cao H, et al. An international collaboration to
harmonize the quantitative plasma Epstein-Barr virus DNA assay
for future biomarker-guided trials in nasopharyngeal carcinoma.
Clin Cancer Res 2013; 19: 2208–15.
50 Kim KY, Le QT, Yom SS, et al. Current state of pcr-based
epstein-barr virus dna testing for nasopharyngeal cancer.
J Natl Cancer Inst 2017; 109(4).
51 Liao XB, Mao YP, Liu LZ, et al. How does magnetic resonance
imaging influence staging according to AJCC staging system for
nasopharyngeal carcinoma compared with computed tomography?
Int J Radiat Oncol Biol Physics 2008; 72: 1368–77.
52 Chen WS, Li JJ, Hong L, Xing ZB, Wang F, Li CQ. Comparison of
MRI, CT and 18F-FDG PET/CT in the diagnosis of local and
metastatic of nasopharyngeal carcinomas: an updated meta analysis
of clinical studies. Am J Transl Res 2016; 8: 4532–47.
53 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.
54 Peng H, Chen L, Tang LL, et al. Significant value of (18)F-FDG-PET/
CT in diagnosing small cervical lymph node metastases in patients
with nasopharyngeal carcinoma treated with intensity-modulated
radiotherapy. Chin J Cancer 2017; 36: 95.
55 Wei J, Pei S, Zhu X. Comparison of 18F-FDG PET/CT, MRI and
SPECT in the diagnosis of local residual/recurrent nasopharyngeal
carcinoma: A meta-analysis. Oral Oncol 2016; 52: 11–7.
56 Chan SC, Yeh CH, Yen TC, et al. Clinical utility of simultaneous
whole-body (18)F-FDG PET/MRI as a single-step imaging modality
in the staging of primary nasopharyngeal carcinoma.
Eur J Nucl Med Mol Imaging 2018; 45: 1297–308.
57 Lin P, Min M, Lee M, et al. Prognostic utility of (18)F-FDG PET-CT
performed prior to and during primary radiotherapy for
nasopharyngeal carcinoma: Index node is a useful prognostic
imaging biomarker site. Radiother Oncol 2016; 120: 87–91.
58 Chen YH, Chang KP, Chu SC, et al. Value of early evaluation of
treatment response using (18)F-FDG PET/CT parameters and the
Epstein-Barr virus DNA load for prediction of outcome in patients
with primary nasopharyngeal carcinoma.
Eur J Nucl Med Mol Imaging 2019; 46: 650–60.
59 Gillies RJ, Kinahan PE, Hricak H. Radiomics: images are more than
pictures, they are data. Radiology 2016; 278: 563–77.
60 Zhang B, Tian J, Dong D, et al. Radiomics features of
multiparametric mri as novel prognostic factors in advanced
nasopharyngeal carcinoma. Clin Cancer Res 2017; 23: 4259–69.

61 Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of
life after intensity-modulated radiotherapy vs. conventional
radiotherapy for early-stage nasopharyngeal carcinoma: initial report
on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys
2006; 66: 981–91.
62 Kam MK, Leung SF, Zee B, et al. Prospective randomized study of
intensity-modulated radiotherapy on salivary gland function in
early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007;
25: 4873–9.
63 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.
 Seminar
64 Zhang B, Mo Z, Du W, Wang Y, Liu L, Wei Y. Intensity-modulated
radiation therapy versus 2D-RT or 3D-CRT for the treatment of
nasopharyngeal carcinoma: a systematic review and meta-analysis.
Oral Oncol 2015; 51: 1041–46.
65 Co J, Mejia MB, Dizon JM. Evidence on effectiveness of
intensity-modulated radiotherapy versus 2-dimensional
radiotherapy in the treatment of nasopharyngeal carcinoma:
meta-analysis and a systematic review of the literature. Head Neck
2016; 38 (suppl 1): E2130–42.
66 Mao YP, Tang LL, Chen L, et al. Prognostic factors and failure
patterns in non-metastatic nasopharyngeal carcinoma after
intensity-modulated radiotherapy. Chin J Cancer 2016; 35: 103.
67 Lewis GD, Holliday EB, Kocak-Uzel E, et al. Intensity-modulated
proton therapy for nasopharyngeal carcinoma: decreased radiation
dose to normal structures and encouraging clinical outcomes.
Head Neck 2016; 38 (suppl 1): E1886–95.
68 Kong L, Gao J, Hu J, et al. Phase I/II trial evaluating concurrent
carbon-ion radiotherapy plus chemotherapy for salvage treatment of
locally recurrent nasopharyngeal carcinoma. Chin J Cancer 2016;
35: 101.
69 Hu J, Bao C, Gao J, et al. Salvage treatment using carbon ion
radiation in patients with locoregionally recurrent nasopharyngeal
carcinoma: Initial results. Cancer 2018; 124: 2427–37.
70 Lee AW, Ng WT, Pan JJ, et al. International guideline for the
delineation of the clinical target volumes (CTV) for nasopharyngeal
carcinoma. Radiother Oncol 2018; 126: 25–36.
71 Sun Y, Yu XL, Luo W, et al. Recommendation for a contouring
method and atlas of organs at risk in nasopharyngeal carcinoma
patients receiving intensity-modulated radiotherapy. Radiother Oncol
2014; 110: 390–97.
72 Tao CJ, Yi JL, Chen NY, et al. Multi-subject atlas-based
auto-segmentation reduces interobserver variation and improves
dosimetric parameter consistency for organs at risk in
nasopharyngeal carcinoma: a multi-institution clinical study.
Radiother Oncol 2015; 115: 407–11.
73 Lin L, Dou Q, Jin YM, et al. Deep learning for automated
contouring of primary tumor volumes by mri for nasopharyngeal
carcinoma. Radiology 2019: 291: 677–86.
74 Colevas AD, Yom SS, Pfister DG, et al. NCCN guidelines insights:
head and neck cancers, version 1.2018. J Natl Compr Canc Netw
2018; 16: 479–90.
75 Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. 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.
76 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.
77 Kwong DL, Sham JS, Au GK, et al. Concurrent and adjuvant
chemotherapy for nasopharyngeal carcinoma: a factorial study.
J Clin Oncol 2004; 22: 2643–53.
78 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.
79 Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus
radiotherapy in patients with advanced nasopharyngeal cancer:
phase III randomized Intergroup study 0099. J Clin Oncol 1998;
16: 1310–17.
80 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.
81 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.
82 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.
78 www.thelancet.com Vol 394 July 6, 2019
83 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.
84 Blanchard P, Lee A, Marguet S, et al. Chemotherapy and
radiotherapy in nasopharyngeal carcinoma: an update of the
MAC-NPC meta-analysis. Lancet Oncol 2015; 16: 645–55.
85 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.
86 Chen L, Hu CS, Chen XZ, et al. Adjuvant chemotherapy in patients
with locoregionally advanced nasopharyngeal carcinoma: Long-term
results of a phase 3 multicentre randomised controlled trial.
Eur J Cancer 2017; 75: 150–8.
87 Peng H, Chen L, Zhang Y, et al. Prognostic value of the cumulative
cisplatin dose during concurrent chemoradiotherapy in
locoregionally advanced nasopharyngeal carcinoma: a secondary
analysis of a prospective phase III clinical trial. Oncologist 2016;
21: 1369–76.
88 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.
89 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.
90 Lv JW, Qi ZY, Zhou GQ, et al. Optimal cumulative cisplatin dose in
nasopharyngeal carcinoma patients receiving additional induction
chemotherapy. Cancer Sci 2018; 109: 751–63.
91 Tang LQ, Chen DP, Guo L, et al. Concurrent chemoradiotherapy
with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal
carcinoma: an open-label, non-inferiority, randomised phase 3 trial.
Lancet Oncol 2018; 19: 461–73.
92 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.
93 Xu C, Zhang LH, Chen YP, et al. Chemoradiotherapy versus
radiotherapy alone in stage II nasopharyngeal carcinoma:
a systemic review and meta-analysis of 2138 patients. J Cancer 2017;
8: 287–97.
94 Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus
fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal
carcinoma: a multicentre, randomised, open-label, phase 3 trial.
Lancet 2016; 388: 1883–92.
95 Bocci G, Kerbel RS. Pharmacokinetics of metronomic
chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol
2016; 13: 659–73.
96 Chen YL, Chang MC, Cheng WF. Metronomic chemotherapy and
immunotherapy in cancer treatment. Cancer Lett 2017; 400: 282–92.
97 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 Oncology Biol Phys 2014; 89: 21–29.
98 Liu YC, Wang WY, Twu CW, et al. Prognostic impact of adjuvant
chemotherapy in high-risk nasopharyngeal carcinoma patients.
Oral Oncol 2017; 64: 15–21.
99 Chua DT, Ma J, Sham JS, et al. Long-term survival after
cisplatin-based induction chemotherapy and radiotherapy for
nasopharyngeal carcinoma: a pooled data analysis of two phase III
trials. J Clin Oncol 2005; 23: 1118–24.
100 Ribassin-Majed L, Marguet S, Lee AW, et al. What is the best
treatment of locally advanced nasopharyngeal carcinoma?
An individual patient data network meta-analysis. J Clin Oncol 2016;
35: 498–505.
101 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.

102 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.
103 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.
104 Huang PY, Zeng Q, Cao KJ, et al. Ten-year outcomes of a
randomised trial for locoregionally advanced nasopharyngeal
carcinoma: a single-institution experience from an endemic area.
Eur J Cancer 2015; 51: 1760–70.
105 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.
106 Sun Y, Li WF, Chen NY, et al. Induction chemotherapy plus
concurrent chemoradiotherapy versus concurrent
chemoradiotherapy alone in locoregionally advanced
nasopharyngeal carcinoma: a phase 3, multicentre, randomised
controlled trial. Lancet Oncol 2016; 17: 1509–20.
107 Li WF, Chen NY, Zhang N, et al. Concurrent chemoradiotherapy
with/without induction chemotherapy in locoregionally advanced
nasopharyngeal carcinoma: Long-term results of phase 3
randomized controlled trial. Int J Cancer 2019; 45: 295–305.
108 Cao SM, Yang Q, Guo L, et al. Neoadjuvant chemotherapy followed
by concurrent chemoradiotherapy versus concurrent
chemoradiotherapy alone in locoregionally advanced
nasopharyngeal carcinoma: a phase III multicentre randomised
controlled trial. Eur J Cancer 2017; 75: 14–23.
109 Frikha M, Auperin A, Tao Y, et al. A randomized trial of induction
docetaxel-cisplatin-5FU followed by concomitant cisplatin-RT
versus concomitant cisplatin-RT in nasopharyngeal carcinoma
(GORTEC 2006-02). Ann Oncol 2018; 29: 731–36.
110 Hong RL, Hsiao CF, Ting LL, et al. Final results of a randomized
phase III trial of induction chemotherapy followed by concurrent
chemoradiotherapy versus concurrent chemoradiotherapy alone in
patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan
Cooperative Oncology Group (TCOG) 1303 Study. Ann Oncol 2018;
29: 1972–79.
111 Chen YP, Tang LL, Yang Q, et al. Induction chemotherapy plus
concurrent chemoradiotherapy in endemic nasopharyngeal
carcinoma: individual patient data pooled analysis of four
randomized trials. Clin Cancer Res 2018; 24: 1824–33.
112 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.
113 Lin GW, Wang LX, Ji M, Qian HZ. The use of MR imaging to detect
residual versus recurrent nasopharyngeal carcinoma following
treatment with radiation therapy. Eur J Radiol 2013; 82: 2240–46.
114 Comoretto M, Balestreri L, Borsatti E, Cimitan M, Franchin G,
Lise M. Detection and restaging of residual and/or recurrent
nasopharyngeal carcinoma after chemotherapy and radiation
therapy: comparison of MR imaging and FDG PET/CT. Radiology
2008; 249: 203–11.
115 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.
116 Zhang Y, Tang LL, Li YQ, Liu X, Liu Q, Ma J. Spontaneous
remission of residual post-therapy plasma Epstein-Barr virus DNA
and its prognostic implication in nasopharyngeal carcinoma:
a large-scale, big-data intelligence platform-based analysis.
Int J Cancer 2019; 144: 2313–19.
117 Zhang MX, Li J, Shen GP, et al. Intensity-modulated radiotherapy
prolongs the survival of patients with nasopharyngeal carcinoma
compared with conventional two-dimensional radiotherapy:
a 10-year experience with a large cohort and long follow-up.
Eur J Cancer 2015; 51: 2587–95.
118 Liu YP, Li H, You R, et al. Surgery for isolated regional failure in
nasopharyngeal carcinoma after radiation: Selective or
comprehensive neck dissection. Laryngoscope 2019; 129: 387–95.
www.thelancet.com Vol 394 July 6, 2019 79
Seminar
119 Li YQ, Tian YM, Tan SH, et al. Prognostic Model for Stratification
of Radioresistant Nasopharynx Carcinoma to Curative Salvage
Radiotherapy. J Clin Oncol 2018; 36: 891–99.
120 Leong YH, Soon YY, Lee KM, Wong LC, Tham IWK, Ho FCH.
Long-term outcomes after reirradiation in nasopharyngeal
carcinoma with intensity-modulated radiotherapy: A meta-analysis.
Head Neck 2018; 40: 622–31.
121 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.
122 Tsang RK, Wei WI. Salvage surgery for nasopharyngeal cancer.
World J Otorhinolaryngol Head Neck Surg 2015; 1: 34–43.
123 Chan JY, Tsang RK, Wei WI. Morbidities after maxillary swing
nasopharyngectomy for recurrent nasopharyngeal carcinoma.
Head Neck 2015; 37: 487–92.
124 Chen MY, Wang SL, Zhu YL, et al. Use of a posterior pedicle nasal
septum and floor mucoperiosteum flap to resurface the
nasopharynx after endoscopic nasopharyngectomy for recurrent
nasopharyngeal carcinoma. Head Neck 2012; 34: 1383–88.
125 Zou X, Han F, Ma WJ, et al. Salvage endoscopic
nasopharyngectomy and intensity-modulated radiotherapy versus
conventional radiotherapy in treating locally recurrent
nasopharyngeal carcinoma. Head Neck 2015; 37: 1108–15.
126 You R, Zou X, Wang SL, et al. New surgical staging system for
patients with recurrent nasopharyngeal carcinoma based on the
AJCC/UICC rTNM classification system. Eur J Cancer 2015;
51: 1771–79.
127 Chan OS, Ngan RK. Individualized treatment in stage IVC
nasopharyngeal carcinoma. Oral Oncol 2014; 50: 791–97.
128 Lee AW, Ng WT, Chan YH, Sze H, Chan C, Lam TH. The battle
against nasopharyngeal cancer. Radiother Oncol 2012; 104: 272–78.
129 Shen LJ, Wang SY, Xie GF, et al. Subdivision of M category for
nasopharyngeal carcinoma with synchronous metastasis: time to
expand the M categorization system. Chin J Cancer 2015; 34: 450–58.
130 Zou X, You R, Liu H, et al. Establishment and validation of M1
stage subdivisions for de novo metastatic nasopharyngeal
carcinoma to better predict prognosis and guide treatment.
Eur J Cancer 2017; 77: 117–26.
131 Sun XS, Liu LT, Liu SL, et al. Identifying optimal candidates for
local treatment of the primary tumor among patients with de novo
metastatic nasopharyngeal carcinoma: a retrospective cohort study
based on Epstein-Barr virus DNA level and tumor response to
palliative chemotherapy. BMC cancer 2019; 19: 92.
132 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.
133 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.
134 Sun P, Chen C, Xia Y, et al. The Ratio of C-Reactive Protein/
albumin is a novel inflammatory predictor of overall survival in
cisplatin-based treated patients with metastatic nasopharyngeal
carcinoma. Dis Markers 2017; 2017: 6570808.
135 Chee J, Loh KS, Tham I, et al. Prognostic stratification of patients
with metastatic nasopharyngeal carcinoma using a clinical and
biochemical scoring system. J Cancer Res Clin Oncol 2017;
143: 2563–70.
136 Shen L, Li W, Wang S, et al. Image-based multilevel subdivision of
M1 category in TNM staging system for metastatic nasopharyngeal
carcinoma. Radiology 2016; 280: 805–14.
137 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.
138 Wang TL, Tan YO. Cisplatin and 5-fluorouracil continuous infusion
for metastatic nasopharyngeal carcinoma. Ann Acad Med Singapore
1991; 20: 601–03.
139 Choo R, Tannock I. Chemotherapy for recurrent or metastatic
carcinoma of the nasopharynx. A review of the Princess Margaret
Hospital experience. Cancer 1991; 68: 2120–24.
140 Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal
carcinoma: current practice and future perspective. J Clin Oncol
2015; 33: 3356–64.
 Seminar
141 Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus
fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal
carcinoma: a multicentre, randomised, open-label, phase 3 trial.
Lancet 2016; 388: 1883–92.
142 Hsu C, Lee SH, Ejadi S, et al. Safety and antitumor activity of
pembrolizumab in patients with programmed death-ligand
1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028
study. J Clin Oncol 2017; 35: 4050–56.
143 Ma BBY, Lim WT, Goh BC, et al. Antitumor activity of nivolumab in
recurrent and metastatic nasopharyngeal carcinoma: an international,
multicenter study of the Mayo Clinic Phase 2 Consortium (NCI-9742).
J Clin Oncol 2018; 36: 1412–18.
144 Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in
combination with gemcitabine plus cisplatin for nasopharyngeal
carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol
2018; 19: 1338–50.
145 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology.
Mutational landscape determines sensitivity to PD-1 blockade in
non-small cell lung cancer. Science 2015; 348: 124–28.
146 Schumacher TN, Schreiber RD. Neoantigens in cancer
immunotherapy. Science 2015; 348: 69–74.
80 www.thelancet.com Vol 394 July 6, 2019
147 Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM,
Vincent BG. Genomic analysis of immune cell infiltrates across
11 tumor types. J Natl Cancer Inst 2016; 108.
148 Roh W, Chen PL, Reuben A, et al. Integrated molecular analysis of
tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals
markers of response and resistance. Sci Transl Med 2017; 9.
149 Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy
correlates with markers of immune evasion and with reduced
response to immunotherapy. Science 2017; 355.
150 Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of
cancer. Immunity 2018; 48: 812–30.e14.
151 Chen YP, Wang YQ, Lv JW, et al. Identification and validation of
novel microenvironment-based immune molecular subgroups of
head and neck squamous cell carcinoma: implications for
immunotherapy. Ann Oncol 2019; 30: 68–75.
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