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Management of Nasopharyngeal Carcinoma: Current Practice and Future

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 VOLUME 33 䡠 NUMBER
JOURNAL OF CLINICAL ONCOLOGY
Anne W.M. Lee, University of Hong
Kong–Shenzhen Hospital, Shenzhen;
Brigette B.Y. Ma and Anthony T.C.
Chan, Chinese University of Hong
Kong; and Wai Tong Ng, Pamela Youde
Nethersole Eastern Hospital, Hong
Kong Special Administrative Region,
People’s Republic of China.
Published online ahead of print at
www.jco.org on September 8, 2015.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Anthony T.C.
Chan, MD, State Key Laboratory in
Oncology in South China, Sir Y.K. Pao
Centre for Cancer, Department of Clini-
cal Oncology, Hong Kong Cancer Insti-
tute, Chinese University of Hong Kong,
Hong Kong SAR, China; e-mail:
anthony@clo.cuhk.edu.hk.
© 2015 by American Society of Clinical
Oncology
0732-183X/15/3329w-3356w/$20.00
DOI: 10.1200/JCO.2015.60.9347
3356 © 2015 by American Society of Clinical Oncology
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
29 䡠 OCTOBER 10 2015
R E V I E W A R T I C L E
Management of Nasopharyngeal Carcinoma: Current
Practice and Future Perspective
Anne W.M. Lee, Brigette B.Y. Ma, Wai Tong Ng, and Anthony T.C. Chan
A B S T R A C T
Nasopharyngeal carcinoma of the undifferentiated subtype is endemic to southern China, and
patient prognosis has improved significantly over the past three decades because of advances
in disease management, diagnostic imaging, radiotherapy technology, and broader application
of systemic therapy. Despite the excellent local control with modern radiotherapy, distant
failure remains a key challenge. Advances in molecular technology have helped to decipher the
molecular pathogenesis of nasopharyngeal carcinoma as well as its etiologic association with
the Epstein-Barr virus. This in turn has led to the discovery of novel biomarkers and drug
targets, rendering this cancer site a current focus for new drug development. This article
reviews and appraises the key literature on the current management of nasopharyngeal
carcinoma and future directions in clinical research.
J Clin Oncol 33:3356-3364. © 2015 by American Society of Clinical Oncology
with advances in diagnostic radiology and treat-
INTRODUCTION
ment. There are three areas in the current (seventh)
Nasopharyngeal carcinoma (NPC) of the undiffer- edition of the AJCC/UICC staging criteria for NPC
entiated subtype remains endemic in southern that may warrant revision in the forthcoming
(eighth) edition. First, the current criterion of N3b
China, with a peak annual incidence approaching 30
per 100,000 persons. Overall prognosis has dramat- stage is defined as disease extension to the supracla-
ically improved over the past three decades because vicular fossa—a triangular region defined by the
superior margin of the sternal end of the clavicle, the
of advances in management, including the improve-
ment of radiotherapy (RT) technology, the broader superior margin of the lateral end of the clavicle, and
application of chemotherapy, and more accurate the point where the neck meets the shoulder. How-
disease staging. Current therapeutic decisions are ever, this definition, which was originally proposed
based mainly on disease stage.1,2 The general con- by Ho,3 is based primarily on clinical examination.
sensus is to treat stage I disease with RT alone, stage There are now substantial data to support that this
II disease with RT with or without concurrent che- region can be extended from the supraclavicular
motherapy (CRT), and stage III to IVB NPC with fossa to lower levels in the neck, including levels IV
CRT. Excellent local control can generally be and Vb. This broader definition enables a more re-
achieved, but distant failure is a key problem, and liable radiologic assessment without affecting the
the treatment outcome of metastatic NPC remains overall prognostic significance of the N3b stage.4,5
disappointing. Another challenge is achieving suc- The second area concerns the definition of T4 dis-
cessful local control with minimal late toxicity, espe- ease as being an invasion of the masticator space,
cially for tumors with intracranial extension. This which was originally intended as a synonym for the
article reviews current challenges and future per- infratemporal fossa, as stated in the sixth edition of
spectives in managing this unique cancer. the AJCC/UICC staging criteria.6 Clarification and
redefinition of this criterion are needed, because pa-
tients with tumor extension confined to the ptery-
STAGING AND PROGNOSTIC FACTORS goid muscles generally have a prognosis that is more
comparable to that of patients with T2 disease rather
Despite its known limitations, TNM staging remains those with T4 disease.7 The third area is that the
the most important prognostic factor in NPC. Con- prognostic differentiation between stage T1 and T3
tinual revision of the American Joint Committee on disease is narrowing with modern treatment; there-
Cancer (AJCC)/International Union Against Can- fore, regrouping is needed to better reflect the results
cer (UICC) staging system is needed to keep pace of contemporary practice.8
 Management of Nasopharyngeal Carcinoma

Besides using anatomic end points in the staging of NPC, there is
increasing evidence that primary tumor volume could be a significant
factor for local control independent of T stage,8 and lactate dehydro-
genase could be a significant factor for distant control independent of
stage group.9 Among the molecular markers, the most studied is
plasma Epstein-Barr virus (EBV) DNA, which is universally associated
with the nonkeratinizing subtype of NPC. In addition to being a good
prognosticator, it is also useful for assessing treatment response and
detecting disease relapse.10-12 Novel prognostic markers using genetic
signatures and microRNA have also shown promising results.13,14
ADVANCES IN RT
Intensity-modulated RT (IMRT) is the current standard of treatment
for NPC. With conformity of dose distribution achieved by sculpting
the high-dose zone for complete coverage of tumor targets while
sparing the critical normal structures, excellent locoregional control
can be achieved by most expert centers15-20,22 (Table 1). Random-
ized controlled trials comparing IMRT with conventional two-
dimensional RT have shown a significant reduction in the risk of
permanent xerostomia, especially in patients with early disease,23,24 as
well as improvement in local control with reduction of other treat-
ment complications.16,21 One major refinement of the delineation of
high-risk regions for elective irradiation is the tailoring of clinical
tumor volume for node-negative patients. In the past, elective RT was
recommended for the bilateral whole neck. There is increasing evi-
dence that the lymphatic spread of NPC follows a fairly predictable
order, with retropharyngeal nodes and the level II neck nodes being
most commonly affected and skip metastases being uncommon. Ret-
rospective and randomized studies have shown that selective neck
irradiation confined to levels II, III, and Va is safe and would not
jeopardize nodal control or survival.25,26 This sparing of the lower
neck and level IB is useful, because the latter allows a better sparing of
the submandibular gland, thus reducing the risk of xerostomia.
To minimize the risk of geographic miss resulting from the highly
conformal dose distribution of IMRT, accuracy in the delineation of
gross tumor volume (GTV), appropriate design of margins and clini-
cal target volume, and precision in RT delivery are important stan-
dards to maintain when prescribing IMRT. Thorough pretreatment
assessment incorporating endoscopy, magnetic resonance imaging,
and positron emission tomography coupled with computed tomog-
raphy (CT), as well as fusion of images from different modalities with
the planning CT images, is fundamental. International protocols, such
as those from the Radiation Therapy Oncology Group,27 represent
useful and practical references, and regular evaluation of treatment
outcome and patterns of failure should be conducted in centers that
practice IMRT to optimize the planning parameters.
The development of image-guided RT from conventional portal
films may improve treatment precision by allowing the checking of
bony structures through onboard images, the cross checking of both
bone and soft tissues by cone-beam CT, and real-time infra-fraction
monitoring. A substantial shrinkage of tumor and parotid glands as
well as changes in body contour may occur during the course of RT,
leading to shifts in dose distribution to both the tumor target and
normal structures.28-30 Adaptive RT consisting of reassessment and
replanning (when indicated) during the course of RT is hence increas-
ingly advocated to ensure the continual appropriateness of dose dis-
tribution. Improvements in locoregional control and quality of life
have been observed with this approach,31 but the optimal timing for
treatment replanning remains an open question. Although technolo-
gies such as in–treatment room imaging, deformable image registra-
tion, and knowledge-based treatment planning tools are being used to
enhance the efficiency of adaptive RT, it is still a labor-intensive pro-
cess. Furthermore, cost effectiveness and long-term impact on thera-
peutic ratios remain to be determined.
Although IMRT can achieve excellent 5-year local control rates
ⱖ 90% for T3 disease, the corresponding rates for T4 disease still range
from 74% to 80% (Table 1).16,18-20,22 Late toxicities, especially

Table 1. Five-Year Treatment Outcome With Intensity-Modulated Radiotherapy

Dose (Gy) T4 Disease (%)

Local Nodal Distant
No. of Per Chemotherapy Control Control Control OS Local Serious Neurologic
Study Patients Total Fraction (%) (%) (%) (%) (%) Patients Control Complications (%)
Lai et al15 512 NR 2.27 81 93 97 84 NR 52 (T3 to T4) 82 NR
Peng et al16 306 70 2.12 60 91 92 NR 80 17ⴱ 82 TLN, 13.1
CN, 3.9
OP, 1.6
Lin et al17 414 66 to 70.95 — 81 95 97 82 80 21 NR NR
30 to 33 fractions
Wu et al18 249 68 to 72 (30 to 32 fractions) — 100 87 88 78 78 33 85 (T3 to T4) TLN, 2.6
30 to 32 fractions CN, 1.5
OP, 1.8
Sun et al19 868 68 2.27 83 92 96 85 NR 19 83 TLN or BS, 5.5
Ng et al20 444 70 2 to 2.12 83 86 92 83 80 23 74 TLN, 0.5
CN, 1.621
Yi et al22 271 70 (T1 to T2) 2.12 52 87 NR 70 79 25 54 and 76† NR
74 (T3 to T4) 2.24

Abbreviations: BS, brainstem injury; CN, cranial nerve injury; NR, not reported; OP, optice nerve or chiasm injury; OS, overall survival; TLN, temporal lobe necrosis.
ⴱ
Randomized study; percentage is based on both treatment arms of 616 patients.
†With and without concurrent chemotherapy, respectively.

www.jco.org © 2015 by American Society of Clinical Oncology 3357

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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
 Lee et al
neurologic damage, are also more common after RT for T3 to T4
NPC.16,19 The general principle is to administer the maximum tumor
dose within the tolerance of critical organs at risk. To optimize the
balance between local control and complications, appropriate design
of treatment dose constraints and more accurate data on the
maximum-tolerated dose regarding organs at risk are needed. The
target volume underdosed (⬍ 65 Gy) is one of the most significant
factors affecting tumor control and overall survival (OS).20 Hence,
modifications of dose constraints with inclusion of the GTV as one of
the top priority parameters and acceptance of higher doses to less
critical structures (eg, temporal lobes and unilateral optic nerve) are
now being tested cautiously.
For large primary tumors abutting or infiltrating critical struc-
tures, one common practice is to add induction chemotherapy to
shrink the tumor bulk for better dose coverage during subsequent RT
plus concurrent cisplatin.32 Other novel strategies that warrant further
investigation include the use of more conformal techniques, such as
proton or heavy particle therapy,33 and the use of selective radio-
sensitizing agents targeting the tumor and radio protectants targeting
the organs at risk. The current practice is to prescribe a fairly uniform
and standardized dose level (approximately 70 Gy) to the whole GTV.
Another future perspective is to individualize the radiation dose. With
the advent of functional positron emission tomography and magnetic
resonance imaging, it may be possible to determine and deliver the
most appropriate dose levels to different parts of the target volume
with IMRT, optimizing the therapeutic ratio for individual patients.
CRT FOR LOCOREGIONALLY ADVANCED DISEASE
With almost half of all patients presenting at an advanced stage, of
whom one third subsequently die as a result of this cancer within 5
years of diagnosis, the treatment of stage III to IVB NPC has
deservedly been the main focus of clinical research in the past
decades.34 The improvement of clinical outcome with the use of
CRT is an important milestone in this endeavor. To date, at least
nine randomized studies have compared concurrent CRT (⫾ ad-
juvant chemotherapy) versus RT alone.35-42 These studies have
reported a significant improvement in event-free survival, and in
some studies, an advantage in OS has been observed, with hazard
ratios (HRs; where reported) for death ranging from 0.51 to 0.71 at
3 to 5 years of follow-up35-37,39 (Table 2). This benefit has been
observed irrespective of the diverse types of chemotherapeutic
regimens used in these studies. However, in some exploratory
analyses, the dose of cisplatin delivered during the concurrent
phase has been shown to influence locoregional control and
OS.40,48 Subgroup analyses of some randomized studies have also
suggested that the OS benefit may be larger in patients with T3 to
T4 disease.35,36
In a recently presented meta-analysis, in which patient-based
data on 4,798 patients with mostly stage III to IVB NPC were analyzed,
the addition of chemotherapy was found to confer an absolute OS
benefit of 6% at 5 years and 8% at 10 years.49 The benefit was signifi-
cant for OS (HR, 0.79; 95% CI, 0.72 to 0.86), progression-free survival
(HR, 0.76; 95% CI, 0.70 to 0.82), locoregional control (HR, 0.74; 95%
CI, 0.65 to 0.85), and distant control (HR, 0.68; 95% CI, 0.60 to
0.76). Despite the widespread acceptance of CRT as the new ther-
apeutic benchmark for stage III to IVB NPC, several unanswered
3358 © 2015 by American Society of Clinical Oncology
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
questions remain. These include the value of adding targeted ther-
apy, induction, or adjuvant chemotherapy to CRT in different
sequences, the value of CRT in patients with stage II NPC, optimi-
zation of patient selection for CRT using predictive biomarkers,
and evaluation of the long-term efficacy and safety of using con-
current chemotherapy with IMRT.
The merit of adding induction chemotherapy to CRT in stage III
to IVB NPC is a subject of intense investigation. The study by Hui et
al50 in 2009 was the first to report an OS benefit with this approach.
Although this study was not powered to detect a survival difference
between the study arms, the significant finding of a 26.5% absolute
improvement in 3-year OS by adding induction cisplatin and do-
cetaxel to CRT did provide a strong impetus for phase III validation.
To date, at least six randomized studies have been initiated or reported
in centers in Hong Kong (ClinicalTrials.gov identifier NCT00379262),
Singapore (NCT00997906),51 Taiwan (NCT00201396), Europe
(NCT00828386; terminated because of low accrual; also randomized
phase II study52), and China (NCT01245959, NCT01536223). The stud-
ies by Tan et al51 and Fountzilas et al,52 which investigated the use of
induction chemotherapy using a triplet regimen before CRT, failed to
achieve an OS benefit at 3 years. A six-arm study from the Hong Kong
NPC study group (NCT00379262) was designed to address questions
concerning drug sequences, RT fractionation, and substitution of
fluorouracil (FU) with capecitabine.53 A total of 803 patients with
stage III to IVB NPC were randomly assigned. Using the Intergroup-
0099 regimen of concurrent cisplatin plus adjuvant cisplatin and FU as
the standard arm, preliminary analyses failed to meet the primary end
points of the study. Subgroup analyses suggested that oral capecitabine
may be a safe alternative to FU, and accelerated RT was not recom-
mended for patients undergoing CRT for locoregionally advanced
NPC.53 It should be noted that the median follow-up durations of the
reported studies are only approximately 3 years; thus, longer
follow-up is needed before definitive conclusions can be drawn re-
garding the utility of adding induction chemotherapy to CRT. One
could argue that the magnitude of any theoretic benefit would be
small; this implies that a much larger phase III study is needed. An
alternate explanation is that perhaps only specific subgroups would
benefit from this approach, such as patients with early metabolic
response to induction chemotherapy.54 The cumulative evidence
on induction chemotherapy in stage III to IVB disease remains
insufficient to change practice at this juncture, and the results of
other phase III studies are eagerly awaited.
Among the recent highlights in research, the role of adjuvant
chemotherapy in stage III to IVB NPC and the use of CRT in stage II
NPC warrant discussion. To date, no randomized phase III studies
have demonstrated a survival advantage with adjuvant chemotherapy.
In the meta-analysis by Blanchard et al,49 the magnitude of the OS
benefit observed in the subgroup receiving CRT plus adjuvant chemo-
therapy (n ⫽ 1,267 patients; HR, 0.65; 95% CI, 0.56 to 0.76) seemed to
be larger than that in the CRT-alone subgroup (n ⫽ 1,834 patients;
HR, 0.80; 95% CI, 0.70 to 0.93). In the largest phase III study reported
to date, Chen et al55 found that the addition of adjuvant cisplatin plus
FU did not improve failure-free survival after a relatively short
follow-up period of 2 years, with an HR of 0.74 (95% CI, 0.49 to 1.10;
P ⫽ .13). Furthermore, compliance was a problem; only 63% of
patients could complete the planned chemotherapy.55 Data from the
current literature do not allow a definitive recommendation to be
JOURNAL OF CLINICAL ONCOLOGY
 www.jco.org
Table 2. Summary of Selected Phase III Studies Comparing Concurrent CRT Versus RT Alone

Study Arms
TNM Stage % Results
No. of Patients/ CRT RT Alone
Author Year II III IV Sample Size Treatment Dose (Gy) CRT (%) RT (%) HRⴱ 95% CI P
Al-Sarraf et al38 1998, 2001 9 91 147 Cisplatin every 3 weeks plus 70
5-year OS RT followed by cisplatin 67 37 .001
plus FU (n ⫽ 14)
5-year PFS 58 29 .001
Chan et al35,43 2002, 2005 28.8 29.4 41.8 350 Cisplatin once per week 66
5-year OS plus RT 72 59 0.71 0.5 to 1.0 .048
5-year PFS 62 52 0.74 0.54 to 1.0 .076
Lin et al44 2003 19.7 80.3 284 Cisplatin every 4 weeks plus 70 to 74
5-year OS FU and RT 72.3 54.2 .002
5-year PFS 71.6 53.0 .001
5-year DMFS 78.7 69.9 .057
Wee et al37 2005 1 45 54 221 Cisplatin every 3 weeks plus 70
3-year OS RT followed by cisplatin 80 65 0.51 0.31 to 0.81 .0061
plus FU
3-year DFS 72 53 0.57 0.38 to 0.87 .0093
2-year 30 13 .0029
relapse
rate
Lee et al45 2011 — 189 Cisplatin every 3 weeks plus 70†‡
3-year OS RT followed by cisplatin 87† and 88‡ 83† and 73‡ 0.52§ 0.28 to 0.97 NS
plus FU
3-year PFS 68† and 63‡ 73† and 88‡
Lee et al41,46 2010 59 41 348 Cisplatin every 3 weeks plus 70
5-year OS RT followed by cisplatin 68 64 0.81 0.58 to 1.13 .22
plus FU
5-year PFS 62 53 0.72 0.53 to 0.98 .035
5-year DFFR 74 68 .32
5-year LRFFR 88 78 .005
Chen et al42 2011 87 13 230 Cisplatin 30 mg/m2 once per 60 to 70
Management of Nasopharyngeal Carcinoma

5-year OS week 94.5 85.6 0.30 0.12 to 0.76 < .001

5-year DMFS 94.8 83.9 < .001
5-year LRS 93 91.1 .29
Zhang et al47 2005, 2013 115 Oxaliplatin plus RT 70 to 74
5-year OS 73.2 60.2 .03

Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

5-year DMFS 74.3 63 .03
Chen et al39 2013 36 64 316 Cisplatin once per week 66
5-year OS plus RT followed by 72 62 0.69 0.48 to 0.99 .043
cisplatin plus FU
5-year PFS 68 57 .015

NOTE. Bold font indicates significance.

Abbreviations: CRT, chemoradiotherapy; DFFR, distant failure–free rate; DFS, disease-free survival; DMFS, disease metastasis–free survival; FFS, failure-free survival; FU, fluorouracil; HR, hazard ratio; LRFFR,

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locoregional failure–free rate; LRS, locoregional relapse free survival; NS, not significant; OS, overall survival; PFS, progression-free survival; RFS, relapse-free survival; RT, radiotherapy.
ⴱ
For concurrent CRT over RT alone.
†Conventional fractionation.
‡Accelerated fractionation.
§Multivariable analysis.

© 2015 by American Society of Clinical Oncology

3359
 Lee et al
made regarding the use of adjuvant chemotherapy after CRT in lo-
coregionally advanced NPC. The current focus of research is on iden-
tifying patient subgroups that may maximally benefit from adjuvant
chemotherapy. Because elevated level of plasma EBV DNA at 6 to 8
weeks after RT could increase the risk of cancer recurrence by almost
12 times,12 researchers from the Hong Kong NPC study group
(NCT00370890) and NRG Oncology (NCT02135042) are investigat-
ing the utility of post-treatment plasma EBV DNA in individualizing
adjuvant chemotherapy.55a
Available data are relatively limited regarding the role of chemo-
therapy for stage II NPC. Chen et al42 randomly assigned 230 patients,
of whom 87% had stage II and 13% had stage III NPC by AJCC/UICC
(seventh edition) criteria, to RT alone versus CRT. They reported a
significant improvement in OS with CRT over RT alone, with 5-year
OS rates of 95% versus 86% and an HR of 0.30 (95% CI, 0.12 to 0.76;
P ⫽ .007). However, the fact that two-dimensional RT was used in this
study suggests that these data should be interpreted in light of the now
broader application of IMRT. The 5-year disease-specific survival
rates in stage I to II NPC are now expected to be 94% to 97% with
IMRT alone in some retrospective series.21,56 In the study by Su et al,56
where 198 patients with stage I to II NPC were treated with IMRT
alone, the 5-year distant metastasis–free rates for T2N0, T1N1, and
T2N1 disease were 98.8%, 100%, and 93.8%, respectively. Given these
excellent results with IMRT alone and the added toxicities of concur-
rent chemotherapy, such as late hearing loss,21 it is debatable whether
CRT should be offered routinely to patients who are undergoing
IMRT for stage II NPC. Chemotherapy should be confined to patients
with high-risk stage II disease with N1 classification and/or parapha-
ryngeal tumor extension; studies investigating other risk factors, such
as tumor size and plasma EBV DNA level, are also warranted in the
future. For instance, up to one third of patients with stage IIB disease
with a high pretreatment level of plasma EBV DNA level may develop
distant failure.57
MANAGEMENT OF RECURRENCE AND DEVELOPMENT OF NEW
SYSTEMIC THERAPIES
Even with the best available treatment in modern practice, retrospec-
tive reports of patients treated with IMRT over the last decade have
revealed the stark reality that 5% to 15% of patients will develop local
failure, and 15% to 30% will experience failure at distant sites.15-24
Despite the varying success of surgery or reirradiation in salvage ther-
apy for highly selected patients with local recurrence, a vast majority of
cases of recurrent disease are only amenable to palliative chemother-
apy. In phase II studies of platinum-based doublets that are in popular
use today, the median OS rates in the first-line setting ranged from a
minimum of 11 to 28 months with regimens containing paclitaxel,
fluorouracil, gemcitabine, or capecitabine.58-60 These figures need to
be interpreted with caution, because selection bias is inherent in these
small single-armed studies, and standards of supportive care have
changed over time. In contrast, the median time to progression in such
studies has remained static at approximately 7.3 to 10 months.58-60
Prolonged survival beyond 5 years has been described only for a
minority of younger patients with oligometastases.61 Therefore, the
use of chemotherapy has reached a therapeutic ceiling in NPC.
It has long been proposed that the molecular pathogenesis of
EBV-associated NPC follows a stepwise progression.62 This transfor-
3360 © 2015 by American Society of Clinical Oncology
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
mation consists of a series of seminal events, which include EBV latent
infection, evasion of host immune surveillance, loss of heterogeneity
at specific chromosomal regions, genetic mutations and activation of
oncogenic signaling pathways, and epigenetic silencing of tumor sup-
pressor genes.62-64 In the first genome-wide sequence analysis of NPC
published recently, Lin et al65 revealed that NPC has a relatively low
mutational rate compared with head and neck squamous cell and
other cancers. Nine significantly mutated genes have been identified as
possible driver mutations for NPC, including TP53 and PIK3CA mu-
tations as well as mutations of genes involved in chromatin transcrip-
tion (BAP1, MLL2, TSHZ3) and cell proliferation (ERBB3, ERBB2,
KRAS, NRAS). The prevalence rates of these mutations are ⱕ 10%.65
The ERBB–phosphatidylinositol 3-kinase (PI3K) signaling pathways
represent one of the most druggable axes in cancer drug development,
and genetic alterations (both mutations and amplification) in these
pathways can be found in 23.4% of NPCs.65 The ubiquitous nature of
type II latent EBV infection in nonkeratinizing NPC has also provided
an impetus for investigating EBV-directed therapies, given the knowl-
edge that activated CD8⫹ T cells are capable of attacking tumor cells
and inducing tumor regression in NPC models.66
On the basis of this insight into the molecular biology of NPC, the
development of novel therapies has largely followed a three-pronged
approach: targeting of signal transduction and angiogenesis, modula-
tion of gene expression, and cancer immunotherapy (Fig 1). Scientific
progress in these fields has somewhat lagged behind the achievements
in basic research, and the best evidence in contemporary literature is
largely limited to exploratory phase II studies. In the palliative and
platinum-refractory populations, studies of epidermal growth factor
receptor inhibitors (eg, gefitinib and cetuximab) and angiogenesis
inhibitors (eg, pazopanib and sunitinib) have either reported a lack of
activity or failed to meet their predefined levels of drug efficacy.67,68
For instance, in the studies of pazopanib and sunitinib, although the
median time to progression of 4.4 months seemed to exceed that
reported with cetuximab plus carboplatin (2.7 months),67,68 the me-
dian time to progression in phase II studies of gemcitabine or capecit-
abine alone in similar populations was 5 to 7.5 months.69-71 Likewise,
in studies of locoregionally advanced NPC, the addition of cetuximab
or bevacizumab to CRT resulted in survival figures that were similar to
or marginally better than historical data on CRT alone.72,73 Another
less common reason for failure in phase II studies was an increased
incidence of drug-related toxicities, such as tumor bleeding with
sunitinib and enhanced RT-related acute mucocutaneous toxicities
with cetuximab.68,73 Perhaps one of the most fundamental barriers to
the development of targeted therapies for NPC lies in the preclinical
stage, where there is a scarcity of authentic nonkeratinizing NPC
models that are exploitable for demonstrating proof of principle of
novel therapeutic approaches.74-76 To date, only the cell line C666-1
and a few patient-derived xenografts that were established in the 1990s
have been shown to stably express the EBV genome in culture.75-79 In
a recent study using RNA sequencing analysis, it was speculated that
some of the cell lines commonly used in NPC studies could have been
contaminated by human papilloma virus– carrying HeLa cells.74 This
shortage of reliable NPC models, especially those that can stably ex-
press certain actionable genetic aberrations in culture, has also con-
tributed to the difficulty of identifying predictive markers of drug
efficacy. This problem has practical implications when designing clin-
ical trials for drugs against ERBB-PI3K signaling in NPC.65 It is well
known that in other cancers, such as head and neck squamous cell
JOURNAL OF CLINICAL ONCOLOGY
 Management of Nasopharyngeal Carcinoma

Cetuximab Bevacizumab
Tumor PD-1
VEGF antibody
vasculature
PD-1R
EGFR VEGFR
Gefitinib Sunitinib
Pazopanib

PTEN
Isoform-specific
PI3K inhibitor TIL

PI3K RAS CD8+

AZA T-cell

CD4+

LMP1/2
T-cell
MK2206
inhibitor

AKT RAF
Dual

APC
HAT

EBNA1
Vaccine
AC AC
mTOR MEK

Auto
MEK inhibitor SAHA T-killer

Fig 1. Systemic strategies (noncytotoxic chemotherapy) for advanced nasopharyngeal carcinoma. Drug names in squares have been evaluated in clinical trials. AC,
acetylase; APC, antigen-presenting cells; auto T-killer, autologous cytotoxic T cell; AZA, azacitadine; EBNA1, Epstein-Barr nuclear antigen-1; EGFR, epidermal growth
factor receptor; HAT, histone acetlyase; LMP1/2, latent membrane proteins 1 and 2; mTOR, mammalian target of rapamycin; PD-1R, programmed death-1 receptor;
PI3K, phosphatidylinositol 3-kinase; SAHA, suberoylanilide hydroxamic acid; TIL, tumor-infiltrating lymphocyte; VEGF, vascular endothelial growth factor; VEGFR,
vascular endothelial growth factor receptor.

cancer, tumors that harbor PIK3CA mutations are more sensitive to
PI3K inhibitors than those that do not.80 With the relatively low
prevalence of PIK3CA mutations in NPC (⬍ 6%),65 one would need
convincing preclinical data to support the decision of whether to
restrict study recruitment based on PIK3CA mutation status. How-
ever, the literature is mixed with regard to whether PIK3CA mutations
could reliably predict response to PI3K–mammalian target of rapa-
mycin inhibitors in existing models of NPC.81,82 Therefore, a more
systematic approach to drug development is needed, and emphasis
should be placed on authenticating existing preclinical models, over-
coming the technical difficulties of establishing new patient-derived
xenograft models of NPC, and adopting a more biomarker-based
approach to developing new drugs.
Cancer immunotherapy represents another pillar of therapeutic
approaches in NPC. This encompasses a broad range of strategies,
including EBV-directed adoptive and active immunotherapies, anti-
bodies, EBV lytic cycle induction, and immune-checkpoint blockade.
The cardinal feature of EBV infection in NPC is that EBV expresses a
set of poorly immunogenic latent type II viral antigens. EB nuclear
antigen-1 (EBNA1) is expressed frequently in NPC and is a dominant
target for CD4⫹ T cells. Latent membrane protein-1 (LMP1) and
LMP2 are expressed in approximately 50% of NPC tumors, and both
are targets for CD8⫹ cytotoxic T lymphocytes (CTLs). Because LMP1
is poorly immunogenic, LMP2 is considered a more likely target
antigen for CD8⫹ CTL-based therapy.83 It has been suggested that
NPC cells have preserved antigen-processing function and can be
recognized by major histocompatibility complex class I–restricted
virus-specific CTLs in vitro.84 However, the downregulation of major
histocompatibility complex class I peptide expression in NPC tu-
mors,85 the relatively lower prevalence of T cells found in patients with
NPC who could recognize HLA-restricted epitopes in LMP2 and
EBNA,86 and the inactivation of tumor infiltrating T cells by the
suppressive tumor microenvironment all add to the challenges of
developing EBV-directed therapies.86 Successive generations of clini-
cal studies have tried to boost anti-EBV responses in circulating
CD8⫹ T cells in patients with NPC through autologous T-cell
transfer87-91 or vaccination with dendritic cells or peptides.92-95 Stud-
ies of T-cell therapy have shown that such strategies are generally safe
and effective in inducing LMP2-specific immune responses, and du-
rable tumor regressions in advanced NPC have been reported in
earlier studies.88,89 Recent studies have focused on sequencing adop-
tive T-cell therapy with chemotherapy in advanced NPC91 and on
optimizing T-cell expansion using novel adenovirus vectors.90 Using a
non– cell-based approach, Hui et al95 reported their experience with a
recombinant vaccinia virus– based vaccine, which encodes a function-
ally inactive fusion protein containing the CD4 epitope–rich
C-terminal half of EBNA1 and CD8 epitope–rich LMP2A. This potent
vaccine could induce T-cell response in ⬎ 80% of patients, in some
cases boosting response to both CD4⫹- and CD8⫹-mediated immu-
nity against EBNA1 and/or LMP2.95 This vaccine is being evaluated in
a phase II trial involving patients who have detectable plasma EBV
DNA after RT or who experience optimal response to palliative che-
motherapy (NCT01094405).
Despite the progress in immunotherapeutic approaches for
NPC, these strategies remain experimental, and implementation is
difficult in clinical practice because of their expense and reliance on
specialized centers. Recent breakthroughs in the treatment of mela-
noma and other cancers with immune-checkpoint inhibitors have

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 Lee et al

rejuvenated enthusiasm in immunotherapy for NPC. Programmed
cell death ligand-1 (PD-L1) is highly expressed by cancer cells and
tumor-infiltrating macrophages in virus-associated malignancies
such as NPC,96 and there is emerging evidence that activation of the
PD-1 pathway may contribute to immune escape in NPC models.97,98
PD-L1 is expressed in up to 90% of NPC tumors,96,97 and because
there is now evidence to suggest that PD-L1 expression may predict
response to PD-L1 antibodies in some cancers, there is sufficient
rationale to initiate studies of PD-L1 inhibitors and related agents
in NPC.
DISCUSSION
The current overview has highlighted the achievements and challenges
in the contemporary management of NPC, and insight into these
issues will set the goals and directions for future research. These goals
maybe thematically summed up as follow: improvement in individu-
alized therapy through better precision in selecting and delivering
treatments, improvement in the integration of multimodal therapies,
and interdisciplinary cooperation and cross-institutional collabora-
tion. The precision of RT planning and delivery could potentially be
refined in individuals through the use of adaptive RT, image-guided
RT, and proton therapy. Likewise, with the discovery of new
driver mutations, putative tumor suppressor genes, and immune-
checkpoint targets in NPC, it is time to adopt a more systematic
approach to new drug development. Emphasis should be placed on
the promotion of interdisciplinary collaboration within and across
institutions in the development of new NPC models, the high-
throughput screening of new compounds in NPC models through
engagement of the interests of pharmaceutical companies, and the
rationalization of clinical trial design based on unmet clinical needs
and preclinical proof-of-principle studies. The concept of individual-
ized therapy also applies to the optimal selection of patients for ad-
junctive chemotherapy during RT, and multinational studies are now
addressing the role of adjuvant chemotherapy in subpopulations with
elevated plasma EBV DNA levels after RT. With the expanding arsenal
and diversity of systemic agents on the horizon, it is only a matter of
time before researchers are faced with the dilemma of how to opti-
mally integrate these agents into conventional therapeutic algorithms.
More well-designed multi-institutional studies are needed, and this
calls for a collective effort among expert centers in harmonizing and
standardizing procedures such as biomarker analysis, disease staging,
and treatment planning.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Anne W.M. Lee, Anthony T.C. Chan
Manuscript writing: All authors
Final approval of manuscript: All authors

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JOURNAL OF CLINICAL ONCOLOGY
 Management of Nasopharyngeal Carcinoma

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Anne W.M. Lee Anthony T.C. Chan
No relationship to disclose Consulting or Advisory Role: Merck, Taiho Pharmaceutical, Roche,
Amgen
Brigette B.Y. Ma
Research Funding: Boehringer Ingelheim, Bristol-Myers Squibb, Eli
Honoraria: Novartis, Bayer, Boehringer Ingelheim
Consulting or Advisory Role: Novartis, Bayer, Boehringer Ingelheim Lilly, Pfizer
Research Funding: Novartis
Wai Tong Ng
No relationship to disclose

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