Hong Kong Med J 2017 Oct;23(5):497–502 | Epub 1 Sep 2017
DOI: 10.12809/hkmj176834
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
REVIEW ARTICLE CME
Beating ‘Guangdong cancer’: a review and update on nasopharyngeal cancer
CS Ho, BPharm
Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong
Kong
Corresponding author: Dr CS Ho (jasonho@link.cuhk.edu.hk)
Abstract
Once endemic in southern China, nasopharyngeal
cancer is becoming less prevalent in Hong Kong.
This is probably due to a better understanding of the
risk factors associated with the disease, its genomic
landscape, advances in radiotherapy technology,
and development of effective systemic agents. More
specifically, the close relationship between Epstein-Barr virus and nasopharyngeal cancer opens up
the possibility of using Epstein-Barr virus DNA
as a biomarker for early detection and monitoring
of the disease. On the other hand, the looming
genomic data for nasopharyngeal cancer aid in the
development of powerful biomarkers and promising
targeted therapy. Clinical use of a combination
of radiotherapy and chemotherapy continues to
increase, while the development of immunotherapy,
such as checkpoint inhibitors, offers hope in
improving treatment outcome.
Introduction
Nasopharyngeal cancer (NPC) was once considered
endemic in the southern part of China. This type of
cancer was so prevalent in Guangdong Province in
southern China in the early 20th century that it was
dubbed ‘Guangdong cancer’.1 Although the name is
now less popular and the incidence of NPC has been
decreasing since then (Fig),2 3 its occurrence in Hong Kong and Southeast Asia is still considerably higher
than in other parts of the world: the age-standardised
incidence rate was 7.9 per 100 000 population in
2014 in Hong Kong,3 compared with less than 1.0 per
100 000 population in North America and Europe.4
The global data from GLOBOCAN in 2012 showed
that 38% of all new cases of NPC were registered in
China.5
While Hong Kong is one of the regions that
experience the most NPC,6 it has also become a centre
for NPC research. Indeed, many important and
landmark studies in NPC were performed in Hong
Kong, where local experts have been responsible for
developing practice guidelines with regard to the
diagnosis, management, and follow-up of NPC.7 8 It is thus interesting to review the updated knowledge
about the aetiology, risk factors, diagnosis, and
treatment strategies of this ‘Guangdong cancer’.
Classification, aetiology, and risk
factors
Classification and staging
Nasopharyngeal cancer can be categorised according
to its histopathology: keratinising, non-keratinising
(which can be further subdivided into differentiated
and undifferentiated forms), and basaloid squamous
cell carcinoma; all of which are to replace the old
numerical classification system.9 In endemic regions
such as Hong Kong, non-keratinising carcinoma
predominates, whereas the keratinising type is more
common in other parts of the world.10
Nasopharyngeal cancer is staged according to
the tumour, node, metastasis system. To assist with
the prognosis and guide treatment decisions, NPC
can be further stratified into five different stages
(stages I, II, III, IVA, and IVB), as suggested by the
latest American Joint Committee on Cancer (8th
edition) cancer staging manual.11
Viral factors
While it is widely believed that NPC is caused by
the interaction of several factors, Epstein-Barr virus
(EBV) infection is undoubtedly the most studied
aetiological factor for NPC. This virus—as a primary
aetiological agent of NPC, specifically the endemic
non-keratinising type—has been supported by a
large body of evidence12; a review in 2012 suggested
that EBV accounted for more than 85% of NPC cases
globally.13 Based on in-situ hybridisation techniques10
and the fact that EBV infects more than 90% of
the population,14 EBV reactivation is considered
necessary in the pathogenesis of NPC; inhibition of
EBV reactivation is currently being investigated as
a possible approach to preventing NPC relapse.15
What triggers the reactivation, however, is less well-defined,
although cigarette smoking is among the
possible reactivating factors.16 17
On the other hand, human papillomavirus
(HPV), a common aetiological agent causing
cervical cancer, is associated with the non-endemic,
keratinising type of NPC, although evidence is
limited due to its low prevalence.18 While EBV and
HPV infections are nearly always mutually exclusive
in the pathogenesis of NPC,9 studies have suggested
that HPV-positive NPC is associated with poorer
outcome when compared with EBV-positive NPC.19
Genetic factors
Genetic susceptibility has attracted intense
interest since the development of various genomic
techniques. A whole-exome sequencing study in
2014 revealed the genetic alterations that affect a
number of cellular pathways, including chromatin
modification, ErbB-phosphatidylinositol-3 kinase
signalling, and autophagy machinery in NPC.20
Epigenetic alterations of various chromosomal
regions, especially those regions with tumour-suppressor
genes, were also found in NPC patients.21
Li et al22 recently identified genomic aberrations
of multiple negative regulators of the nuclear
factor-κB (NF-κB) pathway in 111 EBV-positive
NPC samples in another whole-exome sequencing
study, suggesting the pivotal role of activating the
NF-κB signalling pathway in NPC and the potential
therapeutic applications of NF-κB inhibitors.22 The
researchers also revealed major histocompatibility
complex class I gene aberrations in some of the
samples, and the efficacy of immune checkpoint
inhibitors (discussed below) may be affected in this
subgroup of NPC patients.22 Although much in this
field remains to be elucidated, it is expected that
the genetic research will aid in the development of
powerful biomarkers for the diagnosis, prognosis,
and evaluation of the treatment for NPC.21
Environmental factors
An increased risk of NPC has been associated with a
number of lifestyle factors, among which a history of
salted fish consumption has the strongest association.
Various studies have confirmed its association with
NPC,23 24 and its relationship with the high prevalence of NPC in Hong Kong and neighbouring regions
in the 20th century.6 N-nitrosamine found in the
preserved salted fish is believed to be the carcinogen
concerned.25 Other factors such as the use of Chinese
medicinal herbs and high consumption of fermented
food were also suggested, but the associations were
often inconsistent among studies.24
Diagnosis
Nasendoscopy for a biopsy sample is essential for a
definitive diagnosis of NPC. Detecting and diagnosing
NPC at an early stage is of paramount importance:
the disease stage is significantly correlated with the
outcome in NPC, and early diagnosis may improve
outcomes.12 Cell-free EBV DNA analysis was shown
to have high sensitivity and specificity in detecting
NPC, and has been further validated by various
studies.26 A local study further showed that the
analysis was useful in detecting early-stage NPC in
asymptomatic individuals.27 An expanded phase II
study involving over 20 000 participants to evaluate
its feasibility as a screening tool (NCT02063399) has
just been completed, showing excellent sensitivity
and specificity (97.1% and 98.6%, respectively).28
Participants who were identified with NPC by this
screening tool were detected significantly earlier and
with better outcome when compared with those in a
historical control.28
Other roles of Epstein-Barr virus DNA
With the substantial involvement of EBV in the
pathogenesis of NPC, it is sensible to exploit EBV
DNA as a biomarker in managing patients with NPC.
One such application is the prediction of disease
recurrence after treatment. Post-treatment EBV
DNA level has been shown to be the most powerful
predictor for disease recurrence and long-term
survival in NPC patients of different ethnic origins,
clinical stages, and treatment modalities.29 30 31 32 33 34 35 36 Recently
Lee et al37 demonstrated that serial post–intensity
modulated radiation therapy (IMRT) undetectable
plasma EBV DNA was prognostic of all predefined
survival end-points at 3 years in the modern IMRT era.
Leung et al38 further showed that detectable plasma
EBV DNA level at midcourse of radiotherapy (RT)
or chemoradiotherapy (CRT) is adversely associated
with worse overall survival (OS) and progression-free
survival (PFS). This suggests the possibility of
shifting prognostication from a post-therapy time-point
to midcourse of therapy, and selecting high-risk
patients for therapy intensification by measuring
midcourse plasma EBV DNA level.38
Another notable application is the prediction of
treatment outcome by measuring the clearance rate
of plasma EBV DNA. Following the observation that
EBV DNA was rapidly cleared from the circulation
after surgical resection of NPC,39 subsequent
studies demonstrated that patients with more rapid
clearance of plasma EBV DNA responded better to
chemotherapy or CRT compared with patients with
a slower clearance.40 41 A prospective trial evaluating
the response to chemotherapy by measuring plasma
EBV DNA half-life together with tumour metabolic
response (via fluorodeoxyglucose positron emission
tomographic scan) is currently underway.
Treatment strategies
Radiotherapy
Radiotherapy has long been regarded as the mainstay
of NPC treatment, due to the radiosensitive nature of
the tumour, and the anatomical position of NPC that
limits a surgical approach.10 Of note, IMRT is currently
the preferred approach, with its improved OS and
decreased toxicity,42 advantages in preserving parotid
function and reducing severe xerostomia,43 and
improved quality of life compared with conventional
two-dimensional (2D) RT.44 It is currently used as a
monotherapy for the early stage of NPC.
Since the pre-IMRT era, re-irradiation has
been shown to be effective in non-metastatic,
recurrent NPC (rNPC) patients after primary RT.45 46 47
With its introduction, IMRT has quickly emerged
as the radiation modality of choice for rNPC as
well, with or without the use of chemotherapy. Its
efficacy has been established in various studies,
with documented long-term OS rates ranging from
45% to 65%.48 49 50 51 52 53 54 55 56 Yet, most of the patients in those
studies were treated with conventional 2D-RT in
the pre-IMRT era. In a recent study conducted by
Kong et al,56 77 patients received salvage IMRT for
rNPC after a definitive course of primary IMRT.
While the median OS and PFS were 37.0 and 20.5
months, respectively, of particular note is the re-irradiation
toxicity. Of 34 patients, 18 died from
treatment-induced severe adverse effects without
evidence of disease progression during the study,
including mucosal necrosis, temporal lobe necrosis,
and cranial neuropathy,56 reflecting the limitations
of salvage IMRT in the modern IMRT era. Other
radiation modalities have been proposed, including
particle therapy using proton and carbon ions,57 but
long-term data are not yet available.
Chemotherapy
Chemotherapy is another important modality in
managing NPC, and it is often combined with RT
in the intermediate and advanced stages of NPC.
The benefit of CRT was well-illustrated in a meta-analysis
of seven trials, which showed significantly
improved OS and 10-year PFS in the CRT group
compared with the RT-alone group.58 A platinum-based
regimen is often used as the chemotherapy of
choice, in which cisplatin is most commonly used.10
While it is clear that chemotherapy is essential
in the treatment of advanced NPC, its value as an
add-on induction therapy (preceding CRT) and
adjuvant therapy (following CRT) is less clear.
Regarding induction therapy, a phase III trial recently
showed that the addition of docetaxel, cisplatin, and
fluorouracil prior to CRT was superior to CRT alone
in terms of OS and PFS at 3 years,59 although another
trial using cisplatin and fluorouracil as induction
therapy failed to show significant differences in
OS.60 The role of induction therapy requires further
confirmation from other ongoing phase III trials.
Meanwhile, the use of adjuvant chemotherapy
following CRT is debatable. A phase III trial with
a median follow-up of 68.4 months failed to show
significantly improved OS and PFS after adding
cisplatin and fluorouracil as adjuvant therapy post-CRT in locally advanced NPC,61 but another study
suggested adjuvant chemotherapy might be reserved
for high-risk patients defined by post-treatment
residual EBV DNA.62 63 It should be noted, however, that the benefit of more intensive therapy may be
limited by the late toxicities of high cumulative doses
of chemotherapy, most notably cisplatin, which are
not reported in some of the studies.60 64
Platinum-containing doublet regimens remain
the first-line systemic treatment for recurrent or
metastatic NPC. Cisplatin and fluorouracil have
been the conventional choices.10 A recent study by
Zhang et al65 demonstrated that the combination
of cisplatin plus gemcitabine was superior to the
combination of cisplatin and fluorouracil, in terms
of median PFS (7.0 vs 5.6 months; hazard ratio=0.55;
95% confidence interval, 0.44-0.68), although the
cisplatin-gemcitabine group experienced more
haematological toxicity, such as grade-3 or higher
leukopenia, neutropenia, and thrombocytopenia.65
This randomised controlled trial has thus established
the role of cisplatin and gemcitabine combination
as the chemotherapy of choice in recurrent or
metastatic NPC.
Surgery and targeted therapy
As mentioned above, surgery is usually not
considered in the routine management of NPC; yet
salvage therapy can be considered an option for
selected patients with local recurrence in the neck.66
Molecular targeted therapy is considered hopeful
for many other types of carcinoma, but its efficacy
in treating NPC has been disappointing; studies
of inhibitors of epidermal growth factor receptor
(eg cetuximab) and vascular endothelial growth
factor (eg sunitinib) failed to show superiority over
standard treatments, and were largely limited to
phase II trials.8 Lee et al8 attributed its failure to
the scarcity of authentic NPC models that can be
utilised in the preclinical studies of new drugs, and
increased incidence of drug-related toxicities such
as bleeding. The development of immunotherapy
is therefore exciting as it presents a new hope for
managing NPC.
Immunotherapy
The presence of EBV and the expression of viral
antigens in almost all NPC cases make this
disease an attractive target for the development of
immunotherapy. For example, EBV nuclear antigen
I (EBNA1) and latent membrane protein 2 (LMP2)
are frequently expressed in EBV-associated NPC,
and a recombinant virus–based vaccine that encodes
an inactive fusion protein containing fragments
of EBNA1 and LMP2 was shown to be effective in
inducing T-cell response in a local phase I trial.67 The
vaccine is currently being tested in a phase II clinical
trial (NCT01094405).
As EBV that persists as a latent infection is
controlled by cytotoxic T lymphocytes (CTL),68 it
follows that the use of EBV-specific CTL for NPC
appears logical as a treatment strategy. Adoptive
immunotherapy that includes infusion of autologous
CTL has been tested in a number of clinical trials,
and the results have been promising. For example,
a study in Singapore showed that chemotherapy
followed by EBV-specific CTL achieved a response
rate (full or partial) of 71.4% in 38 patients,69 and
a phase III trial is currently underway to assess its
efficacy (NCT02578641).
Among all the immunotherapies available,
checkpoint inhibitors seem to be the most rapidly
developing. Programmed death ligand–1 (PD-L1)
was found to be expressed on antigen-presenting
cells, and its interaction with the programmed
death–1 (PD-1) receptor on T cells inhibits
downstream signalling of T cell receptors.70 Tumour-associated
PD-L1 was also found to mediate immune
suppression by various other mechanisms, such as
facilitating T cell apoptosis and inducing regulatory
T cells.71 With PD-L1 expressed in many different
carcinomas,72 blockade of PD-L1 and/or the PD-1
receptor has become the focus of new cancer drug
development in the past 5 years.
While PD-L1 inhibitor has recently gained
much attention in the treatment of non–small-cell
lung cancer,73 its progress in the treatment
of advanced NPC is exciting and much awaited.
Pembrolizumab was shown to be well-tolerated
with significant anti-tumour activity in NPC in a
phase Ib trial,74 and is currently in a phase II trial
to confirm the response rate and efficacy in terms
of improvement in OS (NCT02611960). Nivolumab
has just completed phase II trials; the preliminary
results showed that it is active in heavily pre-treated
recurrent or metastatic patients,75 76 and that PD-L1 expression may predict benefits from nivolumab.75
Conclusion
Once a nightmare in the eyes of many Hong Kong
inhabitants, NPC has become less prevalent
in southern China, but it still poses a threat to
Hong Kong citizens as it was ranked as the 10th
most common cancer in the city.3 With clearer
understanding of its pathophysiology and advances
in technology, it is expected that more refined
treatment strategies and novel therapeutic agents
will be available in the near future.
Acknowledgement
I would like to thank Prof Brigette Ma from
Department of Clinical Oncology, The Chinese
University of Hong Kong for her comments and
advice.
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