Annals of Oncology 21 (Supplement 7): vii308–vii312, 2010
doi:10.1093/annonc/mdq277symposium article
Nasopharyngeal carcinoma
A. T. C. Chan*
State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong
With the improvement in local control achieved by more precise imaging and radiotherapy, the predominant mode of
failure for nasopharyngeal carcinoma is distant metastases. Concurrent cisplatin–radiotherapy with or without adjuvant
chemotherapy is the standard treatment approach for stages IIB and above disease. The addition of neoadjuvant
chemotherapy has been most promising, and phase III trial results are awaited. Quantitative Epstein–Barr virus (EBV)
DNA can be applied clinically for disease monitoring and follow-up, and may in future be used for risk stratification
strategies. Targeted therapies against epidermal growth factor receptor and angiogenesis have demonstrated activity,
and immunotherapeutic approaches are being investigated.
Key words: chemoradiotherapy, Epstein–Barr virus, nasopharyngeal carcinoma
epidemiology and aetiology
Nasopharyngeal carcinoma (NPC) is rare with an incidence of
0.5–2 per 100 000 in Europe and the USA [1]. In Southern
China, NPC is endemic, and the incidence is up to 25 per
100 000. Intermediate incidence is seen in Southeast Asia, the
Mediterranean Basin and the Arctic. In endemic NPC, >95%
are classified as the undifferentiated World Health
Organization (WHO) type III and is universally associated with
Epstein–Barr virus (EBV) [2], a strong aetiological factor
interacting with genetic predisposition and dietary intake of
preserved foods. In North America, 25% are classified as WHO
type I keratinizing squamous cell carcinoma (SCC) and 12%
as WHO type II differentiated SCC, which are associated with
classic head and neck aetiological factors including alcohol
and tobacco.
staging and diagnosis
The strong prognostic significance of nodal staging in NPC is
reflected in the UICC/AJCC staging system of 1997, and
retained in the 2002 version which is currently widely used [3].
Definitive diagnosis is made by endoscopic biopsy. Magnetic
resonance imaging (MRI) of the nasopharynx, skull base and
neck is the imaging technique of choice. For patients with
advanced N3 nodal stage and/or clinical evidence of distant
metastases, positron emission tomography–computed
tomography (PET-CT) may be performed [4].
EBV testing
The titre levels of antibodies to EBV immunoglobulin A viral
capsid antigen (IgA VCA) and early antigen (IgA EA) have been
widely used as screening and diagnostic markers for NPC, even
though these markers lack specificity [5]. Furthermore,
IgA VCA/EA levels usually remain elevated even after disease
remission is achieved. In contrast, quantitation of EBV DNA
using a real-time PCR technique is highly sensitive and specific
for NPC and correlates well with tumour burden [6, 7].
Pre-treatment plasma EBV DNA levels have been shown to
complement TNM (tumour–node–metastasis) staging [8], and
elevated EBV DNA levels at 6 weeks after treatment is
a powerful prognosticator of recurrence and survival [9, 10].
EBV DNA can be used clinically to monitor disease response
and recurrence [11, 12], while ongoing studies are addressing
the use of EBV DNA as a screening tool as well as a risk
stratification marker guiding therapy [13].
treatment for locoregional disease
NPC is highly radiosensitive, and radiotherapy (RT) is the
mainstay treatment, achieving a 5-year overall survival of 90%
and 84% for early stage I and IIA disease, respectively [14].
Intensity-modulated radiotherapy (IMRT) may improve local
control and also diminish the risk of xerostomia through
parotid sparing [15, 16].
Stage IIB is considered as intermediate stage disease since
there is increased risk of distant failures [17]. Evidence to
support the use of chemotherapy–radiotherapy (CRT) is
limited in this category due to the small numbers included in
prospective studies. Chang et al. reported marked improvement
in 3-year disease-free survival (DFS) for stage II patients treated
with concurrent CRT [18], and Chua et al. reported the benefit
of induction chemotherapy for intermediate stage disease by
pooling the results for two phase III randomized trials [19].
Until further data emerge, it is recommended that stage IIB
patients should be treated with concurrent CRT which is
indisputably the standard treatment approach for more
advanced NPC [20, 21].
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*Correspondence to: Dr A. T. C. Chan. State Key Laboratory in Oncology in South
China, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese
University of Hong Kong. E-mail: anthony@clo.cuhk.edu.hk
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
In locoregionally advanced stages III, IVA and IVB disease,
concurrent CRT, with or without adjuvant chemotherapy, has
been established as the standard of care based on the
publication of multiple prospective randomized trials, as well as
meta-analyses of these studies demonstrating a reduction of the
risk of death by 18% and an increase in the 5-year overall
survival of 4–6% [22, 23]. Concurrent CRT has been
demonstrated to provide significant improvements in both
local control and distant metastases [24–29].
While it is indisputable that CRT is the standard approach,
different regimens have been adopted in clinical trials and also
in clinical practice. The US Intergroup regimen, which is
accepted as the standard in North America, using cisplatin
100 mg/m2 on days 1, 22 and 43 concurrent with RT followed
by adjuvant cisplatin 80 mg/m2 on day 1 and 5-fluorouracil
(5-FU) 1000 mg/m2 on days 1–4 for three cycles [24], is
associated with significant acute and late toxic effects, and
compliance is limited, especially in endemic areas where the
nutritional status of patients is not as optimal. Weekly cisplatin
40 mg/m2 for 6–8 weeks concurrent with RT has demonstrated
excellent tolerability and efficacy and has been adopted in
many centres as the standard of care [26]. Weekly oxaliplatin
70 mg/m2 has also been compared with RT alone in a small
study, with good tolerability and efficacy [30]. A study of
206 patients demonstrated that the use of carboplatin
compared with cisplatin was associated with better tolerability
and no difference in overall survival or DFS at a median follow-
up of 26 months [31]; however, the modest sample size cannot
definitively prove non-inferiority, and confirmatory trials
would be necessary. Meanwhile, for patients with borderline
renal function or performance status, substitution of
carboplatin for cisplatin can be recommended. Whether the
three cycles of adjuvant chemotherapy in the US Intergroup
regimen is ‘necessary’ remains an open question since no trial
has randomized patients to concurrent CRT plus adjuvant
versus concurrent CRT. Trials of RT plus adjuvant
chemotherapy versus RT alone have all been negative [32, 33],
and compliance with adjuvant chemotherapy due to toxic
effects is difficult after concurrent CRT.
The current standard of care for locoregionally advanced
NPC is concurrent cisplatin–RT, and adjuvant chemotherapy
can be considered optional. A risk stratification study
randomizing patients with residual post-treatment EBV DNA
to chemotherapy versus observation may address this
important clinical question. There has been renewed interest in
the use of neoadjuvant chemotherapy in non-NPC head and
neck cancers with the docetaxel–cisplatin–5-FU regimen [34,
35]. In NPC, meta-analyses of earlier studies of neoadjuvant
chemotherapy followed by RT versus RT alone have
demonstrated improvement in DFS without improvement in
overall survival [22, 23]. Possible explanations include
association with significant treatment-related deaths [36] and
underpowered studies [37, 38].
Combining neoadjuvant chemotherapy and concurrent CRT
hence presents an attractive multidisciplinary treatment
sequence utilizing the most promising benefits of systemic
therapy with better tolerability. Multiple single arm phase II
studies demonstrated acceptable toxic effects using newer
chemotherapy regimens and achieving a highly encouraging
clinical outcome [39–43]. A randomized phase II study of
neoadjuvant docetaxel–cisplatin followed by cisplatin–RT
versus cisplatin–RT demonstrated good tolerability and
improvement in overall survival [44]. There are ongoing phase
III studies addressing whether neoadjuvant chemotherapy plus
concurrent CRT is superior to concurrent CRT with or without
adjuvant chemotherapy.
treatment for recurrent and metastatic
disease
A multidisciplinary approach involving surgeons, radiation and
medical oncologists in the management of locally recurrent
NPC is crucial to salvage a subset of patients amenable to
surgery, or reirradiation with or without systemic therapy.
Detailed surgical and reirradiation techniques and patient
selection are outside the scope of this review [45, 46]. With
increasing local control from the primary treatment of NPC,
the predominant mode of failure is unquestionably distant
metastases.
The median survival of metastatic NPC depends on the site
and volume of metastases. Hui et al. reported that patients with
lung metastases only had superior survival to those with liver or
bone metastases if they were treated in an aggressive manner
[47]. NPC is highly chemosensitive, and first-line doublet
chemotherapy achieves 50–80% response rates, with a median
time to progression of 5–11 months. However, the median
survival is only �12–20 months [48–55]. Combining cisplatin
with either infusional 5-FU or one of the active modern agents
including gemcitabine, paclitaxel, docetaxel, irinotecan and
vinorelbine has not been compared in a randomized manner
and they are considered valid therapy options. Increasing the
number of drugs (‡3) is associated with higher response rates
and toxic effects which have not been demonstrated to lead to
superior survival compared with platinum-based doublets.
Carboplatin is used to substitute for cisplatin in patients with
borderline renal function or performance status. Oxaliplatin
has also been demonstrated to be very active in combination
with gemcitabine [55].
In the second-line setting, gemcitabine, capecitabine,
irinotecan and vinorelbine have been shown to have significant
activity, although the median survival is limited at 7–11 months
[56, 57]. There is clearly an urgent need for novel therapeutics
in this disease setting.
targeted therapy
Epidermal growth factor receptor (EGFR) is highly expressed in
NPC, and strong expression is associated with poor survival
outcome [58, 59]. Combination of the monoclonal antibody
against EGFR, cetuximab, with carboplatin in patients with
metastatic NPC who have failed prior platinum-based therapies
achieved a response rate of 12% and a clinical benefit rate of
60% [60]. Cetuximab has been combined with cisplatin and
IMRT in locoregionally advanced NPC, demonstrating good
tolerability despite a significant incidence of radiation
dermatitis, mucositis and dysphagia [61]. The approach of
adding EGFR-targeted therapy to conventional treatment
Annals of Oncology symposium article
Volume 21 | Supplement 7 | October 2010 doi:10.1093/annonc/mdq277 | vii309
approaches is being actively studied in locoregionally advanced
NPC.
Gefitinib, a tyrosine kinase inbitor against EGFR, has
minimal activity in chemotherapy-refractory metastatic NPC
[62, 63]. In NPC cell lines, gefitinib resistance may be explained
by a persistent p-AKT activation despite successful suppression
of other kinases [64]. EGFR mutations have not been detected
in NPC.
Overexpression of the markers associated with hypoxia,
including hypoxia-inducible factor 1a (HIF-1a), carbonic
anhydrase 9 (CA-9) and vascular endothelial growth factor
(VEGF), is associated with poorer survival outcome in NPC
[65]. A high expression of osteopontin is associated with poorer
response to RT [66]. Prospective studies are needed to validate
the use of these biomarkers as predictors of treatment outcome
and evaluate the therapeutic activities of antiangiogenic
targeted agents in NPC.
immunotherapy and epigenetic therapy
The presence of EBV antigens in NPC cells provides a possible
immotherapeutic target for therapy. Immunotherapy against
NPC cells aims to boost the levels of cytotoxic T lymphocytes
(CTLs) that recognize the subdominant viral antigens such as
EBNA-1, LMP-1 and LMP-2 [67]. Adoptive transfer of CTLs
specific for LMP-2 and EBNA-1 has been tested with limited
success [68]. The antitumour response could be further
enhanced by pulsing the dendritic cells with peptides derived
from LMP-2 [69]. Autologous CTL therapy has been used to
treat 10 NPC patients, with promising results [70].
CpG methylation is associated with silencing of EBV
immunodominant antigens and tumour suppressor genes.
Epigenetic therapies may reactivate the host’s immune response
through demethylation of the genes or antigens. The
demethylating agent 5-azacytidine was shown consistently to
achieve demethylation of the promoter regions in EBV genes
but had limited efficacy in up-regulating the immunodominant
antigens [71]. The combination of 5-azacytidine and a histone
deacetylase inhibitor SAHA is being investigated to test the
hypothesis that restoring both methylation and histone
deacetylation may achieve a greater degree of gene
transcription.
conclusions
Concurrent cisplatin–RT with or without adjuvant
chemotherapy is the current standard of care for locoregionally
immediate and advanced NPC. The use of neoadjuvant
chemotherapy, targeted therapy and EBV DNA risk
stratification strategies is being actively investigated. In
metastatic disease, platinum-based doublet chemotherapy
remains standard treatment while immunological and targeted
approaches are being further developed.
disclosure
The author has received grant support from Research Grants
Council of Hong Kong, Cancer Research UK, Sanofi-Aventis,
Merck-Serono, Pfizer and Eli Lilly.
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