Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma

Epidemiology, etiology, and diagnosis of nasopharyngeal

carcinoma
Authors
Edwin P Hui, MD
Anthony TC Chan, MD
Section Editors
Bruce E Brockstein, MD
David M Brizel, MD
Deputy Editor
Michael E Ross, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2013. | This topic last updated: Oct 5, 2012.

INTRODUCTION — Nasopharyngeal carcinoma is the predominant tumor type arising in

the nasopharynx, the narrow tubular passage behind the nasal cavity. It differs from other
head and neck squamous cell carcinomas in epidemiology, histology, natural history, and
response to treatment.

This topic discusses the epidemiology, etiology, diagnosis, and staging of nasopharyngeal
carcinoma. The pathology and treatment and of nasopharyngeal carcinoma is presented
elsewhere.

 (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma" .)

 (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma" .)
 (See "Pathology of head and neck neoplasms", section on 'Nasopharyngeal carcinoma'
.)

EPIDEMIOLOGY — Worldwide, there are 80,000 incident cases and 50,000 deaths
annually [ 1 ]. Nasopharyngeal carcinoma displays a distinct racial and geographic
distribution, which is reflective of its multifactorial etiology.

Geographic and ethnic distribution — The incidence of nasopharyngeal carcinoma

demonstrates a marked geographical variation. In the United States and Western Europe, it is
rare, with an incidence of 0.5 to 2 per 100,000 [ 2-4 ]. In contrast, nasopharyngeal carcinoma
is endemic in southern China, including Hong Kong, where the incidence may reach 25 cases
per 100,000 per year. Intermediate risk regions include Southeast Asia, North Africa and the
Middle East, and the Arctic. Populations that migrate from areas of high to low risk retain an
elevated risk, although this risk typically diminishes in successive generations [ 3 ].

Sex and age distribution — The incidence of nasopharyngeal carcinoma is two- to threefold
higher in males compared with females.

In high-risk populations, the incidence peaks around 50 to 59 years of age and declines
thereafter. There is also a minor incidence peak observed among adolescents and young
adults in Southeast Asia, the Middle East/North Africa, and the United States. In most low-
risk populations, nasopharyngeal carcinoma incidence increases with increasing age [ 2,3 ].
Secular trend — Nasopharyngeal carcinoma incidence has declined over the past 30 years in
many endemic areas, including Hong Kong, Singapore, and Taiwan [ 5-7 ]. The reasons for
this decline are unclear, although they are generally attributed to lifestyle changes associated
with the rapid economic development that occurred in these areas. As an example, there has
been a decreased use of salted fish in feeding infants and reduced exposure to traditional
preserved food. However, the declining incidence may also be due to population shifts as a
result of altered immigration patterns.

ETIOLOGY — The geographic variation of nasopharyngeal carcinoma incidence suggests a

multifactorial etiology. In endemic populations, risk appears to be due to an interaction of
several factors: Epstein-Barr virus (EBV) infection, genetic predisposition, and
environmental factors such as the high intake of preserved foods and smoking [ 8-11 ].
Furthermore, the increased incidence in younger adults in high and intermediate risk areas
suggests that exposure to a common agent early in life is a critical factor [ 2 ]. In the United
States and Europe, nasopharyngeal carcinoma is more commonly associated with alcohol and
tobacco usage, which are classic risk factors for other head and neck tumors [ 12 ].

Diet — Several dietary practices in endemic areas are thought to contribute to the high
incidence of nasopharyngeal carcinoma [ 2,8-10,13-16 ]:

 The cooking of salt-cured food, which releases volatile nitrosamines that are carried
by steam and distributed over the nasopharyngeal mucosa.
 Early childhood exposure to salted fish, which was traditionally used for weaning.
 High consumption of preserved or fermented foods, including meats, eggs, fruits, and
vegetables, which contain high levels of nitrosamines as well as bacterial mutagens,
direct genotoxins, and EBV-reactivating substances.
 The use of Chinese medicinal herbs, which may contribute either by reactivating EBV
or through a direct promoting effect on EBV-transformed cells.
 The consumption among the Maghrebian population from Tunisia, Algeria, and
Morocco of rancid butter and sheep's fat, which contain butyric acid, a potential EBV
activator and causative agent for nasopharyngeal carcinoma.

Epstein-Barr virus — A large body of evidence supports the role of EBV as a primary
etiologic agent in the pathogenesis of nasopharyngeal carcinoma [ 17-20 ]. This includes the
detection of both EBV DNA and EBV gene expression in precursor lesions and tumor cells.
Nasopharyngeal carcinoma cells express a specific subgroup of EBV latent proteins,
including EBNA-1 and two integral membrane proteins, LMP-1 and LMP-2, along with the
BamHI-A fragment of the EBV genome [ 21,22 ]. Patients with nasopharyngeal carcinoma
also demonstrate specific serologic responses to various gene products of EBV [ 18-20,23,24
]. One such aberrant serologic response associated with nasopharyngeal carcinoma is
immunoglobulin A (IgA) antibodies directed against EBV viral capsid antigen (VCA/IgA).
(See "Virology of Epstein-Barr virus" .)

Smoking has also been associated with nasopharyngeal carcinoma [ 11,25 ]. Smoking has
also been associated with EBV seropositivity and may be involved in the pathogenesis of
nasopharyngeal carcinoma by causing EBV reactivation [ 11 ].

This association of nasopharyngeal carcinoma with EBV infection has been exploited to
develop noninvasive diagnostic tests. It is also being used experimentally to treat advanced
disease. (See 'Epstein-Barr virus testing' below and "Treatment of recurrent and metastatic
nasopharyngeal carcinoma", section on 'Immunotherapy' .)

Human papilloma virus — Human papilloma virus (HPV) was detected in a small subset of
carcinomas involving the nasopharynx, but many of these may represent extension from a
primary cancer of the oropharynx. In one small series of western patients "diagnosed" with
nasopharyngeal cancer, HPV was detected in 4 of 45 cases [ 26 ]. Of the three patients with
HPV-positive carcinomas and available staging information, all were found to have extension
into the oropharynx.

Heredity — Genetic factors may influence the risk of nasopharyngeal carcinoma. One case
control study, for example, suggested that having a first degree relative with nasopharyngeal
carcinoma increased risk sevenfold [ 27 ]. With evidence for clustering within families, some
have recommended screening for first-degree relatives of patients with nasopharyngeal
carcinoma [ 28 ]. (See 'Screening' below.)

Nasopharyngeal carcinoma has been associated with certain HLA haplotypes [ 29-32 ].
Nasopharyngeal carcinoma has also been associated with genetic polymorphisms, such as
CYP2A6, which is a polymorphism of a nitrosamine metabolizing gene [ 33,34 ].

Molecular pathogenesis — Studies have identified critical genetic and epigenetic events in
nasopharyngeal carcinoma. Copy number losses on chromosomes 1p, 3p, 9p, 9q, 11q, 13q,
14q and 16q and recurrent gains on chromosome 1q, 3q, 8q, 12p and 12q are frequently
observed in nasopharyngeal carcinoma.

Although alterations of the well-established tumor suppressor genes, such as TP53 and RB1,
are relatively rare in nasopharyngeal carcinoma tumors, multiple genetic and epigenetic
alterations in other tumor suppressor genes and oncogenes have been detected [ 35 ]. As an
example, the roles of several important tumor suppressor genes (eg, p16 and RASSF1A) and
oncogenes (eg, CCND1) have been described [ 36,37 ].

Although the molecular basis of nasopharyngeal carcinoma pathogenesis is still poorly

understood, pathogenesis and development of nasopharyngeal carcinoma appears to follow a
multistep process [ 37 ]. In individuals from endemic regions, the nasopharyngeal carcinoma
associated genotypes for various alleles, such as HLA and the polymorphic genes for
carcinogen metabolism, detoxification and DNA repair, may predispose the nasopharyngeal
epithelial cells to DNA damage. Chronic exposure to carcinogens such as nitrosamines may
lead to increased DNA damage and the formation of multiple lesions in the nasopharynx with
clonal genetic changes. Genetic and epigenetic changes interact with latent EBV infection to
disrupt major cellular mechanisms and contribute to the initiation and progression of
nasopharyngeal carcinoma.

CLINICAL PRESENTATION — The most common presenting complaints in patients with

nasopharyngeal carcinoma are headache, caused by cranial nerve involvement, and a mass in
the neck, due to cervical node metastases. The clinical triad of a neck mass, nasal obstruction
with epistaxis, and serous otitis media occurs infrequently, although each of these symptoms
occurs commonly.

Nasopharyngeal carcinoma frequently originates from the pharyngeal recess, the fossa of
Rosenmuller. Since this is a clinically occult site, patients may remain asymptomatic for a
prolonged period. The majority of patients present with locally and/or regionally advanced
disease because of this prolonged asymptomatic period or in some cases due to a missed
diagnosis [ 38-40 ].

The primary tumor may present as a smooth bulge in the mucosa, a discrete nodule with or
without surface ulceration, or an infiltrative fungating mass. Erosion into the skull base is
common with or without impairment of cranial nerves [ 41 ]. Cranial nerves III, V, VI, and
VII are most commonly affected because of para-cavernous sinus tumor invasion [ 42-44 ].

Nasopharyngeal carcinoma has a tendency for early metastatic spread [ 40,42,45 ]. Lymph
node metastases are present at diagnosis in 75 to 90 percent of cases and are bilateral nodes in
over 50 percent. Distant metastases are present at initial diagnosis in 5 to 11 percent of
patients.

The location and extent of lymph node metastases are predictive of distant metastases [ 46-48
]. The most frequent sites of distant metastases are bone (75 percent), lung, liver, and distant
nodes [ 45 ]. Multiple paraneoplastic syndromes, including neutrophilia, fever of unknown
origin, hypertrophic osteoarthropathy, and dermatomyositis can occur [ 45,49 ].

HISTOLOGY — Nasopharyngeal carcinoma arises from the epithelial lining of the

nasopharynx.

The World Health Organization (WHO) classifies nasopharyngeal carcinoma into the
following histopathologic types [ 50 ]:

 Keratinizing squamous cell carcinoma (WHO Type I): The sporadic form of
nasopharyngeal carcinoma most commonly is the keratinizing subtype (WHO Type
I).
 Nonkeratinizing carcinoma: This is subdivided into the differentiated (Type II) and
undifferentiated (Type III) forms. The endemic form of nasopharyngeal carcinoma is
commonly the undifferentiated, nonkeratinizing subtype. This is strongly associated
with EBV and has a more favorable prognosis than other types. There is preliminary
evidence that human papillomavirus (HPV) infection may be involved in EBV-
negative nasopharyngeal carcinoma in the United States [ 51,52 ].
 Basaloid squamous cell carcinoma: Basaloid squamous cell carcinoma was added to
the WHO classification of head and neck tumors in 2005. There are few reported
cases, which have been notable for an aggressive clinical course and poor survival [
53 ].

In North America, the relative frequencies of the different histologic subtypes are 25 percent
keratinizing, 12 percent differentiated, and 63 percent undifferentiated. In contrast, the
histological distribution among southern Chinese patients is 2 percent keratinizing, 3 percent
differentiated, and 95 percent undifferentiated [ 54 ]. (See "Pathology of head and neck
neoplasms" .)

STAGING — Nasopharyngeal carcinoma is clinically staged according to the International

Union Against Cancer (UICC) and American Joint Committee on Cancer (AJCC) tumor node
metastasis (TNM) system ( table 1 ) [ 55 ]. The UICC/AJCC TNM staging system, first
published in 1997 and most recently revised in 2010, incorporates key features of the older
Ho staging system [ 46 ].
The current TNM staging system classifies nodal stage according to size and lymph node
location, whether above (N1 or N2) or within the supraclavicular fossa (N3). The
supraclavicular fossa is a triangular zone defined by the superior margin of the sternal end of
the clavicle, the superior margin of the lateral end of the clavicle, and the point where the
neck meets the shoulder [ 55 ].

DIAGNOSTIC EVALUATION — A definitive diagnosis is made by endoscopically-guided

biopsy of the primary tumor or biopsy of other masses or metastases. Routine evaluation
should include history and physical examination, including the cranial nerves, complete
blood counts, and serum biochemistry, including liver function tests and alkaline
phosphatase. Other studies should include chest radiograph, nasopharyngoscopy, and
computed tomography (CT) or magnetic resonance imaging (MRI) of the nasopharynx, skull
base, and neck.

MRI, if available, is preferred over CT. MRI appears to be superior for the identification of
tumor invasion into soft tissue and bony structures, pharyngobasilar fascia obliteration,
invasion into the sinus of Morgagni, skull base invasion, and lymph node metastases in the
carotid and retropharyngeal spaces [ 47,48 ].

For patients with clinical or biochemical evidence of distant metastases or otherwise

considered at high risk for distant metastases (advanced nodal stage, N3), additional imaging
with bone scan, CT of chest and upper abdomen, and/or positron emission tomography (PET)
or integrated PET-CT imaging may be performed [ 47,56-58 ]. Because of its superiority
ability to detect lymph node and bone metastases, we suggest PET scanning, if available [
59,60 ]. (See "Overview of the diagnosis and staging of head and neck cancer" .)

We suggest obtaining pretreatment plasma EBV DNA levels for its prognostic contribution.
(See 'Epstein-Barr virus testing' below.)

EPSTEIN-BARR VIRUS TESTING — The strong etiologic link between EBV infection
and nasopharyngeal carcinoma is supported by the abnormal anti-EBV antibody profiles,
increased circulating EBV DNA levels, and distinct EBV gene expression in tumor cells.
Various indicators of EBV infection have been investigated as an alternative to
histopathologic diagnosis of nasopharyngeal carcinoma, as a method of noninvasive
screening, and for monitoring for disease recurrence.

Screening — Given the high rates of nasopharyngeal carcinoma in specific geographic

regions and among certain families and the high cure rate for early stage nasopharyngeal
carcinoma, screening of high-risk populations has been proposed [ 61-67 ]. Various
noninvasive methods of nasopharyngeal carcinoma detection have been studied; these include
EBV-specific antibody-based assays, measurement of circulating EBV DNA levels, and EBV
DNA and BARF1 oncogene mRNA detection from nasopharyngeal brushings.

In patients with nasopharyngeal carcinoma, the characteristic anti-EBV serologic profile

consists of a sustained rise in antibodies to viral capsid antigen (VCA) and early antigen (EA)
IgA [ 45 ]. In southern China, where nasopharyngeal carcinoma is endemic, EBV serology,
ie, serum VCA/IgA or IgA/EA antibody titers, has been used for population-based screening
[ 61-63 ]. However, EBV-specific serologic screening has limited specificity for
nasopharyngeal carcinoma and an elevated titer may proceed a diagnosis of nasopharyngeal
carcinoma for a period of up to ten years [ 61,62 ].
Quantitation of circulating EBV DNA has also been studied as a method for nasopharyngeal
carcinoma screening, and a large prospective study is ongoing to investigate the use of
plasma EBV DNA in primary screening of nasopharyngeal carcinoma in an endemic area [
64,68,69 ]. The sensitivity and specificity of using circulating EBV DNA for the detection of
nasopharyngeal carcinoma, with real-time polymerase chain reaction analysis (PCR), is 96
and 93 percent, respectively [ 69 ]. The sensitivity is lower when whole blood rather than
plasma DNA is used [ 70 ].

A promising strategy for screening is the use of a confirmatory noninvasive test after positive
serologic results. In one study, the combination of serum VCA/IgA antibody and circulating
EBV DNA had an overall sensitivity (positive result by either marker) of 99 percent, and
EBV DNA identified three-fourths of the false-positive VCA/IgA cases [ 65 ]. These results
suggest that an IgA VCA-based screening protocol augmented by the selective application of
EBV DNA could improve screening accuracy with only a moderate increase in cost.

Others have investigated the measurement of EBV DNA load combined with detection of
BamHI-A rightward frame 1 (BARF1) mRNA detection in NP brushing samples [ 71 ].
BARF1 is a viral oncogene that is exclusively expressed in EBV-positive carcinoma (ie,
nasopharyngeal carcinoma and EBV-positive gastric carcinomas) and is virtually absent from
EBV-associated lymphoma. With relatively good sensitivity and specificity, this method may
also prove to be useful for confirmatory testing.

Although screening for early detection is offered to first-degree relatives with nasopharyngeal
carcinoma by a few oncology centers in Southern China, routine screening has not become a
standard practice in other locations, and the utility of this approach continues to be debated.
The combination of IgA VCA and plasma EBV DNA appears to be the most promising for
screening.

Diagnostic evaluation — Although not currently a routine component in the evaluation of

nasopharyngeal carcinoma, pretreatment plasma EBV DNA levels have been correlated with
outcome [ 72-75 ]. We suggest obtaining pretreatment plasma EBV DNA levels as part of the
diagnostic and staging evaluation for its prognostic contribution. However, there is no
consensus on which EBV DNA level to use as a cutoff; pretreatment levels of 1500 and 4000
have been used [ 72,74,75 ]. (See "Treatment of early and locoregionally advanced
nasopharyngeal carcinoma", section on 'Prognosis' .)

Monitoring for treatment response and recurrence — Monitoring of posttreatment plasma

EBV DNA levels may also have a role in evaluating treatment response and detecting
recurrence [ 72 ]. The sensitivity of EBV DNA in the detection of local recurrence after
radiotherapy (tumors regrowing from an irradiated site) is much lower than that from a
radiation-naive site [ 76 ]. (See "Treatment of early and locoregionally advanced
nasopharyngeal carcinoma" .)

SUMMARY AND RECOMMENDATIONS — Nasopharyngeal carcinoma is an epithelial

neoplasm arising in the nasopharynx.

 Although, nasopharyngeal carcinoma is rare in most parts of the world, it is endemic

in southern China, southeast Asia, north Africa, and the Artic, where undifferentiated,
nonkeratinizing squamous cell carcinoma is the predominant histology. (See
'Epidemiology' above and 'Histology' above.)
  The major etiological factors for endemic nasopharyngeal carcinoma are genetic
susceptibility, early-age exposure to chemical carcinogens, and Epstein-Barr virus
(EBV) infection. (See 'Etiology' above.)
 For the initial diagnostic evaluation of nasopharyngeal carcinoma, we suggest
endoscopically guided biopsy of the primary tumor and magnetic resonance imaging
(MRI) of the nasopharynx, skull base, and neck for assessing locoregional disease
extent. (See 'Diagnostic evaluation' above.)
 For patients with advanced nodal stage (N3) or clinical or biochemical evidence of
distant metastases, we suggest additional imaging with positron emission tomography
(PET) or integrated PET-CT imaging, if available. Otherwise, bone scan and CT of
the chest and abdomen may be obtained. (See 'Diagnostic evaluation' above.)
 We suggest obtaining pretreatment plasma EBV DNA levels for their prognostic
significance. There is emerging evidence supporting serial measurement of plasma
EBV DNA levels to assess treatment response or monitor for recurrence. (See
'Diagnostic evaluation' above and "Treatment of early and locoregionally advanced
nasopharyngeal carcinoma" .)

REFERENCES
1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:
GLOBOCAN 2008. Int J Cancer 2010.
2. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma.
Cancer Epidemiol Biomarkers Prev 2006; 15:1765.
3. Barnes L, Eveson JW, Reichart P, Sidransky D. Pathology and Genetics of Head and
Neck Tumours. In: World Health Organization Classification of Tumors, IARC Press,
Lyon 2005.
4. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence,
Mortality and Prevalence Worldwide. In: IARC CancerBase, 5, IARC Press, Lyon
2005. Vol 2.0.
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.
6. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol
2002; 12:421.
7. Hsu C, Shen YC, Cheng CC, et al. Difference in the incidence trend of
nasopharyngeal and oropharyngeal carcinomas in Taiwan: implication from age-
period-cohort analysis. Cancer Epidemiol Biomarkers Prev 2006; 15:856.
8. Yuan JM, Wang XL, Xiang YB, et al. Preserved foods in relation to risk of
nasopharyngeal carcinoma in Shanghai, China. Int J Cancer 2000; 85:358.
9. Farrow DC, Vaughan TL, Berwick M, et al. Diet and nasopharyngeal cancer in a low-
risk population. Int J Cancer 1998; 78:675.
10. Liebowitz D. Nasopharyngeal carcinoma: the Epstein-Barr virus association. Semin
Oncol 1994; 21:376.
11. Xu F, Xiong D, Xu Y, et al. An Epidemiological and Molecular Study of the
Relationship. J Natl Cancer Inst.
12. Vaughan TL, Shapiro JA, Burt RD, et al. Nasopharyngeal cancer in a low-risk
population: defining risk factors by histological type. Cancer Epidemiol Biomarkers
Prev 1996; 5:587.
13. Hildesheim A, West S, DeVeyra E, et al. Herbal medicine use, Epstein-Barr virus,
and risk of nasopharyngeal carcinoma. Cancer Res 1992; 52:3048.
14. Zeng Y, Zhong JM, Ye SQ, et al. Screening of Epstein-Barr virus early antigen
expression inducers from Chinese medicinal herbs and plants. Biomed Environ Sci
1994; 7:50.
15. Feng BJ, Jalbout M, Ayoub WB, et al. Dietary risk factors for nasopharyngeal
carcinoma in Maghrebian countries. Int J Cancer 2007; 121:1550.
16. Gallicchio L, Matanoski G, Tao XG, et al. Adulthood consumption of preserved and
nonpreserved vegetables and the risk of nasopharyngeal carcinoma: a systematic
review. Int J Cancer 2006; 119:1125.
17. Atula S, Auvinen E, Grenman R, Syrjänen S. Human papillomavirus and Epstein-Barr
virus in epithelial carcinomas of the head and neck region. Anticancer Res 1997;
17:4427.
18. Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with
Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl
J Med 1995; 333:693.
19. Chien YC, Chen JY, Liu MY, et al. Serologic markers of Epstein-Barr virus infection
and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 2001; 345:1877.
20. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer 2004;
4:757.
21. Brooks L, Yao QY, Rickinson AB, Young LS. Epstein-Barr virus latent gene
transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and
LMP2 transcripts. J Virol 1992; 66:2689.
22. Busson P, McCoy R, Sadler R, et al. Consistent transcription of the Epstein-Barr virus
LMP2 gene in nasopharyngeal carcinoma. J Virol 1992; 66:3257.
23. Tune CE, Liavaag PG, Freeman JL, et al. Nasopharyngeal brush biopsies and
detection of nasopharyngeal cancer in a high-risk population. J Natl Cancer Inst 1999;
91:796.
24. Ji MF, Wang DK, Yu YL, et al. Sustained elevation of Epstein-Barr virus antibody
levels preceding clinical onset of nasopharyngeal carcinoma. Br J Cancer 2007;
96:623.
25. Hsu WL, Chen JY, Chien YC, et al. Independent effect of EBV and cigarette smoking
on nasopharyngeal carcinoma: a 20-year follow-up study on 9,622 males without
family history in Taiwan. Cancer Epidemiol Biomarkers Prev 2009; 18:1218.
26. Singhi AD, Califano J, Westra WH. High-risk human papillomavirus in
nasopharyngeal carcinoma. Head Neck 2012; 34:213.
27. Ung A, Chen CJ, Levine PH, et al. Familial and sporadic cases of nasopharyngeal
carcinoma in Taiwan. Anticancer Res 1999; 19:661.
28. Loh KS, Goh BC, Lu J, et al. Familial nasopharyngeal carcinoma in a cohort of 200
patients. Arch Otolaryngol Head Neck Surg 2006; 132:82.
29. Hildesheim A, Apple RJ, Chen CJ, et al. Association of HLA class I and II alleles and
extended haplotypes with nasopharyngeal carcinoma in Taiwan. J Natl Cancer Inst
2002; 94:1780.
30. Lu CC, Chen JC, Jin YT, et al. Genetic susceptibility to nasopharyngeal carcinoma
within the HLA-A locus in Taiwanese. Int J Cancer 2003; 103:745.
31. Feng BJ, Huang W, Shugart YY, et al. Genome-wide scan for familial
nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4. Nat Genet
2002; 31:395.
32. Hu SP, Day NE, Li DR, et al. Further evidence for an HLA-related recessive mutation
in nasopharyngeal carcinoma among the Chinese. Br J Cancer 2005; 92:967.
33. Tiwawech D, Srivatanakul P, Karalak A, Ishida T. Cytochrome P450 2A6
polymorphism in nasopharyngeal carcinoma. Cancer Lett 2006; 241:135.
34. Cao Y, Miao XP, Huang MY, et al. Polymorphisms of XRCC1 genes and risk of
nasopharyngeal carcinoma in the Cantonese population. BMC Cancer 2006; 6:167.
35. Tao Q, Chan AT. Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic
developments. Expert Rev Mol Med 2007; 9:1.
36. Chan AT, Teo PM, Huang DP. Pathogenesis and treatment of nasopharyngeal
carcinoma. Semin Oncol 2004; 31:794.
37. Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell 2004;
5:423.
38. Leong JL, Fong KW, Low WK. Factors contributing to delayed diagnosis in
nasopharyngeal carcinoma. J Laryngol Otol 1999; 113:633.
39. Fandi A, Altun M, Azli N, et al. Nasopharyngeal cancer: epidemiology, staging, and
treatment. Semin Oncol 1994; 21:382.
40. Hsu MM, Tu SM. Nasopharyngeal carcinoma in Taiwan. Clinical manifestations and
results of therapy. Cancer 1983; 52:362.
41. King AD, Lam WW, Leung SF, et al. MRI of local disease in nasopharyngeal
carcinoma: tumour extent vs tumour stage. Br J Radiol 1999; 72:734.
42. Vokes EE, Liebowitz DN, Weichselbaum RR. Nasopharyngeal carcinoma. Lancet
1997; 350:1087.
43. Aiken RD. Neurologic complications of head and neck cancers. Semin Oncol 2006;
33:348.
44. Neel HB 3rd. A prospective evaluation of patients with nasopharyngeal carcinoma: an
overview. J Otolaryngol 1986; 15:137.
45. Altun M, Fandi A, Dupuis O, et al. Undifferentiated nasopharyngeal cancer (UCNT):
current diagnostic and therapeutic aspects. Int J Radiat Oncol Biol Phys 1995; 32:859.
46. Ho JH. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J
Radiat Oncol Biol Phys 1978; 4:182.
47. Sakata K, Hareyama M, Tamakawa M, et al. Prognostic factors of nasopharynx
tumors investigated by MR imaging and the value of MR imaging in the newly
published TNM staging. Int J Radiat Oncol Biol Phys 1999; 43:273.
48. 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 Phys 2008; 72:1368.
49. Cvitkovic E, Bachouchi M, Boussen H, et al. Leukemoid reaction, bone marrow
invasion, fever of unknown origin, and metastatic pattern in the natural history of
advanced undifferentiated carcinoma of nasopharyngeal type: a review of 255
consecutive cases. J Clin Oncol 1993; 11:2434.
50. Pathology and genetics of head and neck tumors. In: World Health Organization
Classification of Tumours, Barnes L, Eveson JW, Reichart P, Sidransky D (Eds),
IARC Press, Lyon 2005.
51. Maxwell JH, Kumar B, Feng FY, et al. HPV-positive/p16-positive/EBV-negative
nasopharyngeal carcinoma in white North Americans. Head Neck 2010; 32:562.
52. Punwaney R, Brandwein MS, Zhang DY, et al. Human papillomavirus may be
common within nasopharyngeal carcinoma of Caucasian Americans: investigation of
Epstein-Barr virus and human papillomavirus in eastern and western nasopharyngeal
carcinoma using ligation-dependent polymerase chain reaction. Head Neck 1999;
21:21.
53. Müller E, Beleites E. The basaloid squamous cell carcinoma of the nasopharynx.
Rhinology 2000; 38:208.
54. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005; 365:2041.
55. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR,
Compton CC, et al (Eds), Springer, New York 2010.
56. Caglar M, Ceylan E, Ozyar E. Frequency of skeletal metastases in nasopharyngeal
carcinoma after initiation of therapy: should bone scans be used for follow-up? Nucl
Med Commun 2003; 24:1231.
57. Lee AW, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with
nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of
failure. Int J Radiat Oncol Biol Phys 1992; 23:261.
58. Chiesa F, De Paoli F. Distant metastases from nasopharyngeal cancer. ORL J
Otorhinolaryngol Relat Spec 2001; 63:214.
59. Chang JT, Chan SC, Yen TC, et al. Nasopharyngeal carcinoma staging by (18)F-
fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys
2005; 62:501.
60. Liu FY, Chang JT, Wang HM, et al. [18F]fluorodeoxyglucose positron emission
tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis
in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol 2006; 24:599.
61. Chua DT, Ji M, Zong Y, Chan K. Screening of nasopharyngeal carcinoma by
serology and nasopharyngoscopy and treatment outcome in endemic region. J Clin
Oncol 2009; 27:308s.
62. Zong YS, Sham JS, Ng MH, et al. Immunoglobulin A against viral capsid antigen of
Epstein-Barr virus and indirect mirror examination of the nasopharynx in the
detection of asymptomatic nasopharyngeal carcinoma. Cancer 1992; 69:3.
63. Zeng Y, Zhang LG, Wu YC, et al. Prospective studies on nasopharyngeal carcinoma
in Epstein-Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China. Int
J Cancer 1985; 36:545.
64. Lo YM, Chan LY, Lo KW, et al. Quantitative analysis of cell-free Epstein-Barr virus
DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 1999;
59:1188.
65. Leung SF, Tam JS, Chan AT, et al. Improved accuracy of detection of
nasopharyngeal carcinoma by combined application of circulating Epstein-Barr virus
DNA and anti-Epstein-Barr viral capsid antigen IgA antibody. Clin Chem 2004;
50:339.
66. Ng WT, Yau TK, Yung RW, et al. Screening for family members of patients with
nasopharyngeal carcinoma. Int J Cancer 2005; 113:998.
67. Cho WC. Nasopharyngeal carcinoma: molecular biomarker discovery and progress.
Mol Cancer 2007; 6:1.
68. Stevens SJ, Verkuijlen SA, Hariwiyanto B, et al. Diagnostic value of measuring
Epstein-Barr virus (EBV) DNA load and carcinoma-specific viral mRNA in relation
to anti-EBV immunoglobulin A (IgA) and IgG antibody levels in blood of
nasopharyngeal carcinoma patients from Indonesia. J Clin Microbiol 2005; 43:3066.
69. Chan KC, Lo YM. Circulating EBV DNA as a tumor marker for nasopharyngeal
carcinoma. Semin Cancer Biol 2002; 12:489.
70. Lit LC, Chan KC, Leung SF, et al. Distribution of cell-free and cell-associated
Epstein-Barr virus (EBV) DNA in the blood of patients with nasopharyngeal
carcinoma and EBV-associated lymphoma. Clin Chem 2004; 50:1842.
71. Stevens SJ, Verkuijlen SA, Hariwiyanto B, et al. Noninvasive diagnosis of
nasopharyngeal carcinoma: nasopharyngeal brushings reveal high Epstein-Barr virus
DNA load and carcinoma-specific viral BARF1 mRNA. Int J Cancer 2006; 119:608.
 72. Leung SF, Zee B, Ma BB, et al. Plasma Epstein-Barr viral deoxyribonucleic acid
quantitation complements tumor-node-metastasis staging prognostication in
nasopharyngeal carcinoma. J Clin Oncol 2006; 24:5414.
73. Liu FF, Frappier L, Kim J, et al. East-West Symposium on nasopharyngeal cancer. Int
J Radiat Oncol Biol Phys 2007; 67:703.
74. Chan AT, Lo YM, Zee B, et al. Plasma Epstein-Barr virus DNA and residual disease
after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst
2002; 94:1614.
75. Lin JC, Wang WY, Chen KY, et al. Quantification of plasma Epstein-Barr virus DNA
in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004; 350:2461.
76. Leung SF, Lo YM, Chan AT, et al. Disparity of sensitivities in detection of radiation-
naïve and postirradiation recurrent nasopharyngeal carcinoma of the undifferentiated
type by quantitative analysis of circulating Epstein-Barr virus DNA1,2. Clin Cancer
Res 2003; 9:3431.

Treatment of early and locoregionally advanced nasopharyngeal carcinoma

Treatment of early and locoregionally advanced nasopharyngeal carcinoma
Authors
Edwin P Hui, MD
Anthony TC Chan, MD
Quynh-Thu Le, MD
Section Editors
Marshall R Posner, MD
Bruce E Brockstein, MD
David M Brizel, MD
Deputy Editor
Michael E Ross, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2013. | This topic last updated: Jul 3, 2012.

INTRODUCTION — Nasopharyngeal carcinoma arises from the lining of the nasopharynx,

the narrow tubular passage behind the nasal cavity. Worldwide, there are about 80,000
incident cases and 50,000 deaths annually, but there is remarkable variation in racial and
geographic distribution [ 1 ]. While rare in most parts of the world, nasopharyngeal cancer is
endemic in southern China, Southeast Asia, North Africa, and the arctic, where
undifferentiated, nonkeratinizing squamous cell carcinoma is the predominant histology.

The treatment of locoregional nasopharyngeal cancer is presented here. Related topics

include:

 (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma" .)

 (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma" .)

STAGING AND CLASSIFICATION — Nasopharyngeal carcinoma is staged according to

the tumor node metastasis (TNM) system of the International Union Against Cancer (UICC)
and American Joint Committee on Cancer (AJCC) ( table 1 ) [ 2 ].

In the 2010 version of the TNM system, changes were made to primary site staging to reflect
the prognostic importance of involvement of the parapharyngeal space [ 2 ]. Specifically,
lesions previously staged as T2a are now classified as T1, and lesions previously staged T2b
are T2. Therefore, previous stage IIA is now included in stage I and stage IIB is now stage II.
However, much of the literature is based upon studies using the older staging system.

The World Health Organization (WHO) classifies nasopharyngeal cancer into three
histopathologic types [ 3 ]:

 Keratinizing squamous cell carcinoma (WHO Type I)

 Nonkeratinizing carcinoma: differentiated (WHO Type II) and undifferentiated
(WHO Type III)
 Basaloid squamous cell carcinoma

GENERAL TREATMENT PRINCIPLES — Nasopharyngeal carcinoma differs from other

head and neck squamous cell carcinomas in its epidemiology, pathology, natural history, and
response to treatment [ 4-6 ]. Radiation therapy (RT) remains the mainstay of treatment for
nasopharyngeal cancer, but RT has evolved over the last decade due to advances in high
precision RT delivery, the integration of chemotherapy, and improvement in tumor imaging
and disease monitoring [ 7 ]. (See "General principles of radiation therapy for head and neck
cancer" .)

Surgery at the primary site is not typically used as first-line treatment because of the deep
anatomical location of the nasopharynx and its close proximity to critical neurovascular
structures. However, neck dissection may be indicated after RT for residual nodal disease or
for an isolated neck recurrence, and nasopharyngectomy may be an option for a small
localized recurrence and are more commonly practiced in Asia. (See "Treatment of recurrent
and metastatic nasopharyngeal carcinoma" .)

Prognostic risk groups — Based on the risk of treatment failure, three prognostic groups can
be defined according to the TNM staging system for nasopharyngeal cancer ( table 1 ):

 Stage I - Early stage

 Stage II - Intermediate stage
 Stage III, IVA, IVB - Advanced stage

Although patients with early stage disease have good outcomes with RT alone, more
intensive treatment strategies are required to manage intermediate and advanced stage
disease.

Management of the neck — Nasopharyngeal cancer has a propensity for early, bilateral
spread to regional lymph nodes in the neck. Thus, all patients, including those with a
clinically negative neck, are treated with bilateral neck irradiation [ 8,9 ].

Endemic vs nonendemic disease — Endemic nasopharyngeal cancer (WHO type III,

undifferentiated carcinoma) appears to be particularly radiosensitive and may be associated
with higher overall survival rates than WHO type I, keratinizing squamous cell carcinoma
(the histology typically encountered in the United States and Western Europe) [ 10,11 ].
However, there is insufficient evidence to suggest that treatment should differ based upon
histopathologic classification.

EARLY (STAGE I) DISEASE — Nasopharyngeal carcinoma has traditionally been treated

with RT because it is a radiosensitive tumor and because its anatomic location limits a
surgical approach. Early (stage I) cancers are treated with RT alone with good locoregional
control. Five-year overall survival rates of 90 percent for stage I have been reported ( table 2 )
[ 12 ]. Evidence from retrospective studies suggests that outcomes have improved due to
advances in RT planning and delivery; improved staging, particularly the use of magnetic
resonance imaging (MRI) rather than computed tomography (CT), also appears to have
contributed [ 12,13 ]. This improvement may reflect stage migration as much as an actual
improvement in treatment.

External beam RT typically is given to a total dose of 70 to 72 Gray (Gy) to the primary
tumor and 50 Gy to the uninvolved neck in single daily fractions of 2.0 Gy, five days per
week over six to seven weeks [ 5,14 ]. A similar dosing schedule is used for more advanced
disease, with 66 to 70 Gy to involved lymph nodes.
Until recently, three-dimensional conformal radiation therapy (3D-CRT) techniques were
considered the standard of care. However, two randomized studies have shown that intensity
modulated radiation therapy (IMRT) is superior to conventional RT in preserving parotid
function and resulted in less severe late xerostomia without affecting local control in patients
with early stage nasopharyngeal carcinoma [ 15,16 ]. Similarly, a cooperative group phase II
study showed that it was feasible to implement IMRT across multiple institutions with an
excellent two-year locoregional-progression-free rate of 91 percent and a 14 percent rate of
grade 2 xerostomia [ 17 ]. These data have converted IMRT into the most commonly
accepted method of radiation delivery in the United States.

Since the dose gradient for IMRT is quite steep, it is important to ensure adequate patient
immobilization and verify daily treatment set-up accuracy. Image-guided radiation therapy
(IGRT) is often used with IMRT for verification of set-up accuracy and for consideration of
adaptive replanning in cases where there is a significant change in the patient’s anatomy due
to rapid tumor shrinkage or weight loss. Although some institutions have performed
dosimetric comparisons between IMRT and intensity modulated proton therapy (IMPT) for
nasopharyngeal carcinoma [ 18,19 ], clinical data on the use of IMPT in nasopharyngeal
carcinoma is lacking. (See "General principles of radiation therapy for head and neck cancer",
section on 'External beam radiation therapy' .)

Significant numbers of patients with early stage disease have not been included in trials of
induction chemotherapy, adjuvant chemotherapy, or concurrent chemoradiotherapy, and it is
unclear whether this group would benefit from combined modality therapy [ 20,21 ].

INTERMEDIATE (STAGE II) DISEASE — Combined modality treatment strategies are

generally recommended for stage II disease because of the elevated distant failure rates seen
in these patients ( table 1 ) [ 22,23 ].

The most extensive data come from a phase III trial in which 230 previously untreated
patients with stage II nasopharyngeal cancer were randomly assigned to RT plus concurrent
weekly cisplatin (30 mg/m 2 ) versus RT alone [ 24 ]. All patients had T1-2N1M0 or
T2N0M0 disease with parapharyngeal space involvement. When patients were restaged
according to the 2010 TNM staging system, 31 patients (13 percent) were reclassified as
stage III.

With a median follow-up of five years, overall survival was significantly improved by the
addition of concurrent cisplatin (five-year overall survival rate of 94.5 versus 85.8 percent,
hazard ratio [HR] 0.30, 95% CI 0.12-0.76). This difference was mainly due to an
improvement in distant metastasis free survival (94.8 versus 83.9 percent) and there was no
statistically significant difference in locoregional relapse free survival (93.0 versus 91.1
percent). Multivariate analysis showed that the number of chemotherapy cycles delivered was
the only independent factor that was associated with survival, progression, and distant control
in this study.

In this trial, the addition of weekly cisplatin to RT was associated with a statistically
significant increase in severe (grade 3 or 4) leukopenia/neutropenia, nausea/vomiting, and
mucositis compared with RT alone (12 versus 0, 8.6 versus 0, and 46 versus 33 percent,
respectively). There was no significant increase in late toxicity.
ADVANCED (STAGE III AND IV) DISEASE — Meta-analyses of randomized controlled
trials concluded that the addition of any chemotherapy (concurrent, induction, or adjuvant) to
definitive radiation therapy (RT) reduces the risk of death by 18 percent and increases overall
five-year survival by 4 to 6 percent [ 25,26 ]. Most of this survival benefit is due to a
reduction in distant failure; concurrent chemoradiotherapy as opposed to induction
chemotherapy or adjuvant chemotherapy demonstrated the most pronounced benefit ( table 3
). Thus, concurrent chemoradiotherapy, with or without induction chemotherapy or post-
chemoradiotherapy adjuvant treatment, now is the standard of care for patients with
advanced, nonmetastatic nasopharyngeal carcinoma (stages III, IVA, and IVB).

Concurrent chemoradiotherapy — Concurrent chemotherapy has been used in patients with

locoregionally advanced head and neck cancer to sensitize tumor to the effects of RT and to
thereby improve tumor control. (See "Methods to overcome radiation resistance in head and
neck cancer" and "Locally advanced squamous cell carcinoma of the head and neck:
Approaches combining chemotherapy and radiation therapy" .)

The United States Intergroup 0099 trial was the first to demonstrate a benefit from concurrent
chemoradiotherapy for the management of locoregionally advanced nasopharyngeal cancer [
27 ]. In this trial, 193 patients with stage III and IV nasopharyngeal cancer were randomly
assigned to concurrent chemoradiotherapy followed by adjuvant chemotherapy or RT alone.
RT consisted of 70 Gy in 35 to 39 fractions of 1.8 to 2.0 Gy daily. Chemotherapy consisted
of cisplatin (100 mg/m 2 on days 1, 22, and 43) concurrent with RT followed by adjuvant
cisplatin (80 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 daily, days 1 through 4)
repeated every four weeks for three cycles.

The study was terminated at the first planned interim analysis. Based upon analysis of 147
patients, concurrent chemoradiotherapy and adjuvant chemotherapy significantly increased
three-year progression-free survival compared with RT alone (69 versus 24 percent) and
overall survival (78 versus 47 percent). This benefit persisted at five years of follow-up [ 28 ].

Subsequently, meta-analyses of multiple randomized trials (most conducted in endemic

regions) in patients with locoregionally advanced nasopharyngeal carcinoma confirmed an
advantage with this approach for locoregional control, disease-free survival, and in some
studies, overall survival advantage ( table 3 ) [ 25,26,29,30 ]. Based upon these results,
concurrent chemoradiotherapy has become the standard of care for advanced nasopharyngeal
cancer in both nonendemic and endemic areas. The role of adjuvant chemotherapy following
concurrent chemoradiotherapy remains uncertain. (See 'Adjuvant chemotherapy' below.)

Concurrent chemotherapy regimen — The chemotherapy regimen used in United States

Intergroup Study 0099 (concurrent cisplatin [100 mg/m 2 on days 1, 22, and 43] followed by
three cycles of adjuvant cisplatin [80 mg/m 2 on day 1] plus fluorouracil [1000 mg/m 2 daily
days 1 through 4], given every four weeks) is considered by many to be the standard [ 27 ].
However, this regimen can be difficult to administer because it is associated with frequent
severe acute and late toxicities, and compliance with the treatment protocol is suboptimal
even in the clinical trials setting [ 27,31,32 ]. Therefore, alternative regimens have been
investigated.

Carboplatin has a more favorable toxicity profile than cisplatin and appears to have similar
efficacy. In a phase III trial, 206 patients were randomly assigned to cisplatin concurrent with
RT followed by three cycles of adjuvant cisplatin and fluorouracil as in the Intergroup 0099
study, or to carboplatin (100 mg/m 2 on days 1, 8, 15, 22, 29, and 36) concurrent with RT and
followed by three cycles of adjuvant chemotherapy consisting of carboplatin (area under the
concentration x time curve [AUC] of 5 on day 1) plus 5-fluorouracil (1000 mg/m 2 over 96
hours) every four weeks, beginning four weeks after the end of RT [ 33 ]. Key results
included the following:

 Fewer patients assigned to the cisplatin arm compared with the carboplatin arm
completed concurrent chemoradiotherapy (59 versus 73 percent) plus three cycles of
adjuvant chemotherapy (42 versus 70 percent).
 Patients treated with cisplatin had more renal toxicity, nausea and vomiting, and
anemia compared with carboplatin (26 versus 0, 59 versus 34, and 47 versus 18
percent, respectively). Weight loss and the need for enteral nutritional support were
also more frequent with cisplatin. Thrombocytopenia was less frequent with cisplatin
(4 versus 12 percent).
 At a median follow-up of 26 months, three-year disease-free survival and overall
survival were similar on both regimens (63 versus 61 and 78 versus 79 percent,
respectively). However, this is very short follow-up for a disease that has a much
longer natural history than other head and neck cancers.

It should be cautioned that the confidence interval of the survival estimates in the above trial
were wide, and confirmatory trials are needed before carboplatin -containing regimens can be
recommended with the same confidence as cisplatin -containing regimens.

Weekly cisplatin (40 mg/m 2 ) has demonstrated good efficacy, but has not been directly
compared to high-dose bolus cisplatin [ 29,34,35 ]. Weekly cisplatin has been shown to be
more effective than RT alone in at least two randomized trials with similar efficacy to that
reported for high-dose cisplatin. Weekly oxaliplatin (70 mg/m 2 over two hours) as concurrent
chemoradiotherapy is superior to RT alone, but has not been compared to cisplatin [ 36 ].

Appropriate alternatives for patients with borderline renal function, older age, or marginal
performance status (ECOG 2 or worse ( table 4 )) include the substitution of carboplatin or
lower dose weekly cisplatin .

Although still investigational, the role of molecularly targeted agents is being studied as a
component of concurrent chemoradiotherapy and sequential therapy regimens:

 Cetuximab – A phase II study of concurrent cetuximab plus cisplatin , given with

intensity-modulated radiotherapy (IMRT) in advanced nasopharyngeal carcinoma,
demonstrated that this strategy is promising [ 37 ]. The preliminary survival outcome
compares favorably with historic data, and further evaluation in a randomized phase
III trial is warranted. (See "Locally advanced squamous cell carcinoma of the head
and neck: Approaches combining chemotherapy and radiation therapy", section on
'Epidermal growth factor inhibition' .)
 Bevacizumab – In a phase II multi-institutional trial, the addition of six doses of
bevacizumab to a standard chemoradiation treatment (the intergroup regimen of
concurrent high dose cisplatin and adjuvant cisplatin-5FU) in patients with stage IIB-
IVB nasopharyngeal carcinoma was feasible [ 37 ]. Further research is needed to
identify those at risk of distant metastasis and hence those who might benefit from the
addition of bevacizumab.
Adjuvant chemotherapy — Three cycles of adjuvant chemotherapy following concurrent
chemoradiotherapy is often used for patients who are fit and have good performance status,
based upon the results of the Intergroup Study 0099 trial [ 27 ]. (See 'Concurrent
chemoradiotherapy' above.)

The most relevant data on the role of adjuvant chemotherapy following concurrent
chemoradiotherapy come from a Chinese phase III trial in 508 patients with nonmetastatic
advanced nasopharyngeal carcinoma [ 38 ]. Patients were randomly assigned to adjuvant
chemotherapy ( cisplatin plus 5- fluorouracil ) or observation following concurrent
chemoradiotherapy with weekly cisplatin. In an initial report from that trial at a median
follow-up of 38 months, there was no statistically significant improvement in the failure free
survival (two-year rate 86 versus 84 percent, HR 0.74, 95% CI 0.49-1.10).

However, this trial is subject to a number of limitations that may have limited the ability of
this trial to demonstrate a benefit from adjuvant chemotherapy following chemoradiotherapy.
These include the relatively short follow-up, the exclusion of patients with T3 or T4 node
negative disease ( table 1 ), and the variability of RT techniques used for patient treatment.

The Hong Kong Nasopharyngeal Cancer Study Group is conducting a phase III randomized
trial (NPC-0501) comparing concurrent-adjuvant chemotherapy with induction-concurrent
chemotherapy regimen (NCT00379262) [ 39 ]. In addition, the Hong Kong Nasopharyngeal
Cancer Study group is conducting a phase III randomized trial (NPC-0502) of adjuvant
chemotherapy in high-risk patients defined by residual EBV DNA following completion of
RT or chemoradiotherapy (NCT00370890) [ 39 ].

Induction chemotherapy — Induction chemotherapy for squamous cell carcinomas in other

head and neck sites appears to reduce the incidence of distant metastases. (See "Locally
advanced squamous cell carcinoma of the head and neck: Approaches combining
chemotherapy and radiation therapy" .)

However, trials of induction chemotherapy in patients with locoregionally advanced

nasopharyngeal carcinoma followed by RT alone have failed to show an improvement in
overall survival or pattern of relapse compared to RT alone [ 40-43 ]. A pooled analysis of
two of the largest trials found that the addition of induction chemotherapy to RT modestly
improved relapse-free and disease-specific survival, although overall survival was not
significantly improved [ 42 ].

Sequential therapy — Sequential therapy, the administration of induction chemotherapy

followed by concurrent chemoradiotherapy, appears promising and may represent an
alternative to concurrent chemoradiotherapy with adjuvant chemotherapy [ 44-50 ].
Furthermore, induction chemotherapy preceding concurrent chemoradiotherapy is more
likely to be successfully administered than adjuvant chemotherapy following concurrent
chemoradiotherapy.

Several uncontrolled phase II studies have explored the sequential use of induction
chemotherapy followed by concurrent chemoradiation approach in nasopharyngeal carcinoma
( table 5 ). The results are encouraging and toxicity has been acceptable. Except for the
feasibility of this approach, it is difficult to draw further conclusion from these uncontrolled
phase II data. There is a concern about the additional toxicity, cost, prolonged treatment
duration, compliance, and impact on late physical function and quality of life that could result
from this approach. Whether sequential therapy improves survival compared with concurrent
chemoradiotherapy alone or concurrent chemoradiotherapy followed by adjuvant
chemotherapy is unknown. (See "Locally advanced squamous cell carcinoma of the head and
neck: Approaches combining chemotherapy and radiation therapy" .)

A randomized phase II trial in patients with advanced nasopharyngeal carcinoma compared

sequential therapy (induction chemotherapy with docetaxel and cisplatin followed by weekly
cisplatin during RT) to concurrent chemoradiotherapy alone (with weekly cisplatin) [ 50 ].
Although induction chemotherapy was associated with high rates of grade 3 and 4
neutropenia (97 percent), patients assigned to sequential therapy were treated with
comparable dose intensities of concurrent cisplatin and had similar acute and late toxicities
and quality of life scores. There was a trend toward improved three-year progression-free
survival with sequential therapy compared with concurrent chemoradiotherapy alone (88
versus 60 percent, p=0.12), and there was a statistically significant increase in overall
survival (94 versus 68 percent).

Several phase III trials are comparing sequential regimens with concurrent
chemoradiotherapy alone:

 A Radiotherapy Oncology Group for Head and Neck Cancer trial is comparing
induction chemotherapy with docetaxel , cisplatin , and 5- fluorouracil (TPF)
followed by weekly cisplatin during RT to concurrent chemoradiotherapy with
weekly cisplatin alone (GORTEC-NPC2006, NCT00828386) [ 51 ].
 The Sun Yat-sen University is studying induction TPF followed by concurrent
cisplatin plus RT compared with RT plus concurrent cisplatin without induction in
stage III-IVB disease (NCT01245959).
 The National Cancer Center of Singapore completed a randomized phase II trial using
a carboplatin , gemcitabine , plus paclitaxel regimen followed by weekly cisplatin
during RT compared with weekly cisplatin plus RT alone in stage III-IVB
nasopharyngeal carcinoma. This has been expanded into a phase III trial
(NCT00997906).
 The Taiwan Cooperative Oncology Group has been testing a multi-agent induction
regimen MEPFL ( mitomycin , epirubicin , cisplatin , 5- fluorouracil , leucovorin )
followed by weekly cisplatin during RT compared with weekly cisplatin plus RT in
stage IV disease (NCT00201396).

In addition, the Hong Kong nasopharyngeal carcinoma study group 0501 trial is exploring the
therapeutic gain by reversing the sequence of the intergroup regimen. It is a six-arm study
that included a comparison of induction-concurrent chemotherapy versus concurrent-adjuvant
chemotherapy in stage III-IVB nasopharyngeal carcinoma (NCT00379262).

Until the results of phase III trials are available, sequential therapy should still be considered
experimental in nasopharyngeal carcinoma. Some experts, however, choose sequential
therapy for large primary tumors (T4 lesions), advanced nodal disease (large burden or
supraclavicular location), or when delivery of a full course of RT is not possible because the
tumor abuts the surrounding critical structures (eg, optic apparatus, brainstem, temporal
lobes).

Alternative RT schedules — Although RT is typically given on a schedule of five treatments

per week in the United States, there is increasing evidence that outcomes in head and neck
squamous cell carcinoma may be improved with alternative fractionation schedules,
including hyperfractionation and accelerated fractionations regimens. (See "Definitive
radiotherapy for advanced head and neck cancer: Dose and fractionation schedule" .)

The potential role of an accelerated RT regimen in nasopharyngeal cancer is illustrated by a

randomized trial that included 189 patients with T3-4,N0-1 disease [ 52 ]. Patients were
randomly assigned to one of four treatment groups, accelerated versus conventional RT (six
versus five treatments per week), with or without adjunctive chemotherapy (concurrent
cisplatin followed by adjuvant cisplatin plus 5- fluorouracil versus no adjunctive
chemotherapy). The combination of an accelerated course of RT plus adjunctive
chemotherapy resulted in a significantly higher five-year failure-free rate compared with
accelerated fractionation without chemotherapy, or conventional fractionation with or without
chemotherapy (88 versus 56, 65, and 63 percent, respectively).

The benefits of the moderately accelerated RT schedule used in this trial require confirmation
before this approach can be widely accepted [ 52 ]. At least two other trials with different
schedules have either increased toxicity or not improved survival [ 53,54 ].

PROGNOSIS — The five-year overall survival for nasopharyngeal carcinoma according to

disease stage in a contemporary case series was 90, 84, 75, and 58 percent for stage I through
IV, respectively ( table 2 ) [ 12 ].

In addition to prognostic factors of T and N stage and location of neck nodes (above or within
the supraclavicular fossa), pre- and posttherapy Epstein-Barr Virus (EBV) DNA levels have
prognostic significance, with higher levels conferring a worse prognosis, stage for stage [
10,55-57 ]. Five-year survival rates according to TNM stage grouping and pretherapy EBV
DNA levels from one case series are as follows [ 57 ]:

 Stage I, II disease, low DNA (<4000 copies/mL) - 91 percent

 Stage I, II disease, high DNA (≥4000 copies/mL) - 64 percent
 Stage III, IV disease, low DNA - 66 percent
 Stage III, IV disease, high DNA - 54 percent

The presence of detectable posttreatment EBV DNA, which may reflect microscopic residual
tumor, appears to provide an even greater estimate of the risk of disease recurrence and death
than pretreatment EBV DNA [ 45,56,58-60 ]. Pretreatment serologic antienzyme level of
EBV DNAse-specific neutralizing antibody (AER) was an independent prognostic factor of
locoregional control, progression-free survival and overall survival in cohort of 1303
nasopharyngeal carcinoma patients. AER correlated strongly with EBV DNA levels, and its
ease in measurement may make it easier to adopt in local laboratories [ 61 ].

POSTTREATMENT FOLLOW-UP

Documentation of remission — Documentation of complete remission in the nasopharynx

and neck through clinical and endoscopic examination and imaging studies is important. Our
preference is to obtain a posttreatment baseline MRI scan of the skull base and neck and a
full body combined positron emission tomography (PET)/computed tomography (CT) scan
approximately three months after treatment completion.
Distinguishing between viable residual tumor, slowly regressing tumor, and posttherapy
changes may be difficult. MRI and PET-CT scans may achieve higher accuracy when
combined rather than individually in detecting residual disease [ 62,63 ]. Obtaining imaging
studies too early, in particular combined PET/CT scans prior to 12 weeks following
treatment, can lead to false positive results.

Surveillance for recurrence — Posttreatment surveillance is important for early detection of

recurrent local or metastatic disease and for monitoring for toxicity. Follow-up includes
periodic examination of the nasopharynx and neck, assessment of cranial nerve function, and
evaluation of systemic complaints. In contrast to other head and neck cancers, periodic upper
endoscopy is typically recommended. (See "Treatment of recurrent and metastatic
nasopharyngeal carcinoma" .)

Nasopharyngeal carcinoma is different from other head and neck cancers in its propensity to
recur much later than tumors arising in other sites. Consequently, we follow patients every
three months for the first two years, every four to six months for years 3 to 5, and annually
thereafter. We suggest an annual chest x-ray, although other experts suggest reimaging only
as indicated by signs and symptoms [ 64 ]. (See "Posttreatment surveillance of squamous
carcinoma of the head and neck" .) As noted above, posttherapy levels of Epstein Barr virus
(EBV) DNA are of prognostic significance, although there is no consensus about what level
to use as a cutoff (both 0 and 500 copies/mL have been used) and the timing of posttreatment
EBV DNA sampling [ 56,58 ]. At present prospective data in support of routine monitoring
by plasma EBV DNA is lacking, although measuring plasma EBV DNA can be a useful
diagnostic aid in suspected recurrence. Posttreatment monitoring of patients by assay of a
nasopharyngeal swab for detection of the EBNA-1 and latent membrane protein-1 genes by
RT-PCR has also been suggested as a means of early detection of recurrent disease, but this
methodology is expensive, not widely available, and has not been prospectively validated [
65 ].

Surveillance after treatment for head and neck cancer is discussed in detail elsewhere. (See
"Posttreatment surveillance of squamous carcinoma of the head and neck" .)

TREATMENT-RELATED COMPLICATIONS — Mucositis is the predominant acute

toxicity associated with RT alone for nasopharyngeal carcinoma. Chemotherapy exacerbates
this toxicity and introduces the risks of neuropathy, emesis, neutropenia, and other
hematologic toxicity [ 27,29,50 ]. Lhermitte’s Syndrome is also common after
chemoradiation for nasopharynx carcinoma.

Xerostomia can be a long lasting or permanent problem, although it often improves with
time. Small trials have suggested that acupuncture may decrease symptoms and increase
salivary flow rate [ 66,67 ]. Additional trials in larger numbers of patients are required to
determine the role of acupuncture in this setting. (See "Complementary and alternative
therapies for cancer", section on 'Pain control and xerostomia' .)

A wide range of other serious, late treatment-related complications can be seen after RT or
concurrent chemoradiotherapy [ 30,53,68-79 ]:

 Temporal lobe necrosis, characterized by memory loss, complex partial seizures, and
hypodense areas in one or both temporal lobes on CT scanning occurs in two to three
percent of patients and is significantly increased with higher doses of RT, some
 altered fractionation techniques, and shorter overall treatment times [ 53,68,76,79 ].
(See "Complications of cranial irradiation", section on 'Late reactions' .)
 Skull base osteoradionecrosis with bleeding from the internal carotid artery is an
uncommon but potentially fatal complication of irradiation for nasopharyngeal
carcinoma [ 77 ]. Pituitary dysfunction can occur, especially in settings of tumor
involvement of the sphenoid sinus or middle cranial fossa. (See "Management of late
complications of head and neck cancer and its treatment", section on
'Osteoradionecrosis and soft tissue necrosis' and "Management of late complications
of head and neck cancer and its treatment", section on 'Carotid artery rupture' and
"Complications of cranial irradiation", section on 'Endocrinopathies' .)
 Delayed bulbar palsy, developing 1 to 18 years post radiation, is reported in up to 20
percent of cases and can result in moderate to severe functional disability [ 73 ].
Deficits may include any combination of deafness, dysarthria, dysphagia, tongue and
palatal weakness, and motor weakness of the sternocleidomastoid, trapezius,
supraspinatus, infraspinatus, and rarely, the deltoid muscle. (See "Complications of
cranial irradiation", section on 'Late reactions' .)
 Neck irradiation places patients at risk for developing hypothyroidism, and thus
monitoring of serum thyroid stimulating hormone (TSH) levels is routine [ 78 ]. (See
"Complications of cranial irradiation", section on 'Hypothyroidism' .)
 Radiation-induced second cancers are frequently EBV-negative, squamous cell
carcinomas and occur in the tongue and temporal bone [ 70,71 ]. (See "Complications
of cranial irradiation", section on 'Radiation-induced tumors' .)
 A range of other, less common toxicities can also be observed, which may be
minimized with optimal RT technique. (See "Management of late complications of
head and neck cancer and its treatment" .)

Late toxicity of chemoradiation — The current practice of adding concurrent and adjuvant
chemotherapy to RT to treat advanced nasopharyngeal carcinoma is based upon the initial
report of the Intergroup-0099 Study [ 27 ]. (See 'Concurrent chemoradiotherapy' above.)

The cumulative incidence of acute toxicity was significantly increased with

chemoradiotherapy compared to RT alone (83 versus 53 percent). Deaths due to disease
progression were significantly decreased (38 versus 24 percent). Although the addition of
concurrent and adjuvant chemotherapy significantly reduced deaths attributable to disease
progression (24 versus 38 percent), the increased deaths attributable to other causes (acute
toxicity, infection, second malignancy, suicide) in the CRT group resulted in a similar five-
year overall survival in the two groups (68 versus 64 percent, hazard ratio 0.81, 95%CI 0.58-
1.13). In contrast, the difference in the long-term toxicity of the intergroup regimen was not
statistically significant in the NPC 9901 trial (five-year incidence of late toxicity 30 versus 24
percent) [ 30 ].

SUMMARY AND RECOMMENDATIONS — Because of the anatomical location of the

nasopharynx and its proximity to critical neurovascular structures, radiation therapy (RT),
rather than surgery, is the mainstay of first-line treatment for early stage nasopharyngeal
carcinoma. For more advanced disease, concurrent chemoradiation reduces the rate of distant
metastasis and improves local control and overall survival compared to RT alone.

 Treatment approaches are based upon the stage of the disease. Despite differences in
prognosis, there is insufficient evidence to suggest that treatment should differ based
upon WHO histopathologic classification. (See 'Prognostic risk groups' above.)
  For patients with early (stage I, ( table 1 )) disease, we recommend RT alone rather
than a combined modality approach ( Grade 1B ). (See 'Early (stage I) disease' above.)
 For patients with intermediate (stage II) disease, we recommend concurrent
chemoradiation rather than RT alone ( Grade 1B ). Concurrent weekly cisplatin
significantly increased acute but not late toxicity. (See 'Intermediate (stage II) disease'
above.)
 For patients with advanced (stage III, IVA, and IVB) disease, we recommend
concurrent chemoradiotherapy ( Grade 1A ). While adjuvant chemotherapy has been a
standard part of many concurrent chemoradiotherapy regimens, its benefit is uncertain
and toxicity is substantial. Adjuvant chemotherapy may be a reasonable option for
patients with high-risk disease and a good performance status. (See 'Advanced (stage
III and IV) disease' above.)
 For eligible patients being treated with concurrent chemoradiotherapy, cisplatin (100
mg/m 2 on days 1, 22, and 43) concurrent with RT is a standard option for patients
with good performance status. (See 'Concurrent chemotherapy regimen' above.)

 Low dose cisplatin (30 to 40 mg/m 2 weekly) concurrent with RT or the substitution of
carboplatin for cisplatin are options for patients with a poor performance status or
comorbidities. (See 'Concurrent chemotherapy regimen' above.)

 Until more data in support of sequential therapy are available, we suggest not using
sequential therapy for most patients with advanced nasopharyngeal carcinoma ( Grade
2C ). However, some experts do choose sequential therapy for large or extensive
primary tumors or advanced nodal disease. (See 'Sequential therapy' above.)
 Given the propensity of nasopharyngeal carcinoma for early and bilateral spread to
regional lymph nodes, we recommend bilateral neck irradiation for all patients, even
those with a clinically negative neck ( Grade 1B ). (See 'Management of the neck'
above.)
 We obtain a posttreatment MRI scan of the skull base and neck and a full body
combined positron emission tomography (PET)/computed tomography (CT) scan at
approximately three months after treatment completion to evaluate treatment response
and to serve as a baseline. (See 'Posttreatment follow-up' above.)
 Nasopharyngeal carcinoma has a propensity to recur much later than other head and
neck cancer sites, both locally and distantly. Consequently, we follow patients every
three months for the first two years, every four to six months for years 3 to 5, and
annually, thereafter. (See 'Posttreatment follow-up' above.)

REFERENCES
1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:
GLOBOCAN 2008. Int J Cancer 2010.
2. AJCC (American Joint Committee on Cancer) Staging Manual, 7th, Edge, SB, Byrd,
DR, Compton, CC, et al (Eds), Springer, New York 2010.
3. Pathology and genetics of head and neck tumors. In: World Health Organization
Classification of Tumours, Barnes, L, Eveson, JW, Reichart, P, Sidransky, D (Eds),
IARC Press, Lyon 2005.
4. Chan AT, Teo PM, Huang DP. Pathogenesis and treatment of nasopharyngeal
carcinoma. Semin Oncol 2004; 31:794.
5. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005; 365:2041.
6. Tao Q, Chan AT. Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic
developments. Expert Rev Mol Med 2007; 9:1.
7. Ma BB, Hui EP, Chan AT. Systemic approach to improving treatment outcome in
nasopharyngeal carcinoma: current and future directions. Cancer Sci 2008; 99:1311.
8. Lee AW, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with
nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of
failure. Int J Radiat Oncol Biol Phys 1992; 23:261.
9. Hsu MM, Tu SM. Nasopharyngeal carcinoma in Taiwan. Clinical manifestations and
results of therapy. Cancer 1983; 52:362.
10. Geara FB, Sanguineti G, Tucker SL, et al. Carcinoma of the nasopharynx treated by
radiotherapy alone: determinants of distant metastasis and survival. Radiother Oncol
1997; 43:53.
11. Sun LM, Li CI, Huang EY, Vaughan TL. Survival differences by race in
nasopharyngeal carcinoma. Am J Epidemiol 2007; 165:271.
12. Lee AW, Sze WM, Au JS, et al. Treatment results for nasopharyngeal carcinoma in
the modern era: the Hong Kong experience. Int J Radiat Oncol Biol Phys 2005;
61:1107.
13. Chua DT, Sham JS, Kwong DL, Au GK. Treatment outcome after radiotherapy alone
for patients with Stage I-II nasopharyngeal carcinoma. Cancer 2003; 98:74.
14. Altun M, Fandi A, Dupuis O, et al. Undifferentiated nasopharyngeal cancer (UCNT):
current diagnostic and therapeutic aspects. Int J Radiat Oncol Biol Phys 1995; 32:859.
15. 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.
16. 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.
17. Lee N, Harris J, Garden AS, et al. Intensity-modulated radiation therapy with or
without chemotherapy for nasopharyngeal carcinoma: radiation therapy oncology
group phase II trial 0225. J Clin Oncol 2009; 27:3684.
18. Taheri-Kadkhoda Z, Björk-Eriksson T, Nill S, et al. Intensity-modulated radiotherapy
of nasopharyngeal carcinoma: a comparative treatment planning study of photons and
protons. Radiat Oncol 2008; 3:4.
19. Widesott L, Pierelli A, Fiorino C, et al. Intensity-modulated proton therapy versus
helical tomotherapy in nasopharynx cancer: planning comparison and NTCP
evaluation. Int J Radiat Oncol Biol Phys 2008; 72:589.
20. Chua DT, Ma J, Sham JS, et al. Improvement of survival after addition of induction
chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma:
Subgroup analysis of two Phase III trials. Int J Radiat Oncol Biol Phys 2006; 65:1300.
21. Cheng SH, Tsai SY, Yen KL, et al. Concomitant radiotherapy and chemotherapy for
early-stage nasopharyngeal carcinoma. J Clin Oncol 2000; 18:2040.
22. National Comprehensive Cancer Network (NCCN) guidelines. Available at:
www.nccn.org (Accessed on May 15, 2012).
23. Chan AT, Grégoire V, Lefebvre JL, et al. Nasopharyngeal cancer: EHNS-ESMO-
ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann
Oncol 2010; 21 Suppl 5:v187.
24. 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.
25. Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advanced
nasopharyngeal carcinoma: an individual patient data meta-analysis of eight
randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 2006; 64:47.
26. Langendijk JA, Leemans CR, Buter J, et al. The additional value of chemotherapy to
radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the
published literature. J Clin Oncol 2004; 22:4604.
27. 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.
28. Al-Sarraf M, LeBlanc M, Giri P, et al. Superiority of five year survival with chemo-
radiotherapy vs radiotherapy in patients with locally advanced nasopharyngeal cancer.
Intergroup (0099) (SWOG 8892, RTOG 8817, ECOG 2388) Phase III study. Final
Report (abstract #905). Proc Am Soc Clin Oncol 2001.
29. Chen Y, Liu MZ, Liang SB, et al. Preliminary results of a prospective randomized
trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with
radiotherapy alone in patients with locoregionally advanced nasopharyngeal
carcinoma in endemic regions of china. Int J Radiat Oncol Biol Phys 2008; 71:1356.
30. 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.
31. 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.
32. Lee AW, Lau WH, Tung SY, et al. Preliminary results of a randomized study on
therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal
carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group.
J Clin Oncol 2005; 23:6966.
33. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al. Chemoradiation comparing
cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised,
non-inferiority, open trial. Eur J Cancer 2007; 43:1399.
34. 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.
35. Chan AT, Teo PM, Ngan RK, et al. Concurrent chemotherapy-radiotherapy compared
with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma:
progression-free survival analysis of a phase III randomized trial. J Clin Oncol 2002;
20:2038.
36. Zhang L, Zhao C, Peng PJ, et al. Phase III study comparing standard radiotherapy
with or without weekly oxaliplatin in treatment of locoregionally advanced
nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005; 23:8461.
37. Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standard
chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG
0615): a phase 2 multi-institutional trial. Lancet Oncol 2012; 13:172.
38. 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.
39. National Institutes of Health Clinical Trials database. file://www.clinicaltrials.gov/
(Accessed on February 08, 2011).
40. Chua DT, Sham JS, Choy D, et al. Preliminary report of the Asian-Oceanian Clinical
Oncology Association randomized trial comparing cisplatin and epirubicin followed
by radiotherapy versus radiotherapy alone in the treatment of patients with
locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical
Oncology Association Nasopharynx Cancer Study Group. Cancer 1998; 83:2270.
41. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy
(cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage
IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on
progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I
trial. Int J Radiat Oncol Biol Phys 1996; 35:463.
42. 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.
43. Ma J, Mai HQ, Hong MH, et al. Results of a prospective randomized trial comparing
neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with
locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 2001; 19:1350.
44. Rischin D, Corry J, Smith J, et al. Excellent disease control and survival in patients
with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol
2002; 20:1845.
45. Chan AT, Ma BB, Lo YM, et al. Phase II study of neoadjuvant carboplatin and
paclitaxel followed by radiotherapy and concurrent cisplatin in patients with
locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with
plasma Epstein-Barr virus DNA. J Clin Oncol 2004; 22:3053.
46. Al-Amro A, Al-Rajhi N, Khafaga Y, et al. Neoadjuvant chemotherapy followed by
concurrent chemo-radiation therapy in locally advanced nasopharyngeal carcinoma.
Int J Radiat Oncol Biol Phys 2005; 62:508.
47. Yau TK, Lee AW, Wong DH, et al. Induction chemotherapy with cisplatin and
gemcitabine followed by accelerated radiotherapy and concurrent cisplatin in patients
with stage IV(A-B) nasopharyngeal carcinoma. Head Neck 2006; 28:880.
48. Lee AW, Lau KY, Hung WM, et al. Potential improvement of tumor control
probability by induction chemotherapy for advanced nasopharyngeal carcinoma.
Radiother Oncol 2008; 87:204.
49. Oh JL, Vokes EE, Kies MS, et al. Induction chemotherapy followed by concomitant
chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal
cancer. Ann Oncol 2003; 14:564.
50. 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.
51. National Institutes of Health Clinical Trials database file://clinicaltrials.gov/.
52. 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.
53. Teo PM, Leung SF, Chan AT, et al. Final report of a randomized trial on altered-
fractionated radiotherapy in nasopharyngeal carcinoma prematurely terminated by
significant increase in neurologic complications. Int J Radiat Oncol Biol Phys 2000;
48:1311.
54. Daoud J, Toumi N, Siala W, et al. Results of a prospective randomised trial
comparing conventional radiotherapy to split course bifractionated radiation therapy
in patients with nasopharyngeal carcinoma. Radiother Oncol 2007; 85:17.
55. Le QT, Jones CD, Yau TK, et al. A comparison study of different PCR assays in
measuring circulating plasma epstein-barr virus DNA levels in patients with
nasopharyngeal carcinoma. Clin Cancer Res 2005; 11:5700.
56. Lin JC, Wang WY, Chen KY, et al. Quantification of plasma Epstein-Barr virus DNA
in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004; 350:2461.
57. Leung SF, Zee B, Ma BB, et al. Plasma Epstein-Barr viral deoxyribonucleic acid
quantitation complements tumor-node-metastasis staging prognostication in
nasopharyngeal carcinoma. J Clin Oncol 2006; 24:5414.
58. Chan AT, Lo YM, Zee B, et al. Plasma Epstein-Barr virus DNA and residual disease
after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst
2002; 94:1614.
59. Lin JC, Wang WY, Liang WM, et al. Long-term prognostic effects of plasma epstein-
barr virus DNA by minor groove binder-probe real-time quantitative PCR on
nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy. Int J
Radiat Oncol Biol Phys 2007; 68:1342.
60. Wang WY, Twu CW, Chen HH, et al. Plasma EBV DNA clearance rate as a novel
prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer
Res 2010; 16:1016.
61. Xu J, Wan XB, Huang XF, et al. Serologic antienzyme rate of Epstein-Barr virus
DNase-specific neutralizing antibody segregates TNM classification in
nasopharyngeal carcinoma. J Clin Oncol 2010; 28:5202.
62. Liu T, Xu W, Yan WL, et al. FDG-PET, CT, MRI for diagnosis of local residual or
recurrent nasopharyngeal carcinoma, which one is the best? A systematic review.
Radiother Oncol 2007; 85:327.
63. Comoretto M, Balestreri L, Borsatti E, et al. 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.
64. Chao SS, Loh KS, Tan LK. Modalities of surveillance in treated nasopharyngeal
cancer. Otolaryngol Head Neck Surg 2003; 129:61.
65. Hao SP, Tsang NM, Chang KP. Monitoring tumor recurrence with nasopharyngeal
swab and latent membrane protein-1 and epstein-barr nuclear antigen-1 gene detection
in treated patients with nasopharyngeal carcinoma. Laryngoscope 2004; 114:2027.
66. Meng Z, Garcia MK, Hu C, et al. Randomized controlled trial of acupuncture for
prevention of radiation-induced xerostomia among patients with nasopharyngeal
carcinoma. Cancer 2012; 118:3337.
67. Meng Z, Kay Garcia M, Hu C, et al. Sham-controlled, randomised, feasibility trial of
acupuncture for prevention of radiation-induced xerostomia among patients with
nasopharyngeal carcinoma. Eur J Cancer 2012; 48:1692.
68. Yeh SA, Tang Y, Lui CC, et al. Treatment outcomes and late complications of 849
patients with nasopharyngeal carcinoma treated with radiotherapy alone. Int J Radiat
Oncol Biol Phys 2005; 62:672.
69. Chen WC, Jackson A, Budnick AS, et al. Sensorineural hearing loss in combined
modality treatment of nasopharyngeal carcinoma. Cancer 2006; 106:820.
70. Teo PM, Chan AT, Leung SF, et al. Increased incidence of tongue cancer after
primary radiotherapy for nasopharyngeal carcinoma--the possibility of radiation
carcinogenesis. Eur J Cancer 1999; 35:219.
71. Goh YH, Chong VF, Low WK. Temporal bone tumours in patients irradiated for
nasopharyngeal neoplasm. J Laryngol Otol 1999; 113:222.
72. Lin YS, Jen YM, Lin JC. Radiation-related cranial nerve palsy in patients with
nasopharyngeal carcinoma. Cancer 2002; 95:404.
 73. Chew NK, Sim BF, Tan CT, et al. Delayed post-irradiation bulbar palsy in
nasopharyngeal carcinoma. Neurology 2001; 57:529.
74. Aiken RD. Neurologic complications of head and neck cancers. Semin Oncol 2006;
33:348.
75. Bhandare N, Kennedy L, Malyapa RS, et al. Hypopituitarism after radiotherapy for
extracranial head and neck cancers. Head Neck 2008; 30:1182.
76. Lee AW, Kwong DL, Leung SF, et al. Factors affecting risk of symptomatic temporal
lobe necrosis: significance of fractional dose and treatment time. Int J Radiat Oncol
Biol Phys 2002; 53:75.
77. Lam HC, Abdullah VJ, Wormald PJ, Van Hasselt CA. Internal carotid artery
hemorrhage after irradiation and osteoradionecrosis of the skull base. Otolaryngol
Head Neck Surg 2001; 125:522.
78. Siala W, Mnejja W, Abid M, et al. Thyroid toxicity after radiotherapy of
nasopharyngeal carcinoma. Ann Endocrinol (Paris) 2011; 72:19.
79. Lam TC, Wong FC, Leung TW, et al. Clinical outcomes of 174 nasopharyngeal
carcinoma patients with radiation-induced temporal lobe necrosis. Int J Radiat Oncol
Biol Phys 2012; 82:e57.

Treatment of recurrent and metastatic nasopharyngeal carcinoma

Treatment of recurrent and metastatic nasopharyngeal carcinoma
Authors
Edwin P Hui, MD
Anthony TC Chan, MD
Quynh-Thu Le, MD
Section Editors
Bruce E Brockstein, MD
David M Brizel, MD
Marshall R Posner, MD
Deputy Editor
Michael E Ross, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2013. | This topic last updated: Oct 31, 2012.

INTRODUCTION — Nasopharyngeal carcinoma arises from the lining of the nasopharynx,

the narrow tubular passage behind the nasal cavity. Worldwide, there are 80,000 incident
cases and 50,000 deaths annually, but there is remarkable variation in racial and geographic
distribution [ 1 ]. While rare in most parts of the world, nasopharyngeal carcinoma is endemic
in southern China, southeast Asia, north Africa, and the arctic, where undifferentiated,
nonkeratinizing squamous cell carcinoma is the predominant histology.

The treatment of residual, recurrent, and metastatic nasopharyngeal cancer is presented here.
Related topics include:

 (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma" .)

 (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma" .)

STAGING AND CLASSIFICATION — Nasopharyngeal carcinoma is staged according to

the International Union Against Cancer (UICC) and American Joint Committee on Cancer
(AJCC) staging system ( table 1 ) [ 2 ]. The World Health Organization (WHO) classifies
nasopharyngeal carcinoma into three histopathologic types [ 3 ]:

 Keratinizing squamous cell carcinoma (WHO Type I)

 Nonkeratinizing carcinoma: differentiated (WHO Type II) and undifferentiated
(WHO Type III)
 Basaloid squamous cell carcinoma

Staging and the histopathologic classification of nasopharyngeal carcinoma are discussed in

more detail separately. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal
carcinoma" .)

LOCOREGIONAL RECURRENCE — Options for the treatment for locoregional

recurrence of nasopharyngeal carcinoma include reirradiation or nasopharyngectomy. The
location of the nasopharynx, its proximity to vital organs, the high radiation doses given for
primary therapy, and chemotherapy and radiation resistance induced by previous therapy
make retreatment challenging.
The stage at the time of recurrence (rTNM) and the interval between the initial treatment and
recurrence are important prognostic factors ( table 1 ) [ 4-7 ]. Patients with a brief disease-
free interval between completion of initial therapy and diagnosis of recurrent disease and
those with advanced recurrent T- and/or N-stage may be best treated with palliative
chemotherapy [ 6,8 ].

A carefully selected subset of patients do achieve long-term survival when managed with
salvage surgery and/or reirradiation. Prior to treatment, a thorough evaluation for
concomitant distant metastases is needed because approximately half of patients with
apparent local recurrence have synchronous distant metastases [ 9,10 ].

Salvage surgery — Nasopharyngectomy is an option for patients with small local

recurrences and no distant metastases. Surgery in this setting is technically challenging; the
goal is to achieve an adequate margin while preserving the neurovascular bundle and
restoring critical mucosal barriers. While anterior approaches are most commonly used,
endoscopic nasopharyngectomy in selected patients may achieve comparable results with
reduced complications [ 11 ].

Three-year survival rates as high as 60 percent after salvage surgery have been reported for
carefully selected patients, but a survival benefit may be restricted to those with T1 or T2
recurrent disease [ 12-15 ]. In addition to high T stage (with skull base, dural, or brain
involvement) ( table 1 ), positive surgical margins, and concurrent nodal metastases have
been associated with poor prognosis [ 16,17 ].

Radical, modified radical, or selective neck dissection is indicated for residual nodal disease
after initial RT or for an isolated neck recurrence.

Adjuvant chemotherapy and postoperative radiation therapy (RT), including conventional

RT, brachytherapy, radiosurgery, and concurrent chemoradiation, are frequently used
following surgical salvage, but there are limited data as to their efficacy [ 14,17 ]

Serious surgical complications include meningitis (the most common cause of perioperative
mortality), osteoradionecrosis, necrosis of the free flap, and aspiration pneumonia [ 12-16 ].
Other commonly seen complications include middle ear effusion, hypernasality, nasal
regurgitation, cerebrospinal rhinorrhea, ectropion, temporary and permanent infra-orbital
numbness, trismus, epiphora (watering eyes), impaired swallowing, and oro-palatal fistula.

Salvage surgery for locally recurrent head and neck cancers is discussed in detail elsewhere.
(See "Treatment of locally recurrent head and neck cancer" .)

Reirradiation — The potential for long-term survival with reirradiation, with or without
induction and/or concurrent chemotherapy, has been suggested by case series and phase II
studies [ 6,18-32 ]. However, reirradiation poses a therapeutic challenge since the dose that
can be delivered safely is limited by previous RT treatments and the tolerance of normal
tissues. Extent of local recurrence and adequate reirradiation dose impact the success of
salvage therapy [ 19 ]. Significant acute and late toxicities must be expected.

Various techniques of reirradiation, individually and combined, have been investigated in this
setting.
  Three-dimensional conformal RT [ 21,33 ]
 Intensity modulated RT (IMRT) [ 31,32 ]
 Intracavitary and interstitial brachytherapy, including implantation of radioactive gold
grains [ 21-23,28-30 ]
 Stereotactic radiosurgery [ 23,29 ]
 Fractionated stereotactic radiotherapy [ 24,25,28 ]
 Proton beam therapy [ 26 ]

The choice of therapeutic approach depends upon local expertise and technical
considerations, such as location and extent of recurrent disease. Reirradiation has also been
combined with cisplatin -based induction and/or concurrent chemotherapy in small case
series [ 18,20 ]. (See "Locally advanced squamous cell carcinoma of the head and neck:
Approaches combining chemotherapy and radiation therapy" .)

Grade 3 to 4 late toxicities occur in at least 5 to 20 percent in some series and consist of
temporal lobe necrosis, cranial nerve palsies, hearing loss, endocrine abnormalities, palatal
fibrosis, trismus, chronic pain, and osteoradionecrosis [ 20,23 ]. (See "Complications of
cranial irradiation" and "Management of late complications of head and neck cancer and its
treatment" .)

Reirradiation for locally recurrent head and neck cancers is discussed in detail elsewhere.
(See "Reirradiation for locally recurrent head and neck cancer" .)

METASTATIC DISEASE — Nasopharyngeal carcinoma is a highly chemosensitive tumor,

with response rates as high as 80 percent with some cisplatin -based regimens. Thus, systemic
chemotherapy is often used for patients with recurrent or metastatic disease, even though it
has not been directly compared with supportive care [ 34 ].

Conventional chemotherapy — A wide range of chemotherapy agents have demonstrated

antitumor activity in patients with advanced or metastatic nasopharyngeal carcinoma; these
include the platinum compounds ( cisplatin , carboplatin ), 5-fluorouracil (including
capecitabine ), methotrexate , taxanes ( paclitaxel , docetaxel ), gemcitabine , bleomycin ,
ifosfamide , anthracyclines, irinotecan , and vinorelbine [ 35-41 ]. Higher response rates have
been observed when these agents are used in combinations, generally including a platinum
compound. [ 42-44 ].

There are no randomized trials that have defined the optimal regimen. The most extensive
data come from a retrospective, single institution study that included 822 patients treated
between 1999 and 2005 [ 34 ]. Patients were treated with one of five regimens ( cisplatin plus
5-fluorouracil, cisplatin plus paclitaxel , cisplatin plus gemcitabine , cisplatin plus 5-
fluorouracil plus paclitaxel, or cisplatin plus bleomycin plus 5-fluorouracil). Response rates
(partial plus complete) with each of these regimens varied between 60 and 74 percent. There
were no statistically significant differences in progression-free survival (median 5.0 to 6.6
months) or overall survival (median 19 to 21 months and three-year survival rates 19 to 21.5
months). Severe toxicity, particularly myelosuppression, was more severe with the cisplatin,
paclitaxel, plus 5-fluorouracil regimen.

The pre- and post-treatment plasma levels of EBV DNA may be a useful prognostic marker.
In a study of 127 patients with metastatic or recurrent nasopharyngeal carcinoma treated with
palliative chemotherapy, both a low pretreatment EBV DNA level and a fall in EBV DNA to
undetectable levels following chemotherapy were associated with improved progression-free
and overall survival [ 45 ]. Similarly, a worse prognosis was associated with an elevated level
of EBV DNA in the previously cited observational series of patients treated with various
cisplatin combination regimens [ 34 ].

Second-line chemotherapy may be considered for patients with a good performance status
who become refractory to cisplatin -based regimens, although response rates are lower than
with first-line therapy. A small number of small studies have reported outcomes of treatment
administered to patients who relapse after cisplatin-based chemotherapy [ 35-38,46-48 ].

Molecularly targeted therapy — Preclinical studies provide a rationale for targeting

epidermal growth factor receptor (EGFR)-mediated signaling as well as genes involved with
tumor hypoxia, such as hypoxia-inducible factor (HIF), vascular endothelial growth factor
(VEGF), human epidermal growth factor receptor 2 (HER2), and c-KIT [ 49 ].

Agents studied include cetuximab [ 50 ], sorafenib [ 51 ], pazopanib [ 52 ], gefitinib [ 53 ],

and erlotinib [ 54 ]. Currently available data with these agents does not define a role for these
agents in patients with nasopharyngeal carcinoma outside of a clinical trial setting.

Immunotherapy — Epstein-Barr virus (EBV) is present in virtually all poorly differentiated

and undifferentiated nonkeratinizing nasopharyngeal carcinoma (WHO type II and III).
Consequently, the viral antigens expressed by the tumor cells are attractive targets for
immunotherapy [ 55,56 ].

Two approaches are being investigated: adoptive immunotherapy, which bypasses antigen
presentation and directly activates effector cells, and active immunotherapy, using EBV
vaccination, which stimulates tumor antigen recognition by the host immune system. These
strategies are investigational at present, although they show promise. (See "The adaptive
cellular immune response" .)

Adoptive immunotherapy — Adoptive transfer of cytotoxic T cells (CTLs) specific for EBV
antigens has proved highly successful as prophylaxis for and treatment of EBV-associated
lymphoproliferative disease (PTLD) arising in solid organ transplant recipients [ 57 ]. These
highly immunogenic lymphomas in immunocompromised hosts, which serve as a model of
virus-targeted immunotherapy for EBV-associated tumors, express all latent EBV antigens
(latency type III). (See "Treatment and prevention of post-transplant lymphoproliferative
disorders", section on 'Adoptive immunotherapy' .)

By contrast, in nasopharyngeal carcinoma and Hodgkin lymphoma, only a restricted set of

less immunogenic viral antigens (latency type II), namely EBNA1 and latent membrane
protein (LMP) 1 and 2, are expressed. EBNA1 is regularly expressed in nasopharyngeal
carcinoma but is a dominant target for CD4+ T cells. Expression of LMP1 and/or LMP2 is
detectable in at least 50 percent of nasopharyngeal carcinoma tumors. LMP1 and LMP2 are
both targets for CD8+ CTLs, but since responses detected in healthy virus carriers indicate
that LMP1 is poorly immunogenic, the most likely target antigen for a CD8+ CTL based
therapy is LMP2 [ 58-60 ]. (See "Virology of Epstein-Barr virus" .)

The first pilot study to treat nasopharyngeal carcinoma using adoptive T cell therapy was
reported in 2001 [ 61 ]. Autologous EBV-transformed B-lymphoblastoid cell line (LCL)
reactivated T cells were generated in vitro and used to treat four advanced cases of
nasopharyngeal carcinoma. No adverse events occurred, and infusion of CTL was associated
with a reduction of plasma EBV load. However, tumor responses were not seen in this pilot
study.

The use of autologous EBV-specific CTL for nasopharyngeal carcinoma has since been
reported in two clinical trials, each with ten patients [ 62,63 ]. Both studies demonstrated that
autologous EBV-specific CTL is safe, induces LMP2 specific immune response, and is
associated with objective responses and control of disease in advanced nasopharyngeal
carcinoma. Interestingly, in one patient with relapsed nasopharyngeal carcinoma, the
adoptive transfer of an allogeneic EBV-specific CTL resulted in temporary stabilization of
disease with local tumor biopsy showing an increase in tumor infiltrating CD8+ T cells [ 64 ].

EBV vaccination — Vaccine strategies include dendritic cells vaccination and viral vectors-
introduced peptides. Dendritic cells, which are professional antigen-presenting cells that are
critical in the activation of naive CD4+ and CD8+ T cells, are generated and maturated ex
vivo, pulsed with tumor antigens, and administered to the patient. The second strategy is a
replication-incompetent adenoviral vaccine that encodes multiple HLA class I-restricted CTL
epitopes from LMP1 and LMP2.

A vaccine of dendritic cells pulsed with peptides derived from LMP2 has been evaluated in
16 nasopharyngeal carcinoma patients with local recurrence or distant metastasis after
conventional treatment [ 65 ]. Peptide specific T cell responses were elicited or boosted in
nine patients, and partial tumor reduction was observed in two patients. Currently, a
therapeutic EBV vaccination trial is ongoing in the United Kingdom and Hong Kong using a
modified vaccinia virus expressing an EBNA1-LMP2 fusion protein to elicit CD4+ and
CD8+ T cells against the two EBV proteins expressed in nasopharyngeal carcinoma patients [
66,67 ]. Meanwhile, an LMP-based polyepitope vaccine has also been developed for EBV-
associated Hodgkins disease and nasopharyngeal carcinoma, and is being tested in clinical
trials [ 68,69 ]. It appears that it is feasible to boost EBV-specific immune response in
nasopharyngeal carcinoma patients and further investigations exploring EBV as a target for
immunotherapy are ongoing.

SUMMARY AND RECOMMENDATIONS — Prolonged survival with treatment of

recurrent and metastatic nasopharyngeal carcinoma is an achievable goal for a subset of
carefully selected patients. Although palliative chemotherapy has not been directly compared
to supportive care alone, metastatic nasopharyngeal carcinoma has demonstrated high
chemosensitivity.

 For appropriately selected patients with small local recurrences (recurrent stage T1
and T2 ( table 1 )), we suggest an aggressive approach, using either surgical salvage
or reirradiation with or without concurrent chemotherapy ( Grade 2C ). These
treatments are associated with significant serious toxicities, but may result in long-
term survival. The decision between surgery or reirradiation is individually tailored,
taking into consideration location and extent of the recurrent tumor and previous
therapies. (See 'Locoregional recurrence' above.)
 For most patients with metastatic nasopharyngeal carcinoma, we suggest palliative
combination chemotherapy ( Grade 2B ). Chemotherapy has a high response rate and
appears likely to improve survival, but has important toxicities. A cisplatin -based
regimen is favored, but other regimens are active. The superiority of any one
 combination has not been demonstrated in randomized trials. (See 'Conventional
chemotherapy' above.)
 Prognostic factors, such as performance status, disease-free interval, and site of
metastatic disease, may be useful when selecting a palliative chemotherapy regimen
and choosing between single agent and combination chemotherapy. (See 'Metastatic
disease' above.)
 For patients who become refractory to cisplatin -based therapy, second line
chemotherapy or clinical trials investigating molecularly targeted therapy or
immunotherapy approaches may provide treatment options. (See 'Molecularly
targeted therapy' above and 'Immunotherapy' above.)

REFERENCES
1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:
GLOBOCAN 2008. Int J Cancer 2010.
2. AJCC (American Joint Committee on Cancer) Staging Manual, 7th, Edge, SB, Byrd,
DR, Compton, CC, et al (Eds), Springer, New York 2010.
3. Pathology and genetics of head and neck tumors. In: World Health Organization
Classification of Tumours, Barnes, L, Eveson, JW, Reichart, P, Sidransky, D (Eds),
IARC Press, Lyon 2005.
4. Lee AW, Foo W, Law SC, et al. Recurrent nasopharyngeal carcinoma: the puzzles of
long latency. Int J Radiat Oncol Biol Phys 1999; 44:149.
5. Chua DT, Sham JS, Hung KN, et al. Predictive factors of tumor control and survival
after radiosurgery for local failures of nasopharyngeal carcinoma. Int J Radiat Oncol
Biol Phys 2006; 66:1415.
6. Teo PM, Kwan WH, Chan AT, et al. How successful is high-dose (> or = 60 Gy)
reirradiation using mainly external beams in salvaging local failures of
nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 1998; 40:897.
7. Smee RI, Meagher NS, Broadley K, et al. Recurrent nasopharyngeal carcinoma:
current management approaches. Am J Clin Oncol 2010; 33:469.
8. Fandi A, Bachouchi M, Azli N, et al. Long-term disease-free survivors in metastatic
undifferentiated carcinoma of nasopharyngeal type. J Clin Oncol 2000; 18:1324.
9. Lee AW, Law SC, Foo W, et al. Retrospective analysis of patients with
nasopharyngeal carcinoma treated during 1976-1985: survival after local recurrence.
Int J Radiat Oncol Biol Phys 1993; 26:773.
10. Loong HH, Ma BB, Chan AT. Update on the management and therapeutic monitoring
of advanced nasopharyngeal cancer. Hematol Oncol Clin North Am 2008; 22:1267.
11. Chen MY, Wen WP, Guo X, et al. Endoscopic nasopharyngectomy for locally
recurrent nasopharyngeal carcinoma. Laryngoscope 2009; 119:516.
12. Fee WE Jr, Moir MS, Choi EC, Goffinet D. Nasopharyngectomy for recurrent
nasopharyngeal cancer: a 2- to 17-year follow-up. Arch Otolaryngol Head Neck Surg
2002; 128:280.
13. Hsu MM, Hong RL, Ting LL, et al. Factors affecting the overall survival after salvage
surgery in patients with recurrent nasopharyngeal carcinoma at the primary site:
experience with 60 cases. Arch Otolaryngol Head Neck Surg 2001; 127:798.
14. Chang KP, Hao SP, Tsang NM, Ueng SH. Salvage surgery for locally recurrent
nasopharyngeal carcinoma-A 10-year experience. Otolaryngol Head Neck Surg 2004;
131:497.
15. Yu KH, Leung SF, Tung SY, et al. Survival outcome of patients with nasopharyngeal
carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal
Carcinoma Study Group. Head Neck 2005; 27:397.
16. To EW, Lai EC, Cheng JH, et al. Nasopharyngectomy for recurrent nasopharyngeal
carcinoma: a review of 31 patients and prognostic factors. Laryngoscope 2002;
112:1877.
17. Hao SP, Tsang NM, Chang KP, et al. Nasopharyngectomy for recurrent
nasopharyngeal carcinoma: a review of 53 patients and prognostic factors. Acta
Otolaryngol 2008; 128:473.
18. Chua DT, Sham JS, Au GK. Induction chemotherapy with cisplatin and gemcitabine
followed by reirradiation for locally recurrent nasopharyngeal carcinoma. Am J Clin
Oncol 2005; 28:464.
19. Lee AW, Foo W, Law SC, et al. Reirradiation for recurrent nasopharyngeal
carcinoma: factors affecting the therapeutic ratio and ways for improvement. Int J
Radiat Oncol Biol Phys 1997; 38:43.
20. Poon D, Yap SP, Wong ZW, et al. Concurrent chemoradiotherapy in locoregionally
recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004; 59:1312.
21. Zheng XK, Chen LH, Chen YQ, Deng XG. Three-dimensional conformal
radiotherapy versus intracavitary brachytherapy for salvage treatment of locally
persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004; 60:165.
22. Leung TW, Tung SY, Wong VY, et al. Nasopharyngeal intracavitary brachytherapy:
the controversy of T2b disease. Cancer 2005; 104:1648.
23. Low JS, Chua ET, Gao F, Wee JT. Stereotactic radiosurgery plus intracavitary
irradiation in the salvage of nasopharyngeal carcinoma. Head Neck 2006; 28:321.
24. Wu SX, Chua DT, Deng ML, et al. Outcome of fractionated stereotactic radiotherapy
for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J
Radiat Oncol Biol Phys 2007; 69:761.
25. Orecchia R, Redda MG, Ragona R, et al. Results of hypofractionated stereotactic re-
irradiation on 13 locally recurrent nasopharyngeal carcinomas. Radiother Oncol 1999;
53:23.
26. Lin R, Slater JD, Yonemoto LT, et al. Nasopharyngeal carcinoma: repeat treatment
with conformal proton therapy--dose-volume histogram analysis. Radiology 1999;
213:489.
27. Pai PC, Chuang CC, Wei KC, et al. Stereotactic radiosurgery for locally recurrent
nasopharyngeal carcinoma. Head Neck 2002; 24:748.
28. Yau TK, Sze WM, Lee WM, et al. Effectiveness of brachytherapy and fractionated
stereotactic radiotherapy boost for persistent nasopharyngeal carcinoma. Head Neck
2004; 26:1024.
29. Chua DT, Wei WI, Sham JS, et al. Stereotactic radiosurgery versus gold grain
implantation in salvaging local failures of nasopharyngeal carcinoma. Int J Radiat
Oncol Biol Phys 2007; 69:469.
30. Koutcher L, Lee N, Zelefsky M, et al. Reirradiation of locally recurrent nasopharynx
cancer with external beam radiotherapy with or without brachytherapy. Int J Radiat
Oncol Biol Phys 2010; 76:130.
31. Lu TX, Mai WY, Teh BS, et al. Initial experience using intensity-modulated
radiotherapy for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys
2004; 58:682.
32. Chua DT, Sham JS, Leung LH, Au GK. Re-irradiation of nasopharyngeal carcinoma
with intensity-modulated radiotherapy. Radiother Oncol 2005; 77:290.
33. Zheng XK, Ma J, Chen LH, et al. Dosimetric and clinical results of three-dimensional
conformal radiotherapy for locally recurrent nasopharyngeal carcinoma. Radiother
Oncol 2005; 75:197.
34. Jin Y, Cai XY, Shi YX, 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.
35. Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with
recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based
chemotherapy. Oral Oncol 2003; 39:361.
36. Ciuleanu E, Irimie A, Ciuleanu TE, et al. Capecitabine as salvage treatment in
relapsed nasopharyngeal carcinoma: a phase II study. J BUON 2008; 13:37.
37. Poon D, Chowbay B, Cheung YB, et al. Phase II study of irinotecan (CPT-11) as
salvage therapy for advanced nasopharyngeal carcinoma. Cancer 2005; 103:576.
38. Ngeow J, Lim WT, Leong SS, et al. Docetaxel is effective in heavily pretreated
patients with disseminated nasopharyngeal carcinoma. Ann Oncol 2011; 22:718.
39. Au E, Tan EH, Ang PT. Activity of paclitaxel by three-hour infusion in Asian patients
with metastatic undifferentiated nasopharyngeal cancer. Ann Oncol 1998; 9:327.
40. Foo KF, Tan EH, Leong SS, et al. Gemcitabine in metastatic nasopharyngeal
carcinoma of the undifferentiated type. Ann Oncol 2002; 13:150.
41. Rischin D, Corry J, Smith J, et al. Excellent disease control and survival in patients
with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol
2002; 20:1845.
42. Chua DT, Kwong DL, Sham JS, et al. A phase II study of ifosfamide, 5-fluorouracil
and leucovorin in patients with recurrent nasopharyngeal carcinoma previously
treated with platinum chemotherapy. Eur J Cancer 2000; 36:736.
43. Dugan M, Choy D, Ngai A, et al. Multicenter phase II trial of mitoxantrone in patients
with advanced nasopharyngeal carcinoma in Southeast Asia: an Asian-Oceanian
Clinical Oncology Association Group study. J Clin Oncol 1993; 11:70.
44. Airoldi M, Gabriele AM, Garzaro M, et al. Induction chemotherapy with cisplatin and
epirubicin followed by radiotherapy and concurrent cisplatin in locally advanced
nasopharyngeal carcinoma observed in a non-endemic population. Radiother Oncol
2009; 92:105.
45. An X, Wang FH, Ding PR, et al. Plasma Epstein-Barr virus DNA level strongly
predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with
palliative chemotherapy. Cancer 2011; 117:3750.
46. Wang CC, Chang JY, Liu TW, et al. Phase II study of gemcitabine plus vinorelbine in
the treatment of cisplatin-resistant nasopharyngeal carcinoma. Head Neck 2006;
28:74.
47. Chen C, Wang FH, Wang ZQ, et al. Salvage gemcitabine-vinorelbine chemotherapy
in patients with metastatic nasopharyngeal carcinoma pretreated with platinum-based
chemotherapy. Oral Oncol 2012.
48. Yau TK, Shum T, Lee AW, et al. A phase II study of pemetrexed combined with
cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma. Oral
Oncol 2012; 48:441.
49. Agulnik M, Siu LL. State-of-the-art management of nasopharyngeal carcinoma:
current and future directions. Br J Cancer 2005; 92:799.
50. Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab in
combination with carboplatin in patients with recurrent or metastatic nasopharyngeal
carcinoma. J Clin Oncol 2005; 23:3568.
51. Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent
or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal
carcinoma. J Clin Oncol 2007; 25:3766.
52. Lim WT, Ng QS, Ivy P, et al. A Phase II study of pazopanib in Asian patients with
recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res 2011; 17:5481.
53. Chua DT, Wei WI, Wong MP, et al. Phase II study of gefitinib for the treatment of
recurrent and metastatic nasopharyngeal carcinoma. Head Neck 2008; 30:863.
54. You B, Le Tourneau C, Chen EX, et al. A Phase II trial of erlotinib as maintenance
treatment after gemcitabine plus platinum-based chemotherapy in patients with
recurrent and/or metastatic nasopharyngeal carcinoma. Am J Clin Oncol 2012;
35:255.
55. Masmoudi A, Toumi N, Khanfir A, et al. Epstein-Barr virus-targeted immunotherapy
for nasopharyngeal carcinoma. Cancer Treat Rev 2007; 33:499.
56. Gottschalk S, Heslop HE, Rooney CM. Adoptive immunotherapy for EBV-associated
malignancies. Leuk Lymphoma 2005; 46:1.
57. Comoli P, Labirio M, Basso S, et al. Infusion of autologous Epstein-Barr virus
(EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative
disorder in solid organ transplant recipients with evidence of active virus replication.
Blood 2002; 99:2592.
58. Whitney BM, Chan AT, Rickinson AB, et al. Frequency of Epstein-Barr virus-
specific cytotoxic T lymphocytes in the blood of Southern Chinese blood donors and
nasopharyngeal carcinoma patients. J Med Virol 2002; 67:359.
59. Lee SP, Chan AT, Cheung ST, et al. CTL control of EBV in nasopharyngeal
carcinoma (NPC): EBV-specific CTL responses in the blood and tumors of NPC
patients and the antigen-processing function of the tumor cells. J Immunol 2000;
165:573.
60. Bell AI, Groves K, Kelly GL, et al. Analysis of Epstein-Barr virus latent gene
expression in endemic Burkitt's lymphoma and nasopharyngeal carcinoma tumour
cells by using quantitative real-time PCR assays. J Gen Virol 2006; 87:2885.
61. Chua D, Huang J, Zheng B, et al. Adoptive transfer of autologous Epstein-Barr virus-
specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 2001; 94:73.
62. Straathof KC, Bollard CM, Popat U, et al. Treatment of nasopharyngeal carcinoma
with Epstein-Barr virus--specific T lymphocytes. Blood 2005; 105:1898.
63. Comoli P, Pedrazzoli P, Maccario R, et al. Cell therapy of stage IV nasopharyngeal
carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J
Clin Oncol 2005; 23:8942.
64. Comoli P, De Palma R, Siena S, et al. Adoptive transfer of allogeneic Epstein-Barr
virus (EBV)-specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-
specific immune response in a patient with EBV-related nasopharyngeal carcinoma.
Ann Oncol 2004; 15:113.
65. Lin CL, Lo WF, Lee TH, et al. Immunization with Epstein-Barr Virus (EBV) peptide-
pulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to
tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer
Res 2002; 62:6952.
66. Taylor GS, Haigh TA, Gudgeon NH, et al. Dual stimulation of Epstein-Barr Virus
(EBV)-specific CD4+- and CD8+-T-cell responses by a chimeric antigen construct:
potential therapeutic vaccine for EBV-positive nasopharyngeal carcinoma. J Virol
2004; 78:768.
67. Hui EP, Ma BB, Chan SL, et al. Therapeutic vaccination with modified vaccinia
Ankara (MVA) encoding Epstein-Barr virus (EBV) target antigens in EBV+
nasopharyngeal carcinoma (NPC) (abstract #3052). J Clin Oncol 26:2008.
68. Duraiswamy J, Sherritt M, Thomson S, et al. Therapeutic LMP1 polyepitope vaccine
for EBV-associated Hodgkin disease and nasopharyngeal carcinoma. Blood 2003;
101:3150.
69. Duraiswamy J, Bharadwaj M, Tellam J, et al. Induction of therapeutic T-cell
responses to subdominant tumor-associated viral oncogene after immunization with
replication-incompetent polyepitope adenovirus vaccine. Cancer Res 2004; 64:1483.