1

Review
Emerging Prognostic Factors in Nasopharyngeal Carcinoma
N. A. Iacovelli1,3, P. Bossi2, C. Fallai1, G. Gardani3, E. Orlandi1

Radiotherapy Unit 2, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy

Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy

University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milan, Italy

Corresponding author: Ester Orlandi, Radiotherapy 2 Unit; Email: ester.orlandi@istitutotumori.mi.i

Citation: Iacovelli N A, Bossi P, Fallai C, Gardani G, Orlandi E. Emerging prognostic factors in Nasopharyngeal
carcinoma. J Nasopharyng Carcinoma, 2014, 1(8): e8. doi:10.15383/jnpc.8.
Competing interests: The authors have declared that no competing interests exist.
Conflict of interest: None.
Copyright:

2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-

access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are
credited.

Abstract: Identification and validation of prognostic factors in NPC has been mainly performed in areas where the
disease is endemic. It is matter of debate if the same variables will retain their impact when applied to non-endemic
areas, with prevalence of other histological subtypes and with a different genetic background.
Keywords: Nasopharyngeal Carcinoma; Prognostic Factors

Introduction

Primary tumor extension (T), lymph node involvement (N) and

Standard treatment for nasopharyngeal carcinoma (NPC) is

distant metastasis (M), i.e. TNM classification, are traditionally

radiotherapy (RT) for early-stage lesions or chemoradiotherapy

considered the most significant prognostic factors in NPC patients.

(CRT) for more advanced lesions (1-2). Technology innovations

Other potential predictors of outcome include sex, age,

in radiation therapy (i.e., intensity modulated radiation therapy,

histological type. Although traditional prognostic factors may

IMRT), in imaging and the use of appropriate combined CRT with

provide some useful clinical information, they cannot predict

the possible adjunct of neoadjuvant chemotherapy have recently

treatment outcome reliably. Besides classical prognostic factors,

improved outcome in NPC (3-7).

new emerging factors predicting outcome in NPC patients have

Predominant pattern of failure in locoregionally advanced NPC

been recently available. Therefore, substantial research efforts

treated with IMRT and chemotherapy is distant metastasis even if

have focused on the identification of novel prognostic factors

loco-regional failures may develop in about 10% of patients (1; 3-

because such a result could allow therapy to be tailored to the

6).

characteristics of an individual patient.

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

In this paper, we sistematically reviewed the literature concerning

anaemia or thrombocytosis during radiotherapy, continuous

clinical, viral, imaging and biomolecular factors potentially

reduction in haemoglobin, high neutrophil-lymphocyte ratio

predicting the prognosis of NPC patients, with a particular

before radiotherapy (16).

emphasis on emerging prognostic factors. This may help in

With regarding to imaging, Liu et al. reported that Magnetic

determining which NPC patients might benefit from more

Resonance Imaging (MRI)-detected cranial nerves (CN) invasion

aggressive treatment and optimizing follow-up protocols.

had an unfavourable impact on the prognosis of NPC (17).

Recently

the

same

authors

retrospectively

analyzed

749

Classical Prognostic Factors

nasopharyngeal carcinoma patients undergoing IMRT and

As with most other tumors, the extent of a NPC as embodied in

reported that in T34 NPC, MRI-detected CN invasion was

the TNM staging system is the most important prognostic factor.

associated with inferior 5-year overall survival, distant metastasis-

The main purpose of TNM staging system is to divide patients

free survival, and locoregional relapse-free survival (p=0.002,

into subgroups according to different prognosis, to guide the

0.003, and 0.012, respectively). Therefore in patients with MRI-

treatment strategy for different risk groups, and to facilitate the

detected CN invasion current CRT strategies might not be

exchange of experience between treatment centers (8). The most

sufficient (18).

recent 7th edition of the UICC/AJCC staging system for NPC,

Finally, among treatment related prognostic factors the total dose

published in 2009, is a common set of recommendations from the

to the tumor is the most important radiation factor for locoregional

initial revision of the previous 6th edition. An important change

control: dose at least of 66 Gy is required for locally advanced

has been the clarification of the role of retropharyngeal lymph

disease (19). However, treatment results for NPC are strictly

node. According to it, N1 classification for NPC is defined as

correlated with the overall treatment time. Kwong et al. reported a

following: unilateral lymph nodes, 6 cm or less, above the

3.3% risk of LRF increasing per additional day of RT

supraclavicular fossa, and/or retropharyngeal lymph nodes, 6 cm

prolongation (20).

or less (unilateral or bilateral)(9). It covers quite a large range of

nodal patterns. Probably N1 patients with different nodal

Emerging Factors

characteristics may have different prognosis. Shi et al. have

Volume of Primary Tumor

recently shown that involvement of both cervical lymph nodes and

Many authors currently suggest that gross primary tumor volume

retropharyngeal lymph nodes may be a potentially prognostic

(GTV-P) should be included in TNM staging as a quantitative

factor for distant metastasis and disease progression in N1 patients

indicator to predict prognosis in NPC patients.

(10).

Dubben et al. firstly reported that GTV-P is a relevant predictor of

Several studies have shown that the T (tumor) staging system

radiotherapy treatment outcome suggesting that individual tumor

developed by UICC/AJCC has its limitations in predicting

volume should always be reported in clinical studies and

prognosis of patients with NPC (11-12), in particular whether the

considered in data analyses (21).

conventional TNM staging system could still predict the prognosis

The significance of the GTV-P on outcome of NPC patients

of NPC patients treated with IMRT need to be reevaluated (13).

treated with IMRT has been evaluated in many studies. Guo et al.

The histological-type World Health Organization type I patients

found GTV-P is an independent prognostic indicator for distant

frequently seen among the Caucasian population were found to be

metastasis and local recurrence in NPC patients after IMRT

associated with adverse prognosis (14-15).

treatment. They selected a GTV-P cut off value of 19 ml and

Chang et al. identified eight clinical independent prognostic

verified this value in a population of 694 patients. The 5-year

factors of greater risk in NPC patients: gender, age, T or N stages,

disease-free survival (DFS), overall survival (OS), local relapse-

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

free survival (LRFS) and distant metastasis-free survival (DMFS)

late toxicities including temporal lobe necrosis (13% vs. 21%),

rates for NPC patients with GTV-P <19 vs. >19 ml were 94.9%

cranial neuropathy (4% vs. 9%), xerostomia, trismus and neck

vs. 64.8%, 97.0% vs. 76.4%, 98.2% vs. 92.5% and 97.1% vs.

fibrosis (28). The trials by Pow et al. and Kam et al. confirmed

75.2%, respectively (all P < 0.05) in all patients. More

significantly better recovery of stimulated salivary flow in patients

importantly, when combined with GTV-P, the predictive ability of

with Stage III irradiated by IMRT (29-30). Pow et al. and Fang et

T classifications was improved (22).

al. further showed significant improvement in xerostomia-related

Also Feng and colleagues found that large GTV-P was an adverse

symptoms and corresponding subscale scores on quality of life

prognostic factor for the 5-year local regional control (LRC) rate

(QoL)(29-31).

(RR 2.454,p=0.002) with a cut off of 40 ml (23).

Recently, the retrospective study by Lee AW on the outcomes of

Wu et al. reported that GTV-P is an independent prognostic factor

1593 consecutive patients treated from 1994 to 2010 showed

in local control, distant metastasis, disease-free survival, and

significantly higher free from distant relapse survival (D-FFRS)

overall survival in NPC. They analyzed 321 patients and found

achieved in the IMRT era. Five-year DSS increased from 78% in

statistically significant correlation between GTV-P and LFFS,

the 2DRT, to 81% in the 3DRT, and 85% in the IMRT era, while

DMFS, DFS, and OS (P < 0.05, all) at univariate and multivariate

the corresponding neurological toxicity rate decreased from 7.4%

analyses, whereas T classification was not an independent

to 3.5% and 1.8% (32).

prognostic factor. According to ROC curve analysis, 49 and 19

Epstein Barr Virus-(EBV)

mL were determined as the cut off points of GTV-P for local

NPC is an EBV related cancer. Quantitative analysis of cell-free

control and distant metastasis, respectively (24).

EBV DNA in plasma of patients with NPC and its value in

Chen et al. also demonstrated that GTV-P predicted survival rate

screening, predicting outcome and monitoring treatment has been

of NPC patients with more accuracy than the AJCC staging

studied (33).

system (25).

Increase of the viral DNA load along with clinical stage (from

Similarly Liang et al. analyzed maximum primary tumor diameter

stage I to IV4) has been assessed in many studies (34-35).

(MPTD) in 333 NPC patients finding it a prognostic factor for OS,

Plasma EBV DNA concentration measured at disease onset is a

FFS and DMFS, and LRFS (26).

strong predictor of outcome (poor survival or frequent relapse)

Finally, according to the above mentioned data indicating current

and it could help in identifying early-stage patients with a greater

TNM staging system limitations, Liu et al. suggest to incorporate

risk of developing distant metastasis (36-37). Low number of pre-

GTV-P into the current TNM staging system to separate NPC

therapy EBV DNA copies have an high negative predictive value

patients into subgroups with different prognosis more accurately

(NPV) for 3-year progression (93%) and a lower positive

(27).

predictive value (PPV) of 41%; 6 to 8 weeks after treatment, NPV

Intensity Modulated Radiation Therapy (IMRT)

and PPV are 83% and 87%, respectively (38). Consensus lack on

Some authors reported a significant improvement in survival and

number of copies cut off to be considered because of differences

reduction of serious toxicity with IMRT compared to conventional

in primer design and cycling number during polymerase chain

radiotherapy. Three randomized trials comparing IMRT versus

reaction (39-40). The test is also useful to monitor response to RT,

two-dimensional radiotherapy (2DRT) have been reported. Peng et

CRT or surgery. In a recent study Yip et al. (41) reviewed 6

al. confirmed significant improvement in therapeutic ratio by

papers from 2003 to 2013 comparing the ability of post-treatment

IMRT: the IMRT group achieved significantly higher 5-year free

EBV DNA loads to detect DM) and local recurrence (LR) or loco-

from local relapse survival (L-FFRS) (91% vs. 84%, p = 0.046)

regional recurrence (LRR): detection rate for DM ranged from

and OS (80% vs. 67%, p = 0.001), with significant reduction in

86% to 96% and that for LR/LRR ranged from 51 to 67%. (42-

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

44). In the same paper, 12 studies with EBV DNA measured

of

EBV-negative

NPC

among

North

Americans,

one

before and after treatment in NPC patients from 2000 to 2013

demonstrating a strong association with oncogenic HPV, and the

were reviewed, showing a consistent drop of the EBV DNA rate

other lacking an association with both EBV and HPV, strongly

after RT (45-46). Patients with recurrence maintained a

correlated with type II and type I WHO NPC respectively,

substantially high rate of post-RT EBV DNA rates (47-48)

suggesting that viral status may be the driving factor behind WHO

whereas patients with no recurrence after RT had drop of EBV

type (69). The data reported by Stenmark et al., support the

DNA rates. The authors observed an even more dramatic response

hypothesis that HPV is a possible etiologic agent in the

of EBV DNA load in patients treated with concurrent CRT (49-

development of NPC among white individuals. Furthermore, the

53) indicating the more effectiveness of chemo-RT in reducing the

authors suggest that in patients with non endemic forms of EBV-

EBV DNA load than RT alone. If viral DNA load persists at

negative NPC, having high rates of locoregional relapse and death,

significant level post-treatment or initially drops to the

intensification of local therapy with either dose-escalated radiation

background level but subsequently rises again, performing

therapy or radiation sensitizing agents may be of benefit.

PET/CT imaging scanning to locate the relapse site is strongly

suggested. Residual EBV DNA load after primary treatment could

Positron Emission Tomography (PET) Imaging

justify adjuvant chemotherapy, putting the basis for an ongoing

2-[Fluorine-18]fluoro-2-deoxy-D-glucose

trial with platinum and gemcitabine (clinicaltrials.gov NCT

emission tomography (PET) is a valuable imaging tool in patients

00370890). EBV encoded small RNAs (EBERs) represent the

with

most abundant EBV viral transcripts and are expressed in many

tomography/computed

tomography

(PET/CT)

EBV-associated diseases. Consequently EBERs (EBER1 and

technical

intrinsically

aligned

EBER2) are used as the target molecule to detect EBV-infected

morphologic data sets. FDG-PET/CT may be considered as a

cells in tissues by in situ hybridization (ISH). EBERs are

standard clinical imaging modality in the staging of NPC and in

abundantly expressed in NPC, with as many as 105107 copies per

the detection of recurrent disease after RT or CRT (70).

cell. EBER positivity is a predictor for improved overall survival

The semiquantitative parameter of PET imaging, standardized

(54). In a recent paper Ke et al. found high EBER expression

uptake value (SUV), which represents glucose metabolism of

levels in NPC patients as a significant positive prognostic factor

tumors, may reflect the aggressiveness of local tumor and the risk

for survival (55).

of metastatic spread. Encouraging results on its prognostic value

NPC.

basis

Dual-modality

for

(FDG)

positron

positron

emission
provides

functional

the
and

in NPC have been reported.

Human Papilloma Virus (HPV)

Lee et al. evaluated 41 patients with non-disseminated NPC

Several studies have detected HPV in NPC patients. In some

undergoing platinum-based concurrent CRT and found that

studies EBV and HPV infections has been found mutually

patients having tumors with high FDG uptake had a significantly

exclusive (56-63). In others cases EBV and HPV coinfections

lower 3-year disease free survival (DFS) rate than patients with

were reported, predominantly in patients from endemic areas (64-

lower tumor FDG uptake (51% vs 91%, P=0.0070). Patients with

68). The clinical significance of HPV infection in NPC is still

an SUV(max) below 8 had a higher DFS than patients with an

unclear, raising the question if the virus is a bystander or if it

SUV(max) of 8 or greater. Therefore they concluded that FDG

could retain a pathogenic role. In a recent paper, tumor HPV

uptake, as measured by the SUV(max), may predict DFS in CRT-

positivity has been demonstrated as an adverse prognostic factor

treated NPC and a high FDG uptake may be useful for identifying

for overall survival, progression-free survival, and locoregional

patients requiring more aggressive treatment (71).

relapse among patients with NPC. The study identifies two subsets

To assess the prognostic value of FDG-PET, Xie et al.

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

retrospectively reviewed the association of SUVmax from FDG-

results suggest that a cut off pSUVmax of the primary tumor at 7.5

PET and the therapy outcome of 62 NPC patients treated with

and nSUVmax of cervical lymph nodes at 6.5 are associated with

radiotherapy. They found that patients having tumors with a lower

poor patient outcome and pSUVmax is a significant prognosticator

SUVmax (<8.0) had significantly better 5-year overall survival

of DFS. As declared in the paper the 2-year follow-up period of

(OS) (P= 0.0187) and DFS (P = 0.0163) than patients with a

the study may be too short to fully assess DFS. Also the study

greater SUVmax (8.0). Patients that showed metabolic complete

population was small with only 46 patients included.

response had a significantly higher 5-year OS (P = 0.0237) and

A larger study was performed by Hung and colleagues, who

DFS (P = 0.0186) than patients with metabolic partial response.

retrospectively evaluated the prognostic value of SUVmax

Poor prognosis was found in patients with the SUVmax of neck

analyzing 371 patients with non disseminated NPC with a median

nodes larger than that at the primary tumor site (SUVmax-N >

follow up of 64 months. They found that NPC patients with a

SUVmax-P) (P = 0.0440) (72).

higher SUVmax (SUVmax-T > 9.3 or SUVmax-N > 7.4) had

Beside SUV, total lesion glycolysis (TLG) has been shown to be

significantly worse DMFS but no difference in LC or RC,

an independent prognostic factors in NPC patients.

suggesting

Chan et al. investigated the prognostic impact of metabolic tumor

prognosticator for identifying patients who could receive more

volume and total lesion glycolysis (TLG) of the primary tumor,

aggressive systemic treatment aimed at reducing distant metastasis

maximal standardized uptake value of the primary tumor and the

(76).

neck lymph nodes in 196 patients with primary stage III-IVb NPC.

Xie et al. evaluated the prognostic significance of metabolic tumor

On multivariable analysis TLG values greater than 330 were

volume (MTV) and metabolic index (MI) from FDG PET/CT in

independently predictive of better OS (P=0.0014) and DFS

41 patients with stage I-IV locally NPC before and after

(P=0.0005). They identified IVa-b stage and TLG values greater

radiotherapy. Those patients having tumors with an MTV below

than 330 as independent predictors of local failure-free survival. In

30 cm3 had significantly better 5-year OS than patients with an

addition, a high maximal standardized uptake value of the neck

MTV of 30 cm3 or greater (84.6:46.7%, p = 0.006) and DFS

lymph nodes (P=0.005), male sex (P=0.041), and stage IVa-b

(73.1:40.0%, p = 0.014). And patients with MI below 130 had

(P=0.009) independently predicted distant failure-free survival

significantly higher 5-year OS (88.0:43.8%, p = 0.002) and DFS

(73).

(76.0:37.5%, = 0.005) than other patients. A principal find of their

Liu et al. in a recent paper analyzed SUVmax in 75 M0

study is that MI is strongly correlated with DFS and OS in patients

nonkeratinizing NPC patients who received FDG-PET before

with NPC treated by radiotherapy, and thus it is a better predictor

IMRT alone or CRT. They found SUVmax category as the only

of long-term survival than MTV and SUV alone. The authors also

significant factor, on multivariate analysis, influencing both the 5-

confirmed that patients who presented with local recurrence or

year local failure-free (p=0.017) and DFS rates (p=0.00).

distant metastasis within 5 years had a significantly higher MI

However, they could not confirm the role of SUVmax in OS rates

than the remaining patients suggesting the intimate correlation

(p = 0.065). So they concluded that SUVmax could be a potential

between the primary MI and tumor recurrence or metastasis (77).

independent prognostic predictor of clinical outcome in patients

Future research can be designed to assess whether modification of

with nasopharyngeal carcinoma treated with IMRT alone or with

therapy or addition of adjuvant therapy can improve the outcome

CCRT and that a high 18F-FDG uptake (SUVmax >5) indicates

and survival of patients with higher SUVmax.

poor outcome in patients with NPC (74).

With regard to the prognostic significance of post treatment PET,

Chan et al. have shown that SUVmax measured on FDG PET/CT

Chan et al. demonstrated that 3-month post-therapy PET scans

is a valuable tool for risk stratification of NPC patients (75). Their

were more sensitive than conventional imaging modalities in the

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

that

high

18F-FDG

uptake

was

valuable

Published:2014-05 -25 DOI:10.15383/jnpc.8

detection of treatment failures in NPC patients (78-79). In a recent

found that a lower ADC value was associated with poorly

paper they indicate the achievement of complete metabolic

differentiated or undifferentiated tumour. They also found a

response (CMR) on post-therapy PET as a favorable prognostic

significant difference in ADC value among small, medium and

factor in stage IVab NPC patients that may inform the clinical

large tumor volume (p = 0.03). ADC value was significantly lower

management after therapy (80). The authors analyzed 165 NPC

(p = 0.003) when metastatic cervical lymph nodes were present

patients with a median follow up of 58 months. They found that

and ADC value correlated inversely with tumor volume (r =

PET imaging performed 3 months after completion of treatment is

0.799, p = 0.03). Limitations of this study were lack of follow up,

superior to conventional work-up for the assessment of treatment

lack of standardized ROI determination for ADC calculation and

response. The results of the 3-month post therapy PET and total

absence of correlation with EBV along with the small number of

lesion glycolysis (TLG) of the primary tumor were independent

patients studied (81).

predictors of overall survival. TNM tumor stage, TLG, and post-

The ADC value before treatment and early changes in ADC

therapy PET findings were independently associated with disease-

during treatment have been correlated with the sensitivity to

free survival (DFS). The results of post-therapy PET were more

radiotherapy and chemotherapy in some tumor types (82-87).

predictive of DFS than TNM tumor stage (P<0.001 vs. P = 0.005).

ADC may have a role in predicting radiotherapy early response in

They therefore suggest a more conservative follow-up approach

NPC patients. Hong et al. correlated the difference between ADC

for stage IVab patients who achieve a CMR after definitive CRT

value before therapy and two weeks after the start of IMRT

in contrast with CR on post therapy conventional work-up which

(ADC) with the presence of a residual tumor at the primary site

is not a reliable prognostic factor to guide surveillance protocols.

three months after the end of radiotherapy. The ADC values of

To date no published studies have addressed the role of an interim

patients with and without residual tumors were significantly

FDG-PET during RT or CRT. Evaluation of FDG-PET uptake by

different (p = .017). Logistic regression analysis indicated that

SUV is semiquantitative and it is difficult to compare SUV cut

ADC was an independent prognostic factor for the short-term

offs between hospitals and patients. More data are needed to

effect of IMRT. This indicates that, two weeks after the start of

support the usefulness of FDG-PET in predicting outcome of NPC

radiotherapy, water molecules diffuse more freely in the

at initial diagnosis and after completion of definitive treatment.

radiosensitive tumors due to increased tissue necrosis and cell

Further confirmation must derive from larger and prospective

disruption. But this study has some limitations: the ADC values

randomized studies.

were not determined after chemotherapy and before radiotherapy;

the best timing for the assessment of ADC still remains to be

Magnetic Resonance Diffusion-Weighted Imaging (MR-DWI)

identified and there is lack of information about the long term

Magnetic resonance diffusion-weighted imaging (MR-DWI) is a

outcome of patients with and without residual tumor (88).

functional imaging technique that, detecting the diffusive state of

water molecules in viable tissue, indirectly reveals the

Biomarkers

microstructural features of a tumor. It can provide a quantitative

Several biomarkers have been studied as prognostic factors in

parameter, the apparent diffusion coefficient (ADC), which can

NPC. For the vast majority only single reports could be found in

indirectly indicate microvascular circulation, cell membrane

literature, therefore their value should be considered of limited

integrity and cell density and can also detect local microscopic

clinical importance. For sake of completeness they will be

changes in the tumor before morphological changes are evident. In

hereafter cited.

a little study which comprised only 30 patients, Razek et al.

Baseline serum C-Reactive Protein (CRP) and C-Reactive Protein

correlated ADC value with prognostic parameters of NPC. They

kinetics were found to be independent prognostic factors in

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

metastatic NPC patients (89).

BAX mRNA-positive NPC (115) and in patients with nuclear

Elevated Lactate dehydrogenase (LDH) (90-92), elevated Beclin-1

expression of p27 (116-117).

(93), increased Galectin-3 expression (94), high pretreatment

Two prognostic markers have greater interest in NPC:

serum levels of CYFRA 21-1 (95), high-expression of protein

overexpression of EGFR has been associated in a recent meta-

tyrosine kinase 6 (PTK6) (96), absence of VEGF expression, high

analysis with poor OS, DFS and LRC, but not DMFS (118).

mitosis and COX-2 expression (97), loss of Krppel-like factor 4

The hypoxia-inducible factors (HIFs) have been significantly

(KLF4) expression (98), nuclear expression of cyclin-dependent

associated with increased mortality risk in many head and neck

kinase 4 (CDK4) (99), high expression of CDC28 protein kinase

cancers. In particular overexpression of the isoform HIF-1 was

regulatory subunit 1B (CKS1B)(100) and joint detection of

significantly associated with worse OS (119).

CD44v6 and CD62P in the peripheral blood or tissues (101) were

If the previous cited single markers could difficultly translate into

reported to be independent prognostic factors of poor outcome in

clinical

NPC patients.

comprehensive signature could reach this goal. Recently, a support

In addition Tropomyosin-related kinase B (TrkB) overexpression

vector machine (SVM)-based methods developed a prognostic

(102), overexpressed fibronectin (103), high serum Matrix

classifier for NPC and validated it in an independent cohort (120).

metalloproteinase-9 (MMP-9) levels (104), high neuropilin-1

Four serum miRNAs (miR-22, miR-572, miR-638 and miR-1234)

(NRP-1) expression (105), high cytoplasmic expression of NR4A2

were demonstrated to be independent prognostic factors, in

(106), topoisomerase II (TOP2A) overexpression (107), high

particular the levels of three miRNAs (miR-22, miR-572 and miR-

stathmin 1 (STMN1) expression (108), serum endostatin level

638) were inversely associated with OS, and the level of miR-

(109) and Raf kinase inhibitory protein (RKIP) expression (110)

1234 was positively associated with OS (121).

were demonstrated to be unfavorable prognostic factors for

Further validation studies are required to confirm the prognostic

patients with NPC.

and predictive role of reported biomarkers.

application

for

selecting

different

treatments,

High expression of Delta-like ligand 4 (DLL4) has been reported

as an independent predictor of decreased DSS. Its expression is

Quality of Life

elevated in metastases compared to the primary tumor. Patients

From the clinical point of view, quality of life (QoL) of the

with dual elevated expression of DLL4 and VEGF carried the

oncologic patients has been considered as one of the most

worst prognosis in terms of OS (111).

important factors. Also in NPC pretreatment QoL has been clearly

Gp96 (GRP94) expression was found to be an independent

showed a prognostic role in the development of metastasis and in

prognostic factor for OS and DFS (112).

determining patients survival (122).

MAP kinase-interacting kinases (Mnk) phosphorylates eukaryotic

translation initiation factor 4E (eIF4E). The expression of p-Mnk1

Future Perspectives

and p-eIF4E in NPC was proved to be independent prognostic

The clinical staging system is the key prognostic determinant for

factors (113).

patients with nasopharyngeal carcinoma in routine clinical

Metastasis-associated gene 1 (MTAl) and Reversion-inducing

practice. Whereas large variations in the clinical outcomes of

cysteine-rich protein with Kazalmotifs (RECK) expressions were

patients with the same cancer stage have been reported, which

independent prognostic factors for survival. Positive MTAl

implies that the present staging system is suboptimal for prognosis

expression and negative RECK expression predicted a higher risk

and there might be other important prognostic indicators. In

of recurrence and a poorer prognosis in NPC (114).

literature several articles dealt with the development of prognostic

An advantage in survival has been demonstrated in patients with

models for metastatic NPC (123-126) and for recurrent NPC

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e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

(127). In only one paper Luo et al. created a prognostic model for

cancer: Phase III randomized Intergroup study 0099. J Clin Oncol

newly diagnosed undisseminated NPC. On the basis of stage (III-

16:1310-1317, 1998.

IV), age (>45 years), anti-enzyme rate of Epstein-Barr virus

3 Lee AW, Tung SY, Chan AT, et al: Preliminary results of a

DNase-specific neutralizing antibody (AER) (> 58%) and absolute

randomized study (NPC-9902 Trial) on therapeutic gain by

neutrophil count (ANC) (> 4.7 109/L) the authors stratified

concurrent chemotherapy and/or accelerated fractionation for

patients into four prognostic groups (128).

locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol

A prognostic model specifically designed for newly diagnosed

Biol Phys 66:142-151, 2006.

NPC is needed to complement the existing clinical staging system

4 Lee AW, Lau WH, Tung SY, et al: Preliminary results of a

in identifying high-risk patients for combined and aggressive

randomized study on therapeutic gain by concurrent chemotherapy

treatment and to guide patients follow up evaluation frequency.

for regionally advanced nasopharyngeal carcinoma: NPC-9901

The aim is the improvement of the survival of these patients.

Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J

Because several radiological, clinical and molecular factors have

Clin Oncol 23:6966-6975, 2005.

been described with predictive or prognostic role in NPC, it is

5 Wee J, Tan EH, Tai BC, et al: Randomized trial of radiotherapy

paramount to be able to integrate them in a more sophisticated

versus concurrent chemoradiotherapy followed by adjuvant

way and to prospectively validate this model, in order to better

chemotherapy in patients with American Joint Committee on

tailor the treatment for each patient than today.

Cancer/International Union against cancer stage III and IV

We strongly suggest that a selection of the previous revised

nasopharyngeal

prognostic factors should be studied in order to create a strong and

Oncol23:6730-6738, 2005.

reliable model to predict survival among NPC patients. The

6 Lee AW, Sze WM, Au JS, et al: Treatment results for

strongest ones are, in our opinion, the primary tumor volume as

nasopharyngeal carcinoma in the modern era: The Hong Kong

detected at MRI, EBV DNA load, SUV max. To verify such a

experience. Int J Radiat Oncol Biol Phys 61:1107-1116, 2005.

prognostic model further evaluation, possibly a large prospective

7 OuYang PY, Xie C, Mao YP, Zhang Y, Liang XX, Su Z, Liu Q,

study, is warranted.

Xie FY; Significant efficacies of neoadjuvant and adjuvant

Identification and validation of prognostic factors in NPC has

chemotherapy for nasopharyngeal carcinoma by meta-analysis of

been mainly performed in areas where the disease is endemic. It is

published literature-based randomized, controlled trials. Ann

matter of debate if the same variables will retain their impact

Oncol. 2013 Aug;24(8):2136-46. doi: 10.1093/annonc/mdt146.

when applied to non-endemic areas, with prevalence of other

Epub 2013 Apr 23.

histological subtypes and with a different genetic background. So

8 Greene FL, Page DL et al (2002) AJCC cancer staging

the future trials should be aimed at verifying the consistence of

handbook from the AJCC cancer staging manual, 6th edn.

such prognostic models in different geographical areas.

Springer, New York, pp 47-60.

cancer

of

the

endemic

variety.

Clin

9 Edge SB, Byrd DR, Carducci MA, Compton CC, Fritz AG,
References

Greene FL, Trotti A: AJCC Cancer Staging Manual. 7th edition.

1 Langendijk JA, Leemans CR, Buter J, et al: The additional value

Philadelphia: Lippincott-Raven; 2009.

of

advanced

10 Qi Shi, Chunying Shen, Lin Kong, Xiaoshen Wang, Jianhui

nasopharyngeal carcinoma: A meta-analysis of the published

Ding, Yunsheng Gao, Tingting Xu and Chaosu Hu; Involvement

literature. J ClinOncol 22:4604-4612, 2004.

of both Cervical Lymph Nodes and Retropharyngeal Lymph

2 Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy

Nodes has prognostic value for N1 patients with Nasopharyngeal

versus radiotherapy in patients with advanced nasopharyngeal

Carcinoma. Radiation Oncology 2014, 9:7.

chemotherapy

to

radiotherapy

in

locally

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

11 Lin S, Pan J, Han L et al (2009) Nasopharyngeal carcinoma

20 Kwong DL, Sham JS, Chua DT, Choy DT, Au GK, Wu PM.

treated

radiation

The effect of interruptions and prolonged treatment time in

therapy: report on the 3-year outcome of a prospective series. Int J

radiotherapy for nasopharyngeal carcinoma. Int. J. Radiat. Oncol.

Radiat Oncol Biol Phys 75:1071-1078.

Biol. Phys. (1997) 39, 703-710.

12 Tham IW, Hee SW, Yeo RM et al (2009) Treatment of

21 Dubben HH, Thames HD, Beck-Bornholdt HP. Tumor volume:

nasopharyngeal

a basic and specific response predictor in radiotherapy. Radiother

with

reduced-volume

intensity-modulated

carcinoma

using

intensity-modulated

radiotherapy-the National Cancer Centre Singapore experience.

Oncol 1998;47:167-74.

Int J Radiat Oncol Biol Phys 75:1481-1486.

22 Guo R, Sun Y, Yu XL, Yin WJ, Li WF, Chen YY, et al. Is

13 D Liu, G Long, Q Mei, G Hu.; Primary tumor volume should

primary tumor volume still a prognostic factor in intensity

be included in the TNM staging system of nasopharyngeal

modulated radiation therapy for nasopharyngeal carcinoma?

carcinoma. Medical Hypotheses 82 (2014) 486-487

Radiother Oncol 2012;104:294-9.

14 Gallo O, Bianchi S, Giannini A, Gallina E, Libonati GA, Fini-

23 Mei Feng, Weidong Wang, Zixuan Fan, Binyu Fu, Jie Li,

Storchi O; Correlations between histopathological and biological

Shichuan Zhang and Jinyi Lang; Tumor volume is an independent

findings in nasopharyngeal carcinoma and its prognostic

prognostic indicator of local control in nasopharyngeal carcinoma

significance. Laryngoscope. 1991 May;101(5):487-93.

patients treated with intensity-modulated radiotherapy. Radiation

15 Kaasa S, Kragh-Jensen E, Bjordal K, Lund E, Evensen JF,

Oncology 2013, 8:208.

Vermund H, Monge O, Boehler P; Prognostic factors in patients

24 Zheng Wu, Yong Su, Rui-Fang Zeng, Mo-Fa Gu, Shao-Min

with nasopharyngeal carcinoma. Acta Oncol. 1993;32(5):531-6.

Huang; Prognostic value of tumor volume for patients with

16 H. Chang, J. Gao, B.Q. Xu, S.P. Guo, R.B. Lu, G. Li, S.M.

nasopharyngeal carcinoma treated with concurrent chemotherapy

Huang, F. Han, Z.G. Liu, Y.L. Tao, Z.W. Tu, C. Chen, X.H. Li,

and intensity-modulated radiotherapy. J Cancer Res Clin Oncol

Y.F. Xia; Haemoglobin, Neutrophil to Lymphocyte Ratio and

(2014) 140:69-76.

Platelet Count Improve Prognosis Prediction of the TNM Staging

25 Chen C, Fei Z, Pan J, Bai P, Chen L. Significance of primary

System

and

tumor volume and T stage on prognosis in nasopharyngeal

Validation in 3237 Patients from a Single Institution. Clinical

carcinoma treated with intensity modulated radiation therapy. Jpn

Oncology 25 (2013) 639e646.

J Clin Oncol 2011;41:537-42.

17 Liu L, Liang S, Li L, Mao Y, Tang L, Tian L, Liao X, Cui C,

26 Shao-Bo Liang, Yan-Ming Deng, Ning Zhang, Rui-Liang Lu,

Lin A, Ma J (2009) Prognostic impact of magnetic resonance

Hai Zhao, Hai-Yang Chen, Shao-En Li, Dong-Sheng Liu and

imaging-detected cranial nerve involvement in nasopharyngeal

Yong Chen; Prognostic significance of maximum primary tumor

carcinoma. Cancer 115: 1995-2003.

diameter in nasopharyngeal carcinoma. BMC Cancer 2013; 13:

18 X Liu, L-Z Liu, Y-P Mao, L Chen, L-L Tang, G-Q Zhou, Y

260.

Sun, D Yue, A-H Lin, L Li and J Ma, Prognostic value of

27 Dongbo Liu, Guoxian Long, Qi Mei, Guoqing Hu; Primary

magnetic resonance imaging-detected cranial nerve invasion in

tumor volume should be included in the TNM staging system of

nasopharyngeal carcinoma. British Journal of Cancer (2014) 110,

nasopharyngeal carcinoma. Medical Hypotheses 82 (2014) 486-

1465-1471 | doi: 10.1038/bjc.2014.27.

487.

19 Teo PM, Leung SF, Tung SY et al. Dose-response relationship

28 Peng G, Wang T, Yang KY, et al. A prospective, randomized

of nasopharyngeal carcinoma above conventional tumoricidal

study comparing outcomes and toxicities of intensity-modulated

level: a study by the Hong Kong nasopharyngeal carcinoma study

radiotherapy vs. conventional two-dimensional radiotherapy for

group (HKNPCSG). Radiother. Oncol. (2006) 79, 27-33.

the treatment of nasopharyngeal carcinoma. Radiother Oncol

in

Nasopharyngeal

Carcinoma:

Development

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

10

t 2012; 104:286-93.

virus DNA is predictive of posttherapy distant failure in patients

29 Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and

with early-stage nasopharyngeal carcinoma of undifferentiated

quality of life after intensity-modulated radiotherapy vs.

type. Cancer 2003; 98: 288-291.

conventional

nasopharyngeal

38 Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, Mo F,

carcinoma: initial report on a randomized controlled clinical trial.

Lai M, Ho S, Huang DP, Johnson PJ. Plasma Epstein-Barr virus

Int J Radiat Oncol Biol Phys 2006;66:981-91.

DNA and residual disease after radiotherapy for undifferentiated

30 Kam MK, Leung SF, Zee B, et al. Prospective randomized

nasopharyngeal carcinoma. J Natl Cancer Inst. 2002 Nov 6;

study of intensitymodulated radiotherapy on salivary gland

94(21): 1614-9.

function in early-stage nasopharyngeal carcinoma patients. J Clin

39 Lin JC, Wang WY, Chen KY, et al. Quantification of plasma

Oncol 2007; 25: 4873-9.

Epstein-Barr virus DNA in patients with advanced nasopharyngeal

31 Fang FM, Chien CY, Tsai WL, et al. Quality of life and

carcinoma. N Engl J Med 2004; 350(24): 2461-70.

survival outcome for patients with nasopharyngeal carcinoma

40 Le QT, Jones CD, Yau TK, et al. A comparison study of

receiving three-dimensional conformal radiotherapy vs. intensity-

different PCR assays in measuring circulating plasma epstein-barr

modulated radiotherapy-a longitudinal study. Int J Radiat Oncol

virus DNA levels in patients with nasopharyngeal carcinoma. Clin

Biol Phys 2008; 72: 356-64.

Cancer Res 2005; 11(16): 5700-7.

32 Lee AW, Ng WT, Chan LL, Hung WM, Chan CC, Sze HC,

41 Timothy T.C. Yip, Roger K.C. Ngan, Alvin H.W. Fong,

Chan OS, Chang AT, Yeung RM; Evolution of treatment for

Stephen C.K. Law; Application of circulating plasma/serum EBV

nasopharyngeal cancer - Success and setback in the intensity-

DNA in the clinical management of nasopharyngeal carcinoma;

modulated radiotherapy era. Radiother Oncol. 2014 Mar 11.

Oral Oncology 2014 in press.

S0167-8140(14)00043-7. doi: 10.1016/j.radonc.2014.02.003.

42 Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et

33 Lo YM, Chan LY, Lo KW, Leung SF, Zhang J, Chan AT, et al.

al. Quantification of plasma Epstein-Barr virus DNA in patients

Quantitative analysis of cell-free Epstein-Barr virus DNA in

with advanced nasopharyngeal carcinoma. N Engl J Med 2004.

plasma of patients with nasopharyngeal carcinoma. Cancer Res

43 Chan AT, Ma BB, Lo YM, Leung SF, Kwan WH, Hui EP, et

1999; 59: 1188-1191.

al. Phase II study of neoadjuvant carboplatin and paclitaxel

34 Ma BB et al. Relationship between pretreatment level of

followed by radiotherapy and concurrent cisplatin in patients with

plasma Epstein-Barr virus DNA, tumor burden, and metabolic

locoregionally advanced nasopharyngeal carcinoma: therapeutic

activity in advanced nasopharyngeal carcinoma. Int J Radiat

monitoring with plasma Epstein-Barr virus DNA. J Clin Oncol

Oncol Biol Phys 2006; 66: 714-20.

2004; 22: 3053-3060.

35 Lo YM et al. Plasma cell-free Epstein-Barr virus DNA

44 Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, et al.

quantitation

carcinoma.

Plasma Epstein-Barr virus DNA and residual disease after

Correlation with clinical staging. Ann NY Acad Sci 2000;906:99-

radiotherapy for undifferentiated nasopharyngeal carcinoma. J

101.

Natl Cancer Inst 2002; 94: 1614-1619.

36 Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et

45 Lin JC, Wang WY, Liang WM, Chou HY, Jan JS, Jiang RS, et

al. Quantification of plasma Epstein-Barr virus DNA in patients

al. Long-term prognostic effects of plasma Epstein-Barr virus

with advanced nasopharyngeal carcinoma. N Engl J Med 2004;

DNA by minor groove binderprobe real-time quantitative PCR on

350: 2461-2470.

nasopharyngeal

37 Leung SF, Chan AT, Zee B, Ma B, Chan LY, Johnson PJ, et al.

chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007; 68(5):

Pretherapy quantitative measurement of circulating Epstein-Barr

1342-8.

radiotherapy

in

patients

for

with

earlystage

nasopharyngeal

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

carcinoma

patients

receiving

concurrent

Published:2014-05 -25 DOI:10.15383/jnpc.8

11

46 Liang FY, Sun W, Han P, Lu X, Lian YN, Huang XM.

nasopharyngeal carcinoma. Cancer 2002; 94: 1997-2006.

Detecting

diagnose

55 Ke Kengjian, Wang Haiyun, Fu Sha, Zhang Zichen, Duan

postradiation nasopharyngeal skull base lesions in nasopharyngeal

Liping, Liu Dabo and Ye Jin; Epstein-Barr virus-encoded RNAs

carcinoma patients: a prospective study. Chin J Cancer 2012;

as a survival predictor in nasopharyngeal carcinoma. Chin Med J

31(3): 142-9.

2014; 127.

47 Leung SF, Lo YM, Chan AT, To KF, To E, Chan LY, et al.

56 Lo EJ, Bell D, Woo JS, et al. Human papillomavirus and WHO

Disparity of sensitivities in detection of radiation-nave and

type I nasopharyngeal carcinoma. Laryngoscope 2010; 120: 1990-

postirradiation recurrent nasopharyngeal carcinoma of the

1997.

undifferentiated type by quantitative analysis of circulating

57 Maxwell JH, Kumar B, Feng FY, et al. HPV-positive/p16-

Epstein-Barr virus DNA. Clin Cancer Res 2003; 9(9): 3431-4.

positive/EBV-negative nasopharyngeal carcinoma in white North

48 Shotelersuk K, Khorprasert C, Sakdikul S, Pornthanakasem W,

Americans.Head Neck 2010; 32: 562-567.

Voravud N, Mutirangura A. Epstein-Barr virus DNA in

58 Punwaney R, Brandwein MS, Zhang DY, et al. Human

serum/plasma as a tumor marker for nasopharyngeal cancer. Clin

papillomavirus may be common within nasopharyngeal carcinoma

Cancer Res 2000; 6(3): 1046-51.

of Caucasian Americans: Investigation of Epstein-Barr virus and

49 Zhang Y, Gao HY, Feng HX, Deng L, Huang MY, Hu B, et al.

human papillomavirus in eastern and western nasopharyngeal

Quantitative analysis of Epstein-Barr virus DNA in plasma and

carcinoma using ligation-dependent polymerase chain reaction.

peripheral blood cells in patients with nasopharyngeal carcinoma.

Head Neck 1999; 21: 21-29.

Zhonghua Yi Xue Za Zhi 2004; 84(12): 982-6.

59 Tung YC, Lin KH, Chu PY, et al. Detection of human

50 Wang WY, Twu CW, Lin WY, Jiang RS, Liang KL, Chen

papilloma virus and Epstein-Barr virus DNA in nasopharyngeal

KW, et al. Plasma Epstein-Barr virus DNA screening followed by

carcinoma

18F-fluoro-2-deoxy-D-glucose positron emission tomography in

by polymerase chain reaction. Kaohsiung J Med Sci 1999;15:256-

detecting post treatment failures of nasopharyngeal carcinoma.

262.

Cancer 2011;117(19):4452-9.

60 Giannoudis A, Ergazaki M, Segas J, et al. Detection of Epstein-

51 Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et

Barr virus and human papillomavirus in nasopharyngeal

al. Quantification of plasma Epstein-Barr virus DNA in patients

carcinoma by the polymerase chain reaction technique. Cancer

with advanced nasopharyngeal carcinoma. N Engl J Med 2004 Jun

Lett 1995;89:177-181.

10; 350(24): 2461-70.

61 Hording U, Nielsen HW, Daugaard S, et al. Human

52 Hong RL, Lin CY, Ting LL, Ko JY, Hsu MM. Comparison of

papillomavirus types 11 and 16 detected in nasopharyngeal

clinical and molecular surveillance in patients with advanced

carcinomas by the polymerase chain reaction. Laryngoscope

nasopharyngeal carcinoma after primary therapy: the potential role

1994;104:99-102.

of quantitative analysis of circulating Epstein-Barr virus DNA.

62 Lin Z, Khong B, Kwok S, et al. Human papillomavirus 16

Cancer 2004; 100(7): 1429-37.

detected in nasopharyngeal carcinomas in Caucasian Americans

53 Kalpoe JS, Dekker PB, van Krieken JH, Baatenburg de Jong

but not in endemic southern Chinese patients. Head Neck 2013

RJ, Kroes AC. Role of Epstein-Barr virus DNA measurement in

Apr 25 [Epubahead of print]. doi: 10.1002/hed.23362.

plasma in the clinical management of nasopharyngeal carcinomain

63 Dogan S, Hedberg ML, Ferris RL, et al. Human papillomavirus

a low risk area. J Clin Pathol 2006; 59(5):537-41.

and Epstein-Barr virus in nasopharyngeal carcinoma in a low-

54 Shi W, Pataki I, MacMillan C, Pintilie M, Payne D, OSullivan

incidence population. Head Neck 2013 Jun 18 [Epub ahead of

B,

print]. doi: 10.1002/hed.23318.

et al.

plasma

Epstein-Barr

Molecular

pathology

virus

DNA

parameters

JNPC http://www.journalofnasopharyngealcarcinoma.org/

to

in

human

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

12

64 Robinson M, Suh YE, Paleri V, et al. Oncogenic human

predictive role for different survival endpoints and impact on

papillomavirus

prognostic stratification.

associated

nasopharyngeal

carcinoma:

An

observational study of correlation with ethnicity, histological

74 Wen-Shan Liu, Ming-Fang Wu, Hsien-Chun Tseng, Jung-Tung

subtype and outcome in a UK population. Infect Agent Cancer

Liu, Jui-Hung Weng, Yueh-Chun Li, and Jong-Kang Lee; The role

2013;8:30.

of pretreatment FDG-PET in nasopharyngeal carcinoma treated

65 Laantri N, Attaleb M, Kandil M, et al. Human papillomavirus

with intensity-modulated radiotherapy. Int. J. Radiation Oncology

detection in moroccan patients with nasopharyngeal carcinoma.

Biol. Phys., Vol. 82, No. 2, pp. 561-566, 2012.

Infect Agent Cancer 2011;6:3.

75 Winnie K. S. Chan, Dora Lai-Wan Kwong, David W. C.

66 Mirzamani N, Salehian P, Farhadi M, et al. Detection of

Yeung, Bingsheng Huang, and Pek-Lan Khong; Prognostic Impact

EBVand HPV in nasopharyngeal carcinoma by in situ

of Standardized Uptake Value of F-18 FDG PET/CT in

hybridization. Exp Mol Pathol 2006;81:231-234.

Nasopharyngeal Carcinoma. Clin Nucl Med 2011;36: 1007-1011.

67 Rassekh CH, Rady PL, Arany I, et al. Combined Epstein-Barr

76 Tsung-Min Hung, Hung-Ming Wang, Chung-Jan Kang,

virus and human papillomavirus infection in nasopharyngeal

Shiang-Fu Huang, Chun-Ta Liao, Sheng-Chieh Chan, Shu-Hang

carcinoma. Laryngoscope 1998;108:362-367.

Ng, I-How Chen, Chien-Yu Lin, Kang-Hsing Fan,Joseph Tung-

68 Tyan YS, Liu ST, Ong WR, et al. Detection of Epstein-Barr

Chieh Chang; Pretreatment 18F-FDG PET standardized uptake

virus and human papillomavirus in head and neck tumors. J Clin

value of primary tumor and neck lymph nodes as a predictor of

Microbiol 1993;31:53-56.

distant metastasis for patients with nasopharyngeal carcinoma.

69 Matthew H. Stenmark, Jonathan B. McHugh, Matthew

Oral Oncology 49 (2013) 169-174.

Schipper, Heather M. Walline, Christine Komarck, Felix Y. Feng,

77 Peng Xie, Jin-Bo Yue, Han-xi Zhao, Xin-Dong Sun, Li Kong,

Francis P. Worden, Gregory T. Wolf, Douglas B. Chepeha, Mark

Zheng Fu, Jin-Ming Yu; Prognostic value of 18F-FDG PET-CT

E. Prince, Carol R. Bradford, Suresh K. Mukherji, Avraham

metabolic index for nasopharyngeal carcinoma. J Cancer Res Clin

Eisbruch, and Thomas E. Carey; Nonendemic HPV-Positive

Oncol (2010) 136:883-889.

Nasopharyngeal Carcinoma: Association With Poor Prognosis. Int

78 Chan SC, Ng SH, Chang JT, Lin CY, Chen YC, Chang YC, et

J Radiation Oncol Biol Phys, Vol. 88, No. 3, pp. 580e588, 2014.

al. Advantages and pitfalls of 18F-fluoro-2-deoxy-D-glucose

70 Yen-Kung Chen, Ru-Hwa Cheng Kwan-Hwa Chi, Jia-Guang

positron emission tomography in detecting locally residual or

Liang, Su-Chen Wang,Yeh-You Shen, Alfred C. Liao, Chen-Tau

recurrent nasopharyngeal carcinoma: comparison with magnetic

Su. Application of 18F-FDG PET/CT in Nasopharyngeal

resonance imaging. Eur J Nucl Med Mol Imaging. 2006;33:1032-

Carcinoma Ann Nucl Med Sci 2007;20:21-32.

40.

71 Lee SW, Nam SY, Im KC, Kim JS, Choi EK, Ahn SD, et al.

79 Chan SC, Yen TC, Ng SH, Lin CY, Wang HM, Liao CT, et al.

Prediction of prognosis using standardized uptake value of 2-

Differential roles of 18F-FDG PET in patients with locoregional

[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography

advanced nasopharyngeal carcinoma after primary curative

for nasopharyngeal carcinomas. Radiother Oncol 2008;87:211-6.

therapy: response evaluation and impact on management. J Nucl

72 Xie P, Yue JB, Fu Z, Feng R, Yu JM. Prognostic value of 18F-

Med. 2006;47:1447-54.

FDG PET/CT before and after radiotherapy for locally advanced

80 Prognostic implications of post-therapy 18F-FDG PET in

nasopharyngeal carcinoma. Ann Oncol 2010;21:1078-82.

patients with locoregionally advanced nasopharyngeal carcinoma

73 Chan SC, Chang JT, Lin CY, Ng SH, Wang HM, Liao CT,

treated with chemoradiotherapy.

Chang CJ, Lin SY, Yen TC. Clinical utility of 18F-FDG PET

81 Razek A, Kamal E; Nasopharyngeal carcinoma: correlation of

parameters in patients with advanced nasopharyngeal carcinoma:

apparent diffusion coefficient value with prognostic parameters.

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Published:2014-05 -25 DOI:10.15383/jnpc.8

13

Radiol med (2013) 118:534-539.

91 Li G, Gao J, Tao YL, et al. Increased pretreatment levels of

82 DeVries AF, Kremser C, Hein PA, et al. Tumor

serum

microcirculation and diffusion predict therapy outcome for

nasopharyngeal carcinoma. Chin J Cancer 2012;31(4):197-206.

primary rectal carcinoma. Int J Radiat Oncol Biol Phys.

92 Xiang-bo Wana, Li Wei, Hao Li, Min Dong, Qu Lin, Xiao-kun

2003;56:958-965.

Maa, Pei-yu Huang, Jing-yun Wen, Xing Li, Jie Chen, Dan-yun

83 Mardor Y, Pfeffer R, Spiegelmann R, et al. Early detection of

Ruan, Ze-xiao Lin, Zhan-hong Chen, Quentin Liu, Xiang-yuan

response to radiation therapy in patients with brain malignancies

Wua, Ming-huang Hong; High pretreatment serum lactate

using conventional and high B-value diffusion-weighted magnetic

dehydrogenase level correlates with disease relapse and predicts

resonance imaging. J Clin Oncol. 2003;21:1094-1100.

an inferior outcome in locally advanced nasopharyngeal

84 Higano S, Yun X, Kumabe T, et al. Malignant astrocytic

carcinoma. European Journal of Cancer (2013) 49, 2356- 2364.

tumors: clinical importance of apparent diffusion coefficient in

93 Wan XB, Fan XJ, Chen MY, et al. Elevated Beclin 1

prediction of grade and prognosis. Radiology. 2006;241:839-846.

expression is correlated with HIF-1alpha in predicting poor

85 Vandecaveye V, Dirix P, De Keyzer F, et al. Predictive value

prognosis

of diffusion-weighted magnetic resonance imaging during

2010;6(3):395-404.

chemoradiotherapy for head and neck squamous cell carcinoma.

94 Acikalin MF, Etiz D, Gurbuz MK, Ozudogru E, Canaz F,

Eur Radiol. 2010;20:1703-1714.

Colak E. Prognostic significance of galectin-3 and cyclin D1

86 Hatakenaka M, Nakamura K, Yabuuchi H, et al. Pretreatment

expression in undifferentiated nasopharyngeal carcinoma. Med

apparent diffusion coefficient of the primary lesion correlates with

Oncol 2012;29(2):742-9.

local

with

95 Zhengbo Wei, Xianjie Zeng, Jian Xu, Xuwei Duan, Jianbo

chemoradiotherapy or radiotherapy. Int J Radiat Oncol Biol Phys.

Yang, Ying Xie, PhD; Prognostic value of the pretreatment serum

2011;81:339-345.

level

87 Chung C, Jalali S, Foltz W, et al. Imaging biomarker dynamics

nasopharyngeal carcinoma: A study of 332 cases. HEAD &

in an intracranial murine glioma study of radiation and

NECK-DOI 10.1002/HED JANUARY 2014.

antiangiogenic

96 Li-na Liu, Pei-yu Huang, Zhi-rui Lin, Li-juan Hu, Jian-zhong

failure

in

head-and-neck

therapy.

Int

cancer

Radiat

treated

Oncol

Biol

Phys.

LDH

of

and

of

ALP

as

poor

prognostic

nasopharyngeal

cytokeratin

fraction

carcinoma.

21-1

in

factors

for

Autophagy

undifferentiated

2013;85:805-812.

Liang, Man-zhi Li, Lin-quan Tang, Mu-sheng Zeng, Qian Zhong

88 Jinsheng Hong, Yiqi Yao; Value of Magnetic Resonance

and Bo-hang Zeng; Protein tyrosine kinase 6 is associated with

Diffusion-Weighted Imaging for the prediction of radiosensitivity

nasopharyngeal carcinoma poor prognosis and metastasis. Journal

in nasopharyngeal carcinoma. Otolaryngology-Head and Neck

of Translational Medicine 2013, 11:140.

Surgery 149(5) 707-713.

97 Tae-Jung Kim, Youn Soo Lee, Jin-Hyung Kang, Yeon-Sil

89 Xia W-X, Ye Y-F, Lu X, Wang L, Ke L-R, et al. (2013) The

Kim, and Chang Suk Kang; Prognostic significance of expression

Impact of Baseline Serum C-Reactive Protein and C-Reactive

of VEGF and Cox-2 in Nasopharyngeal carcinoma and its

Protein Kinetics on the Prognosis of Metastatic Nasopharyngeal

association with expression of C-erbB2 and EGFR. Journal of

Carcinoma Patients Treated with Palliative Chemotherapy. PLoS

Surgical Oncology 2011;103:46-52.

ONE 8(10): e76958. doi:10.1371/journal.pone.0076958.

98 Liu Z, Yang H, Luo W, Jiang Q, Mai C, Chen Y, Zhen Y, Yu

90 Turen S, Ozyar E, Altundag K, Gullu I, Atahan IL. Serum

X, Long X, Fang W. Loss of cytoplasmic KLF4 expression is

lactate dehydrogenase level is a prognostic factor in patients with

correlated

locoregionally advanced nasopharyngeal carcinoma treated with

nasopharyngeal carcinoma. Histopathology. 2013 Sep;63(3):362-

chemoradiotherapy. Cancer Invest 2007;25(5):315-21.

70. doi: 10.1111/his.12176. Epub 2013 Jun 12.

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

with

the

progression

and

poor

prognosis

of

Published:2014-05 -25 DOI:10.15383/jnpc.8

14

99 Jiang Q, Mai C, Yang H, Wu Q, Hua S, Yan C, Long Y, Zhang

TOP2A overexpression as a poor prognostic factor in patients with

Y, Long X, Fang W, Liu Z. Nuclear expression of CDK4

nasopharyngeal carcinoma. Tumor Biol. (2014) 35:179-187.

correlates with disease progression and poor prognosis in human

108 Han-Ping Hsu, Chien-Feng Li, Sung-Wei Lee, Wen-Ren Wu,

nasopharyngeal carcinoma. Histopathology. 2014 Apr;64(5):722-

Tzu-Ju Chen, Kwang-Yu Chang, Shih-Shin Liang, Chia-Jung

30. doi: 10.1111/his.12319. Epub 2013 Dec 31.

Tsai, Yow-Ling Shiue; Overexpression of stathmin 1 confers an

100 Lee SW, Lin CY, Tian YF, Sun DP, Lin LC, Chen LT, Hsing

independent prognostic indicator in nasopharyngeal carcinoma.

CH, Huang CT, Hsu HP, Huang HY, Wu LC, Li CF, Shiue YL

Tumor Biol. (2014) 35:2619-2629.

Overexpression of CDC28 protein kinase regulatory subunit 1B

109 Hao-Yuan Mo, Dong-Hua Luo, Hui-Zhi Qiu, Huai Liu, Qiu-

confers an independent prognostic factor in nasopharyngeal

Yan Chen, Lin-Quan Tang, Zong-Liang Zhong, Pei-Yu Huang,

carcinoma.

Zheng-Jun Zhao, Chang-Qing Zhang, Ying Zhang, Hai-Qiang

APMIS.

2014

Mar;122(3):206-14.

doi:

10.1111/apm.12136. Epub 2013 Jul 24.

Mai; Elevated Serum Endostatin Levels are Associated with Poor

101 Jie Yanga, Lei Lia, Yanxin Rena, Xiaojiang Li, Yanling Tu,

Survival in Patients with Advanced-stage Nasopharyngeal

Jing Ma, Ruimei Sun, Liufang Zhao, Clinical Significance of Joint

Carcinoma. Clinical Oncology 25 (2013) 308e317.

Detection of CD44v6 and CD62P in Nasopharyngeal Carcinoma.

110 Si-Wei Li, MD, Hua Wang, MD, Yan-Qun Xiang, Hai-Bo

Onkologie 2013;36:629-634.

Zhang, Xing Lv, Wei-Xiong Xia; Mu-Sheng Zeng, Hai-Qiang

102 Shi-Sheng Li, Jia-Jia Liu, Shuang Wang, Qing- Lai Tang,

Mai, Ming-Huang Hong, Xiang Guo; Prospective study of

Bing-Bing Liu and Xin-Ming Yang; Clinical significance of TrkB

prognostic value of Raf kinase inhibitory protein and pretreatment

expression in nasopharyngeal carcinoma. Oncology Reports 31:

plasma Epstein-Barr virus DNA for distant metastasis in

665-672, 2014.

locoregionally advanced nasopharyngeal carcinoma. Head &

103 Li-Jung Ma, Sung-Wei Lee, Li-Ching Lin, Tzu-Ju Chen, I-

Neck-Doi 10.1002/Hed April 2013.

Wei Chang, Han-Ping Hsu, Kwang-Yu Chang, Hsuan-Ying

111 Jia-Xing Zhang, Man-Bo Cai, Xiao-Pai Wang, Li-Ping Duan,

Huang, Chien-Feng Li; Fibronectin overexpression is associated

Qiong Shao, Zhu-Ting Tong, Ding-Zhun Liao, Yang-Yang Li,

with latent membrane protein 1 expression and has independent

Ma-Yan Huang, Yi-Xin Zeng, Jian-Yong Shao; Elevated DLL4

prognostic value for nasopharyngeal carcinoma. Tumor Biol.

expression is correlated with VEGF and predicts poor prognosis of

(2014) 35:1703-1712.

nasopharyngeal carcinoma. Med Oncol (2013) 30:390.

104 Daye Cheng, Hong Kong, Yunhui Li; Prognostic value of

112 Jianbo Zhou, Xuping Xiao, Hongmei Yi, Jihua Wang, Xiaoan

interleukin-8 and MMP-9 in nasopharyngeal carcinoma. Eur Arch

Wang, Qiuhang Zhang; Upregulation of Gp96 Correlates with the

Otorhinolaryngol (2014) 271:503-509.

Radiosensitivity and Five-Year Survival Rate of Nasopharyngeal

105 Yu Xu, Peizhong Li, Xin Zhang, Junying Wang, Dongsheng

Carcinoma. ORL 2012;74:164-171.

Gu and Yao Wang; Prognostic implication of neuropilin-1

113 Zheng J, Li J, Xu L, Xie G, Wen Q, et al. (2014)

upregulation in human nasopharyngeal carcinoma. Diagnostic

Phosphorylated Mnk1 and eIF4E Are Associated with Lymph

Pathology 2013, 8:155.

Node Metastasis and Poor Prognosis of Nasopharyngeal

106 Jian Wang, Jing Yang, Bin-Bin Li, Zhi-Wei He; High

Carcinoma.

Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2

doi:10.1371/journal.pone.0089220.

Predicts Poor Survival in Nasopharyngeal Carcinoma. Asian

114 Yan Fei Deng, Dong Ni Zhou, Chun Sheng Ye, Liang Zeng,

Pacific J Cancer Prev, 14 (5), 2805-2809.

Ping Yin; Aberrant Expression Levels of MTAl and RECK in

107 Jui Lan, Hsuan-Ying Huang, Sung-Wei Lee, Tzu-Ju Chen,

Nasopharyngeal

Hui-Chun Tai, Han-Ping Hsu, Kwang-Yu Chang, Chien-Feng Li;

Recurrence, and Prognosis. Annals of Otology, Rhinology &

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

PLoS

ONE

Carcinoma:

Association

9(2):

With

e89220.

Metastasis,

Published:2014-05 -25 DOI:10.15383/jnpc.8

15

Laryngology 121(7): 457-465.

Ling-Long Tang, Wei Jiang, Xu Liu, Yi-Kan Cheng, Qing-Mei

115 Christos K Kontos, Ali Fendri, Abdelmajid Khabir, Raja

He, William C.S. Cho, Li-Zhi Liu, Li Li and Jun Ma; A four-

Mokdad-Gargouri and Andreas Scorilas; Quantitative expression

miRNA signature identified from genome-wide serum miRNA

analysis and prognostic significance of the BCL2-associated X

profiling predicts survival in patients with nasopharyngeal

gene in nasopharyngeal carcinoma: a retrospective cohort study.

carcinoma. Int. J. Cancer (2014): 134, 1359-1368.

BMC Cancer 2013, 13: 293.

122 Fang FM, Tsai WL, Chien CY, Chen HC, Hsu HC, Huang

116 Zhen Liu, Yufei Long, Yajie Zhang, Wei Huang, Xiaobin

TL, Lee TF, Huang HY, Lee CH; Pretreatment quality of life as a

Long, Huiling Yang,Jie Long, Chao Cheng, andWeiyi Fang;

predictor of distant metastasis and survival for patients with

Nuclear p27 Expression Confers a Favorable Outcome for

nasopharyngeal carcinoma. J Clin Oncol. 2010 Oct 1; 28(28):

Nasopharyngeal Carcinoma Patients. Disease Markers Volume 35

4384-9. doi: 10.1200/JCO.2010.28.8324. Epub 2010 Aug 16.

(2013), Issue 6, Pages 925-932.

123 Jin Y, Cai XY, Cai YC, et al. To build a prognostic score

117 Qingping Jiang, Huiling Yang, Chao Cheng, Hanzhen Xiong,

model containing indispensable tumour markers for metastatic

Shaoyan Liu, Jie Long, Yajie Zhang, Weiyi Fang and Zhen Liu;

nasopharyngeal carcinoma in an epidemic area. Eur J Cancer

Decreased P27 protein expression is correlated with the

2012;48(6):882-8.

progression and poor prognosis of nasopharyngeal carcinoma.

124 Ong YK, Heng DM, Chung B, et al. Design of a prognostic

Jiang et al. Diagnostic Pathology 2013, 8:212.

index score for metastatic nasopharyngeal carcinoma. Eur J

118 Wei Sun, Guoxian Long, Junfeng Wang, Qi Mei, Dongbo

Cancer 2003;39(11):1535-41.

Liu, Guoqing Hu; Prognostic role of epidermal growth factor

125 Toh CK, Heng D, Ong YK, Leong SS, Wee J, Tan EH.

receptor in nasopharyngeal carcinoma: A meta-analysis. HEAD &

Validation of a new prognostic index score for disseminated

NECK-DOI 10.1002/HED MONTH 2013.

nasopharyngeal carcinoma. Br J Cancer 2005;92(8):1382-7.

119 Gong L, Zhang W, Zhou J, Lu J, Xiong H, et al. (2013)

126 Chuangzhen Chen, Siqia Chen, Quynh-Thu Le Jianzhou

Prognostic Value of HIFs Expression in Head and Neck Cancer: A

Chen, Zhijian Chen, Dongsheng Li, Mingzhen Zhou,Derui Li;

Systematic

Prognostic model for distant metastasis in locally advanced

Review.

PLoS

ONE

8(9):

e75094.

doi:10.1371/journal.pone.0075094.

nasopharyngeal carcinoma after concurrent chemoradiotherapy.

120 Wang HY, Sun BY, Zhu ZH, Chang ET, To KF, Hwang JS,

Head & NeckDoi 10.1002/Hed Month 2014.

Jiang H, Kam MK, Chen G, Cheah SL, Lee M, Liu ZW, Chen J,

127 Y-M Tian, Y-H Tian, L Zeng, S Liu, Y Guan, T-X Lu and F

Zhang JX, Zhang HZ, He JH, Chen FL, Zhu XD, Huang MY, Liao

Han;

DZ, Fu J, Shao Q, Cai MB, Du ZM, Yan LX, Hu CF, Ng HK,

nasopharyngeal carcinoma with intensity-modulated radiotherapy.

Wee JT, Qian CN, Liu Q, Ernberg I, Ye W, Adami HO, Chan AT,

British Journal of Cancer (2014) 110, 297-303| doi: 10.1038/ bjc.

Zeng YX, Shao JY; Eight-signature classifier for prediction of

2013.715.

nasopharyngeal [corrected] carcinoma survival. J Clin Oncol.

128 Xiao-Lin Luo, Wang He, Hui Huang, Qiu-Yan Chen, Ying

2011 Dec 1;29(34):4516-25. doi: 10.1200/JCO.2010.33.7741.

Liang, Hai-Qiang Mai, Hui-Qiang Huang, Qing-Qing Cai; Design

Epub 2011 Oct 24.

of a Prognostic Score Model for Nasopharyngeal Carcinoma.

121 Na Liu, Rui-Xue Cui, Ying Sun, Rui Guo, Yan-Ping Mao,

Head Neck. 2014 Mar 6. doi: 10.1002/hed.23642.

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

Prognostic

model

for

survival

of

local

recurrent

Published:2014-05 -25 DOI:10.15383/jnpc.8