Emerging Prognostic Factors in Nasopharyngeal Carcinoma
N. A. Iacovelli1,3, P. Bossi2, C. Fallai1, G. Gardani3, E. Orlandi1
1Radiotherapy Unit 2, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy
2Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy
3University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milan, Italy
Corresponding author: Ester Orlandi, Radiotherapy 2 Unit; Email: email@example.com
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
Standard treatment for nasopharyngeal carcinoma (NPC) is radiotherapy (RT) for early-stage lesions or chemoradiotherapy (CRT) for more advanced lesions (1-2). Technology innovations in radiation therapy (i.e., intensity modulated radiation therapy, IMRT), in imaging and the use of appropriate combined CRT with the possible adjunct of neoadjuvant chemotherapy have recently improved outcome in NPC (3-7).
Predominant pattern of failure in locoregionally advanced NPC treated with IMRT and chemotherapy is distant metastasis even if loco-regional failures may develop in about 10% of patients (1; 3-6).
Primary tumor extension (T), lymph node involvement (N) and distant metastasis (M), i.e. TNM classification, are traditionally considered the most significant prognostic factors in NPC patients. Other potential predictors of outcome include sex, age, histological type. Although traditional prognostic factors may provide some useful clinical information, they cannot predict treatment outcome reliably. Besides classical prognostic factors, new emerging factors predicting outcome in NPC patients have been recently available. Therefore, substantial research efforts have focused on the identification of novel prognostic factors because such a result could allow therapy to be tailored to the characteristics of an individual patient.
In this paper, we sistematically reviewed the literature concerning clinical, viral, imaging and biomolecular factors potentially predicting the prognosis of NPC patients, with a particular emphasis on emerging prognostic factors. This may help in determining which NPC patients might benefit from more aggressive treatment and optimizing follow-up protocols.
Classical Prognostic Factors
As with most other tumors, the extent of a NPC as embodied in the TNM staging system is the most important prognostic factor. The main purpose of TNM staging system is to divide patients into subgroups according to different prognosis, to guide the treatment strategy for different risk groups, and to facilitate the exchange of experience between treatment centers (8). The most recent 7th edition of the UICC/AJCC staging system for NPC, published in 2009, is a common set of recommendations from the initial revision of the previous 6th edition. An important change has been the clarification of the role of retropharyngeal lymph node. According to it, N1 classification for NPC is defined as following: unilateral lymph nodes, 6 cm or less, above the supraclavicular fossa, and/or retropharyngeal lymph nodes, 6 cm or less (unilateral or bilateral)(9). It covers quite a large range of nodal patterns. Probably N1 patients with different nodal characteristics may have different prognosis. Shi et al. have recently shown that involvement of both cervical lymph nodes and retropharyngeal lymph nodes may be a potentially prognostic factor for distant metastasis and disease progression in N1 patients (10).
Several studies have shown that the T (tumor) staging system developed by UICC/AJCC has its limitations in predicting prognosis of patients with NPC (11-12), in particular whether the conventional TNM staging system could still predict the prognosis of NPC patients treated with IMRT need to be reevaluated (13).
The histological-type World Health Organization type I patients frequently seen among the Caucasian population were found to be associated with adverse prognosis (14-15).
Chang et al. identified eight clinical independent prognostic factors of greater risk in NPC patients: gender, age, T or N stages, anaemia or thrombocytosis during radiotherapy, continuous reduction in haemoglobin, high neutrophil-lymphocyte ratio before radiotherapy (16).
With regarding to imaging, Liu et al. reported that Magnetic Resonance Imaging (MRI)-detected cranial nerves (CN) invasion had an unfavourable impact on the prognosis of NPC (17). Recently the same authors retrospectively analyzed 749 nasopharyngeal carcinoma patients undergoing IMRT and reported that in T3–4 NPC, MRI-detected CN invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (p=0.002, 0.003, and 0.012, respectively). Therefore in patients with MRI-detected CN invasion current CRT strategies might not be sufficient (18).
Finally, among treatment related prognostic factors the total dose to the tumor is the most important radiation factor for locoregional control: dose at least of 66 Gy is required for locally advanced disease (19). However, treatment results for NPC are strictly correlated with the overall treatment time. Kwong et al. reported a 3.3% risk of LRF increasing per additional day of RT prolongation (20).
Volume of Primary Tumor
Many authors currently suggest that gross primary tumor volume (GTV-P) should be included in TNM staging as a quantitative indicator to predict prognosis in NPC patients.
Dubben et al. firstly reported that GTV-P is a relevant predictor of radiotherapy treatment outcome suggesting that individual tumor volume should always be reported in clinical studies and considered in data analyses (21).
The significance of the GTV-P on outcome of NPC patients treated with IMRT has been evaluated in many studies. Guo et al. found GTV-P is an independent prognostic indicator for distant metastasis and local recurrence in NPC patients after IMRT treatment. They selected a GTV-P cut off value of 19 ml and verified this value in a population of 694 patients. The 5-year disease-free survival (DFS), overall survival (OS), local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) rates for NPC patients with GTV-P <19 vs. >19 ml were 94.9% vs. 64.8%, 97.0% vs. 76.4%, 98.2% vs. 92.5% and 97.1% vs. 75.2%, respectively (all P < 0.05) in all patients. More importantly, when combined with GTV-P, the predictive ability of T classifications was improved (22).
Also Feng and colleagues found that large GTV-P was an adverse prognostic factor for the 5-year local regional control (LRC) rate (RR 2.454,p=0.002) with a cut off of 40 ml (23).
Wu et al. reported that GTV-P is an independent prognostic factor in local control, distant metastasis, disease-free survival, and overall survival in NPC. They analyzed 321 patients and found statistically significant correlation between GTV-P and LFFS, DMFS, DFS, and OS (P < 0.05, all) at univariate and multivariate analyses, whereas T classification was not an independent prognostic factor. According to ROC curve analysis, 49 and 19 mL were determined as the cut off points of GTV-P for local control and distant metastasis, respectively (24).
Chen et al. also demonstrated that GTV-P predicted survival rate of NPC patients with more accuracy than the AJCC staging system (25).
Similarly Liang et al. analyzed maximum primary tumor diameter (MPTD) in 333 NPC patients finding it a prognostic factor for OS, FFS and DMFS, and LRFS (26).
Finally, according to the above mentioned data indicating current TNM staging system limitations, Liu et al. suggest to incorporate GTV-P into the current TNM staging system to separate NPC patients into subgroups with different prognosis more accurately (27).
Intensity Modulated Radiation Therapy (IMRT)
Some authors reported a significant improvement in survival and reduction of serious toxicity with IMRT compared to conventional radiotherapy. Three randomized trials comparing IMRT versus two-dimensional radiotherapy (2DRT) have been reported. Peng et al. confirmed significant improvement in therapeutic ratio by IMRT: the IMRT group achieved significantly higher 5-year free from local relapse survival (L-FFRS) (91% vs. 84%, p = 0.046) and OS (80% vs. 67%, p = 0.001), with significant reduction in late toxicities including temporal lobe necrosis (13% vs. 21%), cranial neuropathy (4% vs. 9%), xerostomia, trismus and neck fibrosis (28). The trials by Pow et al. and Kam et al. confirmed significantly better recovery of stimulated salivary flow in patients with Stage I–II irradiated by IMRT (29-30). Pow et al. and Fang et al. further showed significant improvement in xerostomia-related symptoms and corresponding subscale scores on quality of life (QoL)(29-31).
Recently, the retrospective study by Lee AW on the outcomes of 1593 consecutive patients treated from 1994 to 2010 showed significantly higher free from distant relapse survival (D-FFRS) achieved in the IMRT era. Five-year DSS increased from 78% in the 2DRT, to 81% in the 3DRT, and 85% in the IMRT era, while the corresponding neurological toxicity rate decreased from 7.4% to 3.5% and 1.8% (32).
Epstein Barr Virus-(EBV)
NPC is an EBV related cancer. Quantitative analysis of cell-free EBV DNA in plasma of patients with NPC and its value in screening, predicting outcome and monitoring treatment has been studied (33). Increase of the viral DNA load along with clinical stage (from stage I to IV4) has been assessed in many studies (34-35).
Plasma EBV DNA concentration measured at disease onset is a strong predictor of outcome (poor survival or frequent relapse) and it could help in identifying early-stage patients with a greater risk of developing distant metastasis (36-37). Low number of pre-therapy EBV DNA copies have an high negative predictive value (NPV) for 3-year progression (93%) and a lower positive predictive value (PPV) of 41%; 6 to 8 weeks after treatment, NPV and PPV are 83% and 87%, respectively (38). Consensus lack on number of copies’ cut off to be considered because of differences in primer design and cycling number during polymerase chain reaction (39-40). The test is also useful to monitor response to RT, CRT or surgery. In a recent study Yip et al. (41) reviewed 6 papers from 2003 to 2013 comparing the ability of post-treatment EBV DNA loads to detect DM) and local recurrence (LR) or loco-regional recurrence (LRR): detection rate for DM ranged from 86% to 96% and that for LR/LRR ranged from 51 to 67%. (42-44). In the same paper, 12 studies with EBV DNA measured before and after treatment in NPC patients from 2000 to 2013 were reviewed, showing a consistent drop of the EBV DNA rate after RT (45-46). Patients with recurrence maintained a substantially high rate of post-RT EBV DNA rates (47-48) whereas patients with no recurrence after RT had drop of EBV DNA rates. The authors observed an even more dramatic response of EBV DNA load in patients treated with concurrent CRT (49-53) indicating the more effectiveness of chemo-RT in reducing the EBV DNA load than RT alone. If viral DNA load persists at significant level post-treatment or initially drops to the background level but subsequently rises again, performing PET/CT imaging scanning to locate the relapse site is strongly suggested. Residual EBV DNA load after primary treatment could justify adjuvant chemotherapy, putting the basis for an ongoing trial with platinum and gemcitabine (clinicaltrials.gov NCT 00370890). EBV encoded small RNAs (EBERs) represent the most abundant EBV viral transcripts and are expressed in many EBV-associated diseases. Consequently EBERs (EBER1 and EBER2) are used as the target molecule to detect EBV-infected cells in tissues by in situ hybridization (ISH). EBERs are abundantly expressed in NPC, with as many as 105–107 copies per cell. EBER positivity is a predictor for improved overall survival (54). In a recent paper Ke et al. found high EBER expression levels in NPC patients as a significant positive prognostic factor for survival (55).
Human Papilloma Virus (HPV)
Several studies have detected HPV in NPC patients. In some studies EBV and HPV infections has been found mutually exclusive (56-63). In others cases EBV and HPV coinfections were reported, predominantly in patients from endemic areas (64-68). The clinical significance of HPV infection in NPC is still unclear, raising the question if the virus is a bystander or if it could retain a pathogenic role. In a recent paper, tumor HPV positivity has been demonstrated as an adverse prognostic factor for overall survival, progression-free survival, and locoregional relapse among patients with NPC. The study identifies two subsets of EBV-negative NPC among North Americans, one demonstrating a strong association with oncogenic HPV, and the other lacking an association with both EBV and HPV, strongly correlated with type II and type I WHO NPC respectively, suggesting that viral status may be the driving factor behind WHO type (69). The data reported by Stenmark et al., support the hypothesis that HPV is a possible etiologic agent in the development of NPC among white individuals. Furthermore, the authors suggest that in patients with non endemic forms of EBV-negative NPC, having high rates of locoregional relapse and death, intensification of local therapy with either dose-escalated radiation therapy or radiation sensitizing agents may be of benefit.
Positron Emission Tomography (PET) Imaging
2-[Fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) is a valuable imaging tool in patients with NPC. Dual-modality positron emission tomography/computed tomography (PET/CT) provides the technical basis for intrinsically aligned functional and morphologic data sets. FDG-PET/CT may be considered as a standard clinical imaging modality in the staging of NPC and in the detection of recurrent disease after RT or CRT (70).
The semiquantitative parameter of PET imaging, standardized uptake value (SUV), which represents glucose metabolism of tumors, may reflect the aggressiveness of local tumor and the risk of metastatic spread. Encouraging results on its prognostic value in NPC have been reported.
Lee et al. evaluated 41 patients with non-disseminated NPC undergoing platinum-based concurrent CRT and found that patients having tumors with high FDG uptake had a significantly lower 3-year disease free survival (DFS) rate than patients with lower tumor FDG uptake (51% vs 91%, P=0.0070). Patients with an SUV(max) below 8 had a higher DFS than patients with an SUV(max) of 8 or greater. Therefore they concluded that FDG uptake, as measured by the SUV(max), may predict DFS in CRT-treated NPC and a high FDG uptake may be useful for identifying patients requiring more aggressive treatment (71).
To assess the prognostic value of FDG-PET, Xie et al. retrospectively reviewed the association of SUVmax from FDG-PET and the therapy outcome of 62 NPC patients treated with radiotherapy. They found that patients having tumors with a lower SUVmax (<8.0) had significantly better 5-year overall survival (OS) (P= 0.0187) and DFS (P = 0.0163) than patients with a greater SUVmax (≥8.0). Patients that showed metabolic complete response had a significantly higher 5-year OS (P = 0.0237) and DFS (P = 0.0186) than patients with metabolic partial response. Poor prognosis was found in patients with the SUVmax of neck nodes larger than that at the primary tumor site (SUVmax-N > SUVmax-P) (P = 0.0440) (72). Beside SUV, total lesion glycolysis (TLG) has been shown to be an independent prognostic factors in NPC patients.
Chan et al. investigated the prognostic impact of metabolic tumor volume and total lesion glycolysis (TLG) of the primary tumor, maximal standardized uptake value of the primary tumor and the neck lymph nodes in 196 patients with primary stage III-IVb NPC. On multivariable analysis TLG values greater than 330 were independently predictive of better OS (P=0.0014) and DFS (P=0.0005). They identified IVa-b stage and TLG values greater than 330 as independent predictors of local failure-free survival. In addition, a high maximal standardized uptake value of the neck lymph nodes (P=0.005), male sex (P=0.041), and stage IVa-b (P=0.009) independently predicted distant failure-free survival (73).
Liu et al. in a recent paper analyzed SUVmax in 75 M0 nonkeratinizing NPC patients who received FDG-PET before IMRT alone or CRT. They found SUVmax category as the only significant factor, on multivariate analysis, influencing both the 5-year local failure-free (p=0.017) and DFS rates (p=0.00). However, they could not confirm the role of SUVmax in OS rates (p = 0.065). So they concluded that SUVmax could be a potential independent prognostic predictor of clinical outcome in patients with nasopharyngeal carcinoma treated with IMRT alone or with CCRT and that a high 18F-FDG uptake (SUVmax >5) indicates poor outcome in patients with NPC (74).
Chan et al. have shown that SUVmax measured on FDG PET/CT is a valuable tool for risk stratification of NPC patients (75). Their results suggest that a cut off pSUVmax of the primary tumor at 7.5 and nSUVmax of cervical lymph nodes at 6.5 are associated with poor patient outcome and pSUVmax is a significant prognosticator of DFS. As declared in the paper the 2-year follow-up period of the study may be too short to fully assess DFS. Also the study population was small with only 46 patients included.
A larger study was performed by Hung and colleagues, who retrospectively evaluated the prognostic value of SUVmax analyzing 371 patients with non disseminated NPC with a median follow up of 64 months. They found that NPC patients with a higher SUVmax (SUVmax-T > 9.3 or SUVmax-N > 7.4) had significantly worse DMFS but no difference in LC or RC, suggesting that high 18F-FDG uptake was a valuable prognosticator for identifying patients who could receive more aggressive systemic treatment aimed at reducing distant metastasis (76).
Xie et al. evaluated the prognostic significance of metabolic tumor volume (MTV) and metabolic index (MI) from FDG PET/CT in 41 patients with stage I-IV locally NPC before and after radiotherapy. Those patients having tumors with an MTV below 30 cm3 had significantly better 5-year OS than patients with an MTV of 30 cm3 or greater (84.6:46.7%, p = 0.006) and DFS (73.1:40.0%, p = 0.014). And patients with MI below 130 had significantly higher 5-year OS (88.0:43.8%, p = 0.002) and DFS (76.0:37.5%, = 0.005) than other patients. A principal find of their study is that MI is strongly correlated with DFS and OS in patients with NPC treated by radiotherapy, and thus it is a better predictor of long-term survival than MTV and SUV alone. The authors also confirmed that patients who presented with local recurrence or distant metastasis within 5 years had a significantly higher MI than the remaining patients suggesting the intimate correlation between the primary MI and tumor recurrence or metastasis (77). Future research can be designed to assess whether modification of therapy or addition of adjuvant therapy can improve the outcome and survival of patients with higher SUVmax.
With regard to the prognostic significance of post treatment PET, Chan et al. demonstrated that 3-month post-therapy PET scans were more sensitive than conventional imaging modalities in the detection of treatment failures in NPC patients (78-79). In a recent paper they indicate the achievement of complete metabolic response (CMR) on post-therapy PET as a favorable prognostic factor in stage IVa–b NPC patients that may inform the clinical management after therapy (80). The authors analyzed 165 NPC patients with a median follow up of 58 months. They found that PET imaging performed 3 months after completion of treatment is superior to conventional work-up for the assessment of treatment response. The results of the 3-month post therapy PET and total lesion glycolysis (TLG) of the primary tumor were independent predictors of overall survival. TNM tumor stage, TLG, and post-therapy PET findings were independently associated with disease-free survival (DFS). The results of post-therapy PET were more predictive of DFS than TNM tumor stage (P<0.001 vs. P = 0.005). They therefore suggest a more conservative follow-up approach for stage IVa–b patients who achieve a CMR after definitive CRT in contrast with CR on post therapy conventional work-up which is not a reliable prognostic factor to guide surveillance protocols.
To date no published studies have addressed the role of an interim FDG-PET during RT or CRT. Evaluation of FDG-PET uptake by SUV is semiquantitative and it is difficult to compare SUV cut offs between hospitals and patients. More data are needed to support the usefulness of FDG-PET in predicting outcome of NPC at initial diagnosis and after completion of definitive treatment. Further confirmation must derive from larger and prospective randomized studies.
Magnetic Resonance Diffusion-Weighted Imaging (MR-DWI)
Magnetic resonance diffusion-weighted imaging (MR-DWI) is a functional imaging technique that, detecting the diffusive state of water molecules in viable tissue, indirectly reveals the microstructural features of a tumor. It can provide a quantitative parameter, the apparent diffusion coefficient (ADC), which can indirectly indicate microvascular circulation, cell membrane integrity and cell density and can also detect local microscopic changes in the tumor before morphological changes are evident. In a little study which comprised only 30 patients, Razek et al. correlated ADC value with prognostic parameters of NPC. They found that a lower ADC value was associated with poorly differentiated or undifferentiated tumour. They also found a significant difference in ADC value among small, medium and large tumor volume (p = 0.03). ADC value was significantly lower (p = 0.003) when metastatic cervical lymph nodes were present and ADC value correlated inversely with tumor volume (r = –0.799, p = 0.03). Limitations of this study were lack of follow up, lack of standardized ROI determination for ADC calculation and absence of correlation with EBV along with the small number of patients studied (81).
The ADC value before treatment and early changes in ADC during treatment have been correlated with the sensitivity to radiotherapy and chemotherapy in some tumor types (82-87). ADC may have a role in predicting radiotherapy early response in NPC patients. Hong et al. correlated the difference between ADC value before therapy and two weeks after the start of IMRT (ΔADC) with the presence of a residual tumor at the primary site three months after the end of radiotherapy. The ΔADC values of patients with and without residual tumors were significantly different (p = .017). Logistic regression analysis indicated that ΔADC was an independent prognostic factor for the short-term effect of IMRT. This indicates that, two weeks after the start of radiotherapy, water molecules diffuse more freely in the radiosensitive tumors due to increased tissue necrosis and cell disruption. But this study has some limitations: the ADC values were not determined after chemotherapy and before radiotherapy; the best timing for the assessment of ΔADC still remains to be identified and there is lack of information about the long term outcome of patients with and without residual tumor (88).
Several biomarkers have been studied as prognostic factors in NPC. For the vast majority only single reports could be found in literature, therefore their value should be considered of limited clinical importance. For sake of completeness they will be hereafter cited.
Baseline serum C-Reactive Protein (CRP) and C-Reactive Protein kinetics were found to be independent prognostic factors in metastatic NPC patients (89).
Elevated Lactate dehydrogenase (LDH) (90-92), elevated Beclin-1 (93), increased Galectin-3 expression (94), high pretreatment serum levels of CYFRA 21-1 (95), high-expression of protein tyrosine kinase 6 (PTK6) (96), absence of VEGF expression, high mitosis and COX-2 expression (97), loss of Krüppel-like factor 4 (KLF4) expression (98), nuclear expression of cyclin-dependent kinase 4 (CDK4) (99), high expression of CDC28 protein kinase regulatory subunit 1B (CKS1B)(100) and joint detection of CD44v6 and CD62P in the peripheral blood or tissues (101) were reported to be independent prognostic factors of poor outcome in NPC patients.
In addition Tropomyosin‑related kinase B (TrkB) overexpression (102), overexpressed fibronectin (103), high serum Matrix metalloproteinase-9 (MMP-9) levels (104), high neuropilin-1 (NRP-1) expression (105), high cytoplasmic expression of NR4A2 (106), topoisomerase IIα (TOP2A) overexpression (107), high stathmin 1 (STMN1) expression (108), serum endostatin level (109) and Raf kinase inhibitory protein (RKIP) expression (110) were demonstrated to be unfavorable prognostic factors for patients with NPC.
High expression of Delta-like ligand 4 (DLL4) has been reported as an independent predictor of decreased DSS. Its expression is elevated in metastases compared to the primary tumor. Patients with dual elevated expression of DLL4 and VEGF carried the worst prognosis in terms of OS (111).
Gp96 (GRP94) expression was found to be an independent prognostic factor for OS and DFS (112).
MAP kinase-interacting kinases (Mnk) phosphorylates eukaryotic translation initiation factor 4E (eIF4E). The expression of p-Mnk1 and p-eIF4E in NPC was proved to be independent prognostic factors (113).
Metastasis-associated gene 1 (MTAl) and Reversion-inducing cysteine-rich protein with Kazalmotifs (RECK) expressions were independent prognostic factors for survival. Positive MTAl expression and negative RECK expression predicted a higher risk of recurrence and a poorer prognosis in NPC (114).
An advantage in survival has been demonstrated in patients with BAX mRNA-positive NPC (115) and in patients with nuclear expression of p27 (116-117).
Two prognostic markers have greater interest in NPC: overexpression of EGFR has been associated in a recent meta-
analysis with poor OS, DFS and LRC, but not DMFS (118).
The hypoxia-inducible factors (HIFs) have been significantly associated with increased mortality risk in many head and neck cancers. In particular overexpression of the isoform HIF-1α was significantly associated with worse OS (119).
If the previous cited single markers could difficultly translate into clinical application for selecting different treatments, a comprehensive signature could reach this goal. Recently, a support vector machine (SVM)-based methods developed a prognostic classifier for NPC and validated it in an independent cohort (120).
Four serum miRNAs (miR-22, miR-572, miR-638 and miR-1234) were demonstrated to be independent prognostic factors, in particular the levels of three miRNAs (miR-22, miR-572 and miR-638) were inversely associated with OS, and the level of miR-1234 was positively associated with OS (121).
Further validation studies are required to confirm the prognostic and predictive role of reported biomarkers.
Quality of Life
From the clinical point of view, quality of life (QoL) of the oncologic patients has been considered as one of the most important factors. Also in NPC pretreatment QoL has been clearly showed a prognostic role in the development of metastasis and in determining patients’ survival (122).
The clinical staging system is the key prognostic determinant for patients with nasopharyngeal carcinoma in routine clinical practice. Whereas large variations in the clinical outcomes of patients with the same cancer stage have been reported, which implies that the present staging system is suboptimal for prognosis and there might be other important prognostic indicators. In literature several articles dealt with the development of prognostic models for metastatic NPC (123-126) and for recurrent NPC (127). In only one paper Luo et al. created a prognostic model for newly diagnosed undisseminated NPC. On the basis of stage (III-IV), age (>45 years), anti-enzyme rate of Epstein-Barr virus DNase-specific neutralizing antibody (AER) (> 58%) and absolute neutrophil count (ANC) (> 4.7 × 109/L) the authors stratified patients into four prognostic groups (128).
A prognostic model specifically designed for newly diagnosed NPC is needed to complement the existing clinical staging system in identifying high-risk patients for combined and aggressive treatment and to guide patients’ follow up evaluation frequency. The aim is the improvement of the survival of these patients.
Because several radiological, clinical and molecular factors have been described with predictive or prognostic role in NPC, it is paramount to be able to integrate them in a more sophisticated way and to prospectively validate this model, in order to better tailor the treatment for each patient than today.
We strongly suggest that a selection of the previous revised prognostic factors should be studied in order to create a strong and reliable model to predict survival among NPC patients. The strongest ones are, in our opinion, the primary tumor volume as detected at MRI, EBV DNA load, SUV max. To verify such a prognostic model further evaluation, possibly a large prospective study, is warranted.
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. So the future trials should be aimed at verifying the consistence of such prognostic models in different geographical areas.
1 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 ClinOncol 22:4604-4612, 2004.
2 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 16:1310-1317, 1998.
3 Lee AW, Tung SY, Chan AT, et al: Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 66:142-151, 2006.
4 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 23:6966-6975, 2005.
5 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 Oncol23:6730-6738, 2005.
6 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 61:1107-1116, 2005.
7 OuYang PY, Xie C, Mao YP, Zhang Y, Liang XX, Su Z, Liu Q, Xie FY; Significant efficacies of neoadjuvant and adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials. Ann Oncol. 2013 Aug;24(8):2136-46. doi: 10.1093/annonc/mdt146. Epub 2013 Apr 23.
8 Greene FL, Page DL et al (2002) AJCC cancer staging handbook from the AJCC cancer staging manual, 6th edn. Springer, New York, pp 47-60.
9 Edge SB, Byrd DR, Carducci MA, Compton CC, Fritz AG, Greene FL, Trotti A: AJCC Cancer Staging Manual. 7th edition. Philadelphia: Lippincott-Raven; 2009.
10 Qi Shi, Chunying Shen, Lin Kong, Xiaoshen Wang, Jianhui Ding, Yunsheng Gao, Tingting Xu and Chaosu Hu; Involvement of both Cervical Lymph Nodes and Retropharyngeal Lymph Nodes has prognostic value for N1 patients with Nasopharyngeal Carcinoma. Radiation Oncology 2014, 9:7.
11 Lin S, Pan J, Han L et al (2009) Nasopharyngeal carcinoma
treated with reduced-volume intensity-modulated radiation therapy: report on the 3-year outcome of a prospective series. Int J Radiat Oncol Biol Phys 75:1071-1078.
12 Tham IW, Hee SW, Yeo RM et al (2009) Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy-the National Cancer Centre Singapore experience. Int J Radiat Oncol Biol Phys 75:1481-1486.
13 D Liu, G Long, Q Mei, G Hu.; Primary tumor volume should be included in the TNM staging system of nasopharyngeal carcinoma. Medical Hypotheses 82 (2014) 486-487
14 Gallo O, Bianchi S, Giannini A, Gallina E, Libonati GA, Fini-Storchi O; Correlations between histopathological and biological findings in nasopharyngeal carcinoma and its prognostic significance. Laryngoscope. 1991 May;101(5):487-93.
15 Kaasa S, Kragh-Jensen E, Bjordal K, Lund E, Evensen JF,
Vermund H, Monge O, Boehler P; Prognostic factors in patients with nasopharyngeal carcinoma. Acta Oncol. 1993;32(5):531-6.
16 H. Chang, J. Gao, B.Q. Xu, S.P. Guo, R.B. Lu, G. Li, S.M. Huang, F. Han, Z.G. Liu, Y.L. Tao, Z.W. Tu, C. Chen, X.H. Li, Y.F. Xia; Haemoglobin, Neutrophil to Lymphocyte Ratio and Platelet Count Improve Prognosis Prediction of the TNM Staging System in Nasopharyngeal Carcinoma: Development and Validation in 3237 Patients from a Single Institution. Clinical Oncology 25 (2013) 639e646.
17 Liu L, Liang S, Li L, Mao Y, Tang L, Tian L, Liao X, Cui C, Lin A, Ma J (2009) Prognostic impact of magnetic resonance imaging-detected cranial nerve involvement in nasopharyngeal carcinoma. Cancer 115: 1995-2003.
18 X Liu, L-Z Liu, Y-P Mao, L Chen, L-L Tang, G-Q Zhou, Y Sun, D Yue, A-H Lin, L Li and J Ma, Prognostic value of magnetic resonance imaging-detected cranial nerve invasion in nasopharyngeal carcinoma. British Journal of Cancer (2014) 110, 1465-1471 | doi: 10.1038/bjc.2014.27.
19 Teo PM, Leung SF, Tung SY et al. Dose-response relationship of nasopharyngeal carcinoma above conventional tumoricidal level: a study by the Hong Kong nasopharyngeal carcinoma study group (HKNPCSG). Radiother. Oncol. (2006) 79, 27-33.
20 Kwong DL, Sham JS, Chua DT, Choy DT, Au GK, Wu PM. The effect of interruptions and prolonged treatment time in radiotherapy for nasopharyngeal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. (1997) 39, 703-710.
21 Dubben HH, Thames HD, Beck-Bornholdt HP. Tumor volume: a basic and specific response predictor in radiotherapy. Radiother Oncol 1998;47:167-74.
22 Guo R, Sun Y, Yu XL, Yin WJ, Li WF, Chen YY, et al. Is primary tumor volume still a prognostic factor in intensity modulated radiation therapy for nasopharyngeal carcinoma? Radiother Oncol 2012;104:294-9.
23 Mei Feng, Weidong Wang, Zixuan Fan, Binyu Fu, Jie Li, Shichuan Zhang and Jinyi Lang; Tumor volume is an independent prognostic indicator of local control in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy. Radiation Oncology 2013, 8:208.
24 Zheng Wu, Yong Su, Rui‑Fang Zeng, Mo‑Fa Gu, Shao‑Min Huang; Prognostic value of tumor volume for patients with nasopharyngeal carcinoma treated with concurrent chemotherapy and intensity‑modulated radiotherapy. J Cancer Res Clin Oncol (2014) 140:69-76.
25 Chen C, Fei Z, Pan J, Bai P, Chen L. Significance of primary tumor volume and T stage on prognosis in nasopharyngeal carcinoma treated with intensity modulated radiation therapy. Jpn J Clin Oncol 2011;41:537-42.
26 Shao-Bo Liang, Yan-Ming Deng, Ning Zhang, Rui-Liang Lu, Hai Zhao, Hai-Yang Chen, Shao-En Li, Dong-Sheng Liu and Yong Chen; Prognostic significance of maximum primary tumor diameter in nasopharyngeal carcinoma. BMC Cancer 2013; 13: 260.
27 Dongbo Liu, Guoxian Long, Qi Mei, Guoqing Hu; Primary tumor volume should be included in the TNM staging system of nasopharyngeal carcinoma. Medical Hypotheses 82 (2014) 486-487.
28 Peng G, Wang T, Yang KY, et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol 2012; 104:286-93.
29 Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for earlystage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981-91.
30 Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensitymodulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007; 25: 4873-9.
31 Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving three-dimensional conformal radiotherapy vs. intensity-modulated radiotherapy-a longitudinal study. Int J Radiat Oncol Biol Phys 2008; 72: 356-64.
32 Lee AW, Ng WT, Chan LL, Hung WM, Chan CC, Sze HC,
Chan OS, Chang AT, Yeung RM; Evolution of treatment for nasopharyngeal cancer - Success and setback in the intensity-modulated radiotherapy era. Radiother Oncol. 2014 Mar 11. S0167-8140(14)00043-7. doi: 10.1016/j.radonc.2014.02.003.
33 Lo YM, Chan LY, Lo KW, Leung SF, Zhang J, Chan AT, et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 1999; 59: 1188-1191.
34 Ma BB et al. Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006; 66: 714-20.
35 Lo YM et al. Plasma cell-free Epstein-Barr virus DNA quantitation in patients with nasopharyngeal carcinoma. Correlation with clinical staging. Ann NY Acad Sci 2000;906:99-101.
36 Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004; 350: 2461-2470.
37 Leung SF, Chan AT, Zee B, Ma B, Chan LY, Johnson PJ, et al. Pretherapy quantitative measurement of circulating Epstein-Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer 2003; 98: 288-291.
38 Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, Mo F, Lai M, Ho S, Huang DP, Johnson PJ. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst. 2002 Nov 6; 94(21): 1614-9.
39 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(24): 2461-70.
40 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(16): 5700-7.
41 Timothy T.C. Yip, Roger K.C. Ngan, Alvin H.W. Fong,
Stephen C.K. Law; Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma; Oral Oncology 2014 in press.
42 Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004.
43 Chan AT, Ma BB, Lo YM, Leung SF, Kwan WH, Hui EP, 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: 3053-3060.
44 Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, et al. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst 2002; 94: 1614-1619.
45 Lin JC, Wang WY, Liang WM, Chou HY, Jan JS, Jiang RS, et al. Long-term prognostic effects of plasma Epstein-Barr virus DNA by minor groove binderprobe real-time quantitative PCR on nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007; 68(5): 1342-8.
46 Liang FY, Sun W, Han P, Lu X, Lian YN, Huang XM. Detecting plasma Epstein-Barr virus DNA to diagnose postradiation nasopharyngeal skull base lesions in nasopharyngeal carcinoma patients: a prospective study. Chin J Cancer 2012; 31(3): 142-9.
47 Leung SF, Lo YM, Chan AT, To KF, To E, Chan LY, 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 DNA. Clin Cancer Res 2003; 9(9): 3431-4.
48 Shotelersuk K, Khorprasert C, Sakdikul S, Pornthanakasem W, Voravud N, Mutirangura A. Epstein-Barr virus DNA in serum/plasma as a tumor marker for nasopharyngeal cancer. Clin Cancer Res 2000; 6(3): 1046-51.
49 Zhang Y, Gao HY, Feng HX, Deng L, Huang MY, Hu B, et al. Quantitative analysis of Epstein-Barr virus DNA in plasma and peripheral blood cells in patients with nasopharyngeal carcinoma. Zhonghua Yi Xue Za Zhi 2004; 84(12): 982-6.
50 Wang WY, Twu CW, Lin WY, Jiang RS, Liang KL, Chen KW, et al. Plasma Epstein-Barr virus DNA screening followed by 18F-fluoro-2-deoxy-D-glucose positron emission tomography in detecting post treatment failures of nasopharyngeal carcinoma. Cancer 2011;117(19):4452-9.
51 Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004 Jun 10; 350(24): 2461-70.
52 Hong RL, Lin CY, Ting LL, Ko JY, Hsu MM. Comparison of clinical and molecular surveillance in patients with advanced nasopharyngeal carcinoma after primary therapy: the potential role of quantitative analysis of circulating Epstein-Barr virus DNA. Cancer 2004; 100(7): 1429-37.
53 Kalpoe JS, Dekker PB, van Krieken JH, Baatenburg de Jong RJ, Kroes AC. Role of Epstein-Barr virus DNA measurement in plasma in the clinical management of nasopharyngeal carcinomain a low risk area. J Clin Pathol 2006; 59(5):537-41.
54 Shi W, Pataki I, MacMillan C, Pintilie M, Payne D, O’Sullivan B, et al. Molecular pathology parameters in human nasopharyngeal carcinoma. Cancer 2002; 94: 1997-2006.
55 Ke Kengjian, Wang Haiyun, Fu Sha, Zhang Zichen, Duan Liping, Liu Dabo and Ye Jin; Epstein-Barr virus-encoded RNAs as a survival predictor in nasopharyngeal carcinoma. Chin Med J 2014; 127.
56 Lo EJ, Bell D, Woo JS, et al. Human papillomavirus and WHO
type I nasopharyngeal carcinoma. Laryngoscope 2010; 120: 1990-1997.
57 Maxwell JH, Kumar B, Feng FY, et al. HPV-positive/p16-positive/EBV-negative nasopharyngeal carcinoma in white North Americans.Head Neck 2010; 32: 562-567.
58 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: 21-29.
59 Tung YC, Lin KH, Chu PY, et al. Detection of human papilloma virus and Epstein-Barr virus DNA in nasopharyngeal carcinoma
by polymerase chain reaction. Kaohsiung J Med Sci 1999;15:256-262.
60 Giannoudis A, Ergazaki M, Segas J, et al. Detection of Epstein-Barr virus and human papillomavirus in nasopharyngeal carcinoma by the polymerase chain reaction technique. Cancer Lett 1995;89:177-181.
61 Hording U, Nielsen HW, Daugaard S, et al. Human papillomavirus types 11 and 16 detected in nasopharyngeal carcinomas by the polymerase chain reaction. Laryngoscope 1994;104:99-102.
62 Lin Z, Khong B, Kwok S, et al. Human papillomavirus 16 detected in nasopharyngeal carcinomas in Caucasian Americans but not in endemic southern Chinese patients. Head Neck 2013
Apr 25 [Epubahead of print]. doi: 10.1002/hed.23362.
63 Dogan S, Hedberg ML, Ferris RL, et al. Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a low-incidence population. Head Neck 2013 Jun 18 [Epub ahead of print]. doi: 10.1002/hed.23318.
64 Robinson M, Suh YE, Paleri V, et al. Oncogenic human papillomavirus associated nasopharyngeal carcinoma: An observational study of correlation with ethnicity, histological subtype and outcome in a UK population. Infect Agent Cancer 2013;8:30.
65 Laantri N, Attaleb M, Kandil M, et al. Human papillomavirus detection in moroccan patients with nasopharyngeal carcinoma. Infect Agent Cancer 2011;6:3.
66 Mirzamani N, Salehian P, Farhadi M, et al. Detection of EBVand HPV in nasopharyngeal carcinoma by in situ hybridization. Exp Mol Pathol 2006;81:231-234.
67 Rassekh CH, Rady PL, Arany I, et al. Combined Epstein-Barr virus and human papillomavirus infection in nasopharyngeal carcinoma. Laryngoscope 1998;108:362-367.
68 Tyan YS, Liu ST, Ong WR, et al. Detection of Epstein-Barr virus and human papillomavirus in head and neck tumors. J Clin
69 Matthew H. Stenmark, Jonathan B. McHugh, Matthew Schipper, Heather M. Walline, Christine Komarck, Felix Y. Feng, Francis P. Worden, Gregory T. Wolf, Douglas B. Chepeha, Mark E. Prince, Carol R. Bradford, Suresh K. Mukherji, Avraham Eisbruch, and Thomas E. Carey; Nonendemic HPV-Positive Nasopharyngeal Carcinoma: Association With Poor Prognosis. Int J Radiation Oncol Biol Phys, Vol. 88, No. 3, pp. 580e588, 2014.
70 Yen-Kung Chen, Ru-Hwa Cheng Kwan-Hwa Chi, Jia-Guang Liang, Su-Chen Wang,Yeh-You Shen, Alfred C. Liao, Chen-Tau Su. Application of 18F-FDG PET/CT in Nasopharyngeal Carcinoma Ann Nucl Med Sci 2007;20:21-32.
71 Lee SW, Nam SY, Im KC, Kim JS, Choi EK, Ahn SD, et al. Prediction of prognosis using standardized uptake value of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography for nasopharyngeal carcinomas. Radiother Oncol 2008;87:211-6.
72 Xie P, Yue JB, Fu Z, Feng R, Yu JM. Prognostic value of 18F-FDG PET/CT before and after radiotherapy for locally advanced nasopharyngeal carcinoma. Ann Oncol 2010;21:1078-82.
73 Chan SC, Chang JT, Lin CY, Ng SH, Wang HM, Liao CT, Chang CJ, Lin SY, Yen TC. Clinical utility of 18F-FDG PET parameters in patients with advanced nasopharyngeal carcinoma: predictive role for different survival endpoints and impact on prognostic stratification.
74 Wen-Shan Liu, Ming-Fang Wu, Hsien-Chun Tseng, Jung-Tung Liu, Jui-Hung Weng, Yueh-Chun Li, and Jong-Kang Lee; The role of pretreatment FDG-PET in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 2, pp. 561-566, 2012.
75 Winnie K. S. Chan, Dora Lai-Wan Kwong, David W. C. Yeung, Bingsheng Huang, and Pek-Lan Khong; Prognostic Impact of Standardized Uptake Value of F-18 FDG PET/CT in Nasopharyngeal Carcinoma. Clin Nucl Med 2011;36: 1007-1011.
76 Tsung-Min Hung, Hung-Ming Wang, Chung-Jan Kang, Shiang-Fu Huang, Chun-Ta Liao, Sheng-Chieh Chan, Shu-Hang Ng, I-How Chen, Chien-Yu Lin, Kang-Hsing Fan,Joseph Tung-Chieh Chang; Pretreatment 18F-FDG PET standardized uptake value of primary tumor and neck lymph nodes as a predictor of distant metastasis for patients with nasopharyngeal carcinoma. Oral Oncology 49 (2013) 169-174.
77 Peng Xie, Jin-Bo Yue, Han-xi Zhao, Xin-Dong Sun, Li Kong, Zheng Fu, Jin-Ming Yu; Prognostic value of 18F-FDG PET-CT metabolic index for nasopharyngeal carcinoma. J Cancer Res Clin Oncol (2010) 136:883-889.
78 Chan SC, Ng SH, Chang JT, Lin CY, Chen YC, Chang YC, et al. Advantages and pitfalls of 18F-fluoro-2-deoxy-D-glucose positron emission tomography in detecting locally residual or recurrent nasopharyngeal carcinoma: comparison with magnetic resonance imaging. Eur J Nucl Med Mol Imaging. 2006;33:1032-40.
79 Chan SC, Yen TC, Ng SH, Lin CY, Wang HM, Liao CT, et al. Differential roles of 18F-FDG PET in patients with locoregional advanced nasopharyngeal carcinoma after primary curative therapy: response evaluation and impact on management. J Nucl Med. 2006;47:1447-54.
80 Prognostic implications of post-therapy 18F-FDG PET in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.
81 Razek A, Kamal E; Nasopharyngeal carcinoma: correlation of apparent diffusion coefficient value with prognostic parameters. Radiol med (2013) 118:534-539.
82 DeVries AF, Kremser C, Hein PA, et al. Tumor microcirculation and diffusion predict therapy outcome for primary rectal carcinoma. Int J Radiat Oncol Biol Phys. 2003;56:958-965.
83 Mardor Y, Pfeffer R, Spiegelmann R, et al. Early detection of response to radiation therapy in patients with brain malignancies using conventional and high B-value diffusion-weighted magnetic resonance imaging. J Clin Oncol. 2003;21:1094-1100.
84 Higano S, Yun X, Kumabe T, et al. Malignant astrocytic tumors: clinical importance of apparent diffusion coefficient in prediction of grade and prognosis. Radiology. 2006;241:839-846.
85 Vandecaveye V, Dirix P, De Keyzer F, et al. Predictive value of diffusion-weighted magnetic resonance imaging during chemoradiotherapy for head and neck squamous cell carcinoma. Eur Radiol. 2010;20:1703-1714.
86 Hatakenaka M, Nakamura K, Yabuuchi H, et al. Pretreatment apparent diffusion coefficient of the primary lesion correlates with local failure in head-and-neck cancer treated with chemoradiotherapy or radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81:339-345.
87 Chung C, Jalali S, Foltz W, et al. Imaging biomarker dynamics in an intracranial murine glioma study of radiation and antiangiogenic therapy. Int J Radiat Oncol Biol Phys. 2013;85:805-812.
88 Jinsheng Hong, Yiqi Yao; Value of Magnetic Resonance Diffusion-Weighted Imaging for the prediction of radiosensitivity in nasopharyngeal carcinoma. Otolaryngology-Head and Neck Surgery 149(5) 707-713.
89 Xia W-X, Ye Y-F, Lu X, Wang L, Ke L-R, et al. (2013) The
Impact of Baseline Serum C-Reactive Protein and C-Reactive Protein Kinetics on the Prognosis of Metastatic Nasopharyngeal Carcinoma Patients Treated with Palliative Chemotherapy. PLoS ONE 8(10): e76958. doi:10.1371/journal.pone.0076958.
90 Turen S, Ozyar E, Altundag K, Gullu I, Atahan IL. Serum lactate dehydrogenase level is a prognostic factor in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. Cancer Invest 2007;25(5):315-21.
91 Li G, Gao J, Tao YL, et al. Increased pretreatment levels of serum LDH and ALP as poor prognostic factors for nasopharyngeal carcinoma. Chin J Cancer 2012;31(4):197-206.
92 Xiang-bo Wana, Li Wei, Hao Li, Min Dong, Qu Lin, Xiao-kun Maa, Pei-yu Huang, Jing-yun Wen, Xing Li, Jie Chen, Dan-yun Ruan, Ze-xiao Lin, Zhan-hong Chen, Quentin Liu, Xiang-yuan Wua, Ming-huang Hong; High pretreatment serum lactate dehydrogenase level correlates with disease relapse and predicts an inferior outcome in locally advanced nasopharyngeal carcinoma. European Journal of Cancer (2013) 49, 2356- 2364.
93 Wan XB, Fan XJ, Chen MY, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 2010;6(3):395-404.
94 Acikalin MF, Etiz D, Gurbuz MK, Ozudogru E, Canaz F, Colak E. Prognostic significance of galectin-3 and cyclin D1 expression in undifferentiated nasopharyngeal carcinoma. Med Oncol 2012;29(2):742-9.
95 Zhengbo Wei, Xianjie Zeng, Jian Xu, Xuwei Duan, Jianbo Yang, Ying Xie, PhD; Prognostic value of the pretreatment serum level of cytokeratin fraction 21-1 in undifferentiated nasopharyngeal carcinoma: A study of 332 cases. HEAD & NECK-DOI 10.1002/HED JANUARY 2014.
96 Li-na Liu, Pei-yu Huang, Zhi-rui Lin, Li-juan Hu, Jian-zhong Liang, Man-zhi Li, Lin-quan Tang, Mu-sheng Zeng, Qian Zhong and Bo-hang Zeng; Protein tyrosine kinase 6 is associated with nasopharyngeal carcinoma poor prognosis and metastasis. Journal of Translational Medicine 2013, 11:140.
97 Tae-Jung Kim, Youn Soo Lee, Jin-Hyung Kang, Yeon-Sil
Kim, and Chang Suk Kang; Prognostic significance of expression of VEGF and Cox-2 in Nasopharyngeal carcinoma and its association with expression of C-erbB2 and EGFR. Journal of Surgical Oncology 2011;103:46-52.
98 Liu Z, Yang H, Luo W, Jiang Q, Mai C, Chen Y, Zhen Y, Yu X, Long X, Fang W. Loss of cytoplasmic KLF4 expression is correlated with the progression and poor prognosis of nasopharyngeal carcinoma. Histopathology. 2013 Sep;63(3):362-70. doi: 10.1111/his.12176. Epub 2013 Jun 12.
99 Jiang Q, Mai C, Yang H, Wu Q, Hua S, Yan C, Long Y, Zhang Y, Long X, Fang W, Liu Z. Nuclear expression of CDK4 correlates with disease progression and poor prognosis in human nasopharyngeal carcinoma. Histopathology. 2014 Apr;64(5):722-30. doi: 10.1111/his.12319. Epub 2013 Dec 31.
100 Lee SW, Lin CY, Tian YF, Sun DP, Lin LC, Chen LT, Hsing CH, Huang CT, Hsu HP, Huang HY, Wu LC, Li CF, Shiue YL Overexpression of CDC28 protein kinase regulatory subunit 1B confers an independent prognostic factor in nasopharyngeal carcinoma. APMIS. 2014 Mar;122(3):206-14. doi: 10.1111/apm.12136. Epub 2013 Jul 24.
101 Jie Yanga, Lei Lia, Yanxin Rena, Xiaojiang Li, Yanling Tu, Jing Ma, Ruimei Sun, Liufang Zhao, Clinical Significance of Joint Detection of CD44v6 and CD62P in Nasopharyngeal Carcinoma. Onkologie 2013;36:629-634.
102 Shi-Sheng Li, Jia-Jia Liu, Shuang Wang, Qing- Lai Tang,
Bing-Bing Liu and Xin-Ming Yang; Clinical significance of TrkB expression in nasopharyngeal carcinoma. Oncology Reports 31: 665-672, 2014.
103 Li-Jung Ma, Sung-Wei Lee, Li-Ching Lin, Tzu-Ju Chen, I-Wei Chang, Han-Ping Hsu, Kwang-Yu Chang, Hsuan-Ying Huang, Chien-Feng Li; Fibronectin overexpression is associated with latent membrane protein 1 expression and has independent prognostic value for nasopharyngeal carcinoma. Tumor Biol. (2014) 35:1703-1712.
104 Daye Cheng, Hong Kong, Yunhui Li; Prognostic value of interleukin-8 and MMP-9 in nasopharyngeal carcinoma. Eur Arch Otorhinolaryngol (2014) 271:503-509.
105 Yu Xu, Peizhong Li, Xin Zhang, Junying Wang, Dongsheng Gu and Yao Wang; Prognostic implication of neuropilin-1 upregulation in human nasopharyngeal carcinoma. Diagnostic Pathology 2013, 8:155.
106 Jian Wang, Jing Yang, Bin-Bin Li, Zhi-Wei He; High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma. Asian Pacific J Cancer Prev, 14 (5), 2805-2809.
107 Jui Lan, Hsuan-Ying Huang, Sung-Wei Lee, Tzu-Ju Chen, Hui-Chun Tai, Han-Ping Hsu, Kwang-Yu Chang, Chien-Feng Li; TOP2A overexpression as a poor prognostic factor in patients with nasopharyngeal carcinoma. Tumor Biol. (2014) 35:179-187.
108 Han-Ping Hsu, Chien-Feng Li, Sung-Wei Lee, Wen-Ren Wu, Tzu-Ju Chen, Kwang-Yu Chang, Shih-Shin Liang, Chia-Jung Tsai, Yow-Ling Shiue; Overexpression of stathmin 1 confers an independent prognostic indicator in nasopharyngeal carcinoma. Tumor Biol. (2014) 35:2619-2629.
109 Hao-Yuan Mo, Dong-Hua Luo, Hui-Zhi Qiu, Huai Liu, Qiu-Yan Chen, Lin-Quan Tang, Zong-Liang Zhong, Pei-Yu Huang, Zheng-Jun Zhao, Chang-Qing Zhang, Ying Zhang, Hai-Qiang Mai; Elevated Serum Endostatin Levels are Associated with Poor Survival in Patients with Advanced-stage Nasopharyngeal Carcinoma. Clinical Oncology 25 (2013) 308e317.
110 Si-Wei Li, MD, Hua Wang, MD, Yan-Qun Xiang, Hai-Bo Zhang, Xing Lv, Wei-Xiong Xia; Mu-Sheng Zeng, Hai-Qiang Mai, Ming-Huang Hong, Xiang Guo; Prospective study of prognostic value of Raf kinase inhibitory protein and pretreatment plasma Epstein-Barr virus DNA for distant metastasis in locoregionally advanced nasopharyngeal carcinoma. Head & Neck-Doi 10.1002/Hed April 2013.
111 Jia-Xing Zhang, Man-Bo Cai, Xiao-Pai Wang, Li-Ping Duan, Qiong Shao, Zhu-Ting Tong, Ding-Zhun Liao, Yang-Yang Li, Ma-Yan Huang, Yi-Xin Zeng, Jian-Yong Shao; Elevated DLL4 expression is correlated with VEGF and predicts poor prognosis of nasopharyngeal carcinoma. Med Oncol (2013) 30:390.
112 Jianbo Zhou, Xuping Xiao, Hongmei Yi, Jihua Wang, Xiaoan Wang, Qiuhang Zhang; Upregulation of Gp96 Correlates with the Radiosensitivity and Five-Year Survival Rate of Nasopharyngeal Carcinoma. ORL 2012;74:164-171.
113 Zheng J, Li J, Xu L, Xie G, Wen Q, et al. (2014) Phosphorylated Mnk1 and eIF4E Are Associated with Lymph Node Metastasis and Poor Prognosis of Nasopharyngeal Carcinoma. PLoS ONE 9(2): e89220. doi:10.1371/journal.pone.0089220.
114 Yan Fei Deng, Dong Ni Zhou, Chun Sheng Ye, Liang Zeng, Ping Yin; Aberrant Expression Levels of MTAl and RECK in Nasopharyngeal Carcinoma: Association With Metastasis, Recurrence, and Prognosis. Annals of Otology, Rhinology & Laryngology 121(7): 457-465.
115 Christos K Kontos, Ali Fendri, Abdelmajid Khabir, Raja Mokdad-Gargouri and Andreas Scorilas; Quantitative expression analysis and prognostic significance of the BCL2-associated X gene in nasopharyngeal carcinoma: a retrospective cohort study. BMC Cancer 2013, 13: 293.
116 Zhen Liu, Yufei Long, Yajie Zhang, Wei Huang, Xiaobin Long, Huiling Yang,Jie Long, Chao Cheng, andWeiyi Fang; Nuclear p27 Expression Confers a Favorable Outcome for Nasopharyngeal Carcinoma Patients. Disease Markers Volume 35 (2013), Issue 6, Pages 925-932.
117 Qingping Jiang, Huiling Yang, Chao Cheng, Hanzhen Xiong, Shaoyan Liu, Jie Long, Yajie Zhang, Weiyi Fang and Zhen Liu; Decreased P27 protein expression is correlated with the progression and poor prognosis of nasopharyngeal carcinoma. Jiang et al. Diagnostic Pathology 2013, 8:212.
118 Wei Sun, Guoxian Long, Junfeng Wang, Qi Mei, Dongbo Liu, Guoqing Hu; Prognostic role of epidermal growth factor receptor in nasopharyngeal carcinoma: A meta-analysis. HEAD & NECK-DOI 10.1002/HED MONTH 2013.
119 Gong L, Zhang W, Zhou J, Lu J, Xiong H, et al. (2013) Prognostic Value of HIFs Expression in Head and Neck Cancer: A Systematic Review. PLoS ONE 8(9): e75094. doi:10.1371/journal.pone.0075094.
120 Wang HY, Sun BY, Zhu ZH, Chang ET, To KF, Hwang JS, Jiang H, Kam MK, Chen G, Cheah SL, Lee M, Liu ZW, Chen J, Zhang JX, Zhang HZ, He JH, Chen FL, Zhu XD, Huang MY, Liao DZ, Fu J, Shao Q, Cai MB, Du ZM, Yan LX, Hu CF, Ng HK, Wee JT, Qian CN, Liu Q, Ernberg I, Ye W, Adami HO, Chan AT, Zeng YX, Shao JY; Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival. J Clin Oncol. 2011 Dec 1;29(34):4516-25. doi: 10.1200/JCO.2010.33.7741. Epub 2011 Oct 24.
121 Na Liu, Rui-Xue Cui, Ying Sun, Rui Guo, Yan-Ping Mao, Ling-Long Tang, Wei Jiang, Xu Liu, Yi-Kan Cheng, Qing-Mei He, William C.S. Cho, Li-Zhi Liu, Li Li and Jun Ma; A four-miRNA signature identified from genome-wide serum miRNA profiling predicts survival in patients with nasopharyngeal carcinoma. Int. J. Cancer (2014): 134, 1359-1368.
122 Fang FM, Tsai WL, Chien CY, Chen HC, Hsu HC, Huang TL, Lee TF, Huang HY, Lee CH; Pretreatment quality of life as a predictor of distant metastasis and survival for patients with nasopharyngeal carcinoma. J Clin Oncol. 2010 Oct 1; 28(28): 4384-9. doi: 10.1200/JCO.2010.28.8324. Epub 2010 Aug 16.
123 Jin Y, Cai XY, Cai YC, et al. To build a prognostic score
model containing indispensable tumour markers for metastatic nasopharyngeal carcinoma in an epidemic area. Eur J Cancer 2012;48(6):882-8.
124 Ong YK, Heng DM, Chung B, et al. Design of a prognostic index score for metastatic nasopharyngeal carcinoma. Eur J Cancer 2003;39(11):1535-41.
125 Toh CK, Heng D, Ong YK, Leong SS, Wee J, Tan EH. Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma. Br J Cancer 2005;92(8):1382-7.
126 Chuangzhen Chen, Siqia Chen, Quynh-Thu Le Jianzhou Chen, Zhijian Chen, Dongsheng Li, Mingzhen Zhou,Derui Li; Prognostic model for distant metastasis in locally advanced nasopharyngeal carcinoma after concurrent chemoradiotherapy. Head & Neck—Doi 10.1002/Hed Month 2014.
127 Y-M Tian, Y-H Tian, L Zeng, S Liu, Y Guan, T-X Lu and F Han; Prognostic model for survival of local recurrent nasopharyngeal carcinoma with intensity-modulated radiotherapy. British Journal of Cancer (2014) 110, 297-303| doi: 10.1038/ bjc.
128 Xiao-Lin Luo, Wang He, Hui Huang, Qiu-Yan Chen, Ying Liang, Hai-Qiang Mai, Hui-Qiang Huang, Qing-Qing Cai; Design of a Prognostic Score Model for Nasopharyngeal Carcinoma. Head Neck. 2014 Mar 6. doi: 10.1002/hed.23642.
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Asia Press is a professional Science, Technology and Medicine publisher, who owns rapid publication, Peer-Reviewed, Open Access Journals. Asia Press aims to promote “knowledge sharing”. As you know, the main barrier for free “knowledge sharing” is the cost of publishing and transfer. In order to encourage scholars and scientists to the max, and devote whole power to realize the aim of “knowledge sharing” and the benefit of “all” mankind, Asia Press performs a permanent policy of no charge for publication and access, and always open its door for authors worldwide.
© 2013-2017 by the Asia Press. All rights reserved.
© 2013-2017 by the Asia Press. All rights reserved.