诊断

Review

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: ester.orlandi@istitutotumori.mi.it

 

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: http://journalofnasopharyngealcarcinoma.org/Resource/image/20140307/20140307234733_0340.png2014 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

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).

 

Emerging Factors

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).

 

Biomarkers

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 Tropomyosinrelated 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).

 

Future Perspectives

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.

 

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