诊断

Review

Nasopharyngeal carcinoma: Current treatment options and future directions

Shumaila Saad, Tony J. C Wang

Department of Radiation Oncology, Columbia University, 622 West 168th Street, BNH B-11, New York, NY 10032

Corresponding author: Tony J. C Wang, Email: tjw2117@cumc.columbia.edu

 

Citation: Saad S, Wang TJC. Nasopharyngeal carcinoma: Current treatment options and future directions. J Nasopharyng Carcinoma, 2014, 1(16): e16. doi:10.15383/jnpc.16.

Competing interests:The authors have declared that no competing interests exist.

Conflict of interest: None.

Copyright:image001.gif2014 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: The prevalence of nasopharyngeal carcinoma (NPC) has remained high in endemic regions. Various genetic and epigenetic changes synergistically contribute to NPC pathogenesis. Although NPC is highly radiosensitive and chemosensitive, treatment of patients with advanced locoregional disease remains challenging. Radiation therapy (RT) with or without chemotherapy remains the standard treatment for nasopharyngeal carcinoma with intensity-modulated radiation therapy (IMRT) now the preferred technique over conventional radiotherapy techniques because of its ability to deliver high doses of radiations to target structures while sparing the surrounding healthy tissues. New treatment options including targeted monoclonal antibodies and small molecule tyrosine kinase inhibitors are being studied as well. In this article we will review the current standards of care, new techniques and treatment options for NPC.

Keywords: Nasopharyngeal carcinoma; Radiation therapy; Chemotherapy; Chemoradiotherapy; Targeted therapy

 

Introduction

Nasopharyngeal carcinoma (NPC) is a unique cancer of head and neck, commonly arising from the epithelial lining of the lateral wall of the nasopharynx, particularly at the fossa of Rosenmüller and superior posterior wall. The incidence of this tumor is less common in North America but it is one of the most common malignancies in Southern China, southeast Asia and North Africa [1]. The World Health Organization has classified NPC into 3 histologic subtypes: squamous-cell carcinoma, differentiated non-keratinizing carcinoma and undifferentiated non-keratinizing carcinoma [2]. Non-keratinizing subtype comprises more than 95% of all NPC cases in endemic areas of Southern China [3]. It is more common in men and the rate of incidence generally increases from ages 20 to around 50.  Signs and symptoms at presentation are related to tumor location. Patients with tumor confined to nasopharynx present with symptoms of epistaxis, nasal obstruction and discharge. Extension of tumor to the parapharyngeal space leads to tinnitus and deafness; and involvement of cranial nerve leads to headache, diplopia, facial pain and numbness. Because of the nonspecific nature of symptoms most patients are diagnosed with advanced disease at presentation. Recent reports have suggested that narrow band imaging may be a useful technique for detection of early NPC [4]. Positive biopsy from the nasopharynx tumor is required to make the definitive diagnosis.  According to American Joint Committee on Cancer staging system, patients are designated into stages I, II-A, II-B, III, IV-A, IV-B and IV-C [5].

 

Etiology factors

NPC is usually caused by the combined effects of three etiology factors, the first factor is environmental carcinogens which include cigarette smoke, Cantonese-style salted fish, preserved foods like shrimp paste, and volatile nitrosamines. Volatile nitrosamines induces deoxyribonucleic acid (DNA) damage, chronic inflammation in nasopharyngeal mucosa, and predisposes individuals to Epstein-Barr virus (EBV) infection, thereby increasing the risk of developing NPC. The second factor is genetic susceptibility which includes mutations in one or more genes, genetic polymorphism, and family history of NPC. Genes within the human leukocyte antigen (HLA) region and several non-HLA genes including gamma-aminobutyric acid B receptor 1 (GABBR1) and major histocompatibility complex class I polypeptide-related sequence A (MICA) are strongly associated with NPC [6]. Recent studies have indicated that carcinogen-metabolizing genes and DNA-repair genes play critical roles in determining individual susceptibility to cancers. The third factor is EBV which belongs to the herpes family and infects epithelial cells and B cells of immune system. The association of EBV infection and NPC has already been established by detection of higher antibody titers (Immunoglobulin A and anti-DNase) against EBV in NPC patients [7]. EBV can be detected from the premalignant lesions of the nasopharyngeal epithelium suggesting involvement of EBV with early phases of carcinogenesis.  EBV infection of primary nasopharyngeal epithelial cells does not induce their proliferation, however infection of established epithelial cells harboring multiple genetic alterations has been shown to promote growth and confer tumorigenicity in infected cells [6]. Recent study has shown that Cyclin D1 overexpression in premalignant or dysplastic nasopharyngeal epithelium supports persistence of EBV episomes in infected cells suggestive of existence of genetic alterations in premalignant nasopharyngeal epithelium prior to EBV infection [8]. Because of the strong correlation between NPC and EBV, several studies of NPC are focusing on EBV-related proteins and genes, such as EBER (EBV-encoded RNA) and latent membrane protein1 (LMP-1) [9-11]. LMP-1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells [10]. The relationship of different etiology factors and pathogenesis of NPC is shown in Figure 1.

 

 

Figure 1. Etiology and pathogenesis of NPC

 

 

Oncogenic Alteration in NPC

Advances in understanding of molecular pathogenesis of NPC have led to identification of various genetic and epigenetic aberrations that are common in NPC. The existence of oncogene mutations in NPC patients is related with relapse and metastasis. Mutation, amplification and overexpression of oncogenes involved in pathogenesis of NPC are summarized in Table 1. Important oncogenes such as, CCND1 (Cyclin D1), MDM2 (Mdm2, transformed 3T3 cell double minute 2; p53-binding protein), MYC (v-myc Myelocytomatosis viral oncogene homologue), N-RAS (Neuroblastoma RAS viral (v-ras) oncogene homologue), RAF1 (Raf-1 proto-oncogene, serine/threonine kinase), EGFR (Epidermal growth factor receptor) and PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) are frequently amplified in NPC tissue or cell lines [12]. Overexpression of some genes such as BCL2 (B-cell CLL/lymphoma 2), HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homologue), HER2/ERBB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) have also been reported in NPC [13]. Chromosomal deletion involving region 9p21 and 3p leads to inactivation of tumor suppressor genes including p16, p14ARF p15 and RASSFIA (Ras association domain family member) [13]. Inactivation of these genes promote tumor growth in NPC patients.  Recent data show that PIK3CA, KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) and RAS oncogenes are most susceptible to mutations in NPC [2]. CDK4 (cyclin-dependent kinase 4) is a protein kinase which is important for the transition of G1/S phase of cell cycle progression. Overexpression of CDK4 suppresses the expression of let-7c (tumor suppressing factor) and is an unfavorable prognostic factor in NPC [14]. Lack of cellular differentiation leads to uncontrolled growth and poor prognosis in many solid tumors including NPC. IκB kinase α (IKKα) is a ubiquitous kinase that controls cellular differentiation. Yan et al. reported that IKKα plays a pivotal role in NPC cellular differentiation [15]. Jab1/CSN5 (constitutive photomorphogenic 9 signalosome subunit 5) is an oncoprotein regulated by multiple signaling pathways, and involved in the pathogenesis of NPC [16]. Targeted inactivation of mutations is likely to become a novel strategy for the treatment of NPC in the future.

 

Table 1. Oncogenes involved in pathogenesis of NPC

Mutation

Amplification

Overexpression

PIK3CA (Phosphoinositide 3-kinase, catalytic, alpha polypeptide) [52]

PIK3CA (Phosphoinositide 3-kinase, catalytic, alpha polypeptide) [12]

PIK3CA (Phosphoinositide 3-kinase, catalytic, alpha polypeptide) [53]

DeltaNp63/TP73L (Tumor protein p73-like, p63 splicing variants lacking NH(2)-terminal transactivating domain) [54]

__

DeltaNp63/TP73L (Tumor protein p73-like, p63 splicing variants lacking NH(2)-terminal transactivating domain) [55]

__

CCND1 (Cyclin D1) [56]

CCND1 (Cyclin D1) [57]

__

MYC (v-myc myelocytomatosis viral oncogene homologue ,avian) [58]

MYC (v-myc myelocytomatosis viral oncogene homologue ,avian) [59]

__

EGFR (Epidermal growth factor receptor [12]

EGFR (Epidermal growth factor receptor) [60]

__

NRAS [Neuroblastoma RAS viral (v-ras) oncogene homologue] [12]

A20/TNFAIP3 (Tumor necrosis factor alpha induced protein 3) [61]

__

INT2/FGF3 [Fibroblast growth factor 3) [58]

BCL2 (B-cell CLL/ lymphoma 2) [59, 62]

__

__

HER2/ERBB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) [60]

__

__

HRAS (Harvey rat sarcoma viral oncogene homologue) [12]

__

__

ID1 (Inhibitor of DNA binding protein) [63]

__

__

MDM2 (Mdm2, transformed 3T3 cell double minute 2; p53-binding protein)) [64]

__

__

MET (Met proto-oncogene; hepatocyte growth factor receptor) [65]

 

 

Treatment

Radiation Therapy

The nasopharynx is surrounded anatomically by an array of radiosensitive structures including the temporal lobe, brainstem, spinal cord, optic nerve, chiasm, parotid gland, submandibular gland and pituitary gland which makes radiation treatment planning difficult. Since surgical resection is often not achievable in NPC, standard treatment for NPC is radiotherapy (RT) for early-stage lesions and chemoradiotherapy (CRT) for more advanced diseases. NPC is a radiosensitive tumor, with 5 year survival rates of 66-83% with RT in early stage disease [17-20]. Although conventional RT is helpful in treating NPC, it has more toxic effects, 55% grade 3 and 21% grade 4 toxicities have been reported in the INT0099 trial [21]. Other techniques such as three-dimensional conformal radiation therapy (3D-CRT) precisely maps the location of the tumor, radiation beams are shaped and aimed at the tumor from several directions, which makes it less likely to damage nearby normal tissues. Intensity-modulated radiation therapy (IMRT) is an advanced form of 3D therapy and is the mainstay for the treatment of NPC. A good therapeutic ratio can be achieved with IMRT by giving a high dose to the tumor to achieve a high probability of local control (LC) while minimizing normal tissue complications. The 3-year loco-regional control (LRC) exceeds 90% in both early stage and advanced stage NPC with IMRT [22, 23]. The superiority of IMRT can be confirmed from numerous dosimetric analyses comparing IMRT to conventional RT techniques [24]. Lee et al. treated 87 patients with IMRT, results show 4 year local progression free survival (PFS), regional PFS, distant metastasis free survival (DMFS) and overall survival (OS) rates of 94%, 98%, 66% and 73%, respectively. This result demonstrated that excellent LRC for NPC was achievable with IMRT [25]. Tham et al. conducted a review of 195 patients with non-metastatic NPC treated with IMRT and showed 3-year local recurrence-free survival was 93.1% and a disease-free survival was 82.1% [23]. Memorial Sloan-Kettering hospital treated 74, newly diagnosed nonmetastatic NPC patients with IMRT using accelerated fractionation to 70 Gy; the 3-year LC rate was 91%, regional control 93%, PFS 67%, and OS 83%. LC rates of T1/T2 tumors and T3/ T4 were 100% and 83% respectively [26]. Radiation therapy oncology group (RTOG) phase II trial enrolled 68 NPC patients with stages I-IV in whom IMRT was delivered using standard fractionation. Node positive or high T-stage disease received both CRT as well as adjuvant chemotherapy (AC). Two-year outcomes were reported with LC of 93%, LRC 89%, DMFS 85%, PFS 93%, and OS 80% [27]. NRG Oncology NRG-HN001 trial is currently randomizing NPC patients into two arms based on EBV DNA detection, both arms are receiving RT plus AC; arm 1 cisplatin and 5-Fluorouracil (5-FU), arm 2 gemcitabine and paclitaxel. The primary objective of the study is to determine whether gemcitabine and paclitaxel regimen has superiority over cisplatin and 5-FU regimen to determine PFS.

Radiation therapy, although a very effective treatment for various malignancies, is known to have significant short- and late-term side effects. Side effects of radiation to the upper aerodigestive tract include mucositis, loss of taste, burns, fibrosis, xerostomia, dysphagia, trismus, eustachian tube dysfunction, cranial nerve palsy, carotid stenosis, temporal lobe radionecrosis, general mucosal dysfunction, and post-radiation malignancies. With the application of IMRT, the incidence of radiation-related complications has been reduced [28]. IMRT is superior to 2-dimensional or 3-dimensional conformal radiotherapy due to the ability to spare normal structures, in producing highly conformal dose distributions with steep dose gradients and complex isodose surfaces. Encouraging results of IMRT-treated NPC have been reported in many trials [22, 26, 29, 30] and now IMRT is the preferred and standard of care treatment for NPC according to the National Comprehensive Cancer Network guidelines. Outcomes of NPC patients treated with IMRT with and without chemotherapy are described in Table 2.

 Chemotherapy

Patients diagnosed with locally advanced tumor have poor prognosis with 5 year survival only 35% and around 50% of patients present with disease recurrence when treated with RT alone [31, 32]. CRT has been the standard of care for locally advanced NPC. Several trials have investigated the use of induction, adjuvant and concurrent CRT for the treatment of locally advanced NPC. A phase II RTOG 81-17 trial of locally advanced head and neck cancer patients established that cisplatin is safe and effective regimen when used concurrently with definitive radiotherapy for advance cancer of head and neck. This trial included 124 patients, 22% were NPC patients [33]. Al-Sarraf et al. treated 27 patients with locally advanced NPC with concurrent standard RT and cisplatin, seventy percent of patients completed the course of RT and all three cycles of cisplatin, complete response was achieved in 24 (89%) patients leading to the conclusion that it is an effec­tive and tolerable regimen [34]. An intergroup randomized phase III trial compared RT alone to concurrent CRT using cisplatin followed by adjuvant cisplatin and 5-FU in patients with inoperable NPC. The authors concluded that there was a significant difference in PFS and OS between the two arms and that concurrent CRT is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers [21]. In order to further investigate the results of intergroup trials several phase III trial have been started to compare the results of concurrent chemo-RT versus RT alone. A randomized phase III trial compared concurrent CRT with cisplatin plus fluorouracil in patients with advanced NPC [35]. The trial reported 5-year outcomes with significant difference in PFS 71.6% for the concurrent CRT group compared with 53% for the RT alone group (P =.0012) and OS rates were 72.3% for the concurrent CRT group and 54.2% for the RT alone group (p = 0.0022) [35].

 

Table 2. Outcomes of NPC treated with IMRT with and without chemotherapy

Study

(authors or trial)

N

Time point

(years)

OS (%)

LC (%)

RC (%)

DMFS (%)

Lee et al.[25]

67

4

88

97

98

66

Kwong et al.[66]

    50

     2

    92

    96

    NA

    94

Kam et al.[30]

63

3

90

92

98

79

Lee et al.[27]

    68

     2

    80

    93

     91

    85

Kwong et al.[67]

33

3

100

100

92

100

Lin et al.[68]

    370

     3

     89

     95

    97

     86

Wolden et al.[26]

74

3

83

91

93

78

Lee et al.[27]

68

2

80

93

91

85

Bakst et al.[69]

    25

     3

     89

     91

    91

     91

Tham et al.[23]

195

3

94

90

    N/A

89

Ma et al.[70]

    30

     2

    90

    93

    93

     93

Lin et al.[22]

323

3

90

95

98

90

Lee et al.[49]

    42

     2

    91

    N/A

     N/A

     91

Wong et al.[71]

175

3

87

94

93

87

Xiayun et al.[72]

    54

     3

    88

    95

     98

    86

Ng et al.[73]

193

2

92

95

96

90

Su et al.[74]

    198

     5

    N/A

    97

     98

    98

Xiao et al.[75]

81

5

75

95

    N/A

    N/A

Wang et al.[76]

    138

     3

    83

    94

    96

    80

Lai et al.[77]

512

5

    N/A

92.7

97

84

Kong et al.[78]

    370

     2

    N/A

    95.5

    N/A

    N/A

IMRT=Intensity-modulated radiation therapy, N=No of subjects, OS=Overall survival, LC=Local control, RC=Regional control, DMFS=Distant metastasis free survival

 

In order to investigate the role of induction chemotherapy plus RT for NPC patients the International Nasopharynx Cancer Study Group randomized 168 to radiotherapy alone and 171 to neoadjuvant chemotherapy (bleomycin, epirubicin, and cisplatin) plus radiotherapy. Results have shown that there was a significant difference in disease free survival favoring the chemotherapy arm (p < 0.01) but there was no difference in OS and there was higher treatment related deaths in the induction chemotherapy group (8% vs. 1%) based on 49 months follow up period [36]. A pooled analysis from two phase III randomized trials (Guangzhou and the Asian-Oceanic Clinical Oncology Asso­ciation) comparing induction chemotherapy (cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin) plus RT or RT alone was published in 2005. Based on 5 year survival outcome relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = 0.014), however there was no improvement in the OS [37]. To further understand the difference between induction and concurrent chemotherapy, a randomized phase II trial comparing OS, PFS and toxicities in patients diagnosed with NPC was conducted [38]. Patients were randomly assigned to induction chemotherapy (docetaxel) followed by CRT or CRT alone. Three-year outcomes showed a significant improvement in OS (94.1% vs 67.7%) but no significant change in PFS (88% vs 59%) and acute toxicities [38]. The role of induction chemotherapy in addition to concurrent chemotherapy remains to be defined, some Phase III trials are still ongoing that might address the benefit of induction chemotherapy prior to concurrent CRT [39].

Several clinical trials have compared AC with RT alone addressing the efficacy of AC in locally advanced NPC but showed conflicting results [31]. In 2004, Kwong et al. showed AC did not improve overall outcome in NPC patients. A Phase III trial in China enrolled 251 patients to the concurrent CRT plus AC group and 257 to the concurrent CRT alone group. 2 year failure-free survival rate in the concurrent CRT plus AC group and in concurrent CRT only group was 86% and 84%, respectively. These results suggested that AC did not significantly improve failure-free survival after concurrent CRT in locoregionally advanced NPC [40]. Wei Hu et al. concluded that concurrent CRT using paclitaxel followed by AC is effective and tolerable for locally advanced NPC. Lin et al. from Taiwan showed that concurrent CRT alone was insufficient for high risk patients, so perhaps in high risk patients AC may play a role, still the use of AC remains debatable. Trials comparing RT alone versus CRT are shown in Table 3.

 

Table 3.  Trials comparing Radiotherapy alone versus Chemoradiotherapy

Trial Group

 

stage

Median follow-up

(months)

Time point

(years)

Treatment

OS (%)

PFS (%)

No of patients

Al-Sarraf et al. [21]

III-IV

60

5

RT  70 GY

RT and 3 cycles cisplatin + 3 cycles of cisplatin and  fluorouracil

46

76

 

24

69

 

 

69

78

Chan et al. [79]

Ho’s N2/3 or node ≥ 4 cm

 

66

5

RT  66 GY

RT and weekly cisplatin

58.6

70.3

 

 

52

60

 

176

174

Lin et al. [35]

III-IV

65

5

RT  70-74 GY

RT plus cisplatin and

fluorouracil during week1 and       week 5 of RT

54

 

72

 

53

 

72

 

143

 

141

Kwong et al. [32]

Ho’s T3 or N2/3 or node ≥ 4 cm

 

37

3

RT  62.5-68 GY

RT, uracil and tegafur+ cisplatin           and fluorouracil/ vinblastine, bleomycin and methotrexate for 6 cycles

77

87

 

 

58

69

109

110

Zhang et al. [80]

III-IV

24

2

RT  70-74 GY

RT and 6 cycles of oxaliplatin

 

 

77

100

 

 

83

96

 

56

59

Wee et al. [81]

III-IV

38

3

RT  70 GY

RT and 3 cycles of cisplatin+3 cycles of  cisplatin and

fluorouracil

 

 

65

80

 

 

53

72

 

110

111

Lee et al. [82]

III-IV

Any T,N2-3

25

5

RT  70 GY

RT and 3 cycles of cisplatin+3 cycles of  cisplatin and  fluorouracil

 

 

 

 

64

68

 

 

53

62

176

172

Lee et al. [83]

III-IV

T3-T4,N0-I

35

3

RT  70 GY

RT and 3 cycles of cisplatin+3 cycles of  cisplatin and  fluorouracil

Accelerated-fractionation RT(ART)  70 GY

ART and 3 cycles of cisplatin+3 cycles of  cisplatin and fluorouracil

83

87

 

 

73

 

88

 

68

73

 

 

63

 

88

 

 

49

47

 

 

48

 

50

Chen et al. [84]

III-IV

29

2

RT  70 GY

RT and 7 cycles of cisplatin+3 cycles of  cisplatin and

fluorouracil

 

80

90

 

73

85

 

158

158

RT=Radiation therapy, OS=Overall survival, PFS=Progression free survival

 

Targeted therapies

Mutations play a key role in tumor cell proliferation, apoptosis, tumor-induced angiogenesis and metastasis. NPC is a highly invasive and metastatic tumor, targeted therapy for NPC has made considerable progress in recent years. Several trials are ongoing to investigate the role of monoclonal antibodies, tyrosine kinase inhibitors, and Met (Met proto-oncogene; hepatocyte growth factor receptor) inhibitors in NPC. Met activation induces proliferation in many types of cancers including NPC; recent study results have shown that the monoclonal antibody SAIT301 inhibits Met activation as well as the downstream EGR-1 (early growth response protein) expression in NPC cell lines [41]. Overexpression of Interleukin-6 (IL-6) has also been observed in NPC cell lines. IL-6 mainly promotes cell migration and invasion and these effects are mediated through matrix metalloproteinase-2 (MMP-2) and MMP-9. Sun et al. showed that treatment with monoclonal anti-human IL-6R antibody (anti-IL-6R mAb) resulted in decreased proliferation, migration and invasion capabilities of NPC cells [42].

EGFR is overexpressed in a variety of tumors, especially in head and neck cancer (80-100%) [43]. Cetuximab (monoclonal antibody) binds specifically to EGFR and blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased matrix metalloproteinase and vascular endothelial growth factor production. The role of cetuximab in the treatment of squamous cell cancer of the head and neck cancer has been well established however little research has been done on use of cetuximab in NPC. ENCORE study showed that the combined treatment modality of IMRT and concurrent chemotherapy and cetuximab in advanced NPC resulted in a promising clinical response. Recent study comparing cetuximab plus IMRT with and without chemotherapy in advance NPC concluded that a combination of monoclonal antibody plus IMRT is effective and well tolerated regimen with or without chemotherapy [44]. Currently, another anti-EGFR antibody, nimotuzumab, is under investigation with CRT for locally advanced NPC. Gefitinib plays a key role in the treatment of patients with recurrent or metastatic NPC, but its effects varies among NPC patients [45, 46]. Other EGFR tyrosine kinase inhibitors such as sorafenib have also been investigated in NPC but further research is necessary to understand their potential efficacy [47]. Vascular endothelial growth factor (VEGF) is a signal protein that stimulates vasculogenesis and angiogenesis. VEGF has been found to be overexpressed in 67% of NPC and leads to tumor metastasis [48]. Bevacizumab, a monoclonal antibody that inhibits VEGF, is currently being investigated with CRT [49]. Hypoxia inducible factor 1-alpha (HIF1-alpha) is a hypoxia inducible transcription factor which upregulates the expression of various important mediators of angiogenesis such as VEGF. HIF1-alpha is overexpressed in 50% of NPC and is associated with shorter survival following radiotherapy in patients with advanced NPC [50]. Immunotherapy has recently emerged as an effective tool for the treatment of EBV-associated malignancies. There is emerging data supporting the potential application of cytotoxic T lymphocyte (CTL)-based therapy, on the backbone of chemotherapy and as a salvage treatment in NPC [51].

 

Future directions

Given the complex nature of this disease and the high risk for development of distant failures, new treatment regimens need to be developed for these patients. Understanding the risk factors will greatly improve current clinical management of NPC in endemic regions.

IMRT is now frequently used for NPC; understanding the practical aspects of treatment planning is required to maximize the benefit of this technology. Further exploration of the role of targeted agents such as inhibitors of EGFR and VEGF, is necessary. Given the importance of EBV-mediated dysregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related NPC. Adoptive immunotherapy with EBV-specific CTL awaits further investigation. Proton therapy is a type of external beam radiotherapy which uses a beam of protons to irradiate diseased cancer tissue. The chief advantage of proton therapy is the ability to more precisely localize the delivery of radiation. The role of proton therapy in NPC remains unclear. Certainly, the treatment strategies for NPC will continue to change and evolve as a better understanding of the molecular and immune mechanisms is achieved.

 

References

1. Yu MC, Yuan JM: Epidemiology of nasopharyngeal carcinoma. Seminars in cancer biology 12(6), 421-429 (2002).

2. Zhang ZC, Fu S, Wang F, Wang HY, Zeng YX, Shao JY: Oncogene mutational profile in nasopharyngeal carcinoma. OncoTargets and therapy 7, 457-467 (2014).

3. Ao R, Fu R, Dong D, Zhu X, Liu H, Xie K: Discerning primary tumors from metastases in synchronous nasopharyngeal squamous cell carcinoma and cutaneous squamous cell carcinoma: A case report and review of the literature. Oncology letters 7(5), 1391-1394 (2014).

4. Wang WH, Lin YC, Lee KF, Weng HH: Nasopharyngeal carcinoma detected by narrow-band imaging endoscopy. Oral oncology 47(8), 736-741 (2011).

5. Ouyang PY, Su Z, Ma XH, Mao YP, Liu MZ, Xie FY: Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system. British journal of cancer 109(12), 2987-2997 (2013).

6. Tsao SW, Yip YL, Tsang CM et al.: Etiological factors of nasopharyngeal carcinoma. Oral oncology 50(5), 330-338 (2014).

7. Chien YC, Chen JY, Liu MY et al.: Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. The New England journal of medicine 345(26), 1877-1882 (2001).

8. Tsang CM, Yip YL, Lo KW et al.: Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 109(50), E3473-3482 (2012).

9. Xu Y, Shi Y, Yuan Q et al.: Epstein-Barr Virus encoded LMP1 regulates cyclin D1 promoter activity by nuclear EGFR and STAT3 in CNE1 cells. Journal of experimental & clinical cancer research : CR 32(1), 90 (2013).

10. Xiao L, Hu ZY, Dong X et al.: Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene, (2014).

11. Gou Y, Sun C, Hu L et al.: [Correlation between DNA damage and EB virus infection in nasopharyngeal carcinoma]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 30(2), 184-187 (2014).

12. Hui AB, Lo KW, Teo PM, To KF, Huang DP: Genome wide detection of oncogene amplifications in nasopharyngeal carcinoma by array based comparative genomic hybridization. International journal of oncology 20(3), 467-473 (2002).

13. Tao Q, Chan AT: Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. Expert reviews in molecular medicine 9(12), 1-24 (2007).

14. Liu Z, Long X, Chao C et al.: Knocking down CDK4 mediates the elevation of let-7c suppressing cell growth in nasopharyngeal carcinoma. BMC cancer 14(1), 274 (2014).

15. Yan M, Zhang Y, He B et al.: IKKalpha restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation. Nature communications 5, 3661 (2014).

16. Pan Y, Claret FX: Targeting Jab1/CSN5 in nasopharyngeal carcinoma. Cancer letters 326(2), 155-160 (2012).

17. Chen C, Yi W, Gao J et al.: Alternative endpoints to the 5-year overall survival and locoregional control for nasopharyngeal carcinoma: A retrospective analysis of 2,450 patients. Molecular and clinical oncology 2(3), 385-392 (2014).

18. Yi JL, Gao L, Huang XD et al.: Nasopharyngeal carcinoma treated by radical radiotherapy alone: Ten-year experience of a single institution. International journal of radiation oncology, biology, physics 65(1), 161-168 (2006).

19. Chen CY, Han F, Zhao C et al.: Treatment results and late complications of 556 patients with locally advanced nasopharyngeal carcinoma treated with radiotherapy alone. The British journal of radiology 82(978), 452-458 (2009).

20. Lee AW, Sze WM, Au JS et al.: Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. International journal of radiation oncology, biology, physics 61(4), 1107-1116 (2005).

21. Al-Sarraf M, Leblanc M, Giri PG et al.: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 16(4), 1310-1317 (1998).

22. Lin S, Pan J, Han L, Zhang X, Liao X, Lu JJ: Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: report on the 3-year outcome of a prospective series. International journal of radiation oncology, biology, physics 75(4), 1071-1078 (2009).

23. Tham IW, Hee SW, Yeo RM et al.: Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy-the national cancer centre singapore experience. International journal of radiation oncology, biology, physics 75(5), 1481-1486 (2009).

24. 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. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 104(3), 286-293 (2012).

25. Lee N, Xia P, Quivey JM et al.: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. International journal of radiation oncology, biology, physics 53(1), 12-22 (2002).

26. Wolden SL, Chen WC, Pfister DG, Kraus DH, Berry SL, Zelefsky MJ: Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience. International journal of radiation oncology, biology, physics 64(1), 57-62 (2006).

27. Lee N, Harris J, Garden AS et al.: Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma: radiation therapy oncology group phase II trial 0225. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(22), 3684-3690 (2009).

28. Zeng L, Tian YM, Sun XM et al.: Late toxicities after intensity-modulated radiotherapy for nasopharyngeal carcinoma: patient and treatment-related risk factors. British journal of cancer 110(1), 49-54 (2014).

29. Cao CN, Luo JW, Gao L et al.: Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for T4 nasopharyngeal carcinoma. Oral oncology 49(2), 175-181 (2013).

30. Kam MK, Teo PM, Chau RM et al.: Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. International journal of radiation oncology, biology, physics 60(5), 1440-1450 (2004).

31. Hu W, Ding W, Yang H et al.: Weekly paclitaxel with concurrent radiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 93(3), 488-491 (2009).

32. Kwong DL, Sham JS, Au GK et al.: Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22(13), 2643-2653 (2004).

33. Al-Sarraf M, Pajak TF, Marcial VA et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59(2), 259-265 (1987).

34. Al-Sarraf M, Pajak TF, Cooper JS, Mohiuddin M, Herskovic A, Ager PJ: Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: a radiation therapy oncology group study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 8(8), 1342-1351 (1990).

35. Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21(4), 631-637 (2003).

36. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International journal of radiation oncology, biology, physics 35(3), 463-469 (1996).

37. Chua DT, Ma J, Sham JS et al.: Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(6), 1118-1124 (2005).

38. Hui EP, Ma BB, Leung SF et al.: Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(2), 242-249 (2009).

39. Fountzilas G, Ciuleanu E, Bobos M et al.: Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 23(2), 427-435 (2012).

40. Chen L, Hu CS, Chen XZ et al.: Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. The lancet oncology 13(2), 163-171 (2012).

41. Lee BS, Kang S, Kim KA et al.: Met degradation by SAIT301, a Met monoclonal antibody, reduces the invasion and migration of nasopharyngeal cancer cells via inhibition of EGR-1 expression. Cell death & disease 5, e1159 (2014).

42. Sun W, Liu DB, Li WW et al.: Interleukin-6 promotes the migration and invasion of nasopharyngeal carcinoma cell lines and upregulates the expression of MMP-2 and MMP-9. International journal of oncology 44(5), 1551-1560 (2014).

43. Forastiere AA, Burtness BA: Epidermal growth factor receptor inhibition in head and neck cancer--more insights, but more questions. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 25(16), 2152-2155 (2007).

44. Niu X, Hu C, Kong L: Experience with combination of cetuximab plus intensity-modulated radiotherapy with or without chemotherapy for locoregionally advanced nasopharyngeal carcinoma. Journal of cancer research and clinical oncology 139(6), 1063-1071 (2013).

45. Chua DT, Sham JS, Au GK: A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral oncology 39(4), 361-366 (2003).

46. Chua DT, Wei WI, Wong MP, Sham JS, Nicholls J, Au GK: Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head & neck 30(7), 863-867 (2008).

47. Razak AR, Siu LL, Le Tourneau C: Molecular targeted therapies in all histologies of head and neck cancers: an update. Current opinion in oncology 22(3), 212-220 (2010).

48. Krishna SM, James S, Balaram P: Expression of VEGF as prognosticator in primary nasopharyngeal cancer and its relation to EBV status. Virus research 115(1), 85-90 (2006).

49. Lee NY, Zhang Q, Pfister DG et al.: Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. The lancet oncology 13(2), 172-180 (2012).

50. Hui EP, Chan AT, Pezzella F et al.: Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clinical cancer research : an official journal of the American Association for Cancer Research 8(8), 2595-2604 (2002).

51. Haque T, Wilkie GM, Jones MM et al.: Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 110(4), 1123-1131 (2007).

52. Fang Y, Guan X, Guo Y et al.: Analysis of genetic alterations in primary nasopharyngeal carcinoma by comparative genomic hybridization. Genes, chromosomes & cancer 30(3), 254-260 (2001).

53. Or YY, Hui AB, Tam KY, Huang DP, Lo KW: Characterization of chromosome 3q and 12q amplicons in nasopharyngeal carcinoma cell lines. International journal of oncology 26(1), 49-56 (2005).

54. Chu WK, Lee KC, Chow SE, Chen JK: Dual regulation of the DeltaNp63 transcriptional activity by DeltaNp63 in human nasopharyngeal carcinoma cell. Biochemical and biophysical research communications 342(4), 1356-1360 (2006).

55. Crook T, Nicholls JM, Brooks L, O'nions J, Allday MJ: High level expression of deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? Oncogene 19(30), 3439-3444 (2000).

56. Hui AB, Or YY, Takano H et al.: Array-based comparative genomic hybridization analysis identified cyclin D1 as a target oncogene at 11q13.3 in nasopharyngeal carcinoma. Cancer research 65(18), 8125-8133 (2005).

57. Lai JP,  Tong CL,  Hong C et al.:  Association  between  high initial tissue levels of cyclin d1 and recurrence of nasopharyngeal carcinoma. The Laryngoscope 112(2), 402-408 (2002).

58. Fan CS, Wong N, Leung SF et al.: Frequent c-myc and Int-2 overrepresentations in nasopharyngeal carcinoma. Human pathology 31(2), 169-178 (2000).

59. Yu Y, Dong W, Li X, Yu E, Zhou X, Li S: Significance of c-Myc and Bcl-2 protein expression in nasopharyngeal carcinoma. Archives of otolaryngology--head & neck surgery 129(12), 1322-1326 (2003).

60. Ma BB, Poon TC, To KF et al.: Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma--a prospective study. Head & neck 25(10), 864-872 (2003).

61. Codd JD, Salisbury JR, Packham G, Nicholson LJ: A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma. The Journal of pathology 187(5), 549-555 (1999).

62. Sheu LF, Chen A, Meng CL, Ho KC, Lin FG, Lee WH: Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: association with p53 expression. Human pathology 28(5), 556-562 (1997).

63. Cheung HW, Ling MT, Tsao SW, Wong YC, Wang X: Id-1-induced Raf/MEK pathway activation is essential for its protective role against taxol-induced apoptosis in nasopharyngeal carcinoma cells. Carcinogenesis 25(6), 881-887 (2004).

64. Wu HC, Lu TY, Lee JJ et al.: MDM2 expression in EBV-infected nasopharyngeal carcinoma cells. Laboratory investigation; a journal of technical methods and pathology 84(12), 1547-1556 (2004).

65. Qian CN, Guo X, Cao B et al.: Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma. Cancer research 62(2), 589-596 (2002).

66. Kwong DL, Sham JS, Leung LH et al.: Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma. International journal of radiation oncology, biology, physics 64(2), 374-381 (2006).

67. Kwong DL, Pow EH, Sham JS et al.: Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function. Cancer 101(7), 1584-1593 (2004).

68. Lin S, Lu JJ, Han L, Chen Q, Pan J: Sequential chemotherapy and intensity-modulated radiation therapy in the management of locoregionally advanced nasopharyngeal carcinoma: experience of 370 consecutive cases. BMC cancer 10, 39 (2010).

69. Bakst RL, Lee N, Pfister DG et al.: Hypofractionated dose-painting intensity modulated radiation therapy with chemotherapy for nasopharyngeal carcinoma: a prospective trial. International journal of radiation oncology, biology, physics 80(1), 148-153 (2011).

70. Ma BB, Kam MK, Leung SF et al.: A phase II study of concurrent cetuximab-cisplatin and intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 23(5), 1287-1292 (2012).

71. Wong FC, Ng AW, Lee VH et al.: Whole-field simultaneous integrated-boost intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma. International journal of radiation oncology, biology, physics 76(1), 138-145 (2010).

72. He X, Ou D, Ying H, Zhu G, Hu C, Liu T: Experience with combination of cisplatin plus gemcitabine chemotherapy and intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 269(3), 1027-1033 (2012).

73. Ng WT, Lee MC, Hung WM et al.: Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for nasopharyngeal carcinoma. International journal of radiation oncology, biology, physics 79(2), 420-428 (2011).

74. Su SF, Han F, Zhao C et al.: Long-term outcomes of early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy alone. International journal of radiation oncology, biology, physics 82(1), 327-333 (2012).

75. Xiao WW, Huang SM, Han F et al.: Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer 117(9), 1874-1883 (2011).

76. Wang J, Shi M, Hsia Y et al.: Failure patterns and survival in patients with nasopharyngeal carcinoma treated with intensity modulated radiation in Northwest China: a pilot study. Radiation oncology (London, England) 7, 2 (2012).

77. Lai SZ, Li WF, Chen L et al.: How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? International journal of radiation oncology, biology, physics 80(3), 661-668 (2011).

78. Kong F, Ying H, Du C et al.: Patterns of local-regional failure after primary intensity modulated radiotherapy for nasopharyngeal carcinoma. Radiation oncology (London, England) 9, 60 (2014).

79. Chan AT, Leung SF, Ngan RK et al.: Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. Journal of the National Cancer Institute 97(7), 536-539 (2005).

80. Zhang L, Zhao C, Peng PJ et al.: Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(33), 8461-8468 (2005).

81. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(27), 6730-6738 (2005).

82. Lee AW, Tung SY, Chua DT et al.: Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. Journal of the National Cancer Institute 102(15), 1188-1198 (2010).

83. Lee AW,  Tung SY,  Chan AT et al.:  A  randomized  trial  on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 98(1), 15-22 (2011).

84. Chen Y, Liu MZ, Liang SB et al.: Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china. International journal of radiation oncology, biology, physics 71(5), 1356-1364 (2008).

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

eISSN: 2312-0398

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.