**4. Risk factors**

Since the first case of this malignancy was recorded in 1901 [32], the etiology of the NPC has not been identified as a mystery. Risk factors for NPC, most commonly in men [33], include a family history of NPC, EBV infection, low intake of fresh vegetables and fruits, high consumption of salt-canned fish, smoking and Cantonese races [34]. On the other side, a reduced risk may be associated with a history of infectious mononucleosis (IM) and HLA genotypes [35]. Other potential risk factors are the genetic polymorphism in glutathione S-transferase M1 (*GSTM1*), *GSTT1*, cytochrome P450 2E1 (CYP2E1) and CYP2A6 [36], possibly high consumption of other preserved foods [37, 38] and the history of chronic respiratory diseases. The exposures to dust and formaldehyde, nickel exposure and consumption of herbal medicine are less established risk factors [39].

#### **4.1 Epstein-Barr virus (EBV)**

The relationship of NPC to EBV-associated is known and proven, and EBV infection is one of the common infectious agents in the population. This relationship concluded the hypothesis that an EBV subtype of NPC plays a role in increasing the incidence of NPC in the epidemic regions. The association between EBV infection and nasopharyngeal carcinoma is very strong and has been demonstrated in several studies [40].

In the nucleus of malignant cells there are approximately 30 copies of the EBV gene. Most versions refer to the presence of "small circular chromosomes" called episomes. In some cases, these episomes are adjacent to the viral DNA releases. The use of serological and virological tests is recommended to diagnose and study the populations at risk. In areas with an increased incidence of nasopharyngeal carcinoma, high levels of IgA antibodies with EBV capsid antigen and Epstein-Barr nuclear antigen are considered to be a valuable screening test or the new prediction model combining VCA/IgA and EBNA1/IgA which will improve diagnosis of NPC and could identify high-risk population [41].

#### **4.2 Familial history and genetic susceptibility**

It is known that families with a history of cancer, particularly nasopharyngeal carcinoma, are 4 to 10 times more likely to develop nasopharyngeal carcinoma. Some studies have reported that familial clustering is stable in areas with a high incidence of NPC [42] and in areas with low to moderate incidence [43]. In southern China, where NPC is endemic, more than 5% reported NPC with a positive family history of NPC in cases with first-degree family history [44]. Evidence and studies of previous case control studies have shown indifferent populations that the odds ratios for people between 2 and 20 with history of NPC and history of first-degree family were compared to people without such a medical history [45]. This size of association is among the highest in any malignant disease. In nasopharyngeal carcinoma the genetic research focuses on genes of human leukocyte antigen. Where it occurred in subjects with presence of EBV and weak HLA allele, the antigens likely increased the risk of developing nasopharyngeal carcinoma. The development of NPC less likely in people with the presence of EBV associated with strong HLA allele. In etiology of NPC, it is possible that genetics and environmental exposure play a common role. Four correlation studies with susceptibility sites of 4p15.1\_q12, 6p2153, 3p21.31e21.2 and 5p13 in NPC families of a single major susceptibility gene were observed and reported, supported by the results of NPC complex family segregation analysis, indicating that this the pathogens of NPC includes the interaction of many environmental and genetic factors [46, 47].

The genetic factor is one of the notable features of the race distribution in the cantonese population. The shared roles of environmental factors, lifestyle and genetics should not be ignored. Whether familial NPC cases differ significantly from sporadic cases in terms of clinical features (such as histopathology, stage of disease, and prognosis), gender, race, age, EBV sera, genetic risk factors, and environmental risk factors [48].

#### **4.3 Exposure to carcinogens**

#### *4.3.1 Salt-preserved foods and fish*

Several studies have reported that eating fish with salt is considered a risk factor for cancer. For the Chinese, the relative risk of developing pharyngeal cancer is lower among weekly consumers than those who use very little or no salt-canned

fish. Overall it was about 1.4 to 3.2 [36, 37]. The relative risks are between 1.8 and 7.5 for those who consume daily [49, 50]. The risk of developing nasopharyngeal carcinoma is higher with other canning foods such as fruits, vegetables, eggs and meat in Southeast Asia, Southern China, the Middle East, North Africa and the Arctic [51]. This preservative food is also implicated in people found in low-incidence areas of northern China and the United States [52].

### *4.3.2 Exposure to smoking and occupational products*

The direct relationship between nasopharyngeal carcinoma and smoking was confirmed by reports that people who had smoked cigarettes for ten years or more were more likely to develop NPC [53]. Several studies have confirmed that cigarette smoking is linked to nasopharyngeal carcinoma. The relationship pattern between the risk of developing nasopharyngeal carcinoma and smoking depends on the dose, especially in well-differentiated nasopharyngeal carcinoma [54]. Lin et al. [55] compared the surroundings of NPC patient with those of neighboring controls in Taiwan and found that cigarettes were smoking and working in poorly ventilated rooms was closely related to the NPC.

Another study found that long-term cigarette smoking was linked to the NPC, but only to a minor extent exposure to cigarette smoke through passive exposure to smoking and alcohol consumption is not associated with a disease risk [56].

#### *4.3.3 Oral hygiene*

There is a connection between poor oral hygiene in the elderly and cancers of the head, neck, esophagus and stomach [57]. In NPC, periodontal disease can increase recurrent inflammation and thus increase possibility of developing NPC as the inflammatory response may be on the way to promoting carcinogenesis, Zhiwei Liu et al 2016 suggested poor oral health may increase risk of NPC [58]. In addition, When more teeth are lost, the bacterial load also increases. Some types of bacteria are involved in the increased production of nitrosamine, which is thought to be carcinogenic and has been linked to the development of NPC. Poor oral hygiene can also increase the risk of NPC by EBV stimulation and proliferation, as evidenced by higher viral loads in people with periodontitis more than others [59].

#### *4.3.4 Other risk factors*

The relationship between alcohol consumption and nasopharyngeal carcinoma has been documented in complicated ways. Several studies have documented that there is no clear confirmation of a relationship between the risk of nasopharyngeal carcinoma and alcohol consumption [60]. Other studies confirmed the relation between nasopharyngeal carcinoma and the exposure to wood dust. Several studies have shown an increased risk of developing nasopharyngeal carcinoma after exposure to formaldehyde [61]. Exposure to other chemicals or stimuli such as smoke, steam, cotton dust, chemicals, flammable products, or solvents such as chlorophenol and phenoxy acid increases the risk of developing nasopharyngeal carcinoma [62]. An association between nasal cavity and sinus cancer and the textile work has also been reported [63]. In addition, several other non-dietary risk factors for nasopharyngeal carcinoma have been included [64]. It has been reported that occupational exposure to combustion products and cotton dust is independently related to NPC risk. The risk of developing NPC also increases through occupational exposure to formaldehyde and not through exposure to wood dust [65]. However, this association appears to be specific to squamous cell carcinoma. In addition,

eating canned foods has been linked to NPC at a young age and risk in all population groups [33]. Studies and data on inhalation of different types of smoke/fumes/ dust show that inhalants can play an important role, although they can secondary as a catalyst is the high incidence of NPC in various geographic regions of the world.

#### **5. Treatment**

#### **5.1 Radiation therapy**

Radiation therapy is the first type of cancer treatment method for non-invasive nasopharyngeal carcinoma (NPC) due to anatomical limitations and high sensitivity to radiation. One of the treatment method is with two-dimensional radiation therapy (2DRT), which has been converted to 3D compliant radiation therapy, and particularly highly modified radiation therapy (IMRT), is an important step forward in the treatment of NPC.

IMRT use was first reported in 2000 by the University of California at San Francisco. The results with 100% local control and a 4-year operating system are a dramatic 94%.

The second phase of II trails 0225 by the Radiation Oncology Group then showed that it is possible to transfer IMRT to a multi-institutional setting [66]. Three comparative randomized trials studies of IMRT and 2DRT have been applied. Chen et al. The studies confirmed a significant improvement in the therapeutic ratio by IMRT: The use of IMRT in patients with NPC demonstrated an improved terminal therapeutic ratio compared to 2DRT over a follow-up period of more than 10 years with significant improvement in OS, FFS, and L-FFS [67].

#### **5.2 Adjuvant and neoadjuvant chemotherapy**

While chemotherapy given concurrently with RT offers consistent benefits, the adjuvant chemotherapy role after alternative chemoradiotherapy is uncertain. The chemotherapy induction attempts for cases with local metastasis which include concomitant chemotherapy and radiation therapy, followed by adjuvant chemotherapy, in which an increased rate of NPC relapse in remote locations was observed in a large proportion of patients. These studies have shown the usefulness of this strategy for the OS. The administration of adjuvant chemotherapy was associated with significant toxicity, with 25-45% of the patients exhibiting high grade toxicities [68]. In addition, some research studies evaluating chemoradiotherapy protocols without adjuvant chemotherapy which provided similar results to studies using simultaneous and adjuvant chemotherapy, raising questions about the actual results and benefits of adjuvant chemotherapy for NPC control [69].

In theory, novel chemotherapy can prevent micrometastases earlier and also facilitate the mapping of RT by decreasing local metastasis, especially in large tumors. So far, phase III studies on novel adjuvant chemotherapy with postradiation therapy alone have proven no difference in OS compared to RT [70]. An up to date meta-analysis of MAC-NPC contained data from a number of induction chemotherapy studies and showed statistically excellent results in survival without disease progression, but not in OS [71]. Increased cases with leukopenia and neutropenia rates observed during the CRT period [72]. This confirms the primary interest in the new induction/adjuvant approach, which could interfere with the delivery of chemotherapy with effective doses and/or radiation therapy during the period of CRT or increased toxicity and outweigh the potential benefits of the induction-based approach.
