The Global, Regional, and National Burden of Nasopharyngeal Carcinoma and Its Attributable Risk Factors in 194 Countries and Territories, 2007– 2017

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Introduction
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor usually originates in the Fossa of Rossenmueller [1]. NPC is uncommon in most areas of the world but poses a signi cant public health burden in endemic regions [2].
Although there are periodic literatures indicating that the incidence of and mortality from NPC is declining in endemic areas [3], no detailed quantitative global, regional, or national estimates of the NPC incidence and NPC-associated disability-adjusted life years (DALYs) and deaths are available across countries and territories.In this article, the data of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 was used to assess the global, regional, and national incidence of NPC and NPC-associated DALYs and deaths,in addition to its associated risk factors,across 194 countries and territories, for the years 2007 to 2017. Such information is of great medical signi cance for the prevention of NPC among highrisk groups in key geographic areas.

Overview
The general methodology of GBD 2017 has been presented elsewhere [4][5][6][7]. GBD 2017 systematically studied 359 diseases and injuries, 282 causes of death, and 84 behavioral, environmental, occupational, and metabolic risk factors. GBD 2017 is based on a geographical hierarchy consisting of 194 countries and territories grouped into 21 regions and 7 GBD super-regions. The GBD Study followed the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement [8].

Data sources
Data on the burden of NPC comes from an online database, the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool), which is a continuously updated global collaboration that uses the latest epidemiological data to compare and evaluate the health loss caused by 359 diseases in 194 countries and regions.

Disability-adjusted life years (DALYs)
In this article, DALYs was used as the standard indicator to quantify the burden 6 and was calculated by combining years of life lost (YLLs) and years lived with disability (YLDs). In GBD 2017, the average disability weight was multiplied by the age-, sex-, and region-speci c prevalence to derive YLDs. The disability weight is used to determine the severity of the disease and ranges from 0 (completely healthy) to 1 (equivalent to death).

Socio-demographic index (SDI)
In this study, the state of socioeconomic development of the country is re ected in SDI which was modi ed in GBD 2017 [4][5][6]. SDI is combined of the total fertility rate of the population under 25, average education level of the population over 15 years old, and lag-distributed income per capita on a scale from 0 (less developed) to 1 (most developed) [9].

Risk factors
The literature on risk factors and risk-attributable DALY and death had been reported before [10]. The assessment of exposure level and risk-attributable DALYs and deaths was estimated by the comparative risk assessment framework from 2007 to 2017. The proportions of DALYs and deaths that could be attributed to a speci c risk were assessed by the counterfactual scenario of theoretical minimum risk exposure level [10].

Statistical analysis
Rate per 100,000 population was age-standardized in the light of the GBD world population [9]. The 95% uncertainty interval (UI) was reported for estimates,in the process of cancer assessment, the calculation method of UIs were 2.5% and 97.5% of the distribution of 1000 lots, with the uncertainty disseminated through each step.

Results
The incidence counts and age-standardized incidence rate per 100,000 population by countries and territories Table 1 shows the number of incident NPC cases for 2017, the age-standardized incidence rate per 100,000 for 2017, the percentage change in all-age incidence counts, and the percentage change in agestandardized incidence rates between 2007 and 2017 by countries and territories. Globally, from 2007 to 2017, the number of incident NPC cases increased to 10 Fig. 1D). In all years from 2007 to 2017, the gender patterns between males and females were similar, although the numbers and rates of males were always higher than females (Supplementary Tables 1 and 2).
In 2017, at the geographic region level,the highest age-standardized incidence rates of NPC were observed at Oceania (3. Fig. 1D).
At the country level, global maps of the age-standardized NPC incidence rates in 2017 and the percentage change in them from 2007 to 2017 were presented in Table 2 and Fig. 2A Fig. 2D). Figure 3A shows the NPC incidence rate in 2017 at the global level by SDI regions across different age groups from 15 to over 80 years. The NPC incidence rate increased in most regions from ages 15 to 54 years, reaching a peak in the 65-69-year age group in the high-SDI regions and in the 70-74-year age group in the low-middle-SDI regions. Globally, the high-middle-SDI and middle-SDI groups showed similar age-speci c patterns:the NPC incidence rate increased up to 50-54 years, decreased until 55-59 years, and then increased again. Figure 4A displays the global-and regional-level observed age-standardized NPC incidence rates from 2007 to 2017 and the prospective rates based on the SDI values. The age-standardized incidence rate in most regions decreases with the increase of SDI, especially in Southeast Asia.
The DALY counts and age-standardized DALYs rate per 100,000 population by countries and territories  Fig. 1E).
Global maps of the age-standardized DALY rates of NPC in 2017 and the percentage change in the agestandardized DALY rates from 2007 to 2017 at the country level are presented in Table 2 and Fig. 2B Fig. 2E).
Figures 3B shows the 2017 DALY rates of NPC at the global level by SDI regions across different age groups from 15 to over 80 years. The DALY rate increased in most regions from ages 15 to 59 years. In 2017, the DALY rate peaked in the 60-64-year age group globally.In the middle-SDI regions, the DALY rate peaked in the 65-69-year age.And in the high-SDI, low-middle-SDI, and low-SDI regions, the DALY rate peaked in the55-59-year age group. In the high-middle-SDI regions, the DALY rate increased up to 50-54 years, decreased until 55-59 years, and then increased again. Figure 4B displays the global-and regional-level observed age-standardized NPC DALY rates from 2007 to 2017 and the prospective rates based on the SDI values. The age-standardized DALY rate in most regions decreases with the increase of SDI, especially in Southeast Asia.
The death counts and age-standardized deaths rate per 100,000 population by countries and territories  Fig. 1F).
Global maps of the age-standardized death rates of NPC in 2017 and the percentage change in them from 2007 to 2017 at the nation level are displayed in Table 2 and Fig. 2C Fig. 2F). Figure 3C shows the NPC-speci c death rate in 2017 at the global level by SDI regions across different age groups from 15 to over 80 years. In most regions,the death rate increased from ages 15 to 74 years. In 2017, the death rate peaked in the over-80-year age group in the high-SDI and middle-SDI groups. In the low-middle-SDI and low-SDI groups and globally, the NPC-speci c death rate increased up to 70-74 years, declined until 75-79 years, and then increased again. Figure 4C dispiays the global-and regional-level observed age-standardized NPC death rates from 2007 to 2017 and the prospective rates based on the SDI values. The age-standardized death rate in most regions decreased with the increase of SDI, especially in Southeast Asia.
The numbers of risk-attributable DALYs and death and the percentage changes in the risk-attributable agestandardized DALYs and death rates globally In 2017, occupational exposure to formaldehyde, smoking, alcohol use, and diet low in fruits were the primary four risk factors contributing to both DALYs and deaths of NPC. The rst leading contributor to the age-standardized DALYs rate was alcohol use (11.57 [9.69-13.35]), representing a decrease of 3.59% Consistent with our ndings, a global study also found decreasing trends in age-standardized rates of NPC incidence in southern and eastern Asia, North America, and the Nordic countries [3]. Nevertheless, absolute numbers of new NPC cases and NPC-attributable DALYs and deaths have increased as a result of population growth and aging. We observed that the age-standardized incidence, DALY, and death rates in 2017 were highest in the middle-SDI quintiles, whereas the largest percentage decrease in these rates were observed in the high-SDI quintiles, as NPC is a rare cancer in developed areas. The reason may be related to early prevention, screening, diagnosis and later treatment in developed areas.
The current standard NPC treatment incorporates radiation therapy combined with chemotherapy. However, due to the anatomical characteristics of the nasopharyngeal cavity and the biological characteristics of NPC, conventional local radiotherapy often involves important surrounding organs and tissues, which results in a series of side effects and sequelae [12]. Newly emerging treatments, such as immunology and targeted therapy [13][14][15], and the use of vaccines to prevent and treat EBV-infected potential NPC patients [16][17] (preventive vaccines and therapeutic vaccines) contributed to the decline of DALY and death rates.
Of the 21 regions analyzed, the highest age-standardized incidence in 2017, DALY, and death rates of NPC were observed in Oceania, Southeast Asia, and East Asia (at least double of those found in other areas). Furthermore, the Caribbean and South Asia showed the highest increases in the age-standardized incidence, DALY, and death rates of NPC from 2007 to 2017. NPC is endemic in southern China and Southeast Asia [18], and the decreases in China were probably due to the implementation of Epstein-Barr virus (EBV) screening for early diagnosis and prevention strategies, increased public awareness, and transform of eating habits [19][20][21]. The declines of DALY and death rates in some areas might partly due to a reduction in incidence rates. Improvements in diagnostic strategies and treatment methods were also main enabler [22][23].
We found that 77.42% of the new NPC cases were concentrated in Asian 2017. However, several high-risk countries in Asia, such as Indonesia, Malaysia, Philippines, Thailand, and China, showed a downward trend in age-standardized DALY rates and death rates of NPC, which may contribute to the overall global NPC burden. In addition, we observed the highest increase in the age-standardized incidence, DALY, and death rates of NPC in Ukraine, Jamaica, and Dominican Republic during 2007 to 2017. The exact reason for this observation requires further investigation in light of the actual situation in each country.
Currently, the etiology of NPC remains unclear, although there are clear epidemiological characteristics of regional aggregation and ethnic sensitivity. Compelling evidence suggests that genetic factors, EBV infection, environmental factors (e.g., premature exposure to chemical carcinogens, especially salted sh in southern China) are important etiological models of NPC [18]. In our study, occupational exposure to formaldehyde, smoking, alcohol use, and diet low in fruits were found to be the four main risk factors contributing to NPC both DALYs and deaths in 2017, suggesting that primary prevention should be focused on controlling and staying away from these risk factors. The risk-attributable age-standardized DALY and death rates of NPC both showed a signi cant decrease from 2007 to 2017, especially with respect to smoking (− 10.05% and − 8.17%, respectively); this may have bene ted from the World Health Organization (WHO)'s introduction of the MPOWER policy, which was created to help implement the WHO Framework Convention on Tobacco Control so that signi cant progress can be made in global tobacco control. In order to further reduce the burden of NPC worldwide, the main implementation measures should focus on the control of NPC-related risk factors, such as prohibiting smoking in public places, reducing alcohol consumption, averting detrimental occupational exposures, and increasing the intake of fresh fruits and vegetables.
For head and neck cancer, the primary risk factors are smoking pack-years, alcoholism, and human papilloma virus infection for oropharyngeal cancer. As the cause of NPC is not yet clear, effective etiological prevention is impossible. The detection and tracking of multiple indicators for high-risk groups so as to achieve early detection and early diagnosis for secondary prevention is a feasible strategy. Notably, the early symptoms of NPC are similar to those of benign nasopharyngeal lesions, and early screening has not been widely popularized. Less than 20% of NPC patients are diagnosed early, and the vast majority of NPC patients are diagnosed in the middle and late stages [24]. EBV serology is the most important screening strategy, a study has revealed that EBV screening is cost-effective for NPC [3].
To our knowledge, this is the rst study to provide a contemporary comprehensive assessment of the estimated NPC burden at the global, regional, and national levels by age, sex, and socio-demographic status in 194 countries and territories over time. We used the SDI to identify areas wherein the NPC burden is better or worse than expected. We also reported the DALYs, an intuitive comprehensive indicator that explains both the mortality and morbidity associated with a disease. These analyses enabled the contextualization of the disease burden via cross-disease and cross-geographic comparisons.
However, our research also has limitations. The calculations in GBD 2017 were based on an algorithm that used the currently available data in each country. As NPC is a rare disease, data in some regions might be limited; therefore, the UIs were wider in areas where fewer data points were available.
In conclusion, from 2007 to 2017, the global burden of NPC has decreased continuously, especially in the middle-SDI quintiles, Southeast Asia, East Asia,and various other countries. The decreased burdens of risk-attributable DALY and death rates were mainly attributable to changes in alcohol use, smoking, and consumption of diet low in fruits. Interventions should be targeted at the established high-risk populations and regions.