The global, regional, and national burden of nasopharyngeal carcinoma and its attributable risk factors in 204 countries and territories, 1990–2019

Abstract Background Nasopharyngeal carcinoma (NPC) is uncommon in most areas of the world but poses a significant public health burden in endemic regions. Objectives We provide an overview of the most recent global epidemiology of nasopharyngeal cancer (NPC). Methods We estimated the burden of NPC in 204 countries and territories by age, sex, and Socio-Demographic Index (SDI) from 1990 to 2019. Results At the GBD regional level, the most severe age-standardized incidence in 2019 occurred in East Asia. From 1990 to 2019, the East Asia and High-income Asia Pacific had the greatest increase in percentage in age-standardized incidence. Central Asia and the Caribbean had the greatest increase in percentage in age-standardized disability-adjusted life-years (DALY) and death rates. At the national level, Cabo Verde, Romania, and the Cyprus reported the largest percentage increases in the age-standardized incidence. Cabo Verde, Romania, and Jamaica reported the largest increases in the age-standardized DALY and death rates. Conclusions The global age-standardized incidence of NPC increased globally between 1990 and 2019, especially in the East Asia.


Introduction
Nasopharyngeal carcinoma (NPC) is uncommon in most areas of the world but poses a significant public health burden in endemic regions [1]. Nasopharyngeal carcinoma is a common malignant tumor in southern China and Southeast Asian countries, with an incidence of 10-50/100,000 [2]. Due to the hidden location of nasopharyngeal cancer, most patients have developed to advanced stage when they are diagnosed. Studies have confirmed that the survival of early stage patients is significantly better than that of late stage patients, so the early diagnosis of nasopharyngeal carcinoma is of great significance. Several studies have shown that the titers of EB virus-related antibodies NA1/IgA and VCA/IgA in patients with nasopharyngeal carcinoma are increased [1], and these antibodies have been widely used in the early diagnosis and screening of nasopharyngeal carcinoma.
Although the periodic literature indicates 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. Herein, data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 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 204 countries and territories from 1990 to 2019. Such information is of great medical significance for the prevention of NPC among high-risk groups in key geographic areas.

Overview
The general methodology of GBD 2019 has been presented elsewhere [4][5][6][7][8]. GBD 2019 systematically studied 369 diseases and injuries along with 87 behavioral, environmental, occupational, and metabolic risk factors. GBD 2019 is based on a geographical hierarchy consisting of 204 countries and territories grouped into 21 regions and 7 GBD superregions. The GBD Study followed the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement [9]. The Medical Ethics Committee at Ningbo Medical Center Lihuili Hospital reviewed and approved this study (KY2021PJ229). Table 1 shows the number of incident NPC cases for 2019, the age-standardized incidence rate per 100,000 for 2019, the percentage change in all age incidence counts, and the percentage change in age-standardized incidence rates between 1990 and 2019 by countries and territories. Globally, from 1990 to 2019, the number of incident NPC cases increased to 176,501.78, representing an increase of 1.61% in the number of global incident cases. The agestandardized incidence rate of NPC was 2.12 per 100,000 population in 2019, representing an increase of 0.37% from 1990 to 2019.
In 2019, the high-middle SDI quintiles (3.58 per 100,000 population) had the highest age-standardized incidence rate of NPC among all seven super-regions (Table 1 and Figure  1(A)). The low SDI and low-middle SDI quintiles were the only quintiles to experience a decrease in the percentage change in age-standardized incidence rate (À0.26%, and À0.19%), whereas the high-middle SDI showed the greatest increase (1.11%) ( Table 1 and Figure 1(D)). In all years from 1990 to 2019, the numbers and rates of males were always higher than those for females (Supplementary Tables  1 and 2).
At the country level, global maps of the age-standardized NPC incidence rates in 2019 and the percentage change in them from 1990 to 2019 are presented in Table 2 and Figure 2(A, D). The highest age-standardized NPC incidence rate per 100,000 population in 2019 was observed in Singapore (10.81), followed by Malaysia (6.08), and Greenland (6.00). In contrast, the lowest age-standardized rates in 2019 were found in Niger (0.11), Mozambique (0.14), and Sao Tome and Principe (0.15) ( Table 2 and Figure 2(A)).
The percentage change in the age-standardized NPC incidence rates from 1990 to 2019 revealed a significant difference between nations, with Cabo Verde (2.16%), Romania (1.96%), and Cyprus (1.59%) showing the largest increases. In contrast, Greenland (À0.45%), Kuwait (À0.45%), and Latvia (À0.41%) showed the greatest decreases during this period (Table 2 and Figure 2(D)). Figure 3(A) shows the NPC incidence rate in 2019 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. Figure 4(A) displays the global-and regional-level agestandardized NPC incidence rates observed from 1990 to 2019 and the prospective rates based on the SDI values. The age-standardized incidence rate in most regions decreased 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  Figure 1(B)). All super-regions showed a decreasing trend of age-standardized DALY rate, while the largest percentage decrease over the study period was observed in the Middle SDI quintiles (À0.43%) ( Table 1 and Figure 1(E)).
In 2019, the geographic regions with the highest agestandardized DALY rates of NPC per 100,000 population were Southeast Asia, with 52.27, East Asia with 46.29, and Eastern Sub-Saharan Africa with 38.43 (Table 1 and Figure  1(B)). From 1990 to 2019, among the 21 analyzed regions, East Asia (À0.50%), Southern Latin America (À0.46%), and Western Europe (À0.44%) showed the largest decreases. In contrast, Central Asia (0.18%) had the largest increase in the age-standardized DALY rate of NPC, followed by the Caribbean (0.13%) ( Table 1 and Figure 1(E)).
Global maps of the age-standardized DALY rates of NPC in 2019 and the percentage change in the age-standardized DALY rates from 1990 to 2019 at the country level are presented in Table 2 and Figure 2(B, E). The highest age-standardized DALY rate of NPC per 100,000 population was observed in Malaysia (152.29), followed by Greenland (137.74), and Brunei Darussalam (89.85) . The lowest agestandardized rates in 2019 were observed in Finland (3.25), Sweden (3.31), and Chile (3.34) ( Table 2 and Figure 2(B)).
The percentage change in the age-standardized DALY rates of NPC from 1990 to 2019 also revealed a dramatic difference between nations, with Cabo Verde (1.96%), Romania (1.18%), and Jamaica (0.87%) displaying the largest increases. In contrast, Singapore (À0.69%), France (À0.64%), and Kuwait (À0.6%) showed the largest decreases during this period (Table 2 and Figure 2(E)). Figure 3(B) shows the 2019 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 2019, the DALY rate peaked in the 60-64-year age group globally. In the high-SDI, low-middle-SDI, and low-SDI regions, the DALY rate peaked in the 55-59-year age group. Figure 4(B) displays the global-and regional-level agestandardized NPC DALY rates observed from 1990 to 2019 and the prospective rates based on SDI values. The agestandardized DALY rate in most regions decreased with the increase of SDI, especially in Southeast Asia. The death counts and age-standardized death rate per 100,000 population by countries and territories        Figure 1(C)). The largest percentage decrease in the agestandardized death rate from 1990 to 2019 was observed in the Middle-SDI countries (À0.40%) ( Table 1 and Figure 1(F)). The geographic regions with the highest age-standardized death rates of NPC per 100,000 were Southeast Asia with 1.74, East Asia with 1.45, and Oceania with 1.25 (Table 1 and Figure 1(C)). Among the 21 regions analyzed, East Asia (À0.50%), Southern Latin America (À0.45%), and Western Europe (À0.44%) showed the largest decreases in age-standardized death rate of NPC from 1990 to 2019. In contrast, Central Asia showed the highest increase (0.19%), followed by the Caribbean (0.12%) and Central Europe (0.05%) ( Table 1 and Figure 1(F)).
Global maps of the age-standardized death rates of NPC in 2019 and the percentage change in them from 1990 to 2019 at the national level are displayed in Table 2 and Figure 2(C, F). The highest age-standardized death rate of NPC per 100,000 population was observed in Malaysia (4.76), followed by Greenland (4.68) and Brunei Darussalam (2.91). The least age-standardized death rates in 2019 were observed in Finland (0.10), Norway (0.10), and Sweden (0.1) ( Table 2 and Figure 2(C)).
The percentage change in age-standardized death rates of NPC from 1990 to 2019 also varied greatly between countries, with Cabo Verde (1.86%), Romania (1.24%), and Jamaica (0.77%) displaying the largest increases. In contrast, Singapore (À0.68%), France (À0.64%), and Estonia (À0.58%) showed the largest decreases during this period ( Table 2 and Figure 2(F)). Figure 3(C) shows the NPC-specific death rate in 2019 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 2019, the death rate peaked in the over-80-year age group in the high-SDI groups. In the low-middle-SDI and low-SDI groups and globally, the NPC-specific death rate increased to 70-74 years, declined until 75-79 years, and then increased again. Figure 4(C) displays the global-and regional-level agestandardized NPC death rates observed from 1990 to 2019 and the prospective rates based on SDI values. The agestandardized 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 Table 3 reveals the numbers and age-standardized rate of risk-attributable DALYs and deaths of NPC in 2019 and the percentage changes in numbers and age-standardized rate of risk-attributable DALY and death for each cause. Globally, 1.11 million DALYs and 34.93 thousand deaths were ascribed to GBD-reported risk factors in 2019, which increased by 0.41% and 0.47% from 1990 to 2019. Between 1990 and 2019, the age-standardized risk-attributable DALY rate decreased to 13.42 per 100,000 population, representing a decrease of 0.27%. Meanwhile, the age-standardized riskattributable death rate decreased to 0.42 per 100,000 population, representing a decrease of 0.26%.
In 2019, the first leading contributor to the age-standardized DALYs rate was behavioral risks (13.10), representing a decrease of 0.27% from 1990 to 2019. This was followed by alcohol use (9.64), representing a decrease of 0.22%, and then tobacco and smoking (6.24), representing a decrease of 0.33%.
The highest risk-attributable age-standardized death rates were associated with behavioral risks (0.42), representing a decrease of 0.26% from 1990 to 2019. This was followed by alcohol use (0.29), representing a decrease of 0.22%, and then tobacco and smoking (0.21), representing a decrease of 0.31%.

Discussion
This report provides the latest available estimates of incidence of NPC, together with its associated DALYs and death rates, in 204 countries and territories from 1990 to 2019. Between 1990 and 2019, the age-standardized incidence rate increased by 0.37%, the age-standardized DALY rate decreased by 0.33%, and the age-standardized death rate decreased by 0.31%. Consistent with our findings, a global study 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 DALY and death rates in 2019 were the highest in the middle-SDI quintiles while the largest percentage decrease in these rates was also observed in the middle-SDI quintiles, as NPC is a rare cancer in developed areas. This may be attributable to early prevention, screening, diagnosis, and subsequent treatment in developed areas.
The current standard NPC treatment combines radiation therapy and 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 [12]. Newly emerging treatments, such as immunology and targeted therapy [13], as well as the use of vaccines to prevent and treat EBV-infected potential NPC patients [14] have contributed to the decline of DALY and death rates.
In consistent with other findings [15,16], the highest age-standardized incidence in 2019, DALY, and death rates of NPC were observed in Oceania, Southeast Asia, and East Asia, and the Caribbean and South Asia showed the highest increases in the age-standardized incidence, DALY, and death rates of NPC from 1990 to 2019. This suggests that there are obvious differences in the incidence of NPC among different races and ethnicities [15,16], and the incidence of yellow race is much higher than that of other races.
NPC is endemic in southern China and Southeast Asia [17]; the decreases in China are likely due to the implementation of Epstein-Barr virus (EBV) screening for early diagnosis and prevention strategies, increased public awareness, and the transformation of eating habits [18]. The declines of DALY and death rates in some areas might partly be due to a reduction in incidence rates. Improvements in diagnostic strategies and treatment methods were also major contributing factors [19].
We found that 77.42% of the new NPC cases in 2019 were concentrated in Asia. However, several high-risk countries in Asia, such as Indonesia, Malaysia, Philippines, Thailand, and China, showed a downward trend in agestandardized DALY rates and death rates of NPC, potentially contributing 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 from 1990 to 2019. The precise reason for this discrepancy requires further investigation bearing in mind the unique circumstances 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 are important etiological models of NPC [17]. In our study, occupational exposure to behavioral risks, alcohol use, smoking, and tobacco were found to be the four main risk factors contributing to NPC in terms of both DALYs and deaths in 2019, suggesting that primary prevention should be focused on controlling and avoiding these risks. The risk-attributable age-standardized DALY and death rates of NPC each showed a significant decrease from 1990 to 2019, especially with respect to smoking (À0.33% and À0.31%, respectively); this may have benefited from the WHO's introduction of the MPOWER policy.
Notably, early symptoms of NPC are similar to those of benign nasopharyngeal lesions, although early screening has not been widely popularized. Less than 20% of NPC patients are diagnosed early, whereas the vast majority of NPC patients are diagnosed in the middle and late stages [20]. EBV serology is the most important screening strategy: one study revealed that EBV screening is cost-effective for NPC [3].
To our knowledge, this is the first 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 204 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 the morbidity associated with a disease. However, our research also has limitations. The calculations in GBD 2019 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.

Conclusions
From 1990 to 2019, the global burden of NPC has decreased continuously, especially in the middle-SDI quintiles, East Asia, Southern Latin America and various other countries. The decreased burdens of risk-attributable DALY and death rates were mainly attributable to changes in behavioral risks, alcohol use, smoking, and tobacco. Interventions should target the established highrisk populations and regions.