Epidemiology and Population Screening

C H A P T E R

4 Epidemiology and Population Screening Zhi-Ming Mai1, Jia-Huang Lin1, Dennis Kai Ming Ip1, Sai-Yin Ho1, Yap-Hang Chan2, Tai-Hing Lam1 1

School of Public Health, University of Hong Kong, Hong Kong, China; 2Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China

O U T L I N E Introduction

65

Knowledge Gaps

74

Descriptive Epidemiology Geographic Distribution Secular Trends of Incidence and Mortality Family History of Cancer or Nasopharyngeal Carcinoma Environmental Factors (including Lifestyle Factors) Socioeconomic Status Consumption of Salted Fish Tobacco Smoking Consumption of Milk Vitamin D Deficiency

65 65 66

Data Collection

74

Hospital Versus Community Controls

75

Individual Versus Frequency Matching

75

67 67 67 68 68 70 72

Individual Participant Data Meta-Analysis of Nasopharyngeal Carcinoma Case-Control Study

75

Population Screening

73

Methodological Considerations for Future Epidemiological Studies on Nasopharyngeal Carcinoma

74

Conclusions

75

Acknowledgments

76

References

77

Commentary on Chapter 4: Epidemiology and Population Screening

81

References

83

INTRODUCTION Nasopharyngeal carcinoma (NPC) is an uncommon cancer with a unique pattern of geographical distribution. Globally, 86,691 NPC cases were diagnosed in 2012, accounting for 0.6% of all cancers reported.1 Multiple factors are implicated in its etiology, including EpsteineBarr virus (EBV) infection, genetic susceptibility, and environmental and lifestyle-related factors.

DESCRIPTIVE EPIDEMIOLOGY Geographic Distribution For most parts of the world, NPC is a rare disease, with an age-standardized incidence rate (ASIR) of less than one per 100,000 person-years for both sexes.1 Over 70% of new cases were reported in East and Southeast Asia, and the Nasopharyngeal Carcinoma https://doi.org/10.1016/B978-0-12-814936-2.00004-3

65

Copyright © 2019 Elsevier Inc. All rights reserved.

66

4. EPIDEMIOLOGY AND POPULATION SCREENING

remainder mainly in South-Central Asia, and North and East Africa. In this chapter, incidence refers to ASIR, unless stated otherwise. The same applies to mortality rate. Southeast Asia is an area with the highest NPC incidence, with an overall ASIR of 4.3 per 100,000 person-years. Substantial incidence variations are observed even within China in the Han ethnic groups of similar genetic origin. In general, the incidence in China increases geographically from north to south,2,3 with ASIRs reaching very high levels in Guangdong Province, including Zhongshan (26.8 in men and 10.7 in women in 2003e07),4 Guangzhou (w16.0 and 7.0 in 2011),5 Sihui (30.3 and 13.1 in 2011),6 and Hong Kong (13.0 and 4.0 in 2015).7 High ASIRs are also reported in Guangxi, Hainan, Hunan, and Fujian provinces.8 According to Cancer Incidence in Five Continents Volume IeX, high ASIRs of NPC were reported in emigrants of Southern Chinese origin, including immigrant populations in Singapore (12.6 per 100,000 person-years in men and 4.1 in women, 2003e07), Malaysia (8.3 and 2.9, 2003e07), the Philippines (5.5 and 2.0, 2003e07), Vietnam (10.4 and 4.6, 1993e97 in Hanoi and 4.8 and 1.7, 1995e98 in Ho Chi Minh City), Thailand (3.1 and 1.3, 2003e07), and the United States including Hawaii (7.6 and 3.4, 2003e07) and California (5.9 and 1.9, 2003e07). High ASIRs were also reported in some arctic regions, including Canada (9.2 and 6.0, 1983e97), Greenland (12.7 and 9.2, 1992e2002), Alaska (7.8 and 2.4, 1992e2002), Algeria (7.6 and 3.4, 2003e07) and Tunisia (4.6 and 1.9, 1998e2002).

Secular Trends of Incidence and Mortality In the past few decades, ASIRs of NPC have decreased in nearly all the high-incidence regions and in immigrant Chinese populations in the United States and several European countries.9 The five most prominent decreasing trends of incidence in men were reported in American Indian/Alaska Natives in 1992e2012 (average annual percent changes [AAPCs,10 a summary measure of the trend over a prespecified fixed interval. It is used as a single number to describe the average annual percent changes over a period of multiple years.]:
5.4%), Russia 1994e2007 (
4.0%), Hong Kong China 1983e2012 (
3.2%), India 1993e2007 (
2.6%), Singapore 1990e2007 (
2.5%) and the Philippines 1983e2007 (
2.5%).9 In women, the five most prominent decreasing trends were observed in American Indian/ Alaska Natives in 1992e2012 (AAPCs:
5.4%), Hong Kong China 1983e2012 (
4.1%), Singapore 1987e2007 (
3.7%), the Chinese mainland 2000e2011 (
3.3%) and the Philippines 1983e2007 (
3.2%). In Singapore, where NPC incidence rates were available for the longest period (for 37 years, 1970e2007), the incidence trends were stable in men in 1970e1990 (AAPCs: 0.2%) and in women in 1970e1987 (0.1%), but appeared to be decreasing in men after 1990 (
2.5%, 1990e2007) and in women after 1987 (
3.7%, 1987e2007). During similar periods, a greater decline was also observed in Hong Kong (APPCs:
3.2% in men,
5.2% in women), and the ASIR in men and women combined decreased by 67%, from 24.6/100,000 person-years in 1983 to 8.1 in 2015.7 In Taiwan, a decreasing trend (11.2e8.6/ 100,000 person-years by 23% for men, and 4.4 to 3.0/100,000 person-years by 30% for women) was also observed in 1981e2000.11 However, in other NPC endemic regions, the trends varied in different periods. For example, Zhongshan reported an increasing trend of ASIR in men and women combined between 1970 (14.0 per 100,000 person-years) and 1999 (17.0),8 but the incidence rate has decreased in recent years.12 In Sihui (1983e2011)6 and Cangwu (1978/ 1983e2002)13 counties of Southern China, the ASIRs have remained stable in 1987e2011, suggesting an influence of economic development on secular trends.14,15 Besides, substantial increases were observed in some nonendemic regions between about 1990 and 2010, including Brazil (AAPCs: 6.1% in men, 7.1% in women), England (1.7% in women, but not in men), and Slovakia (1.4% in men, but not in women). Age-standardized mortality rates (ASMRs) were also decreasing in NPC endemic regions, most substantially in Hong Kong China in 1970e2013 (AAPC:
3.1% in men,
4.0% in women), Singapore 1984/ 85e2013 (
2.2% and
3.1%), the Chinese mainland 2000e2011 (
2.5% and
2.2%), and Asian or Pacific Islanders of the United States 1990e2012 (
3.7% and
2.5%). Declines were also observed over the last three decades in many developed regions with low NPC risk, including the United States, Canada, Czech Republic, France, Germany, Malta, Slovakia, Spain, the United Kingdom, Croatia, Republic of Moldova, the Netherlands, Australia, and Hungary. However, increasing trends of NPC mortality were observed over a similar period in several countries, including South Korea, the Philippines, Brazil, Bulgaria, Greece, Portugal, Serbia, and Belgium. The underlying causes, while specific primary prevention programs are lacking, are poorly understood. As most of the available incidence data are regional with varying population coverage, data completeness and representativeness, particularly in some low- and middle-income countries where NPC risk was high, reliable population-based cancer registries covering all countries are urgently needed. In addition, although being

DESCRIPTIVE EPIDEMIOLOGY

67

important etiology-related factors for NPC, information on race and histological subtypes of NPC is seldom collected and hence not available in most populations. We recommend that such information should be routinely collected by all cancer registries, following the approach of Global Initiative for Cancer Registry Development c/o International Agency for Research on Cancer (IARC), World Health Organization. As NPC is decreasing in most parts of the world, in places where elevated incidence rates are observed, whether these increases are real or due to raised awareness and improved diagnosis should be examined and clarified. If it is the former, it is alarming and the causes should be identified urgently.

Family History of Cancer or Nasopharyngeal Carcinoma A positive family history of NPC in first-degree relatives (FDRs) has been consistently reported as a risk factor of NPC in studies in both endemic and nonendemic regions.16 Compared with those without family history, individuals reporting a positive family history of NPC in FDRs had a 4 to over 20-fold risk of the disease.17,18 A cohort study that followed the entire population born in Greenland with 134 NPC cases in 1973e2002 showed a significant relative risk (RR) of 8.0 (95% confidence interval [CI] 1.1e3.9) in those with family history of NPC in FDRs.19 Another cohort study from Taiwan by Hsu et al. with 43 NPC cases in more than 10,000 subjects followed for 22 years showed a significant hazard ratio (HR, which indicates RR) of 6.8 (95% CI 2.3e20.1) in subjects with a family history of NPC in first-, second-, and third-degree relatives.20 A case-control study conducted in Hong Kong in 2010e2012 with 352 NPC cases and 410 controls also showed a significantly increased risk (odds ratio [OR] as an estimate of RR, 4.52, 95% CI 2.39e8.55) in subjects with family history of NPC in FDRs.21 A family history of NPC is a very strong predictor for NPC, suggesting that on top of environmental factors, genetic factors also play an important role in the etiology of NPC. Family history of other types of cancer and the risk of NPC has not been well explored. One case-control study from Guangzhou by Ren et al.22 in 2010 included 1845 incident cases of NPC and 2275 controls. They observed a significant association between family history of any cancer in FDRs and the risk of NPC (OR 1.72, 95% CI 1.47e2.03), and the risk increased with the number of such FDRs (p for trend <0.01). The family history of head and neck cancer in NPC patients’ parents (OR 2.01, 95% CI 1.08e3.75) and lung and breast cancer in NPC patients’ siblings (lung: OR 2.73, 95% CI 1.25e5.96; breast: OR 2.50, 95% CI 1.08e5.76) were also associated with higher NPC risks. Under the University of Hong Kong Center for NPC Research and the Area of Excellence (AoE) Scheme of University Grants Committee/Research Grants Council of Hong Kong, our Multicenter Case-Control study, also funded by the World Cancer Research Fund WCRF, has found consistent results that having a family history of any cancer (except NPC) or NPC in FDR(s) was significantly associated with higher risk of NPC. Studies of immigrant populations have shown that NPC incidence in Chinese immigrants is higher than that in African Americans and Caucasians in the United States. NPC risk of Chinese immigrants to the United States is lower in later generations than in the first generation, but the incidence is still higher than those of other ethnic groups.23,24 The diminishing risks due to family history in the context of socioeconomic improvement (and the associated decline in environmental risk factors, such as diet) suggest strong geneeenvironment interaction. Future research should examine whether and how genetic factors interact with environmental (including lifestyle) risk factors in different generations and ethnic groups.

Environmental Factors (including Lifestyle Factors) Socioeconomic Status While lower socioeconomic status (SES) has been shown to link to increased risk and poorer survival in head and neck cancer,25,26 its role in NPC risk and survival has rarely received research attention. Few reports have shown the association between SES and the risk of NPC. One case-control study in Turkey, including 183 NPC cases and 183 healthy controls matched by sex and age in 2011, reported “a significant association between low SES (low, middle, high) and elevated NPC risk” (low: OR 1.00; middle: OR 0.08, 95% CI 0.01e0.69; high: OR 0.21, 95% CI 0.03e1.77).27 One population-based follow-up study in 2002e2006 with 4691 NPC patients in Taiwan by Chang et al. showed that in NPC patients younger than 65 years, the 5-year overall survival rates were the worst in those with low SES living in disadvantaged neighborhoods.28 However, the ecological study using data from the US National Cancer Institute (NCI), Surveillance, Epidemiology, and End Results Program reported no clear NPC incidence patterns by countylevel SES.18

68

4. EPIDEMIOLOGY AND POPULATION SCREENING

NPC incidence has decreased without specific primary prevention in almost all NPC endemic regions in the past four decades. Many of these regions have had rapid economic growth during the same periods. Taking Hong Kong as an example, the incidence declined from 24.6 to 8.1/100,000 in 1983e2015 in both sexes.29 According to the World Bank, the per capita GDP in Hong Kong increased from US$1893 in 1973 to $43,681 (by about 2200%) in 2016. The rapid economic growth has resulted in great changes in lifestyle including diet. Our preliminary analysis of the NPC Multicenter Case-Control Study in Hong Kong has shown that higher socioeconomic status was associated with less smoking, alcohol drinking, and occupational exposure to carcinogens, shorter duration of sun exposure, and lower risk of NPC, respectively. The ecological and individual negative association of NPC risk with socioeconomic development and status, respectively, suggests that the decline in NPC could be continuing, if improvements in socioeconomic factors mean reducing exposure to specific risk factors such as specific dietary components. Studies of the factors for such decline, including individual exposure strongly related to socioeconomic development, and ecological studies of such factors and NPC time trends in different countries or regions are warranted. Consumption of Salted Fish Dietary consumption of Cantonese-style salted fish is classified as a group I carcinogen for NPC by the IARC since 1992.30 Cantonese-style salted fish used to be one of the cheapest foods in Southern Chinese to supplement rice and it was probably widely consumed in the past in many poorer areas where NPC is common. Cantonesestyle salted fish rice porridge was the traditional staple diet for infants and children about two decades ago. Salted food including salted fish is also one of the traditional foods in other NPC endemic regions, such as North Africa and the Arctic. Cantonese-style salted fish is prepared by salting, brining, or a combination of these methods.30 Fish are generally not gutted before salting, and some salted fish are fermented, but some are not. Insect infestation could be a severe problem during drying of salted fish. In Southern China, the average annual temperature and humidity are high and favor bacterial growth.17 The mechanism of how consumption of salted fish causes NPC is not established, but is thought to be due to exposure to N-nitroso compounds, for example, nitrosamine (group IIA carcinogen by IARC) and/or reactivation of latent EBV infection.17,30 It is remarkable that no group I carcinogens have been established as the underlying cancer causing ingredients of a group I food carcinogen. The evidence of salted fish having a role in NPC development was first reported by Ho when boat people (Tanka people) were observed to have twice the risk of NPC compared with other land-dwelling people in Hong Kong in the 1960s. He hypothesized that as a staple diet, salted fish might account for the excess risk.31e33 Almost all studies of salted fish and the risk of NPC were conducted in Chinese. All studies on salted fish and NPC were case-control studies, and no cohort study has yet been published. The ORs of NPC for salted fish consumption weekly versus never or rare consumption ranged from 1.1 to 37.7, while the ORs for daily consumption ranged from 1.8 to 17.4.17,18 These great variations in ORs are puzzling, and the very high ORs could be due to small numbers in the denominators and/or recall bias. A case-control study on Alaska Natives with 31 NPC cases diagnosed 1966e1976 reported a positive association with salted fish consumption in childhood.34 In the positive studies, salted fish consumption in childhood and during weaning showed the strongest association, while the association of adult consumption was weaker. Only modestly increased risks were found in most studies and the three largest studies (with more than 500 cases),17,18,30 and increased risks were observed for only the most exposed individuals. Smaller risks have been observed in more recent studies;16 the evidence suggests the strength of the association has declined over time.17,30 Our preliminary analysis from the NPC Multicenter Case-Control Study in Hong Kong has also shown a positive association with salted fish consumption (monthly, weekly, and daily) in childhood, adolescence, and adulthood. This pattern of declining strength of association has been explained by several reasons17: (1) the NPC cases in earlier studies were younger; (2) salted fish consumption and production were not well documented; (3) the economic development in the community and individuals, and a shift toward greater availability and affordability of commercially produced products (such as canned fish and meat) and fresh produce resulted in the decline of salted fish consumption and increasing consumption of healthier foods, such as fresh fish, vegetables, and fruits.15 Tobacco Smoking Tobacco contains at least 250 harmful chemicals and it is classified as a group I carcinogen by IARC.17,30 Tobacco is one of the most well-known causal factors for many cancers and diseases.35 Unlike other cancers, it is still uncertain whether the association between smoking and NPC is causal NPC was considered being causally related to smoking by IARC17 based on 14 case-control studies and six cohort studies. Studies with nonsignificant results

DESCRIPTIVE EPIDEMIOLOGY

69

were not included in the report. Studies with poor quality and studies that merged pharynx cancer with NPC cases were also used to support the causal association in the IARC report. The most updated review in the US Surgeon General Report in 201435 showed an updated list with additional diseases that were newly considered as causally linked to smoking, but NPC was not included. No conclusion has been reached by other authoritative organizations. The relationship between smoking and the risk of NPC was studied in both endemic and nonendemic regions. The quality of the available evidence varied widely. Most were case-control studies, which tend to overestimate associations. Evidence from prospective studies, which should give stronger observational evidence than case-control studies, remains limited. Only six cohort studies were published.36e41 Tumors of different cell types may have different causes or risk factors. Undifferentiated nonkeratinizing carcinoma is the predominant NPC cell type in endemic regions and keratinizing squamous cell carcinoma in nonendemic regions. Hence, the association of NPC with smoking should better be examined separately in endemic and nonendemic regions, or by cell type. Examination by each cell type for each region would be limited by the small number of cases of the rare cell type in a specific region. Pooling of individual cell type data of different studies from different regions is needed. We found six cohort studies; two were conducted in low NPC risk regions36,38 and five in NPC endemic regions.37,39e41 In the low-risk region, a US cohort study on 248,046 veterans with 48 NPC deaths after 26 years of follow-up reported a statistically significant dose-response relationship of NPC risk with the amount of daily smoking, but no significant trend for the smoking duration or cumulative consumption.36 The British Doctors’ Cohort Study 50-year follow-up paper with only four NPC cases suggested that smoking “might be” related to NPC risk.38 For cohort studies in NPC endemic regions, Liaw et al.37 from Taiwan followed 14,397 Chinese subjects for 12 years, and found 16 NPC deaths, and reported a nonsignificantly increased risk of NPC with smoking status (RR 3.9, 95% CI 0.9e17.0), daily smoking amount (cigarettes/day) (10: RR 3.6, 95% CI 0.8e16.3; 11e20: RR 3.3, 95% CI: 0.8e14.0; >20: RR 3.1, 95% CI 0.3e31.5; p for trend ¼ 0.13), smoking duration (years) (20: RR 4.4, 95% CI 0.8e23.5; 21e30: RR 2.6, 95% CI 0.5e15.1; >30: RR 3.5, 95% CI 0.8e15.1; p for trend ¼ 0.22), age at starting smoking (years) (20: RR 3.3, 95% CI 0.8e14.1; 21e24: RR 4.8, 95% CI 1.0e23.5; >24: RR 2.8, 95% CI 0.5e14.8; p for trend ¼ 0.07), and cumulative cigarette smoking (pack-years) (<20: RR 3.2, 95% CI 0.7e14.5; 20e40: RR 3.9, 95% CI 0.9e16.7; >41: RR 2.8, 95% CI 0.4e18.9; p for trend ¼ 0.13). Another Chinese study in Taiwan by Hsu et al.40 on 9622 subjects with 32 NPC cases after 22 years of follow-up reported significantly increased NPC risks for smoking >30 pack-years (HR 3.0, 95% CI 1.3e7.2) and smoking duration longer than 30 years (HR 3.2, 95% CI 1.2e8.8), but no other significant results were found. The study by Friborg et al. in Singapore39 with the largest number of NPC new cases (n ¼ 173) so far, after 61,320 Singapore Chinese subjects were followed up for 12 years, reported a significantly increased risk for smoking for >40 years (RR 2.0, 95% CI 1.2e3.3). Daily smoking amount and age at starting smoking were not associated with NPC risk. The latest published cohort study by Lin et al. in Guangzhou41 with 34 NPC deaths after following 101,823 Chinese subjects for 10 years reported a significant dose-response trend between smoking status (daily smokers vs. never smokers) (HR 2.95, 95% CI 1.01e78.68), smoking amount (cigarettes/day) (1e14: HR 1.74, 95% CI 0.45e6.79; 15þ: HR 4.00, 95% CI 1.29e12.35; p for trend ¼ 0.012), smoking duration (years) (1e9: HR 3.07; 95% CI 0.69e13.62; 10þ: HR 2.93, 95% CI 0.97e8.89; p for trend ¼ 0.064), smoking cumulative consumption (pack-years) (<10: HR 1.76, 95% CI 0.45e6.89; 10þ: HR 4.03; 95% CI 1.29e12.58; p for trend ¼ 0.014), and the risk of NPC, suggesting that smoking is likely to be causally associated with NPC. Two meta-analyses42,43 on reported summary results at study level (not on individual participant data) have showed a higher risk of NPC for higher and heavier smoking consumption than no-smoking. The meta-analysis42 in 2013 included four cohort studies and 28 case-control studies in both endemic and nonendemic regions. A total of 415,266 subjects and 10,274 NPC cases were included. The pooled OR was 1.60 (95% CI 1.38e1.87) for all 32 studies, 1.63 (95% CI 1.38e1.98) for the 28 case-control studies, and 1.38 (95% CI 0.96e1.98) for the four cohort studies. However, substantial heterogeneity was reported in the results from all 32 studies (I2 ¼ 80%, P < .01) and from the 28 casecontrol studies (I2 ¼ 82%, P < .01). No heterogeneity (I2 ¼ 39%, P < .18) was reported for the four cohort studies, but the number of cohort studies was insufficient for subgroup analysis in endemic and nonendemic regions. The recent meta-analysis43 in 2017 included 17 case-control studies and four cohort studies in both endemic and nonendemic regions. A total of 429,464 subjects and 5960 NPC cases were included. The pooled OR was 1.56 (95% CI 1.32e1.83) for all 19 studies, 1.61 (95% CI 1.36e1.91) for the 17 case-control studies, and 1.11 (95% CI 0.84e1.83) for the two cohort studies. Again, the results from all 21 studies (I2 ¼ 66.8%, P < .001) and the 19 case-control studies (I2 ¼ 65.8%, P < .001) showed substantial heterogeneity. In these two meta-analyses, the pooled ORs for case-control studies were higher than those for cohort studies, suggesting that case-control studies might have overestimated the ORs. The nonsignificant results from cohort studies cannot provide robust evidence to support causation.

70

4. EPIDEMIOLOGY AND POPULATION SCREENING

Under the NPC Epidemiology Theme, recognizing the preceding limitations, we have invited principal authors of published cohort studies to participate in an individual participant data (IPD) meta-analysis. We focused on cohorts in NPC endemic regions as the cell type would be predominantly undifferentiated nonkeratinizing carcinoma, and the number of cases would be greater. We have identified six eligible cohorts, and all have participated (two each from Guangzhou and Taiwan, one each from Hong Kong and Singapore). The pooled dataset included more than 3 million subjects and more than 400 NPC fatal and nonfatal cases. The preliminary results have shown clear and significant dose-response relationship of NPC risk with smoking, as analyzed by different indicators of exposure (ever smokers, daily smokers, daily smoking amount, years of smoking, and smoking cumulative consumption vs. never smokers). Such results should become the strongest observational evidence to support smoking as a causal factor of NPC. Consumption of Milk The endemic regions of NPC are marked by rapid economic growth in the past few decades, and such growth paralleled with the decline in NPC risk. However, the underlying causes remain largely unclear. Economic development has also brought great changes of lifestyle, including decreased consumption of preserved food and increased consumption of various fresh food. In recent years, declines in salted fish consumption per capita were observed globally. Under the NPC Epidemiology Theme, we conducted ecological studies to investigate the longitudinal trends in ASIRs and ASMRs of NPC across eight regions and their correlations with secular trends in salted fish. In Hong Kong, China, we found decreasing trends of NPC ASIR and ASMR over the past three decades, which were correlated with corresponding secular changes in salted fish consumption per capita (for 10 cumulative years for ASIR, Pearson r 0.729 (men), 0.674 (women); for ASMR, Pearson r 0.943 (men), 0.622 (women), all P < .05 except for female ASMR). However, such correlations were not statistically significant after adjusting for decreasing tobacco and increasing vegetable consumption per capita (for 10 cumulative years for ASIR, beta [b] regression coefficient: 2.077 [men], 0.339 [women]; for ASMR, Pearson r 0.289 [men], 1.992 [women], all P > .05). Moreover, in seven other regions (the Chinese mainland, Finland, Japan, Portugal, Singapore, the United Kingdom and the United States), we found no clear or consistent patterns in the relationship between salted fish consumption with NPC ASIR and ASMR.15 Our ecological results suggested that the decreasing trend of NPC incidence may be due to factors other than salted fish. Milk consumption is generally high in nonendemic regions of NPC, but is much lower in endemic regions. However, in Asia, milk consumption has greatly increased in the more developed and westernized countries, although it is still far lower than Western countries. Evidence of milk consumption and NPC is very limited. A case-control study on Chinese in Malaysia showed that milk consumption with daily meals was a protective factor for NPC (OR 0.6, P < .01).44 A more recent case-control study in Taiwan showed a protective, but nonsignificant association between milk consumption and NPC (OR 0.90, 95% CI 0.48e1.69).45 However, a case-control study in a population of Caucasian ancestry showed an increased but nonsignificant NPC risk for elevated milk consumption (OR 1.40, 95% CI 0.84e2.34).46 Another case-control study showed that consumption of rancid butter was a significant risk factor for NPC (OR 2.5, 95% CI 1.4e4.5) in the Maghrebian population from Tunisia, Algeria, and Morocco.47 The available results were from studies conducted a few decades ago before the changes of dietary patterns with rapid economic development in endemic regions of NPC.44,45,48,49 Milk and dairy products have long been recognized as an important food source, which contains a great amount of calcium, vitamin B-6, and vitamin B-12. The 2007 World Cancer Research Fund/American Institute for Cancer Research (AICR) Second Expert Report suggests that about 30%e40% of cancer cases are potentially preventable through changes in food consumption patterns and that milk consumption probably protects against colorectal cancer and shows limited, but suggestive level of evidence for protection against bladder cancer.50 We, therefore, assessed the ecologic correlations of milk and dairy product per capita consumption with NPC incidence. Ecological Study To assess the population disease impact from changes over decades in the consumption of food items that are suspected to be harmful or protective, ecological studies are the most cost-effective approach (and could be the only feasible method) to provide quick albeit preliminary evidence at low cost. We investigated the correlations of NPC incidence and milk consumption per capita in 48 countries/regions with comprehensive and reliable cancer and food statistics data. Details about the design, methods, and subjects have been described elsewhere.14 Briefly, incidence rates in 1998e2002 for NPC (ICD-10: C11) were obtained from Cancer Incidence in Five Continents (Vol. IX). Data of milk consumption per capita in 1968e2002 were obtained from the Food and Agriculture Organization of the United Nations. Spearman correlation analysis yielded correlation coefficients between milk

DESCRIPTIVE EPIDEMIOLOGY

71

consumption per capita and NPC incidence rates and the multiplicative model yielded regression coefficients between milk consumption and log NPC incidence rates adjusting for socioeconomic status in 48 countries/regions. More detailed analysis was conducted for Hong Kong because Hong Kong has the highest NPC risk and data of several NPC risk factors for more than 20 years. Multivariate linear regression and time-lagged analysis were used to examine such correlation in Hong Kong in 1983e2009. Negative correlations between increased per capita consumption of different types of dairy products and decreased NPC incidence rates were observed in 48 countries/regions in 1998e2002. Increased consumption in most types of dairy products in 1968e2002 correlated with decreased incidence rates in 1998e2002 across different time lags in time-lagged analyses, except for cheese consumption. The negative correlations remained significant after adjusting for socioeconomic status (Human Development Index). In Hong Kong, negative and significant correlations between increased milk consumption at 10-year lagged and decreased incidence rates were also observed after adjusting for consumption of salted fish, cigarette, fresh vegetable, and socioeconomic status (Gross Demographic Index). Our findings that milk consumption could be protective are also biologically plausible when several milk constituents are considered. Calcium Milk and dairy products contain high levels of calcium.51 The protective associations of calcium have been observed in a meta-analysis on colorectal cancer52 and in two prospective cohort studies on breast cancer and ovarian cancer.53,54 Given the extensive effects of calcium in cancer and the downregulation of the suppressor gene CACNA2D3 in NPC, calcium might have similar antitumor effects on NPC, namely inducing apoptosis and antagonizing cancer cell proliferation and invasion.55 Milk Fat Milk fat contains numerous potential antitumor constituents, including conjugated linoleic acid, sphingomyelin, and butyric acid.56 Conjugated linoleic acid plays a role in the suppression of proliferation in colorectal, breast, and lung cancer cell lines in animal models, and a recent meta-analysis on breast cancer has reported such protective associations.57 Sphingomyelin, found in the plasma membrane of most mammalian cells, is a known protective factor against cancer, through participating in transmembrane signal transduction and cell regulation.58 Ceramide, one of the bioactive metabolites of sphingomyelin, plays a role in combating tumors through mediating immune system signaling pathways for the activation and amplification of antigen-specific T- and B-cell clones.59 Finally, butter contains about 3%e4% of the glyceride form of butyric acid, which has essential roles in impeding proliferation, and inducing differentiation and apoptosis in a wide range of cancer cell lines.58 However, a recent NPC case-control study by Feng et al. (2007) in Maghrebian countries has suggested that butyric acid might be a risk factor for NPC by activating latent EBV into a lytic cycle.47 Milk Proteins and Folate Milk and dairy products are important sources of protein. Cancer preventive effects have been associated with milk proteins and peptides. One of the milk proteins, bovine lactoferrin, has drawn considerable interest because of its antiinflammatory and antiviral activities. Numerous in vivo studies have shown that bovine lactoferrin reduces carcinogenesis in different rodent organs (breast, lung, esophagus, colon, and bladder) and impedes angiogenesis, although the mechanisms of this effect are still unclear.51 Milk and fermented dairy products are good sources of folate and folate-binding proteins. The concentration of folate in cow’s milk ranges from 5 to 10 mg/100g with seasonal variation.60 Folate is important in metabolism and DNA methylation/replication/repair and deficiencies contribute to carcinogenesis. A systematic review summarizes the epidemiological evidence and suggests that folate might act as a cancer prevention agent, particularly in colon and breast cancer.61 Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism and its genetic variants are associated with cancer risk.62 In NPC, MTHFR genetic polymorphisms are associated with genetic risk in smokers,63 highlighting the importance of gene-environmental interactions and NPC risk. Our NPC ecological results of negative and significant correlations between increased milk consumption per capita and decreased NPC incidence rates in 48 countries/regions and in Hong Kong should be considered as hypothesis-generating evidence, which supports further studies (such as case-control studies) on individual milk consumption and NPC. Nasopharyngeal Carcinoma Multicenter Case-Control Study To investigate the association between milk consumption and NPC risk at the individual level, our NPC Multicenter Case-Control Study aimed to investigate the role of the environmental (including lifestyle) factors on the risk of NPC in contemporary Hong Kong. Details about the design, methods, and subjects have been described elsewhere.64 In this chapter, we used the preliminary results in 2014e2016. Briefly, 669 histologically confirmed NPC

72

4. EPIDEMIOLOGY AND POPULATION SCREENING

incident cases aged 18e86 years, and 1180 non-NPC controls randomly selected from patients (with frequency matching) in five major regional hospitals (Pamela Youde Nethersole Eastern Hospital, Princess Margaret Hospital, Queen Elizabeth Hospital, Queen Mary Hospital, and Tuen Mun Hospital), which treat more than 70% of all NPC cases in Hong Kong, were included in the present preliminary analysis. A computer-assisted, self-administered questionnaire was used to collect the information on consumption of fresh milk, milk powder, other dairy products (cheese, yogurt, and ice cream), and other factors or exposure. Reinterviewing of the 140 subjects showed good agreement of milk intake between the first interview and reinterview. In early life periods, fair-to-substantial reliability coefficients for frequency and portion of fresh milk and powdered milk consumption were found (0.70, 0.65, 0.51, and 0.40 at age 6e12, and 0.74, 0.53, 0.44, and 0.35 in those at age 13e18, respectively). More details have been reported in Scientific Reports (https://doi.org/10.1038/s41598018-25046-y). Multivariate logistic regression yielded ORs of NPC for milk intake in childhood (age 6e12 years) and adolescence (13e18) separately, adjusting for sex, birth place, and housing type at age 10 years. Our preliminary results that higher fresh milk intake in both childhood and adolescence was associated with lower risks of NPC would be the first evidence at the individual level that milk intake in childhood and adolescence could be a protective factor. The results, if confirmed later, could shed light on the potential preventive strategies of NPC. Vitamin D Deficiency In recent years, vitamin D has reemerged as a versatile nutritional component that has antiinflammatory and immunomodulatory effects, in addition to its classical musculoskeletal effects and newly recognized cardiometabolic effects. The antiinflammatory and immunomodulatory effects of vitamin D have raised immense interest for its potential role in cancer prevention. In the 2018 WCRF/AICR Third Expert Report, evidence regarding foods containing vitamin D was summarized as limited-suggestive for decreased risk of colorectal cancer, while effects of sunlight exposure, the major source of vitamin D, were relatively unknown. Further research showed inverse associations between serum vitamin D and colorectal cancer,65e69 with a recent confirmation by meta-analysis,70 while results regarding other cancers were inconsistent.70e73 Nevertheless, currently no reports have answered this question. Studies showed that the hormonal form of vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH)2D3], impacts both the innate immunity74 and specific immunity. The latter is mainly mediated via affecting function of cells belonging to the monocyte/macrophage lineage through the vitamin D receptor (VDR), in turn regulating cellular apoptosis,75 and also through 1,25(OH)2D3-binding macromolecules in B lymphocytes affecting immunoglobulin production.76 Numerous studies showed that vitamin D has protective effects against bacterial infection,77 in particular pulmonary tuberculosis.78,79 Many studies also focused on the beneficial effects of vitamin D against viral infections.80 For instance, vitamin D levels and/or sunlight exposure have been associated with influenza infections81,82 and acute viral respiratory tract infections overall83 and depressed vitamin D status of HIV-infected women is associated with worse HIV disease progression and clinical outcomes including mortality,84 as well as increased perinatal and postnatal vertical HIV transmission to newborns.85 VDR gene polymorphisms are associated with differential susceptibility to chronic hepatitis B infection86,87 and disease activity,88 dengue hemorrhagic fever,89 primary HIV infection,90 and also disease progression in AIDS91,92 and clinical outcomes in HIV-positive patients. Randomized controlled trials have shown that vitamin D supplementation reduces influenza in schoolchildren.93,94 Emerging evidence suggests that vitamin D impacts on EBV infection and viral activity.95,96 For instance, multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system strongly associated with EBV infection, shows increased risk with higher latitudes, where sunlight exposure is reduced and vitamin D deficiency is common.97 While EBV infection is controlled primarily by specific immune responses mediated by cytotoxic CD8þ T cells, which eliminates proliferating and infected B cells,98 recent studies have shown that vitamin D has a direct immunomodulatory effect on CD8þ T cells,99 which may explain its protective effects against multiple sclerosis. Vitamin D modulates the immune response to EBV infection by suppression of T-cell proliferation,95 alteration of the immune responses to EBV through inhibiting the activation of autoreactive T-cells,95 or increased protective innate immunity mediated by cathelicidin.100 Changes in vitamin D further impact immune surveillance and facilitate viral reactivation from infected B cells.101 Previous studies have shown that activating VDR-responsive gene transcription inhibits cellular proliferation and promotes cell growth arrest and apoptosis,102 and the transactivation activity of VDR is enhanced by binding to 1,25(OH)2D3.103 Interestingly, a study104 has further shown that EBV-encoded EBNA-3 nuclear protein, a member of the EBNA3 family proteins involved in antiapoptotic activities, binds to the VDR protein complex and blocks transcription of its

POPULATION SCREENING

73

target genes both at the basal level and upon activation by its ligand 1,25(OH)2D3. Therefore, given the close relationship between EBV infection and NPC, these results may imply that the inhibition of antiapoptotic activity of vitamin D by EBV EBNA-3 through downregulation of the VDR-dependent gene transcription pathway could be a mediating mechanism for NPC pathogenesis. Nevertheless, currently no reports have answered this question. Vitamin D deficiency is common in Hong Kong and highly reversible through controlled levels of dietary modification or supplementation.105e107 If a causal role in NPC is confirmed, vitamin D deficiency can be combated with community strategies and promotion of healthy lifestyle regarding nutrition and physical activity, which are feasible and socially acceptable, and likely to benefit the community against other cancers and chronic diseases at the same time. Results from such studies may also form the basis of a clinical trial testing vitamin D supplementation as a possible novel prevention and/or treatment in susceptible subjects (e.g., risk-stratified according to EBV serological markers).

POPULATION SCREENING As a result of the anatomic location of the nasopharynx and nonspecificity of initial symptoms, many NPC cases are only diagnosed late at stages III or IV, with a suboptimal prognosis despite aggressive concurrent chemoradiation therapy.108 On the other hand, early-stage NPC is basically curable and has a 10-year survival rate approaching 90% or higher.109 Effective screening for identifying cases of early-stage NPC in asymptomatic individuals for early intervention may, therefore, have important potential for substantially reducing disease-specific morbidity and mortality of the disease. Among different diagnostic methods for NPC, EBV serology and nasopharyngoscopy are the most extensively explored approach for screening. Several early pilots in the 1970s explored the use of immunoglobulin A (IgA) antibodies to EBV viral capsid antigen (VCA/IgA) and early antigen (EA/IgA) measured by immunofluorescence assay for screening in several high risk counties in Southern China.110e113 Although the detection of NPC cases at an early stage was increased,111,113 their widespread use for population screening was limited by the low positive predictive value, time-consuming protocols, and high intraobserver variability due to the lack of standardized methods.114 A recent NPC cluster randomized trial in two cities in Southern China (Sihui and Zhongshan) employed a combination of EBV VCA/IgA and EBV nuclear antigen-1 (EBNA1/IgA) by enzyme-linked immunosorbent assay (ELISA), or indirect mirror examination in the nasopharynx and/or lymphatic palpation (IMPL) for mass screening. Fiber optic endoscopy and/or pathologic biopsy were offered to people judged to have high risk for NPC by either screening approach. In the 41 cases of NPC diagnosed from a total of 28,688 individuals screened, 68.3% (28/41) were of an early stage, with 38 (92.7%) from the serological group and seven (17.1%) from the IMPL group.115 Given that most people have been infected with EBV, the positive predictive value (4.4%, 38/862) of these immunology tests was unsatisfactory. A total of 95.6% of the high risk subjects required further invasive and expensive diagnostic examinations. Testing for circulating EBV DNA from NPC patients with both high sensitivity and specificity may become a potential complementary screening tool to distinguish NPC patients from seropositive subjects. In the same trial with further measurement of plasma EBV DNA load, however, EBV DNA load has been found to have limited value in screening patients who had early-stage NPC and predicting NPC development.116 A systematic review in 2015 examined 31 studies on NPC screening, and highlighted that no study reported sufficient data to determine the effectiveness of a screening program for NPC, and called for high quality studies that assess long term outcomes, such as NPC-specific mortality, and cost-effectiveness and quality of life.117 In a new study published in 2017, the use of circulating cell-free EBV DNA in plasma was explored as a biomarker for NPC screening in asymptomatic men aged 40e62 recruited from NPC health education sessions in Hong Kong.118 Among 309 individuals from 20,174 screened, who had persistently positive EBV DNA in plasma tested 4 weeks apart, NPC was confirmed in 34 by endoscopic examination and/or magnetic resonance imaging (MRI), giving a positive predictive value of 11%. Compared with figures reported from a previous historical cohort119 and the local cancer registry,35 NPC cases identified by the screening program included more stage I or II disease (71% vs. 20%), and were associated with a higher 3-year progression-free survival (97% vs. 70%). Note that the absolute increase of survival was 27 percentage points (97% vs. 70%), and the relative increase was 39% (27%/70%). Although this finding highlighted the potential of cell-free EBV DNA as a screening tool comparing screening with no screening or comparing different screening methods, results from randomized controlled trials (RCTs) and other studies are needed to properly assess the possible confounding effect of baseline differences of healthy

74

4. EPIDEMIOLOGY AND POPULATION SCREENING

subjects from the community and others from a historical cohort or other sources, lead-time and other biases, and the effectiveness and cost-effectiveness of different screening methods for mass screening. Further, the test of cell-free EBV DNA may be not feasible in endemic countries/regions of NPC where most are low- or middle-income countries/regions.120 In a study published in 2018, a two-step serological screening scheme was used to improve the positive predictive value of the serological screening strategy that is more feasible. The combination of EBNA1/IgA and VCA/IgA was used in the first step of screening, and anti-EAs were used in the second step of screening. In a prospective cohort of 4200 subjects in Zhongshan China, using the combination of EAD/IgA and TK/IgA in the second step increased the positive predictive value (from 4.7% to 18.5%).120 As the incidence of NPC is declining in various endemic areas, the positive predictive value would also be declining, making a proper assessment of the pros and cons of mass screening especially important.

METHODOLOGICAL CONSIDERATIONS FOR FUTURE EPIDEMIOLOGICAL STUDIES ON NASOPHARYNGEAL CARCINOMA Knowledge Gaps 1. Publication bias was observed in the literature on NPC, except for studies on salted fish. 2. The etiology of NPC, particularly for the declines in incidence rates in regions where NPC is endemic.

Data Collection Traditional observational epidemiological studies, especially for case-control studies, will continue to be the most important study design for rare cancers and other diseases. However, in case-control studies, it is difficult to improve and assess the quality of the past exposure data from face-to-face questionnaire interview. The difficulties apply to even the best-trained research staff and to the subjects at old age, with varying health conditions and cognitive ability, especially for questions that require a retrospective recall of exposure decades ago or during childhood or infancy. Hence, data from case-control studies are often subject to recall errors (random and systemic). Loss of memory or careless reporting would result in a bias toward null. Differential recall with cases trying harder to remember and recall more exposure than controls (especially healthy community controls) would lead to a bias away from null. Data from interviewers are also subject to bias, also away from null, as blinding of case-control status is often impracticable. Recognizing these problems, we have improved the methods in our Hong Kong NPC Multicenter Case-Control study and share our experiences as follows. 1. Exposure to putative risk or protective factors at different time points in the life of an individual could have different or no effects on a disease, such as cancer, which occurs decades later. For NPC, early life exposure should be more relevant because of the prevalence peaks at younger age than many other common cancers. However, more recent exposure could also be important if they interact with genetic factors or EBV later. We used the life course approach to assess lifestyle, dietary, and environmental exposure during four well-defined life course periods. These four periods are (1) weaning period, (2) early childhood, (3) adolescence, and (4) adulthood to represent lifelong adult exposure up to 10 years before the diagnosis of NPC. This approach could help patients anchor their memory at significant life course milestones (such as education, work, marriage, and diagnosis of a chronic disease), reduce memory errors, and clarify the time sequence of exposure and disease. 2. To reduce interviewer bias and be more efficient, we designed a computer-assisted self-administered questionnaire and encouraged the subjects to answer the questions on a tablet by touch screen. The subjects were assisted by the interviewer or interviewed, if necessary. Pictures and photos were displayed on the screen to guide the subjects to choose an answer, such as different body shape figures from very thin to grossly obese in childhood and adulthood, food and drink items and portion size, and skin color of the hands. We noted that most subjects liked this method more than being interviewed orally. The computer also has built-in design to check for logic and other errors. We also saved much costs for coding and data entry from paper questionnaires and avoided such errors. This method is more environmentally friendly and data security measures can be better safeguarded.

CONCLUSIONS

75

3. To ensure the reliability of the data, test-retest reliability is required for the questionnaire interview. No such study was conducted for NPC, except for the Hong Kong Multicenter Case-Control Study in 2014e18. We have published the reliability of our questionnaire of reinterviewing 140 subjects with an interval of at least 2 weeks showing the acceptable reliability of data, and shared the questionnaire (https://doi.org/10.1038/s41598-01825046-y).

Hospital Versus Community Controls In case-control studies, the choice of using controls from hospital patients or from relatively healthy people in the community is often a dilemma, as each has its pros and cons. Healthy controls are very unlikely to have the disease to be studied, and the ability to recall is not adversely affected by illness. However, they are usually busy and, hence, less likely to accept a long interview, resulting in a lower response rate and more volunteer bias. Their mindset is very different from cases who have a serious disease (such as cancer), and the community settings for the interviews are very different (with more disturbance from other people or the environment, for example) from the hospital wards. These could lead to less cooperation, attention, and recall effort to detailed questioning, resulting in overreporting of null exposure. Hospital patients (controls) also suffering from a serious disease (but not the disease in question) would have a more similar mindset and interviewing contexts as the cases and should be less subject to the aforementioned problems. However, their diseases might be associated with the risk factors being studied, which could lead to a bias toward null. We decided to use hospital controls from patients with the proviso that patients with any specific disease should not exceed 15% of all controls in the study. This would help minimize the bias. For any risk factors that might be associated with both the disease in question and the control’s disease, the risk (ORs) observed would be underestimated, but more likely to be real. Sensitivity analysis can also be done to check the ORs (effect size) by eliminating controls with any specific diseases one by one.

Individual Versus Frequency Matching The multicenter NCI-funded lymphoma case-control study including Hong Kong used individual matching. We found that this process was very time-consuming. Eligible controls (with eligible control diseases, fit and available for interview) were not readily available even in a big hospital, and further individual matching by sex and age to a specific case meant no matched controls on a specific day for that case during some hospital visits by interviewers. Hence, we used frequency matching for our NPC case-control study by interviewing as many eligible controls during each hospital visit and monitoring the age-sex pattern of cases and controls. This was much more efficient and we interviewed more controls (with a ratio of one case to two controls), when we found that the number of available NPC cases was lower than we expected (Fig. 4.1), because NPC incidence has been declining.

Individual Participant Data Meta-Analysis of Nasopharyngeal Carcinoma Case-Control Study An IPD meta-analysis of cohort study will provide the strongest evidence for observational studies. Even combining all existing cohort studies, for example, our IPD meta-analysis of smoking and NPC still only had a few hundred NPC cases in total. The sample size may be too small to conduct further comprehensive or subgroup analysis. It is time-consuming and expensive to conduct a mega cohort study for NPC. Although case-control studies are more efficient than cohort studies, the former tend to overestimate the OR and the evidence is deemed weaker than cohort studies. However, IPD meta-analysis of NPC case-control studies will increase the sample size substantially and should be organized for further testing of unresolved hypotheses.

CONCLUSIONS In this chapter, the distribution and major (classical and novel) risk factors of NPC were discussed. Surveillance of known and potential risk or protective factors of NPC and ecological studies should be conducted. While data on adult smoking behaviors might be available for various populations, data on other risk factors such as salted fish consumption, especially in children, are scarce. Surveillance of NPC risk factors will inform health promotion programs designed to raise awareness of the public. Given the strong genetic predisposition of NPC, such programs should ensure coverage of first-degree relatives of NPC patients.

76

4. EPIDEMIOLOGY AND POPULATION SCREENING

FIGURE 4.1

NPC cases and hospital controls by age and sex.

We have examined the classical risk factors of NPC. Specifically, we found more definitive evidence by IPD metaanalysis of cohort studies that smoking is likely a causal factor. More stringent tobacco control policies through tax increase and other legislation are needed to reduce smoking initiation, promote cessation, and protect people from exposure to tobacco smoke. This is particularly important for the Mainland of China, where 54.0% of men and 2.6% of women are current smokers in 2010.121 Reducing consumption of tobacco will also prevent many other cancers and chronic diseases. Further, our studies have suggested potential novel protective factors, such as SES and milk consumption. Besides, vitamin D may also be protective because of its impact on EBV activity. These findings can potentially translate into important primary prevention strategies. EBV serology and plasma DNA analysis shows potential for detecting early-stage NPC, but evidence of effectiveness from RCTs are needed before it can be used for mass screening. Key knowledge gaps for future epidemiological research on NPC have been identified. We have also shared our experiences from the improved methods used in the NPC Multicenter Case-Control Study in Hong Kong. It is recommended that IPD meta-analyses of NPC cohort and/or case-control studies should be conducted, and the interactions between genetic and environmental factors should be further examined to provide further insights into the etiology of this rare cancer. International or multicenter collaborations are urgently needed.

Acknowledgments Zhi-Ming Mai and Jia-Huang Lin contributed equally to this book chapter. The AoE NPC Multicenter Case-Control Study in Hong Kong was funded by the Hong Kong RGC Area of Excellence Scheme (AoE/M-06/08), World Cancer Research Fund UK (WCRF UK), and Wereld Kanker Onderzoek Fonds (WCRF NL), as part of the WCRF International grant program (2011/460). We wish to thank all members of AoE Epidemiology theme: Prof. Maria Lung, Prof. Anne Lee, Prof. Dora Kwong, Dr. WT Ng, Dr. Roger Ngan, Dr. Alice Ng, Dr. KT Yuen, Dr. Maggie Lo, Dr. Jun Xu, Dr. Amy Chiang, Dr. Will Chan, Mr. Thomas Chiang, Miss Solange Cheung, Miss Jennifer Lam, Miss Krystal Sanchez, Miss Yolly Chan, Mr. Kevin Kwok, Mr. Chris Yeung, Miss Candies Cheung, Miss Debby Cheung, Mr. Isaac Lui, Mr. Michael Wong, Miss Fion Tsui, and Mr. Hoi Wa Wong for their remarkable contributions to the study.

REFERENCES

77

References 1. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr. 2. Feng BJ. Descriptive, environmental and genetic epidemiology of nasopharyngeal carcinoma. Nasopharyngeal carcinoma: keys for translational medicine and biology. In: Busson P, ed. Advances in Experimental Medicine and Biology. New York: Springer; 2013:23e41. 3. Chang ET, Adami H. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15:1765e1777. 4. Forman D, Bray F, Brewster D, et al. Cancer Incidence in Five Continents. Vol. X. 2014. 5. Li K, Lin GZ, Shen JC, et al. Time trends of nasopharyngeal carcinoma in urban Guangzhou over a 12-year period (2000e2011): declines in both incidence and mortality. Asian Pac J Cancer Prev. 2014;15:9899e9903. 6. Zhang LF, Li YH, Xie SH, et al. Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui county, Guangdong Province, south China: an age-period-cohort analysis. Chin J Canc. 2015;34:15. 7. Hospital Authority: Hong Kong Cancer Registry website. www3.ha.org.hk/cancereg/statistics.html. 8. Cao SM, Simons MJ, Qian CN. The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Canc. 2011;30:114. 9. Tang LL, Chen WQ, Xue WQ, et al. Global trends in incidence and mortality of nasopharyngeal carcinoma. Cancer Lett. 2016;374:22e30. 10. Clegg LX, Hankey BF, Tiwari R, et al. Estimating average annual per cent change in trend analysis. Stat Med. 2009;28:3670e3682. 11. Hsu C, Shen YC, Cheng CC, et al. Difference in the incidence trend of nasopharyngeal and oropharyngeal carcinomas in Taiwan: implication from age-period-cohort analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:856e861. 12. Wei KR, Zheng RS, Zhang SW, et al. Nasopharyngeal carcinoma incidence and mortality in China. Chin J Canc. 2013;36:2017. 13. Jia W, Huang Q, Liao J, et al. Trends in incidence and mortality of nasopharyngeal carcinoma over a 20e25 year period (1978/1983e2002) in Sihui and Cangwu counties in southern China. BMC Cancer. 2006;6:178. 14. Mai Z, Lo C, Xu J, et al. Milk consumption in relation to incidence of nasopharyngeal carcinoma in 48 countries/regions. BMC Cancer. 2015;15:1. 15. Lau HY, Leung CM, Chan YH, et al. Secular trends of salted fish consumption and nasopharyngeal carcinoma: a multi-jurisdiction ecological study in 8 regions from 3 continents. BMC Cancer. 2013;13:298. 16. Jia WH, Qin HD. Non-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review. Sem Cancer Biol. 22. 17. Personal Habits and Indoor Combustions. Lyon: International Agency for Research on Cancer; 2012:1e538. 18. Thun MJL, Cerhan MS, Haiman JR, Schottenfeld C. David Cancer Epidemiology and Prevention. Oxford University Press; 2017. 19. Friborg J, Wohlfahrt J, Koch A, et al. Cancer susceptibility in nasopharyngeal carcinoma families: a population-based cohort study. Cancer Res. 2005;65:8567e8572. 20. Hsu WL,Yu YC, Chien YC, et al. Familial tendency and risk of nasopharyngeal carcinoma in taiwan: effects of covariates on risk. Am J Epidemiol. 2011;173:292e299. 21. Xie SH, Yu IT, Tse LA, et al. Tobacco smoking, family history, and the risk of nasopharyngeal carcinoma: a caseereferent study in Hong Kong Chinese. Cancer Causes Control. 2015;26:913. 22. Ren ZF, Liu WS, Qin HD, et al. Effect of family history of cancers and environmental factors on risk of nasopharyngeal carcinoma in Guangdong, China. Cancer Epidemiol. 2010;34:419e424. 23. Chen CJ, You SL, Lin LH, et al. Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol. 2002;32:S66eS81. 24. Sun LM, Epplein M, Li CI, et al. Trends in the incidence rates of nasopharyngeal carcinoma among Chinese Americans living in Los Angeles County and the San Francisco metropolitan area, 1992e2002. Am J Epidemiol. 2005;162:1174e1178. 25. Gao P, Yang X, Suo C, Yuan Z, et al. Socioeconomic status is inversely associated with esophageal squamous cell carcinoma risk: results from a population-based case-control study in China. Oncotarget. 2018;9:6911e6923. 26. Chu KP, Shema S, Wu S, et al. Head and neck cancer-specific survival based on socioeconomic status in Asians and Pacific Islanders. Cancer. 2011;117:1935e1945. 27. Turkoz FC, Celenkoglu G, Dogu GG, Kalender ME, Coskun U, et al. Risk factors of nasopharyngeal carcinoma in Turkey-an epidemiological survey of the Anatolian Society of Medical Oncology. Asian Pac J Cancer Prev. 2011;12:3017e3021. 28. Chang TS, Chang CM, Hsu TW, et al. The combined effect of individual and neighborhood socioeconomic status on nasopharyngeal cancer survival. PLoS One. 2013;8:e73889. 29. Registry HKC. Hong Kong Cancer Statistics. 1983-2015. 30. Some Naturally Occurring Substances. Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins. Lyon: International Agency for Research on Cancer; 1993:1e599. 31. Ho J. Nasopharyngeal carcinoma(NPC). Adv Cancer Res. 1972:167e189. 32. Ho J. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Rad Oncol Biol Phys. 1978;4:191e198. 33. Ho J. Nasopharyngeal carcinoma in Hong Kong. In: Muir CSS, Koh WP, eds. Cancer of the Nasopharynx. Copenhagen: Munksgaard; 1967: 58e63. 34. Lanier A, Bender T, Talbot M, et al. Nasopharyngeal carcinoma in Alaskan Eskimos Indians, and Aleuts: a review of cases and study of Epstein-Barr virus, HLA, and environmental risk factors. Cancer. 1980;46:2100e2106. 35. The 2014 Surgeon Jeneral’s Report: "The Health Consequences of Smokinge50 Years of Progress": A Paradigm Shift in Cancer Care. U.S Department of Health and Human Services; 2014. 36. Chow WH, McLaughlin JK, Hrubec Z, et al. Tobacco use and nasopharyngeal carcinoma in a cohort of US veterans. Int J Cancer. 1993;55: 538e540. 37. Liaw KM, Chen CJ. Mortality attributable to cigarette smoking in Taiwan: a 12-year follow-up study. Tob Control. 1998;7:141e148. 38. Doll R, Peto R, Boreham J, et al. Mortality from cancer in relation to smoking: 50 years observations on British doctors. Br J Cancer. 2005;92: 426e429. 39. Friborg JT, Yuan JM, Wang R, et al. A prospective study of tobacco and alcohol use as risk factors for pharyngeal carcinomas in Singapore Chinese. Cancer. 2007;109:1183e1191. 40. Hsu WL, Chen JY, Chien YC, et al. Independent effect of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-year follow-up study on 9,622 males without family history in Taiwan. Cancer Epidemiol Biomarkers Prev. 2009;18:1218e1226.

78

4. EPIDEMIOLOGY AND POPULATION SCREENING

41. Lin JH, Jiang CQ, Ho SY, et al. Smoking and nasopharyngeal carcinoma mortality: a cohort study of 101,823 adults in Guangzhou, China. BMC Cancer. 2015;15:906. 42. Xue WQ, Qin HD, Ruan HL, et al. Quantitative association of tobacco smoking with the risk of nasopharyngeal carcinoma: a comprehensive meta-analysis of studies conducted between 1979 and 2011. Am J Epidemiol. 2013;178:325e338. 43. Long M, Fu Z, Li P, et al. Cigarette smoking and the risk of nasopharyngeal carcinoma: a meta-analysis of epidemiological studies. BMJ Open. 2017;7:e016582. 44. Armstrong RW, Kannan KM, Armstrong MJ. Self-specific environments associated with nasopharyngeal carcinoma in Selangor, Malaysia. Soc Sci Med. 1978;12:149e156. 45. Hsu WL, Pan WH, Chien YC, et al. Lowered risk of nasopharyngeal carcinoma and intake of plant vitamin, fresh fish, green tea and coffee: a case-control study in Taiwan. PLoS One. 2012;7:e41779. 46. Polesel J, Serraino D, Negri E, et al. Consumption of fruit, vegetables, and other food groups and the risk of nasopharyngeal carcinoma. Cancer Causes Control. 2013;24:1157e1165. 47. Feng BJ, Jalbout M, Ayoub WB, et al. Dietary risk factors for nasopharyngeal carcinoma in Maghrebian countries. Int J Cancer. 2007;121: 1550e1555. 48. Yu MC, Huang TB, Henderson BE. Diet and nasopharyngeal carcinoma: a case-control study in Guangzhou, China. Int J Cancer. 1989;43: 1077e1082. 49. Yuan JM, Wang XL, Xiang YB, et al. Preserved foods in relation to risk of nasopharyngeal carcinoma in Shanghai, China. Int J Cancer. 2000;85: 358e363. 50. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR; 2007. 51. Davoodi H, Esmaeili S, Mortazavian A. Effects of milk and milk products consumption on cancer: a review. Compr Rev Food Sci Food Saf. 2013; 12:249e264. 52. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology. 2010;138:2029e2043. e10. 53. McCullough ML, Rodriguez C, Diver WR, et al. Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev. 2005;14:2898e2904. 54. Park Y, Leitzmann MF, Subar AF, et al. Dairy food, calcium, and risk of cancer in the NIH-AARP Diet and Health Study. Arch Intern Med. 2009; 169:391. 55. Wong AMG, Kong KL, Chen L, et al. Characterization of CACNA2D3 as a putative tumor suppressor gene in the development and progression of nasopharyngeal carcinoma. Int J Cancer. 2013;133:2284e2295. 56. Parodi PW. Cows’ milk fat components as potential anticarcinogenic agents. J Nutr. 1997;127:1055e1060. 57. Dong J, Zhang L, He K, et al. Dairy consumption and risk of breast cancer: a meta-analysis of prospective cohort studies. Breast Canc Res Treat. 2011;127:23e31. 58. Parodi P. Conjugated linoleic acid and other anticarcinogenic agents of bovine milk fat. J Dairy Sci. 1999;82:1339e1349. 59. Ballou LR, Laulederkind SJ, Rosloniec EF, et al. Ceramide signalling and the immune response. Biochim Biophys Acta Lipids Lipid Metab. 1996; 1301:273e287. 60. Forsse´n KM, Jagerstad MI, Wigertz K, et al. Folates and dairy products: a critical update. J Am Coll Nutr. 2000;19:100Se110S. 61. Prinz-Langenohl R, Fohr I, Pietrzik K. Beneficial role for folate in the prevention of colorectal and breast cancer. Eur J Nutr. 2001;40:98e105. 62. Lee MS, Asomaning K, Su L, et al. MTHFR polymorphisms, folate intake and carcinogen DNA adducts in the lung. Int J Cancer. 2012;131: 1203e1209. 63. Cao Y, Miao XP, Huang MY, et al. Polymorphisms of methylenetetrahydrofolate reductase are associated with a high risk of nasopharyngeal carcinoma in a smoking population from Southern China. Mol Carcinog. 2010;49:928e934. 64. Mai ZM, Lin JH, Lung ML, Lam TH. Intake of fish oil/cod liver oil/omega-3 and vitamin D supplements associated with lower risk of nasopharyngeal carcinoma: preliminary results from a hospital-based case-control study in Hong Kong, China. In: IEA World Congress of Epidemiology. 2017 (Saitama, Japan). 65. Garland CF, Comstock GW, Garland FC, et al. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. 1989;2: 1176e1178. 66. Wu K, Feskanich D, Fuchs CS, et al. A nested case control study of plasma 25-hydroxyvitamin D concentrations and risk of colorectal cancer. J Natl Cancer Inst. 2007;99:1120e1129. 67. Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. BMJ. 2010;340. b5500. 68. Woolcott CG, Wilkens LR, Nomura AM, et al. Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2010;19:130e134. 69. Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2004;13:1502e1508. 70. Gandini S, Boniol M, Haukka J, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011;128:1414e1424. 71. Engel P, Fagherazzi G, Boutten A, et al. Serum 25(OH) vitamin D and risk of breast cancer: a nested case-control study from the French E3N cohort. Cancer Epidemiol Biomarkers Prev. 2010;19:2341e2350. 72. Helzlsouer KJ. Overview of the cohort consortium vitamin D pooling project of rarer cancers. Am J Epidemiol. 2010;172:4e9. 73. Grant WB. Re: Overview of the cohort consortium vitamin D pooling project of rarer cancers. Am J Epidemiol. 2010;172:1210e1211. author reply 1211-2. 74. Karlsson J, Carlsson G, Larne O, et al. Vitamin D3 induces pro-LL-37 expression in myeloid precursors from patients with severe congenital neutropenia. J Leukoc Biol. 2008;84:1279e1286. 75. Hewison M, Dabrowski M, Vadher S, et al. Antisense inhibition of vitamin D receptor expression induces apoptosis in monoblastoid U937 cells. J Immunol. 1996;156:4391e4400.

REFERENCES

79

76. Provvedini DM, Tsoukas CD, Deftos LJ, et al. 1 alpha,25-Dihydroxyvitamin D3-binding macromolecules in human B lymphocytes: effects on immunoglobulin production. J Immunol. 1986;136:2734e2740. 77. Hewison M. Antibacterial effects of vitamin D. Nat Rev Endocrinol. 2011. 78. Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet. 2011;377:242e250. 79. Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2009;179:843e850. 80. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011. 81. Grant WB. The roles of vitamin D, temperature, and viral infections in seasonal risk of acquiring asthma. Am J Respir Crit Care Med. 2009;179: 1072. author reply 1072-3. 82. Hayes DP. Influenza pandemics, solar activity cycles, and vitamin D. Med Hypotheses. 2010;74:831e834. 83. Sabetta JR, DePetrillo P, Cipriani RJ, et al. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5:e11088. 84. Mehta S, Giovannucci E, Mugusi FM, et al. Vitamin D status of HIV-infected women and its association with HIV disease progression, anemia, and mortality. PLoS One. 2010;5:e8770. 85. Mehta S, Hunter DJ, Mugusi FM, et al. Perinatal outcomes, including mother-to-child transmission of HIV, and child mortality and their association with maternal vitamin D status in Tanzania. J Infect Dis. 2009;200:1022e1030. 86. Bellamy R, Ruwende C, Corrah T, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis. 1999;179:721e724. 87. Arababadi MK, Pourfathollah AA, Jafarzadeh A, et al. Association of exon 9 but not intron 8 VDR polymorphisms with occult HBV infection in south-eastern Iranian patients. J Gastroenterol Hepatol. 2010;25:90e93. 88. Huang YW, Liao YT, Chen W, et al. Vitamin D receptor gene polymorphisms and distinct clinical phenotypes of hepatitis B carriers in Taiwan. Genes Immun. 2010;11:87e93. 89. Loke H, Bethell D, Phuong CX, et al. Susceptibility to dengue hemorrhagic fever in vietnam: evidence of an association with variation in the vitamin d receptor and Fc gamma receptor IIa genes. Am J Trop Med Hyg. 2002;67:102e106. 90. Alagarasu K, Selvaraj P, Swaminathan S, et al. 5’ regulatory and 3’ untranslated region polymorphisms of vitamin D receptor gene in south Indian HIV and HIV-TB patients. J Clin Immunol. 2009;29:196e204. 91. Nieto G, Barber Y, Rubio MC, et al. Association between AIDS disease progression rates and the Fok-I polymorphism of the VDR gene in a cohort of HIV-1 seropositive patients. J Steroid Biochem Mol Biol. 2004;89e90:199e207. 92. Barber Y, Rubio C, Fernandez E, et al. Host genetic background at CCR5 chemokine receptor and vitamin D receptor loci and human immunodeficiency virus (HIV) type 1 disease progression among HIV-seropositive injection drug users. J Infect Dis. 2001;184:1279e1288. 93. Yamshchikov AV, Desai NS, Blumberg HM, et al. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract. 2009;15:438e449. 94. Urashima M, Segawa T, Okazaki M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91:1255e1260. 95. Holmoy T. Vitamin D status modulates the immune response to Epstein-Barr virus: synergistic effect of risk factors in multiple sclerosis. Med Hypotheses. 2008;70:66e69. 96. Hayes CE. Donald Acheson E: a unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med Hypotheses. 2008;71:85e90. 97. Grant WB. Latitude and multiple sclerosis prevalence: vitamin D reduces risk of Epstein-Barr virus infection. Mult Scler. 2010;16:374e375, 373; author reply. 98. Hislop AD, Taylor GS, Sauce D, et al. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol. 2007;25:587e617. 99. Lysandropoulos AP, Jaquiery E, Jilek S, et al. Vitamin D has a direct immunomodulatory effect on CD8þ T cells of patients with early multiple sclerosis and healthy control subjects. J Neuroimmunol. 2011. 100. Pender MP. The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis. Neuroscientist. 2011. 101. Agborsangaya CB, Lehtinen T, Toriola AT, et al. Association between Epstein-Barr virus infection and risk for development of pregnancyassociated breast cancer: joint effect with vitamin D? Eur J Cancer. 2011;47:116e120. 102. Banerjee P, Chatterjee M. Antiproliferative role of vitamin D and its analogsea brief overview. Mol Cell Biochem. 2003;253:247e254. 103. Dusso AS, Brown AJ, Slatopolsky E, Vitamin D. Am J Physiol Renal Physiol. 2005;289:F8eF28. 104. Yenamandra SP, Hellman U, Kempkes B, et al. Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. Cell Mol Life Sci. 2010;67:4249e4256. 105. Woo J, Lam CW, Leung J, et al. Very high rates of vitamin D insufficiency in women of child-bearing age living in Beijing and Hong Kong. Br J Nutr. 2008;99:1330e1334. 106. Xu C, Perera RA, Chan Y-H, et al. Determinants of serum 25-hydroxyvitamin D in Hong Kong. Br J Nutr. 2015;114:144e151. 107. Wang EW, Siu PM, Pang MY, et al. Vitamin D deficiency, oxidative stress and antioxidant status: only weak association seen in the absence of advanced age, obesity or pre-existing disease. Br J Nutr. 2017;118:11e16. 108. Cheng SH, Liu TW, Jian JJ, et al. Concomitant chemotherapy and radiotherapy for locally advanced nasopharyngeal carcinoma. Cancer J Sci Am. 1997;3:100e106. 109. Chua DT, Sham JS, Kwong DL, et al. Treatment outcome after radiotherapy alone for patients with Stage I-II nasopharyngeal carcinoma. Cancer. 2003;98:74e80. 110. Zeng Y, Zhang LG, Li HY, et al. Serological mass survey for early detection of nasopharyngeal carcinoma in Wuzhou City, China. Int J Cancer. 1982;29:139e141. 111. Zeng Y, Zhong JM, Li LY, et al. Follow-up studies on Epstein-Barr virus IgA/VCA antibody-positive persons in Zangwu county, China. Intervirology. 1983;20:190e194.

80

4. EPIDEMIOLOGY AND POPULATION SCREENING

112. Zeng Y, Zhang LG, Wu YC, et al. Prospective studies on nasopharyngeal carcinoma in Epstein-Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China. Int J Cancer. 1985;36:545e547. 113. Zong YS, Sham JS, Ng MH, et al. Immunoglobulin A against viral capsid antigen of Epstein-Barr virus and indirect mirror examination of the nasopharynx in the detection of asymptomatic nasopharyngeal carcinoma. Cancer. 1992;69:3e7. 114. Karray H, Ayadi W, Fki L, et al. Comparison of three different serological techniques for primary diagnosis and monitoring of nasopharyngeal carcinoma in two age groups from Tunisia. J Med Virol. 2005;75:593e602. 115. Liu Z, Ji MF, Huang QH, et al. Two Epstein-Barr virus-related serologic antibody tests in nasopharyngeal carcinoma screening: results from the initial phase of a cluster randomized controlled trial in Southern China. Am J Epidemiol. 2013;177:242e250. 116. Ji MF, Huang QH, Yu X, et al. Evaluation of plasma Epstein-Barr virus DNA load to distinguish nasopharyngeal carcinoma patients from healthy high-risk populations in Southern China. Cancer. 2014;120:1353e1360. 117. Yang S, Wu S, Zhou J, et al. Screening for nasopharyngeal cancer. Cochrane Database Syst Rev. 2015. CD008423. 118. Chan KCA, Woo JKS, King A, et al. Analysis of plasma Epstein-Barr virus DNA to screen for nasopharyngeal cancer. N Engl J Med. 2017;377: 513e522. 119. Li J, Zou X, Wu YL, et al. A comparison between the sixth and seventh editions of the UICC/AJCC staging system for nasopharyngeal carcinoma in a Chinese cohort. PLoS One. 2014;9:e116261. 120. Li T, Guo X, Ji M, et al. Establishment and validation of a two-step screening scheme for improved performance of serological screening of nasopharyngeal carcinoma. Cancer Med. 2018. 121. Liu S, Zhang M, Yang L, et al. Prevalence and patterns of tobacco smoking among Chinese adult men and women: findings of the 2010 national smoking survey. J Epidemiol Commun Health. 2017;71:154e161.

Commentary on Chapter 4: Epidemiology and Population Screening Weimin Ye Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Nasopharyngeal carcinoma (NPC) is characterized by its unique geographic distribution and strong association with EpsteineBarr virus (EBV). In this chapter, the authors have systematically reviewed the geographic distribution, secular trend, and risk factors for NPC. They have also discussed briefly population screening strategies, as well as methodological considerations when designing studies to explore risk factors for NPC. The declining secular trends of NPC in many high-risk regions and populations in the past few decades can be cheered as an unplanned triumph. However, the underlying causes for the declining trends are unclear, although improved socioeconomic status has been proposed as the explanation. Surprisingly, NPC incidence remained stable in endemic areas in southern China,1 despite rapid economic development since the 1980s. In contrast, another infection-related malignancy (i.e., stomach cancer) has shown declining trends in most parts of mainland China. This discrepancy might be explained by the importance of early exposure for NPC. Thus it might take a longer time lag before improved socioeconomic status effects on NPC incidence, which are the cases in Hong Kong, Taiwan, and Singapore, in which about 30 years of time lag has been witnessed. If this hypothesis is true, we might expect to see NPC incidence starting to decline in southern China in 2010e20. NPC is among the malignancies showing strong associations with a family history of cancer. The obvious familial cluster of NPC might be attributable to shared genetic susceptibility, as well as shared early life exposure. In a population-based case-control study comprising approximately 2500 cases and 2500 controls, known as NPC Genes, Environment, and EBV (NPCGEE) study,2 which was conducted by our group and collaborators in endemic areas of southern China, a first-degree family history of NPC was associated with a 4.6-fold excess risk of NPC.3 The excess risk was more prominent for a maternal than paternal history, as well as for a sibling than parental history, which, if confirmed, again emphasizes the importance of early exposure for nasopharyngeal carcinogenesis. In addition, we created kinship cohorts for both cases and controls, and estimated lifetime cumulative risk of NPC among different types of first-degree relatives.3 The cumulative NPC risk up to age 74 years among cases’ relatives was 3.7% and for controls’ relatives, 0.9%. Contrary to the results of a hospital-based case-control study conducted in Guangzhou,4 we did not find NPC risk associated with a family history of any non-NPC cancer (OR ¼ 1.1, 95% CI 0.9e1.3). For the environmental risk factors for NPC, the authors have discussed socioeconomic status, salted fish consumption, tobacco smoking, milk consumption, and vitamin D deficiency. Improved socioeconomic status has been attributed to the declining NPC incidence in several high-risk countries/areas, although the underlying individual exposure are yet to be disclosed. Consumption of salted fish, especially in early life, has been classified as a group I carcinogen by the International Agency for Research on Cancer. However, recent studies have generally shown decreased strength of associations, including the results from the previously mentioned NPCGEE study in southern China (unpublished data). The authors have provided some explanations for this phenomenon, and using an ecological study, they further concluded that decreasing consumption of salted fish might not explain the declining NPC incidence in Hong Kong. Tobacco smoking has been proposed as a causal factor for NPC, especially based on the preliminary results from a pooled analysis of cohort studies from endemic regions conducted by the authors, although the strength of the association is only modest. In the NPCGEE study in southern China, passive smoking exposure during childhood and from a spouse during adulthood was also found to be independently associated with an increased NPC risk in never-smoking men and women,5 adding further evidence to support the role of tobacco in nasopharyngeal carcinogenesis. The novel hypothesis proposed by the authors that milk consumption might decrease the risk of NPC is interesting. They performed an ecological study and used data from their hospital-based case-control study to test this hypothesis, and the results from both studies support the notion. They further discussed potential mechanisms, including potential influence by high levels of calcium, milk fat, milk protein, and folate in milk and other dairy products. These nutrients have been found to have anticancer effects through various pathways, like inducing apoptosis, antiinflammation, antiproliferation, and DNA methylation. Further epidemiological studies are needed to confirm these results. The authors further hypothesized that vitamin D deficiency contributes to increase the risk of NPC. They have discussed extensively many possible mechanisms. However, the north-to-south gradient of increasing NPC incidence in China seems to contradict this hypothesis, as sunlight exposure, the major source of vitamin D, increases

82

4. EPIDEMIOLOGY AND POPULATION SCREENING

from northern to southern China. Thus, further studies, especially cohort studies with biobanked baseline blood samples, are needed to test this hypothesis. There are some other important environmental risk factors for NPC not covered in this chapter and the interested readers can refer to another review.6 In some studies, domestic exposure to other smoke due to poor ventilation have been found to increase NPC risk, while other studies showed null results. Results about incense or antimosquito coil burning and NPC risk are also inconsistent. Occupational exposure to formaldehyde and wood dust have been found to increase NPC risk. However, whether exposure to other types of dust increases the risk of NPC is still unclear. Higher consumption of fresh fruits and vegetables has been consistently linked with a decreased risk of NPC. Alcohol intake seems not related to NPC, while there is suggestive evidence that tea drinking might decrease NPC risk. Given the 2:3 male:female ratio of NPC incidence, a protective effect of female hormones is worth further investigation. Chinese herbal medicines, herbal tea, and traditional Cantonese soups using dried plants have also been suggested to increase NPC risk, although so far results are conflicting. However, in vitro studies have found that some commonly used plants in endemic areas in southern China can induce EBV lytic antigen expression.7 Although EBV has been causally related to NPC, it is still unknown whether there are specific viral strains contributing to NPC occurrence. With the development of modern sequencing technologies, whole genome sequencing data of EBV strains isolated from subjects with different diseases accumulate rapidly.8 This might help to find EBV genomic variations related to NPC risk. For example, in a recent report, a single nucleotide polymorphism (SNP) in the EBV-encoded RPMS1 gene is significantly associated with NPC risk, and incorporation of this variation significantly improves risk predication model for NPC.9 Ongoing efforts are being made to incorporate more SNPs and to validate the results in other study settings. Other infections might also contribute to NPC occurrence. Traditionally, chronic infections in the ear, nose, and throat have been associated with an increased risk of NPC. However, in a recent report based on the previously mentioned NPCGEE study, these diseases are most likely early indications rather than causes of NPC, as most significant associations became nonsignificant after restricting exposure 5 years before interview.10 Infections related to reduced immunity, such as HIV/AIDS11 and chronic hepatitis B,12 have been found to increase NPC risk, although more studies are needed to confirm these findings. In the NPCGEE study in southern China, poor oral health has also been found to increase NPC risk. Although underlying mechanisms are only speculative, bacterial overgrowth and facilitation of EBV reactivation have been proposed as possible pathways.13 Besides infections, the role of the microbiome in the nasopharynx on NPC occurrence has gained attention recently. Anaerobic bacteria in the nasopharynx are found to be able to produce n-butyrate, which together with phorbol ester can enhance EBV-mediated B-cell transformation and promote NPC development in rats.14 In a preliminary analysis of NPC patients recruited from southern China, the most common five phyla in the nasopharynx of these patients are Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes, and Thermi (unpublished data). However, how the nasopharyngeal microbiome interacts with EBV to promote NPC occurrence will require longitudinal cohort studies to disentangle the puzzle. Population screening of NPC has been initiated in the early 1970s in southern China. As summarized in the chapter by the authors, the previous assay has the disadvantages of being time-consuming and difficult to standardize, but later the introduction of the ELISA assay has overcome most of these shortcomings. However, the low positive prediction value means that many subjects need to undergo invasive and expensive examination and close annual follow-up. Thus a number of efforts have been made for further risk-stratification among high-risk subjects. These efforts include measuring circulating cell-free EBV DNA in plasma and other EBV-related antibodies. In addition, in a recent report measuring EBV DNA load directly in the nasopharynx can also help reduce the number of patients who require close follow-up among high-risk subjects.15 The authors also discussed methodological issues for future epidemiological studies, which is most welcome for field epidemiologists. Our knowledge about the risk factors for NPC is still limited, largely due to lack of rigorously designed case-control studies and informative cohort studies. In their recent hospital-based case-control study, modern technologies have been applied to ensure high-quality data collection from questionnaires, including using a life-course approach to assess lifestyle and other environmental exposure, development of a computer-aided questionnaire, and assessment of test-retest reliability. These measures will help reduce recall error and hopefully improve the quality of questionnaire data. Due to the relative rarity of NPC, case-control studies will probably be the main study design in the near future. Most previous case-control studies are hospital-based, which is also the case for the study conducted by the authors. They have discussed several points in the design of hospital-based study, and advocated the use of hospital-based controls and frequency matching. While these measures might reduce somewhat recall and selection biases, the fundamental principles need to be kept in mind, when designing case-control studies. As illustrated in Fig. 4.2, the first step is to clearly define a study base, that is, person-years to be experienced by a well-defined study

REFERENCES

83

FIGURE 4.2 Schematic illustration of the design of a case-control study.

population during a fixed time period. Then the next step is to identify and recruit as complete as possible all new cases arising from the study base. Controls should be a randomly selected subset from the study base. To comply with these rules, hospital-based design usually has inherent difficulties. Thus, whenever possible, populationbased design is preferred. In our recent article,2 we have illustrated how to conduct the NPCGEE study (a population-based case-control study) in southern China. Cohort studies are usually preferred as the influences from recall and selection biases might be less of a concern compared to case-control studies. However, mega cohorts might be needed as NPC is a rare cancer in most places. Also most cohort studies are multipurpose ones and the questionnaire usually is not targeted on a specific disease. Thus some specific questions relevant to NPC, like early-life consumption of salted fish, exposure to dust and fumes, and so on, might not be listed in the questionnaire. Further, except in endemic areas, collection of pathological reports for all NPC cases arising from the cohort, for the proper histopathological classification, might also be challenging. Thus in the near future, both well-designed and executed case-control and cohort studies are needed, and as pointed out by the authors, meta-analysis based on individual participant data is a good supplement. To summarize, well-designed case-control studies and informative cohort studies are needed to further understand etiological factors for NPC, which will guide the development of primary prevention measures. Technological developments, including whole genome sequencing of the human genome and EBV genome, along with metagenomics, will enable us to explore the roles of geneeEBVeenvironment interactions in the development of NPC. For this purpose, international collaborations, including pooling of individual participant data from studies across continents, will be the key for success. Comprehensive profiling of serum EBV antibodies might bring the hope of risk-stratification of high-risk subjects, to further increase cost-effectiveness of population screening for NPC.

References 1. Jia WH, Huang QH, Liao J, et al. Trends in incidence and mortality of nasopharyngeal carcinoma over a 20-25 year period (1978/1983-2002) in Sihui and Cangwu counties in southern China. BMC Cancer. 2006;6:178. 2. Ye WM, Chang ET, Liu ZW, et al. Development of a population-based cancer case-control study in southern China. Oncotarget. 2017;8: 87073e87085. 3. Liu Z, Chang ET, Liu Q, et al. Quantification of familial risk of nasopharyngeal carcinoma in a high-incidence area. Cancer. 2017. 4. Ren ZF, Liu WS, Qin HD, et al. Effect of family history of cancers and environmental factors on risk of nasopharyngeal carcinoma in Guangdong, China. Cancer Epidemiol. 2010;34:419e424. 5. Chang ET, Liu Z, Hildesheim A, et al. Active and passive smoking and risk of nasopharyngeal carcinoma: a population-based case-control study in southern China. Am J Epidemiol. 2017:1e9. 6. Chang ET, Adami HO. Nasopharyngeal cancer. In: Adami HO, Hunter DJ, Lagiou P, et al., eds. Textbook of Cancer Epidemiology. third edition. U.S.A., Oxford University Press; 2018:159e181. 7. Zeng Y, Zhong JM, Mo YK, et al. Epstein-Barr virus early antigen induction in Raji cells by Chinese medicinal herbs. Intervirology. 1983;19: 201e204. 8. Kwok H, Chiang AK. From conventional to next generation sequencing of Epstein-Barr virus genomes. Viruses. 2016;8:60. 9. Cui Q, Feng FT, Xu M, et al. Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. Oncotarget. 2016. 10. Xiao X, Zhang Z, Chang ET, et al. Medical history, medication use, and risk of nasopharyngeal carcinoma. Am J Epidemiol. 2018.

84

4. EPIDEMIOLOGY AND POPULATION SCREENING

11. Shebl FM, Bhatia K, Engels EA. Salivary gland and nasopharyngeal cancers in individuals with acquired immunodeficiency syndrome in United States. Int J Cancer. 2010;126:2503e2508. 12. Ye YF, Xiang YQ, Fang F, et al. Hepatitis B virus infection and risk of nasopharyngeal carcinoma in southern China. Cancer Epidemiol Biomarkers Prev. 2015;24:1766e1773. 13. Liu Z, Chang ET, Liu Q, et al. Oral hygiene and risk of nasopharyngeal carcinoma-A population-based case-control study in China. Cancer Epidemiol Biomarkers Prev. 2016;25:1201e1207. 14. Zeng Y, Zhong JM, Ye SQ, et al. Screening of Epstein-Barr virus early antigen expression inducers from Chinese medicinal herbs and plants. Biomed Environ Sci. 1994;7:50e55. 15. Chen Y, Zhao W, Lin L, et al. Nasopharyngeal Epstein-Barr virus load: an efficient supplementary method for population-based nasopharyngeal carcinoma screening. PLoS One. 2015;10:e0132669.