ARTICLE IN PRESS

Cancer Letters ■■ (2016) ■■–■■

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Cancer Letters
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

1 Q2 Original Articles
2
3 Global trends in incidence and mortality of nasopharyngeal
4 carcinoma
5
6 Q1 Ling-Ling Tang a,1, Wan-Qing Chen b,1, Wen-Qiong Xue a, Yong-Qiao He a,
7 Rong-Shou Zheng b, Yi-Xin Zeng a, Wei-Hua Jia a,*
a School of Public Health & Cancer Center, Sun Yat-Sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for
8
9 Cancer Medicine, Guangzhou 510060, China
10 b
National Office for Cancer Prevention and Control & National Central Cancer Registry, National Cancer Center, Beijing 100021, China
11
12
13 A R T I C L E I N F O A B S T R A C T
14
15
16 Article history: Nasopharyngeal carcinoma (NPC) is a rare malignancy with an extraordinarily skewed geographic dis-
17
18 Received 6 December 2015 tribution worldwide. Although decreasing trends in incidence and mortality of NPC have been sporadically
19
20 Received in revised form 22 January 2016 reported in some high-risk areas, no comprehensive description of the global trends has ever been made.
21 Accepted 22 January 2016
22 We accessed incidence (1970–2007) and mortality (1970–2013) data from multiple sources, with the
23
24 main ones being the Cancer Incidence in Five Continents (CI5) series and the World Health Organiza-
25
26 Keywords:
tion (WHO) cancer mortality database. During the entire period studied, age-standardized incidence rates
27 Nasopharyngeal carcinoma
28
29 Incidence
(ASIRs) of NPC decreased significantly in southern and eastern Asia, north America and Nordic coun-
30
31 Mortality tries with average annual percent changes (AAPCs) of −0.9% to −5.4% in males and −1.1% to −4.1% in females.
32
33 Joinpoint analysis Declines in age-standardized mortality rates (ASMRs) are even more remarkable and extensive, with AAPCs
34
35 Trends varying from −0.9% and −0.8% to −3.7% and −6.5% in males and females, respectively. Decreasing trends
36 in NPC incidence are probably due to tobacco control, changes in diets and economic development. De-
37 clines in mortality rates are the results of advancements in diagnostic and radiotherapy techniques, as
38 well as decreased incidence rates.
39 © 2016 Published by Elsevier Ireland Ltd.

40

41 Introduction According to the 1991 WHO classification, NPC is classified into 66

42 two major histological subtypes, namely keratinizing squamous cell 67
43 Nasopharyngeal carcinoma is an enigmatic malignancy, which carcinoma (KSCC) and non-keratinizing carcinoma, with the latter 68
44 exhibits marked racial and geographical differences. It is rare in most further divided into differentiated and undifferentiated carcino- 69
45 parts of the world, with age-standardized rates (ASRs) in incidence mas [2]. Non-keratinizing carcinoma makes up the majority of NPC 70
46 well below 1 per 100,000 person-years for both genders, but it is cases in high-risk areas, while the keratinizing type is predomi- 71
47 rather prevalent in southern China, southeast Asia and northern Africa nant in low-incidence regions [3,4]. 72
48 [1]. It was estimated that there were 86,691 incident cases (60,896 NPC is caused by complex etiological factors, including Epstein– 73
49 in males and 25,795 in females) and 50,831 deaths (35,753 in males Barr virus (EBV) infection, genetic predisposition and other 74
50 and 15,075 in females) of NPC in 2012 worldwide, and the inci- environmental risk factors such as smoking, salted-fish consump- 75
51 dence rate and mortality rate in men (1.7/100,000 and 1.0/100,000) tion and occupational exposures [5]. Though the oncogenic 76
52 were 2–3 times those in women (0.7/100,000 and 0.4/100,000) [1]. mechanism of EBV is yet to be revealed, population-based evi- 77
dence shows that nearly all of the undifferentiated NPC cases are 78
53
EBV-related in intermediate- and high-incidence areas [6]. Com- 79
54 pared with KSCC, differentiated and undifferentiated non-keratinizing 80
55 Abbreviations: NPC, nasopharyngeal carcinoma; EBV, Epstein–Barr virus; KSCC, carcinomas are more commonly associated with elevated Epstein– 81
56 keratinizing squamous cell carcinoma; ASRs, age-standardized rates; ASIRs, age-
Barr virus titers [7]. In addition to EBV infection, genetic factor is 82
57 standardized incidence rates; ASMRs, age-standardized mortality rates; APCs, annual
58 percent changes; AAPCs, average annual percent changes; HLA, human leukocyte another critical contributor to NPC risk. An abundance of studies 83
59 antigen; WHO, World Health Organization; CI5, Cancer Incidence in Five Conti- have identified the associations between NPC development and 84
60 nents; SEER, Surveillance, Epidemiology, and End Results; NCCR, National Central certain human leukocyte antigen (HLA) alleles [8,9] and genetic poly- 85
61 Cancer Registry; USA, CA, LA, United States of America, California, Los Angeles; CHIS, morphisms [10,11], which have partly explained the question of why 86
62 the Center for Health Information and Statistics.
63 Q3 * Corresponding author. Tel.: +86 020 8734 3195; fax: +86 020 8734 3392.
only some specific subgroups are susceptible to NPC. Non-viral en- 87
64 E-mail address: jiaweih@mail.sysu.edu.cn (W.-H. Jia). vironmental risk factors, including tobacco smoking [12], intake 88
65 1 Co-first author. of salted fish and other salt-preserved food [13–15], are firmly 89

http://dx.doi.org/10.1016/j.canlet.2016.01.040
0304-3835/© 2016 Published by Elsevier Ireland Ltd.

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90 believed to increase the risk of developing NPC, and adequate con- Results 161
91 sumption of fresh vegetables and fruits is a protective factor for NPC 162
92 [15,16]; however, the causal relationships between NPC and other Distribution by region and population 163
93 environmental factors such as alcohol consumption, herbal product 164
94 use, occupational exposures to formaldehyde or other noxious chemi- Geographically, ASIRs of NPC are less than 1 per 100,000 person- 165
95 cals and betel nut chewing haven’t been confirmed to date [17]. years for both genders in most areas of the world, and they are 166
96 Previously, encouraging reductions in incidence and mortality intermediate (5–15/100,000 in men) in regions including Malay- 167
97 of NPC has been reported in some regions such as Hong Kong [18], sia, Singapore, Indonesia and Viet Nam in southeast Asia, Micronesia, 168
98 Guangzhou [19], Taiwan [20], Singapore [21], The Netherlands [22] Algeria and Kenya in northern Africa, but they can reach as high as 169
99 and among migrated Chinese [23,24], while trends were relatively 20/100,000 in southern China. A similar pattern may be observed 170
100 stable in other locations such as Wuhan [25], Sihui [26] and Cangwu for geographic variation in NPC mortality rates (Figs. 1–3). 171
101 [27]. However, no report has ever given an overview of the recent From the perspective of population distribution, as shown in Fig. 3, 172
102 global trends in NPC incidence and mortality. Moreover, the past ASRs of NPC in 2003–2007 were highest in populations from 173
103 half-century has witnessed dramatic changes in populations’ eating Zhongshan and Hong Kong of southern China; intermediate in 174
104 habits, living conditions and lifestyles, which may have jointly altered Chinese overseas (Singapore; USA, Hawaii; USA, California, Los 175
105 the epidemiological trends of NPC. In this study, our purpose was Angeles (USA, CA, LA)), populations from southeast Asia (Malay- 176
106 to comprehensively depict the recent global incidence and mortal- sia, Philippines, Thailand) and from north Africa (Algeria), Philippine 177
107 ity trends of NPC, thus shedding some light on the underlying migrants, people from western Asia (Saudi Arabia, Kuwait, Turkey) 178
108 influencing factors and better planning future preventive mea- and other scattered populations (Uganda, Malta, Singapore, Spain); 179
109 sures and control strategies on NPC. and lowest in Caucasians from America and Europe. Rates in men 180
110 are usually 2–3 times those in women, and women tended to have 181
lower mortality incidence rate ratios in most of the cases 182
111 Materials and methods
(Supplementary Table S2). Of all the countries or regions studied, 183
112 Data source the lowest ratios in both men and women were noted in Thailand 184
(males: 0.21, females: 0.15), while the ratios in both genders are 185
113 ASIRs of NPC were calculated by using raw data from Cancer Incidence in Five higher than 0.50 in Costa Rica and some European countries such 186
114 Continents (CI5) Volume X [28], and fifty populations were selected to describe the
as Malta, Slovakia, and Croatia. 187
115 latest incidence rates of NPC worldwide. To plot the incidence trends of NPC, inci-
116 dence data for 1970–2007 were derived from CI5plus, which contains annual cancer 188
117 incidence data up to 2007 from selected cancer registries [29]. Registries with at
118 least 15 years of incidence records were included, and incident cases and popula- Incidence trends 189
119 tions from different registries of the same country were aggregated to attain the largest 190
120 population coverage.
121 ASMRs of NPC for 2003–2007 were obtained from the WHO cancer mortality
Significant decreasing trends in ASIRs of NPC were observed in 191
122 online database [30], and forty five populations were selected to represent the global nearly all of the high-incidence areas, some ethnic populations in 192
123 pattern in NPC mortality. To analyze the time trends of NPC mortality, national mor- the USA and several European countries during the full range of study 193
124 tality data (at least 15 years) for 35 countries were extracted from the same database period (Fig. 4, Supplementary Table S3). Globally, the average annual 194
125 over the period 1970–2013.
percent decreases were most prominent in American Indian/ 195
126 Complementary incidence and mortality data were further obtained from the
127 Surveillance, Epidemiology, and End Results (SEER) Program database of the Na- Alaska Natives from USA SEER 13 registries (AAPC: −5.4% in males), 196
128 tional Cancer Institute to gather more detailed, ethnic-specific information [31]. Nordic St Petersburg of Russia (−4.0% in males), Hong Kong of China (−3.2% 197
129 countries, which consist of five countries (Denmark, Finland, Iceland, Norway and in males, −4.1% in females), Manila of Philippines (−2.5% in males, 198
130 Sweden) as well as their autonomous regions (the Åland Islands, the Faroe Islands −3.2% in females), Chinese mainland (−2.0% in males, −3.3% in 199
131 and Greenland), were regarded as a whole to be analyzed with data derived from
132 the NORDCAN database [32]. Rates for 2000–2011 in the Chinese mainland were
females), Japan (−1.9% in males, −3.1% in females), Chinese females 200
133 provided by the National Central Cancer Registry (NCCR) of China to generate the from USA, CA, LA (−3.1%) and Mumbai of India (−2.6% in males). De- 201
134 recent trends, and 22 registries with 12 consecutive years of data in 13 provinces clines with statistical significance were also observed in both genders 202
135 and municipalities were included. Incidence data for the period of 1983–2012 for in Asian or Pacific Islanders from USA SEER 13 registries (−2.3% in 203
136 Hong Kong were obtained from the Census and Statistics Department of Hong Kong
males, −2.4% in females), Chinese residents in Singapore (−1.3% 204
137 [33], and demographic data for the corresponding years were extracted from the
138 United Nations World Population Prospects [34]. in males, −2.0% in females), Nordic countries (−1.3% in males, −1.2% 205
139 To sum up, a total of 34 populations from 26 countries were selected for ana- in females) as well as Whites (−1.1% in males, −1.1% in females) and 206
140 lyzing incidence trends; data for ten of these countries (Israel, Singapore, Costa Rica, Blacks (−0.9% in males, −2.0% in females) from USA SEER 9 regis- 207
141 Croatia, The Netherlands, Nordic countries including Denmark, Finland, Iceland, tries; in males from The Netherlands (−1.4%); and in females from 208
142 Norway and Sweden) are national. The aggregated registries are listed in Table S1
Canada (−2.9%). However, significant increases were noted in a mi- 209
143 of the supplementary materials. We chose 45 populations in total from 40 coun-
144 tries to analyze mortality trends. On account of the ethnic variation of NPC, we nority of populations, as follows: Brazil (6.1% in male, 7.1% in female); 210
145 reported trends in different ethnic groups, respectively, for multiethnic countries. females in UK, England (1.7%) and males in Slovakia (1.4%). No sig- 211
146 nificant change was observed in other regions. 212
AAPCs for the most recent 10 years (1998–2007) were basical- 213
147 Data analysis
ly in line with the AAPCs for the whole study period with a few 214
148 Joinpoint regression analysis (Joinpoint Trend Analysis Software, Version 4.1.1- exceptions (Figs. 4 and 5A, Supplementary Table S3). The inci- 215
149 August 2014) was utilized to quantitatively describe incidence and mortality trends dence decline in Hong Kong females seems to have sped up since 216
150 of NPC [35]. A logarithmic transformation was made to ASRs, which was used as a 1997, with a greater AAPC of −5.2% compared to −2.9% in previous 217
151 dependent variable, with years being the independent variable. Three was speci-
years. No statistically significant decrease has been observed among 218
152 fied as the maximum number of joinpoints, and estimated annual percent changes
153 (APCs) were calculated to measure the direction and magnitude of trends for all seg- Chinese residents in Singapore until the end of the 1980s, and in- 219
154 ments in the regression lines. AAPCs for the full range of the concerned period and cidence rates dropped with an annual change of 2.6% and 3.7% in 220
155 for the most recent 10 years (1998–2007) were calculated respectively to measure men and women, respectively, ever since. For Jewish males in Israel, 221
156 the secular and current trends of NPC. Moreover, we fitted locally weighted regres-
the incidence rate has been stable during 1970–1980, and it began 222
157 sion (Lowess) curves with a bandwidth of 0.3 to describe the trends by using Stata/
158 SE 12.0, and a log scale was employed to facilitate comparisons between registries
to decrease significantly with 1.1% of annual change thereafter. The 223
159 or countries. All data were aggregated by 5-year age groups, and all rates were di- same situation existed in Canadian males, with a 2.9% annual de- 224
160 rectly standardized to the 1960 Segi world standard population. crease starting from 1984. 225

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226 Fig. 1. Global estimates of national age-standardized incidence rates of nasopharyngeal carcinoma in (A) men and (B) women for all ages.

227

228 Mortality trends Bulgaria and Czechoslovakia (1970–1991, the country was sepa- 249
229 rated into the Czech Republic and Slovakia in 1993), as well as in 250
230 Mortality trends of NPC during the whole study period varied males in Greece and females in Belgium. 251
231 between different geographic areas (Fig. 4, Supplementary Table S4). As far as the recent trends for 1998–2007 were concerned, de- 252
232 ASMRs went down significantly in NPC high-risk areas, most strik- creasing trends in many countries or regions were even more obvious 253
233 ingly in Hong Kong of China (AAPC: −3.1% in males, −4.0% in females), with greater annual percent changes in rates observed (Figs. 4 and 254
234 Singapore (−2.2% in males, −3.1% in females), Israel (−2.2% in males, 5B, Supplementary Table S4). In Hong Kong, the mortality rate in 255
235 −3.5% in females), and the Chinese mainland (−2.5% in males, −2.2% males has been decreasing since the beginning of the study period, 256
236 in females). Significant declines in both genders were also ob- and it has declined more drastically since the 1980s. However, the 257
237 served in the USA, Canada and some countries in Europe (Czech situation was a bit different in Singapore, where no obvious decline 258
238 Republic, France, Germany, Malta, Nordic countries, Slovakia, Spain in mortality rate was noted until 1990 for men and 1984 for women. 259
239 and Scotland, England and Wales in UK). Furthermore, the decreas- In South Africa, great declines in the mortality of NPC have been 260
240 ing trends were statistically significant in the following populations: achieved in both sexes since 1998, with AAPC equal to −3.6% and 261
241 Croatia, Republic of Moldova, The Netherlands, and the UK, and −5.0% in men and women, respectively. In Belgium, one of the low- 262
242 females in Austria, Australia and Hungary. From a global perspec- incidence areas, there were even striking increases in death rates 263
243 tive, the most dramatic decline in females was observed in Slovakia before significant declines took place in 1993 for both genders. 264
244 (−6.5%), followed by Austria (−4.2%), Hong Kong (−4.0%) and Israel Though incidence and mortality trends of NPC vary greatly among 265
245 (−3.5%); in males the most dramatic decline was noted in Malta different areas, commonalities still exist according to our results. 266
246 (−3.6%), followed by Hong Kong (−3.1%), Republic of Moldova (−2.8%) Taking a closer look at the trends in each line segment, we found 267
247 and Nordic countries (−2.7%). However, opposite trends were ob- that NPC ASRs in many countries and regions all experienced a tran- 268
248 served in both genders from Republic of Korea, Philippines, Brazil, sition from increasing trends or stable conditions to ultimately 269

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270 Fig. 2. Global estimates of national age-standardized mortality rates of nasopharyngeal carcinoma in (A) men and (B) women for all ages.

271

272 decreasing trends, even though the magnitude of the trends and areas. Moreover, mass screening through serological detection of 294
273 the exact turning points in time may differ from region to region the EBV antibody, advances in diagnostic methods and treatment 295
274 (Supplementary Tables S3 and S4). strategies are also important contributing factors. Still, the mortal- 296
275 ity rates of NPC have significantly increased in a few areas. For 297
276 Discussion Republic of Korea and Thailand, the results might be greatly influ- 298
277 enced by the registration coverage and data quality since the reported 299
278 Over the past decades, substantial declines in NPC incidence rates deaths experienced extraordinarily steep rises over the years, and 300
279 were observed in nearly all of the Asian areas studied, especially the real trends were masked. While in other regions such as Phil- 301
280 in high-incidence regions such as Hong Kong, Singapore and Taiwan, ippines, Brazil and Bulgaria, the exact reasons for the increasing 302
281 which has also been widely reported in previous studies [18,20,24]. mortality rates of NPC still warrant further investigation and the 303
282 Although incidence in most of the low-risk areas remained stable, actual situation in each country has to be reckoned with. When 304
283 significant decreasing trends in some populations are still note- AAPCs for 1998–2007, the latest ten years in our study period, and 305
284 worthy (both genders in Nordic countries and Whites, Blacks and those for the whole range of the study period were compared, more 306
285 Asian or Pacific Islanders in the USA, Canadian females, Chinese populations showed statistically significant declines in incidence and 307
286 females in the USA, CA, LA, males in Russia, Netherlands and Amer- mortality and the magnitude of the decreasing trends seemed greater 308
287 ican Indian/Alaska Native males in the USA). Compared with for the recent period. One reasonable explanation might be a de- 309
288 incidence rates, declines in mortality trends seemed more encour- crease in exposure to some risk factors because the environment 310
289 aging. We noted significant reductions in mortality rates in 32 and has undergone tremendous changes over the years, and another pos- 311
290 28 populations for men and women among the 45 populations, and sibility could be the effect of certain preventive measures and 312
291 reductions in incidence were noted in 16 and 12 populations for treatment strategies implemented in the recent decades. General- 313
292 men and women, respectively, out of 34 populations. Decreased in- ly, both the incidence and mortality rates of NPC were higher 314
293 cidence rates may partly account for the mortality declines in some in men than women, demonstrating men are more prone to NPC. 315

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320 Fig. 3. Age-standardized (A) incidence and (B) mortality rates of nasopharyngeal carcinoma in both sexes for all ages, 2003–2007.

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Moreover, in most of the cases, mortality incidence rate ratios in 323

women were lower than men, suggesting that the survival rates may 324
be higher in the former. Many previous studies have reported a better 325
prognosis in women than men, and this was presumably associ- 326
ated with the gender differences in lifestyle behavioral factors, 327
diagnostic delays and biologic traits such as sex hormones [36–38]. 328
A study conducted in the Sun Yat-Sen University Cancer Center 329
showed that the rate of female patients diagnosed at an early clin- 330
ical stage was nearly two times that of male patients, and the 331
favorable prognosis in females persists after stratification by clin- 332
ical stages [37]. By propensity-matched analysis, a recent 333
retrospective study conducted in the same institute also sug- 334
gested that the female sex is an independent and protective 335
prognostic factor of NPC regardless of tumor stage for premeno- 336
pausal patients, but the significant advantage decreased during 337
menopause and vanished in the postmenopausal period [38]. The 338
results further supported the hypothesis that the better prognosis 339
in female patients is highly related to intrinsic physiological factors, 340
especially estrogen and the estrogen receptor. It has been re- 341
ported that estrogen can exert a protective influence on the risk of 342
developing NPC in females [39], but whether the protective effect 343
also holds for survival is unknown. More convincing and robust ev- 344
idence needs to be supplied in the future. Furthermore, the lowest 345
mortality incidence rate ratios in both sexes were noted in Thai- 346
land (males: 0.21, females: 0.15), which may be a manifestation of 347
high survival rate in the country. However, the possibilities that in- 348
cidence was over-reported or mortality was underreported can’t be 349
excluded. In contrast, the ratios in both genders are higher than 0.50 350
in Costa Rica and some European countries such as Malta, Slova- 351
kia, and Croatia, possibly suggesting higher case fatality risk in those 352
areas. 353
Given that NPC is associated with multiple etiological factors and 354
the pathogenic mechanism is yet to be clarified, interpreting the 355
trends accurately can be challenging. However, hypotheses could 356
be made based on available data and former studies. It’s believed 357
that EBV infection plays a key role in NPC occurrence, but the reason 358
that NPC is only prevalent in a few specific populations while in- 359
fection with EBV is ubiquitous worldwide remains a puzzle. Though 360
genomic diversity of EBV from NPC and other EBV-associated tumor 361
types has been studied [40,41], the role of EBV genome diversity 362
in the pathogenesis of NPC has yet to be elucidated, and whether 363
variations of the EBV genotype over time influence incidence trends 364
of NPC is unclear. Considering genetic predisposition is relatively 365
stable in populations, it’s reasonable to postulate that the trends’ 366
variations of NPC were mainly attributed to changes in other en- 367
vironmental risk factors. 368
Tobacco smoking has long been recognized as one of the major 369
environmental risk factors of NPC. According to our published meta- 370
analysis, the risk of developing NPC for smokers was approximately 371
1.6 times the risk for non-smokers, with an obvious dose-dependent 372
relationship, and the associations were stronger in low-risk popu- 373
lations and for KSCC [12]. Moreover, it was reported that the decline 374
in incidence among Chinese Americans and males in Hong Kong had 375
in a large part resulted from the reductions in the rate of KSCC [3,23]. 376
Because KSCC is the histological type most significantly related to 377
smoking [12], the alleviated smoking prevalence seems to be a con- 378
vincing explanation for the decreasing trends in NPC incidence, 379
especially in low-risk areas where KSCC is the predominant histo- 380
logical type [42]. However, while smoking prevalence has been 381
effectively controlled in vast areas in Europe [43], significant de- 382
clines in ASIRs were only observed in a few populations (both sexes 383
in Nordic countries, males in The Netherlands and Russia). More con- 384
fusingly, in contrast to other regions, increasing incidence trends 385
321 Fig. 4. Trends in incidence and mortality of NPC in men and women for all ages. were noted in Slovakian males, females in England of the UK and 386
322 “M” for males, “F” for females.
both sexes in Brazil, though the smoking rates have dropped in all 387
of the above populations during the corresponding period [43,44]. 388

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389 Fig. 5. Average annual percent changes (AAPCs) in (A) incidence and (B) mortality of NPC for 1998–2007 in men and women, all ages. AAPCs in China are for 2000–2009.
390 *Significantly different from 0 at alpha = 0.05. (A) USA, CA, LA = USA, California, Los Angeles. Data for “USA: White” and “USA: Black” are for SEER 9 registries (Atlanta, Con-
391 necticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, and Utah); data for “USA: Asian or Pacific Islander”, “USA: American Indian/
392 Alaska Native”, “USA: Hispanic”, “USA: White Hispanic” and “USA: White Non-Hispanic” are for SEER 13 registries (SEER 9, plus Los Angeles, San Jose-Monterey, Rural Georgia
393 and the Alaska Native Tumor Registry). (B) AAPCs in Philippines are for 1994–2003.

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394 It is possible that the beneficial effects brought by tobacco control terpreted with caution, and awareness must be raised when 460
395 were offset or masked by other risk factors such as air pollution and examining trends in incidence and mortality for the same country 461
396 severe alcohol drinking. and comparing our results with previous findings. Moreover, due 462
397 Specific dietary pattern is another highly dubious influencing to the data limitation, trends by histologic subtypes were not de- 463
398 factor of NPC, and it has been widely reported in high-risk areas, picted here. With regard to the above drawbacks, concerted efforts 464
399 especially in southern China where residents used to consume a large have to be made by governments and anti-cancer organizations or 465
400 amount of salted fish and other pickled foods [45,46]. Frequent intake associations for establishing a well-functioning network of 466
401 of those salt-preserved foods was thought to be a risk factor of de- population-based cancer registries globally, and regular profession- 467
402 veloping NPC, as the N-nitrosamines contained in them is a type al training should be given to personnel who are in charge of cancer 468
403 of carcinogenic substance [15]. Note that the dietary structure of registration. 469
404 people in southern China has been greatly modified over the recent To further reduce the burden brought by nasopharyngeal car- 470
405 years, and salted fish is no longer a staple food in daily diets; the cinoma worldwide, primary prevention strategies should mainly 471
406 decreasing incidence trend over 1980–1999 observed in Hong Kong focus on modifiable etiological factors, including banning smoking 472
407 was postulated to be a result of this changed dietary pattern [18]. in public areas, reducing intakes of salted fish and preserved foods, 473
408 A subsequent study revealed that the incidence decline in Hong Kong avoiding harmful occupational exposures and increasing consump- 474
409 was primarily attributed to the decrease in KSCC (decreased from tion of fresh fruits and vegetables. Moreover, other measures such 475
410 21.5% in 1988 to 6.9% in 2002) and unknown type NPC, indicating as mass screening in high-risk populations via early serological de- 476
411 that tobacco control has also played a part in the decreasing trend tection, vaccine development, and effective treatment programs are 477
412 [3]. Nevertheless, considering the low smoking rate in females from also of paramount importance in preventing the disease. 478
413 high-risk areas, variation in dietary patterns may be a more im- 479
414 portant contributor to the observed decreasing trends in females, Acknowledgments 480
415 while smoking rate has a greater influence on trends in males. Note 481
416 that the proportion of histologically verified NPC cases has in- This study was supported by grants from the National Natural 482
417 creased (from 76% to 97.3%) during 1998–2002, and misclassification Science Funds for Distinguished Young Scholars (No. 81325018), Gua- 483
418 bias could exist, so the result must be interpreted with caution. ngdong High-level Personnel of Special Support Program (No. 484
419 We observed encouraging decreasing trends in incidence as well 2014TX01R201), National Science & Technology Pillar Program during 485
420 as mortality of NPC in the Chinese mainland. Previously, general de- the Twelfth Five-year Plan Period (No. 2014BAI09B10), Science and 486
421 clines in mortality rates in the whole country have been reported Technology Planning Project of Guangdong Province, China 487
422 with national profiles for 1987–1999 from the Center for Health In- (2011B031800218) and the National Natural Science Foundation of 488
423 formation and Statistics (CHIS) of the Ministry of Health [47] and China (81201747). 489
424 with data from three retrospective nationwide all death-causes sam- 490
425 pling surveys during 1973–2005 [48]. However, NPC incidence trend Conflict of interest 491
426 at the national level hasn’t been studied formerly. Here in our study, 492
427 the results showed that the overall incidence rate in China has de- We wish to confirm that there are no known conflicts of inter- 493
428 creased during 2000–2011 with an annual percent change of −2.0% est associated with this publication and there has been no significant 494
429 and −3.3% in men and women, respectively. Still, due to the great financial support for this work that could have influenced its 495
430 nationwide geographical variation of NPC, it’s noteworthy that the outcome. 496
431 overall trend is just a crude estimate, which may disagree with trends 497
432 at a subnational level. For example, a significant decline in inci- Appendix: Supplementary material 498
433 dence (AAPC: −3.26% in males, −5.74% in females) of NPC in urban 499
434 Guangzhou was observed for the period of 2000–2011 [19]. However, Supplementary data to this article can be found online at 500
435 in Sihui, another high-risk region, the NPC incidence rate was main- doi:10.1016/j.canlet.2016.01.040. 501
436 tained at a high level for the recent period [26]. Since Guangzhou 502
437 is a developed metropolitan that has undergone drastic environ- References 503
438 mental changes along with economic development, the process 504
439 might be quite similar to that experienced by other high-risk areas [1] J. Ferlay, I. Soerjomataram, M. Ervik, R. Dikshit, S. Eser, C. Mathers, et al. 505
440 such as Singapore and Hong Kong. In contrast, Sihui is an under- GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC 506
441 developed region, where the risk factors for NPC could be relatively CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research 507
on Cancer. <http://globocan.iarc.fr>, 2013 (accessed 03.15). Q4 508
442 stable over the long period. However, to uncover the exact reasons [2] K. Shanmugaratnam, L.H. Sobin, International histological classification of 509
443 behind this, more detailed research has to be performed in the high- tumours, in: K. Shanmugaratnam, L.H. Sobin (Eds.), Histological Typing of 510
444 risk areas. Tumours of the Upper Respiratory Tract and Ear, second ed., World Health 511
Organization, Geneva, 1991, pp. 32–33. 512
445 This is the first study to systematically summarize the global [3] L.A. Tse, I.T. Yu, O.W. Mang, S.L. Wong, Incidence rate trends of histological 513
446 trends in NPC incidence and mortality, through which we are able subtypes of nasopharyngeal carcinoma in Hong Kong, Br. J. Cancer 95 (2006) 514
447 to have a comprehensive view of the epidemiological status of NPC 1269–1273. 515
[4] J.E. Marks, J.L. Phillips, H.R. Menck, The National Cancer Data Base report on 516
448 worldwide and to examine the advances made on combating the the relationship of race and national origin to the histology of nasopharyngeal 517
449 neoplasm, thus allowing for better planning of future prevention carcinoma, Cancer 83 (1998) 582–588. 518
450 and control programs. However, our research has been greatly limited [5] E.T. Chang, H.O. Adami, The enigmatic epidemiology of nasopharyngeal 519
451 by the paucity of qualified data, especially in regard to low- and
carcinoma, Cancer Epidemiol. Biomarkers Prev. 15 (2006) 1765–1777. 520
[6] C. de Martel, J. Ferlay, S. Franceschi, J. Vignat, F. Bray, D. Forman, et al., Global 521
452 middle-income countries and regions where a great number of high- burden of cancers attributable to infections in 2008: a review and synthetic 522
453 risk populations reside. The completeness of data may vary among analysis, Lancet Oncol. 13 (2012) 607–615. 523
454 different areas, which has a fundamental influence on the accura- [7] H.B. Neel 3rd, G.R. Pearson, W.F. Taylor, Antibodies to Epstein-Barr virus in 524
patients with nasopharyngeal carcinoma and in comparison groups, Ann. Otol. 525
455 cy and validity of the results. Moreover, because mortality data are Rhinol. Laryngol. 93 (1984) 477–482. 526
456 national while the incidence data under study are mostly regional [8] A. Hildesheim, R.J. Apple, C.J. Chen, S.S. Wang, Y.J. Cheng, W. Klitz, et al., 527
457 with different population coverage, the representativeness of the Association of HLA class I and II alleles and extended haplotypes with 528
nasopharyngeal carcinoma in Taiwan, J. Natl Cancer Inst. 94 (2002) 1780–1789. 529
458 estimated incidence trends might be impaired to some extent. Taking [9] K.P. Tse, W.H. Su, K.P. Chang, N.M. Tsang, C.J. Yu, P. Tang, et al., Genome-wide 530
459 the aforementioned into consideration, the results should be in- association study reveals multiple nasopharyngeal carcinoma-associated loci 531

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532 within the HLA region at chromosome 6p21.3, Am. J. Hum. Genet. 85 (2009) 1983–2002) in Sihui and Cangwu counties in southern China, BMC Cancer 6 592
533 194–203. (2006) 178. 593
534 [10] W.H. Jia, Q.H. Pan, H.D. Qin, Y.F. Xu, G.P. Shen, L. Chen, et al., A case-control and [28] D. Forman, F. Bray, D.H. Brewster, C. Gombe Mbalawa, B. Kohler, M. Piñeros, 594
535 a family-based association study revealing an association between CYP2E1 et al., Cancer Incidence in Five Continents Vol. X, International Agency for 595
536 polymorphisms and nasopharyngeal carcinoma risk in Cantonese, Research on Cancer, Lyon. IARC Scientific Publication No. 164. 596
537 Carcinogenesis 30 (2009) 2031–2036. [29] J. Ferlay, F. Bray, E. Steliarova-Foucher, D. Forman Cancer Incidence in Five 597
538 [11] J.X. Bei, Y. Li, W.H. Jia, B.J. Feng, G. Zhou, L.Z. Chen, et al., A genome-wide Continents, CI5plus. IARC CancerBase No. 9. International Agency for Research 598
539 association study of nasopharyngeal carcinoma identifies three new on Cancer, Lyon. <http://ci5.iarc.fr>, 2014 (accessed 03.15). 599
540 susceptibility loci, Nat. Genet. 42 (2010) 599–603. [30] World Health Organization. WHO Mortality Database. <http://www.who.int/ 600
541 [12] W.Q. Xue, H.D. Qin, H.L. Ruan, Y.Y. Shugart, W.H. Jia, Quantitative association healthinfo/statistics/mortality_rawdata/en/index.html>, (accessed 11.14). 601
542 of tobacco smoking with the risk of nasopharyngeal carcinoma: a [31] National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance 602
543 comprehensive meta-analysis of studies conducted between 1979 and 2011, Systems Branch, Surveillance, Epidemiology, and End Results (SEER) Program 603
544 Am. J. Epidemiol. 178 (2013) 325–338. SEER*Stat Database, released April 2015, based on the November 2014 604
545 [13] X. Guo, R.C. Johnson, H. Deng, J. Liao, L. Guan, G.W. Nelson, et al., Evaluation submission. <http://seer.cancer.gov/canques/>, (accessed 03.15). 605
546 of nonviral risk factors for nasopharyngeal carcinoma in a high-risk population [32] G. Engholm, J. Ferlay, N. Christensen, A.M.T. Kejs, T.B. Johannesen, S. Khan, et al. 606
547 of Southern China, Int. J. Cancer 124 (2009) 2942–2947. NORDCAN: Cancer Incidence, Mortality, Prevalence and Survival in the Nordic 607
548 [14] W.H. Jia, X.Y. Luo, B.J. Feng, H.L. Ruan, J.X. Bei, W.S. Liu, et al., Traditional Countries, Version 7.1 (09.07.2015). Association of the Nordic Cancer Registries. 608
549 Cantonese diet and nasopharyngeal carcinoma risk: a large-scale case-control Danish Cancer Society. <http://www.ancr.nu>, (accessed 07.15). 609
550 study in Guangdong, China, BMC Cancer 10 (2010) 446. [33] Hospital Authority: Hong Kong Cancer Registry web site. <www3.ha.org.hk/ 610
551 [15] L. Gallicchio, G. Matanoski, X.G. Tao, L. Chen, T.K. Lam, K. Boyd, et al., Adulthood cancereg/statistics.html>, (accessed 05.15). 611
552 consumption of preserved and nonpreserved vegetables and the risk of [34] United Nations, World Population Prospects, the 2012 Revision. 612
553 nasopharyngeal carcinoma: a systematic review, Int. J. Cancer 119 (2006) <http://esa.un.org/unpd/wpp/index.htm>, (accessed 05.15). 613
554 1125–1135. [35] Statistical Methodology and Applications Branch, Surveillance Research Program, 614
555 [16] T.J. Key, N.E. Allen, E.A. Spencer, R.C. Travis, The effect of diet on risk of cancer, National Cancer Institute. Joinpoint Regression Program, Version 4.2.0 – April 615
556 Lancet 360 (2002) 861–868. 2015. 616
557 [17] W.H. Jia, H.D. Qin, Non-viral environmental risk factors for nasopharyngeal [36] G. Xiao, Y. Cao, X. Qiu, W. Wang, Y. Wang, Influence of gender and age on 617
558 carcinoma: a systematic review, Semin. Cancer Biol. 22 (2012) 117–126. the survival of patients with nasopharyngeal carcinoma, BMC Cancer 13 (2013) 618
559 [18] A.W. Lee, W. Foo, O. Mang, W.M. Sze, R. Chappell, W.H. Lau, et al., Changing 226. 619
560 epidemiology of nasopharyngeal carcinoma in Hong Kong over a 20-year period [37] X. Lu, F.L. Wang, X. Guo, L. Wang, H.B. Zhang, W.X. Xia, et al., Favorable prognosis 620
561 (1980–99): an encouraging reduction in both incidence and mortality, Int. J. of female patients with nasopharyngeal carcinoma, Chin. J. Cancer 32 (2013) 621
562 Cancer 103 (2003) 680–685. 283–288. 622
563 [19] K. Li, G.-Z. Lin, J.-C. Shen, Q. Zhou, Time trends of nasopharyngeal carcinoma [38] P.Y. OuYang, L.N. Zhang, X.W. Lan, C. Xie, W.W. Zhang, Q.X. Wang, et al., The 623
564 in urban Guangzhou over a 12-year period (2000–2011): declines in both significant survival advantage of female sex in nasopharyngeal carcinoma: a 624
565 incidence and mortality, Asian Pac. J. Cancer P. 15 (2014) 9899–9903. propensity-matched analysis, Br. J. Cancer 112 (2015) 1554–1561. 625
566 [20] C. Hsu, Y.C. Shen, C.C. Cheng, R.L. Hong, C.J. Chang, A.L. Cheng, Difference in [39] S.H. Xie, I.T.S. Yu, L.A. Tse, O.W.K. Mang, L. Yue, Sex difference in the incidence 626
567 the incidence trend of nasopharyngeal and oropharyngeal carcinomas in Taiwan: of nasopharyngeal carcinoma in Hong Kong 1983–2008: suggestion of a 627
568 implication from age-period-cohort analysis, Cancer Epidemiol. Biomarkers Prev. potential protective role of oestrogen, Eur. J. Cancer 49 (2013) 150–155. 628
569 15 (2006) 856–861. [40] A.L. Palser, N.E. Grayson, R.E. White, C. Corton, S. Correia, M.M. Ba Abdullah, 629
570 [21] K.S. Chia, A. Seow, H.P. Lee, K. Shanmugaratnam:Trends in Cancer Incidence et al., Genome diversity of Epstein-Barr virus from multiple tumor types and 630
571 in Singapore 1968–2007. Singapore Cancer Registry, Report No. 7, 2000. normal infection, J. Virol. 89 (2015) 5222–5237. 631
572 [22] M. Arnold, M.A. Wildeman, O. Visser, H.E. Karim-Kos, J.M. Middeldorp, R. Fles, [41] H. Kwok, C.W. Wu, A.L. Palser, P. Kellam, P.C. Sham, D.L. Kwong, et al., Genomic 632
573 et al., Lower mortality from nasopharyngeal cancer in The Netherlands since diversity of Epstein-Barr virus genomes isolated from primary nasopharyngeal 633
574 1970 with differential incidence trends in histopathology, Oral Oncol. 49 (2013) carcinoma biopsy samples, J. Virol. 88 (2014) 10662–10672. 634
575 237–243. [42] T.L. Vaughan, J.A. Shapiro, R.D. Burt, G.M. Swanson, M. Berwick, C.F. Lynch, et al., 635
576 [23] L.M. Sun, M. Epplein, C.I. Li, T.L. Vaughan, N.S. Weiss, Trends in the incidence Nasopharyngeal cancer in a low-risk population: defining risk factors by 636
577 rates of nasopharyngeal carcinoma among Chinese Americans living in Los histological type, Cancer Epidemiol. Biomarkers Prev. 5 (1996) 587–593. 637
578 Angeles County and the San Francisco metropolitan area, 1992–2002, Am. J. [43] WHO global report on trends in prevalence of tobacco smoking. 638
579 Epidemiol. 162 (2005) 1174–1178. <http://www.who.int/iris/handle/10665/156262>, 2015 (accessed 06.15). 639
580 [24] J. Luo, K.S. Chia, S.E. Chia, M. Reilly, C.S. Tan, W. Ye, Secular trends of [44] Lifestyle Statistics HaSCIC, Statistics on Smoking: England, 2013. 640
581 nasopharyngeal carcinoma incidence in Singapore, Hong Kong and Los Angeles <www.hscic.gov.uk>, 2013 (accessed 06.15). 641
582 Chinese populations, 1973–1997, Eur. J. Epidemiol. 22 (2007) 513–521. [45] J.H. Ho, D.P. Huang, Y.Y. Fong, Salted fish and nasopharyngeal carcinoma in 642
583 [25] S.H. Xie, J. Gong, N.N. Yang, L.A. Tse, Y.Q. Yan, I.T. Yu, Time trends and age-period- southern Chinese, Lancet 2 (1978) 626. 643
584 cohort analyses on incidence rates of nasopharyngeal carcinoma during [46] M.C. Yu, J.H. Ho, S.H. Lai, B.E. Henderson, Cantonese-style salted fish as a cause 644
585 1993–2007 in Wuhan, China, Cancer Epidemiol. 36 (2012) 8–10. of nasopharyngeal carcinoma: report of a case-control study in Hong Kong, 645
586 [26] L.F. Zhang, Y.H. Li, S.H. Xie, W. Ling, S.H. Chen, Q. Liu, et al., Incidence trend of Cancer Res. 46 (1986) 956–961. 646
587 nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong [47] L. Yang, D.M. Parkin, L. Li, Y. Chen, Time trends in cancer mortality in China: 647
588 Province, South China: an age-period-cohort analysis, Chin. J. Cancer 34 (2015) 1987–1999, Int. J. Cancer 106 (2003) 771–783. 648
589 15. [48] T.-R. Huang, S.-W. Zhang, W.-Q. Chen, W. Deng, C.-Y. Zhang, X.-J. Zhou, et al., 649
590 [27] W.H. Jia, Q.H. Huang, J. Liao, W. Ye, Y.Y. Shugart, Q. Liu, et al., Trends in incidence Trends in nasopharyngeal carcinoma mortality in China, 1973–2005, Asian Pac. 650
591 and mortality of nasopharyngeal carcinoma over a 20–25 year period (1978/ J. Cancer P. 13 (2012) 2495–2502. 651

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