Non-viral Environmental Risk Factors for Nasopharyngeal Carcinoma a Systematic Review

Smoking and nasopharyngeal cancer: individual information meta-analysis of half dozen prospective studies on 334 935 men

Jia Huang Lin,

School of Public Health, Li Ka Shing Kinesthesia of Medicine, University of Hong Kong

,

Hong Kong

Centre for Nasopharyngeal Carcinoma Research (CNPCR), Enquiry Grants Council Area of Excellence Scheme, University of Hong Kong

,

Hong Kong

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Scientific discipline Middle

, Beijing,

China

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Chi Pang Wen,

Establish of Population Wellness Sciences, National Health Institutes

, Zhunan,

Taiwan

Graduate Institute of Clinical Medical Science, China Medical University

, Taichung,

Taiwan

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Chao Qiang Jiang,

Guangzhou No.12 Hospital

, Guangzhou,

China

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Jian-Min Yuan,

Sectionalisation of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh

, Pittsburgh, PA,

USA

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh

, Pittsburgh, PA,

U.s.a.

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Chien Jen Chen,

Genomics Research Eye

, Academia Sinica, Taipei,

Taiwan

Graduate Plant of Epidemiology and Preventive Medicine, Higher of Public Health, National Taiwan University

, Taipei,

Taiwan

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Sai Yin Ho,

School of Public Health, Li Ka Shing Faculty of Medicine, Academy of Hong Kong

,

Hong Kong

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Wayne Gao,

Primary'south Programme in Global Health and Development, Taipei Medical University

, Taipei,

Taiwan

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Weisen Zhang,

Guangzhou No.12 Hospital

, Guangzhou,

China

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Renwei Wang,

Division of Cancer Command and Population Sciences, UPMC Hillman Cancer Middle, University of Pittsburgh

, Pittsburgh, PA,

USA

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Yin-Chu Chien,

Genomics Research Centre

, Academia Sinica, Taipei,

Taiwan

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Articulation first authors, contributing equally to the paper.

Author Notes

Editorial decision:

16 February 2021

Abstract

Background

The role of smoking in nasopharyngeal carcinoma (NPC) remains uncertain, especially in owned regions. We conducted an individual participant data (IPD) meta-analysis of prospective cohort studies to investigate the associations betwixt smoking exposure and risk of NPC.

Methods

We obtained private participant information of 334 935 male person participants from six eligible population-based cohorts in NPC-endemic regions, including two each in Guangzhou and Taiwan, and one each in Hong Kong and Singapore. We used one- and two-stage approaches IPD meta-analysis and Cox proportional chance models to summate take a chance ratios (HRs) and 95% confidence intervals (CIs) of NPC for smoking exposure adjusting for age and drinking status.

Results

During 2 961 315 person-years of follow-upward, 399 NPC evens were ascertained. Risks of NPC were higher in e'er versus never smokers (HR_one-stage = one.32, 95% CI = one.07-i.63, P=0.0088; HR_ii-stage = i.27, 1.01-1.lx, 0.04). These positive associations appeared to be stronger in ever smokers who consumed sixteen+ cigarettes/day (Hr_i-stage = 1.67, 95% CI = i.29-two.16, P=0.0001), and in those who started smoking at age younger than sixteen (ii.16, one.33-3.50, 0.0103), with dose-response relationships (P-values for trend = 0.0028 and 0.0103, respectively). Quitting (versus daily smoking) showed a small reduced risk (stopped for five+ years: HR_one-stage = 0.91, 95% CI = 0.60-1.39, P=0.66; for former smokers: Hour_two-stage = 0.84, 0.61-1.fourteen, 0.26).

Conclusions

This first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational show that smoking increased NPC gamble in men. NPC should be added to the 12–16 cancer sites known to be tobacco-related cancers. Strong tobacco control policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions.

Key Messages

• This first individual participant data (IPD) meta-analysis from vi population-based prospective cohorts in endemic regions of nasopharyngeal carcinoma (NPC) assessed the associations between smoking exposure and risk of NPC in men.

• Ever smokers had 32% higher risks of NPC than never smokers.

• Smokers who consumed 16+ cigarettes per day had 67% higher risks of NPC.

• Smokers who started smoking younger than historic period 16 showed the highest HR (hazard rato) of 2.16.

Introduction

Nasopharyngeal carcinoma (NPC) has a distinctive geographical variation, ^{1 , two} with over 70% of 129 000 new cases of NPC in 2018 diagnosed in East and Southward-East asia. ³ Despite its similar cell or tissue lineage, NPC presents an epidemiological pattern distinct from most types of caput and neck cancer that have been confirmed to be smoking related. ^4–6 The 2012 International Agency for Research on Cancer (IARC) Monograph considered cigarette smoking to be causally related to NPC. ⁷ However, the association betwixt smoking and NPC has not been concluded to be causal in the 2014 US Surgeon General's Written report. ^eight

Previous epidemiological studies on the association between smoking and NPC have shown inconsistent results. Such association appeared to be stronger in case-control studies ^9–34 than cohort studies, ^35–39 probably because case-control studies are subject to recall bias. In addition, positive associations were mainly observed in non-endemic regions of NPC, where the major NPC histological type is squamous jail cell carcinoma. ^{40 , 41} Prospective epidemiological data are very limited in endemic regions, where the major histological type is non-keratinizing undifferentiated carcinoma. ⁴² Only two summary aggregate data meta-analyses accept reported that smoking was associated with higher risks of NPC in non-endemic regions, but not in owned regions. ^{43 , 44} Individual participant information (IPD) meta-analysis is considered to be the 'gold standard' of systematic review and can provide the strongest evidence from observational studies. ⁴⁵ As smoking may have different roles in different subtypes of NPC, divide analyses would be ideal. However, information on subtypes was rarely nerveless by previous cohort studies and the numbers of NPC events were small, so pooling private information restricting to studies in endemic regions, having over 95% of non-keratinizing undifferentiated carcinoma NPC, could reverberate the association for non-keratinizing undifferentiated carcinoma. We conducted an IPD meta-analysis to assess the associations betwixt smoking history and risk of NPC in endemic regions.

Methods

Ethics Approval

The Guangzhou Biobank Accomplice Study has ethics approval from the Guangzhou Medical Ethics Committee of the Chinese Medical Association, Guangzhou, China (Co-Principal Investigator: Prof. Lam Tai-Hing). The Guangzhou Occupational Cohort Written report obtained ethics approval from the Ethics Commission, Faculty of Medicine, and the University of Hong Kong. Permission to use data was granted past Guangzhou Occupational Diseases Prevention and Treatment Eye (Principal Investigator: Prof. Lam Tai-Hing). The Hong Kong Elderly Health Service Cohort Study obtained ethics approval from the University of Hong Kong–Infirmary Authority Hong Kong Westward Cluster Articulation Institutional Review Board (Principal Investigator: Prof. Lam Tai-Hing). The Singapore Chinese Health Study was approved by the Institutional Review Boards of the Academy of Southern California and the National University of Singapore (Principal Investigator: Prof. Yuan Jian-Min). The Taiwan Cohort conducted in 1984 was approved by the institutional review board of the College of Public Health National Taiwan Academy (Principal Investigator: Prof. Chen Chien-Jen). The Taiwan MJ Cohort was approved at the National Health Research Institutes and at China Medical University Hospital (Principal Investigator: Prof. Wen Chi-Pang).

Search strategy, cohort choice criteria and written report sample

Nosotros identified prospective cohort studies in endemic regions published in Chinese or English from January 1970 to November 2019 from PubMed, Web of Science, CNKI and Wanfang. An endemic region was defined as having an age-standardized incidence rate (ASIR) greater than 8 per 100 000 person-years in men. Manual search was also done by reviewing references in relevant articles. Iii published cohort studies from endemic regions were found in the literature review from Taiwan, ³⁸ Guangzhou ³⁹ and Singapore. ³⁷ Three other cohorts in endemic regions, including Taiwan, ⁴⁶ Guangzhou ⁴⁷ and Hong Kong, ⁴⁸ with ascertainment of NPC and smoking information, were identified past manual search, though they had no publication on NPC. The inclusion criteria were: (i) the cohort written report was conducted in NPC-endemic regions with ASIR ≥8/100 000 persons-years in men; (ii) pick of participants was not based on history of any previous chronic disease; (iii) the accomplice included sufficient NPC events with a male crude bloodshed ≥4/100 000 person-years or male rough event rate ≥10/100 000 person-years; (iv) the accomplice had baseline information on sex, age and smoking and alcohol consumption; (v) the mean duration of follow-up of the accomplice was ≥5 years; (vi) participants in the cohort were anile 18+; and (vii) the main investigator of the eligible study agreed to provide private-level data.

All the six cohorts identified in the literature search were eligible. Each of the principal investigators has agreed to join the NPC Accomplice Study Collaboration (NPC-CSC). With a data request sheet ( Supplementary Effigy S1, available as Supplementary information at IJE online), we obtained data on NPC event (fatal or non-fatal cases), demographic characteristics (sex, historic period and educational level), smoking and drinking status, medical history at baseline, duration of follow-up, and vital status ( Supplementary Figure S2, available as Supplementary data at IJE online). All studies had obtained ethics approval and informed consent for their studies. All participants provided informed consent. This paper follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for Individual Patient Information reporting guidelines. ⁴⁹

Follow-upwardly and consequence

Participants were followed from the baseline in each cohort to the date of outset example of non-fatal or fatal NPC event, or the date of death from other causes or the last follow-upward date in each cohort (Table 1). All vi studies classified NPC events by the International Nomenclature of Disease (ICD) Revision 9 or 10. Malignant neoplasm of nasopharynx was coded as 147 in ICD-9 or C11 in ICD-ten. We excluded deaths that occurred inside 2 years from baseline. Missing duration of follow-up (one NPC event in the Taiwan Accomplice 1984, xi NPC events in the Taiwan MJ Cohort, and 104 participants in the Guangzhou Biobank Cohort Study) was imputed using the median follow-upward years of each cohort.

Tabular array 1

Baseline characteristics of private cohorts and the combined cohort in the meta-analyses (men simply)

Study	Taiwan Cohort 1984 (included men only)	Guangzhou Occupational Cohort	Singapore Chinese Wellness Study	Hong Kong Elderly Health Service Cohort	Guangzhou Biobank Cohort Study	Taiwan MJ Cohort	Combined cohort
Cohort reference number	38	39	37	48	47	46	37–39, 46–48
Regions	Taiwan	Guangzhou	Singapore	Hong Kong	Guangzhou	Taiwan	Endemic regions
Enrolment/last follow-up date	1984-86/2011	1988-92/1999	1993-99/2008	1998-2001/2012	2003-08/2017	1994-2006/2008	1984-2008/2017
Median baseline survey year	1985	1990	1996	1999	2005	1999	1996
Population source	Population register	Health check-up	Population register	Health check-up	Health check-upwardly	Health check-up	NA
Male participants	9428	87 327	26 654	21 764	6952	182 810	334 935
Hateful (SD) age at baseline survey, years	51.6 (12.five)	41.2 (v.ix)	56.5 (7.9)	71.9 (v.3)	64.iv (6.7)	40.6 (13.six)	44.viii (14.2)
Mean (SD) follow-up, years	21.four (7.five)	7.iii (0.7)	12.ii (3.1)	11.0 (three.two)	11.three (2.half-dozen)	8.1 (3.3)	eight.8 (iv.0)
No. of NPC example	42	30	117	23	20	167	399
Drinking condition, no. (%)
Never	7577 (80.iv)	72 205 (82.seven)	18 200 (68.3)	15 771 (72.v)	3530 (l.8)	117 371 (64.2)	234 654 (seventy.one)
Ever	1851 (19.half-dozen)	15 122 (17.3)	8454 (31.seven)	5993 (27.five)	3422 (49.two)	65 439 (35.8)	100 281 (29.ix)
Smoking condition, no. (%)
Never	3277 (34.eight)	xl 099 (45.9)	11 342 (42.6)	13 125 (60.iii)	2190 (31.5)	87 678 (48.0)	157 711 (47.one)
Ever	6151 (65.ii)	47 228 (54.1)	15 312 (57.v)	8639 (39.7)	4762 (68.5)	95 132 (52.0)	177 224 (52.9)
Smoking condition, no. of NPC deaths
Never	3	6	16	xiv	2	12	53
Always	fourteen	24	28	9	11	37	123
Smoking status, no. of NPC new cases
Never	9	NA	37	NA	1	47	94
E'er	16	NA	36	NA	6	71	129

Study	Taiwan Accomplice 1984 (included men only)	Guangzhou Occupational Accomplice	Singapore Chinese Health Study	Hong Kong Elderly Health Service Cohort	Guangzhou Biobank Cohort Report	Taiwan MJ Cohort	Combined cohort
Cohort reference number	38	39	37	48	47	46	37–39, 46–48
Regions	Taiwan	Guangzhou	Singapore	Hong Kong	Guangzhou	Taiwan	Owned regions
Enrolment/last follow-up date	1984-86/2011	1988-92/1999	1993-99/2008	1998-2001/2012	2003-08/2017	1994-2006/2008	1984-2008/2017
Median baseline survey year	1985	1990	1996	1999	2005	1999	1996
Population source	Population register	Health check-upwards	Population register	Health cheque-up	Health cheque-up	Health check-up	NA
Male person participants	9428	87 327	26 654	21 764	6952	182 810	334 935
Hateful (SD) historic period at baseline survey, years	51.6 (12.five)	41.2 (five.ix)	56.5 (7.9)	71.9 (5.three)	64.4 (6.vii)	twoscore.6 (13.6)	44.8 (xiv.two)
Mean (SD) follow-up, years	21.iv (vii.5)	7.three (0.7)	12.2 (3.ane)	11.0 (iii.2)	11.iii (2.vi)	8.i (iii.iii)	8.8 (4.0)
No. of NPC case	42	30	117	23	twenty	167	399
Drinking status, no. (%)
Never	7577 (80.4)	72 205 (82.7)	18 200 (68.3)	fifteen 771 (72.5)	3530 (50.eight)	117 371 (64.2)	234 654 (70.1)
Ever	1851 (19.6)	15 122 (17.three)	8454 (31.vii)	5993 (27.5)	3422 (49.two)	65 439 (35.eight)	100 281 (29.nine)
Smoking condition, no. (%)
Never	3277 (34.8)	twoscore 099 (45.9)	11 342 (42.6)	13 125 (threescore.3)	2190 (31.5)	87 678 (48.0)	157 711 (47.1)
Ever	6151 (65.2)	47 228 (54.ane)	xv 312 (57.5)	8639 (39.7)	4762 (68.5)	95 132 (52.0)	177 224 (52.9)
Smoking status, no. of NPC deaths
Never	3	half dozen	16	14	2	12	53
E'er	14	24	28	9	11	37	123
Smoking status, no. of NPC new cases
Never	9	NA	37	NA	ane	47	94
Ever	sixteen	NA	36	NA	vi	71	129

Ever smokers included daily smokers and former smokers, and occasional smokers were excluded. Guangzhou Occupational Cohort and Hong Kong Elderly Health Service Accomplice had mortality information only.

SD, standard deviation; NPC, nasopharyngeal carcinoma; NA, not applicable.

Table 1

Baseline characteristics of private cohorts and the combined accomplice in the meta-analyses (men only)

Written report	Taiwan Cohort 1984 (included men only)	Guangzhou Occupational Cohort	Singapore Chinese Health Study	Hong Kong Elderly Health Service Cohort	Guangzhou Biobank Accomplice Study	Taiwan MJ Accomplice	Combined cohort
Cohort reference number	38	39	37	48	47	46	37–39, 46–48
Regions	Taiwan	Guangzhou	Singapore	Hong Kong	Guangzhou	Taiwan	Owned regions
Enrolment/last follow-up date	1984-86/2011	1988-92/1999	1993-99/2008	1998-2001/2012	2003-08/2017	1994-2006/2008	1984-2008/2017
Median baseline survey year	1985	1990	1996	1999	2005	1999	1996
Population source	Population register	Wellness check-up	Population register	Health bank check-up	Health bank check-upwardly	Health check-up	NA
Male participants	9428	87 327	26 654	21 764	6952	182 810	334 935
Mean (SD) age at baseline survey, years	51.half-dozen (12.v)	41.two (5.nine)	56.v (vii.9)	71.9 (5.3)	64.four (half-dozen.vii)	forty.vi (13.6)	44.viii (14.2)
Mean (SD) follow-upwards, years	21.four (7.5)	7.iii (0.7)	12.2 (3.1)	11.0 (iii.2)	11.3 (two.vi)	8.1 (3.3)	8.viii (4.0)
No. of NPC case	42	30	117	23	20	167	399
Drinking condition, no. (%)
Never	7577 (80.4)	72 205 (82.7)	xviii 200 (68.3)	xv 771 (72.5)	3530 (50.8)	117 371 (64.2)	234 654 (seventy.1)
E'er	1851 (nineteen.half-dozen)	15 122 (17.3)	8454 (31.7)	5993 (27.five)	3422 (49.2)	65 439 (35.viii)	100 281 (29.ix)
Smoking status, no. (%)
Never	3277 (34.8)	40 099 (45.9)	11 342 (42.six)	thirteen 125 (lx.iii)	2190 (31.v)	87 678 (48.0)	157 711 (47.1)
Ever	6151 (65.ii)	47 228 (54.1)	fifteen 312 (57.five)	8639 (39.vii)	4762 (68.5)	95 132 (52.0)	177 224 (52.9)
Smoking status, no. of NPC deaths
Never	3	vi	16	xiv	2	12	53
E'er	fourteen	24	28	ix	11	37	123
Smoking status, no. of NPC new cases
Never	9	NA	37	NA	i	47	94
Ever	xvi	NA	36	NA	6	71	129

Study	Taiwan Cohort 1984 (included men merely)	Guangzhou Occupational Accomplice	Singapore Chinese Health Report	Hong Kong Elderly Health Service Accomplice	Guangzhou Biobank Accomplice Written report	Taiwan MJ Cohort	Combined cohort
Cohort reference number	38	39	37	48	47	46	37–39, 46–48
Regions	Taiwan	Guangzhou	Singapore	Hong Kong	Guangzhou	Taiwan	Endemic regions
Enrolment/concluding follow-up date	1984-86/2011	1988-92/1999	1993-99/2008	1998-2001/2012	2003-08/2017	1994-2006/2008	1984-2008/2017
Median baseline survey year	1985	1990	1996	1999	2005	1999	1996
Population source	Population annals	Health check-up	Population register	Health check-upwardly	Health check-up	Wellness bank check-upwardly	NA
Male participants	9428	87 327	26 654	21 764	6952	182 810	334 935
Hateful (SD) age at baseline survey, years	51.six (12.five)	41.two (5.9)	56.5 (7.9)	71.9 (five.three)	64.four (half-dozen.7)	40.6 (13.6)	44.8 (14.two)
Mean (SD) follow-up, years	21.four (7.v)	vii.iii (0.seven)	12.2 (3.1)	11.0 (3.2)	11.three (2.6)	8.1 (3.3)	eight.8 (four.0)
No. of NPC case	42	30	117	23	20	167	399
Drinking status, no. (%)
Never	7577 (80.4)	72 205 (82.7)	xviii 200 (68.iii)	15 771 (72.5)	3530 (50.8)	117 371 (64.2)	234 654 (70.ane)
Ever	1851 (19.six)	15 122 (17.3)	8454 (31.7)	5993 (27.v)	3422 (49.2)	65 439 (35.8)	100 281 (29.9)
Smoking status, no. (%)
Never	3277 (34.8)	40 099 (45.9)	11 342 (42.half dozen)	13 125 (60.3)	2190 (31.5)	87 678 (48.0)	157 711 (47.1)
Ever	6151 (65.2)	47 228 (54.1)	15 312 (57.v)	8639 (39.vii)	4762 (68.five)	95 132 (52.0)	177 224 (52.9)
Smoking condition, no. of NPC deaths
Never	3	6	16	14	2	12	53
Always	14	24	28	9	11	37	123
Smoking status, no. of NPC new cases
Never	9	NA	37	NA	1	47	94
E'er	xvi	NA	36	NA	half dozen	71	129

Ever smokers included daily smokers and former smokers, and occasional smokers were excluded. Guangzhou Occupational Cohort and Hong Kong Elderly Wellness Service Cohort had mortality data only.

SD, standard deviation; NPC, nasopharyngeal carcinoma; NA, non applicative.

Smoking exposure cess

Information on smoking was obtained from the baseline questionnaire. Smoking exposure in ever smokers (including daily smokers and sometime smokers) was classified into different categories and compared with never smokers. Cumulative consumption (pack-years) was calculated by multiplying the number of packs (20 cigarettes per pack) smoked per twenty-four hours by the number of years smoked. Smoking categories were first grouped into five-unit (eastward.one thousand. five cigarettes per twenty-four hours/years/pack-years) intervals, and so the intervals were regrouped if the number of events in a five-unit interval was too small for analysis. In the analyses of quitting, fourth dimension since quitting was classified into 4 groups: daily smokers (reference group), quitters who had stopped smoking for <5, 5+ years and never smokers.

Statistical analyses

Participants with missing data on cigarette smoking or booze drinking at baseline were excluded. We also excluded participants with prevalent NPC or cancer at baseline because the disease status might have changed the subjects' smoking habits. Due to the small number of e'er smokers amid women (7.6%; Supplementary Table S1, bachelor as Supplementary data at IJE online) and missing data (95%) on occasional smokers, the present analysis excluded female participants and occasional smokers.

We examined the association between smoking exposure and NPC events by computing hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for age and drinking status. The Cox proportional hazard assumption was checked using Schoenfeld residuals, and no evidence of violation of the assumption was found. We conducted one-stage meta-analyses that analysed IPD from all cohorts simultaneously, and also used the two-phase random-effect arroyo to compare the associations for smoking (ever smokers versus never smokers) and quitting status (former smokers versus daily smokers). ⁵⁰ Smoking cumulative consumption (pack-years) was selected to examine whatsoever threshold of a great increase in the HR for smoking as information technology included both smoking corporeality and smoking duration. Never smokers were used every bit the referent to compare with 30 consecutive cut-off points (>1, >two, …… >29, >30 pack-years) in smoking cumulative consumption, and 30 HRs were calculated. The heterogeneity of HRs across the studies was measured past the I² and Q statistics. Funnel plots were used to bank check for publication bias. Missing values for smoking exposure were coded as separate categories and included as indicator variables in the models, except for in dose-response analyses. To appraise dose-response effects of smoking duration, smoking cumulative consumption, age at starting smoking and quitting elapsing, a exam for trend was examined treating these factors every bit ordinal variables among ever smokers only. Statistical interactions by alcohol were assessed based on the likelihood ratio test that compared nested models with and without interaction terms.

Several sensitivity analyses were conducted. We repeated analyses in daily smokers (versus never smokers). We also conducted a sensitivity assay excluding 116 participants with missing follow-upwards data for the associations between smoking exposure and NPC events, which did non essentially affect our results ( Supplementary Table S2, available as Supplementary data at IJE online). Considering the clan of smoking with NPC mortality and incidence outcomes may be dissimilar, we examined the associations with fatal (NPC bloodshed) and non-fatal (NPC incidence) events separately, and the results were similar. All statistical analyses were conducted with Stata version fifteen.0 (StataCorp LLC, Higher Station, TX), and all tests were two-sided.

Results

Of 334 935 male participants (median follow-upwards of 8.8 years, standard departure of 4.0) from six studies in regions owned for NPC, 399 NPC events were ascertained (Table 1).

Risks of NPC were consistently higher in always smokers, daily smokers and old smokers (versus never smokers) (Table 2). The corresponding adjusted HRs were, respectively, i.44 (95% CI = 1.17-1.76, P=0.0005), one.49 (1.xx-1.85, 0.0003) and 1.28 (0.94-i.74, 0.xi) in Model ane (adjusted for age), and 1.32 (i.07-1.63, 0.0088), 1.37 (1.10-i.71, 0.0058) and 1.xix (0.87-1.62, 0.28) in Model ii (adjusted for historic period and drinking status). The risks of NPC for smoking were stronger in ever smokers (versus never) who consumed 16+ cigarettes per day (adjusted Hour = one.67, 95% CI = ane.29-ii.16, P=0.0001) and who started smoking at historic period younger than sixteen (2.16, 1.33-iii.50, 0.0103) with dose-response relationships (both P-values for trend < 0.05). The associations of smoking exposure with NPC incidence and bloodshed were like ( Supplementary Table S3, available as Supplementary information at IJE online) and remained in daily smokers ( Supplementary Table S4, available as Supplementary information at IJE online). Quitting (versus daily smoking) showed a pocket-size reduced risk (for quitting duration < 5 years: adjusted Hour = 1.22, 95% CI = 0.78-1.xc, P=0.38; v+ years: 0.91, 0.60-1.39, 0.66). Figure 1 shows that HRs were consistently >1 and steadily increased with greater cut-off points of pack-year, suggesting no threshold event.

Figure 1

Adjusted hazard ratios of nasopharyngeal carcinoma for smoking cumulative consumption (pack-years) at each of xxx sequent cut-off points in male ever smokers (daily smokers and former smokers combined)

Effigy 1

Adjusted hazard ratios of nasopharyngeal carcinoma for smoking cumulative consumption (pack-years) at each of 30 consecutive cut-off points in male person ever smokers (daily smokers and one-time smokers combined)

Table two

Hazard ratios of NPC in male person ever smokers in the one-stage approach IPD meta-assay of the combined accomplice

Exposures and categories	Person-years (Full: 2 961 315)	NPC events (n = 399)	Event charge per unit of NPC per 100 000 person-years (95% CI)			Model 1 (95% CI)				Model 2 (95% CI)
Never smokers	1 360 051	147	10.eight	(9.2-	12.7)		Ref				Ref
Smoking condition 1
Ever smokers	1 601 263	252	15.vii	(13.9-	17.8)	i.44	(1.17-	1.76)	***	ane.32	(1.07-	1.63)	**
Smoking status two
Daily smokers	i 250 684	190	xv.ii	(13.2-	17.5)	ane.49	(1.20-	1.85)	***	i.37	(1.x-	one.71)	**
Former smokers	345 257	lx	17.4	(13.5-	22.4)	i.28	(0.94-	1.74)		1.19	(0.87-	1.62)
Smoking amount in ever smokers, cigarettes/day
1-15	912 741	116	12.7	(10.6-	12.2)	1.20	(0.94-	1.53)		1.11	(0.87-	one.43)
sixteen+	496 559	105	21.one	(17.5-	25.6)	1.82	(one.42-	two.34)	****	1.67	(ane.29-	2.16)	***
P for tendencya							0.0022				0.0028
Smoking duration in ever smokers, years
Never	1 213 532	133	eleven.0	(nine.2-	13.0)		Ref				Ref
one-15	572 694	43	7.5	(v.6-	x.1)	0.83	(0.58-	1.18)		0.78	(0.55-	ane.12)
16-35	429 234	88	20.5	(16.6-	25.3)	1.72	(ane.32-	2.26)	***	1.59	(ane.20-	two.09)	**
36+	280 254	72	25.7	(twenty.iv-	32.four)	1.66	(one.22-	two.27)	**	1.l	(1.09-	2.05)	*
P for tendencya							0.19				0.31
Smoking cumulative consumption in e'er smokers, pack-years
Never	ane 213 532	133	11.0	(nine.2-	thirteen.0)		Ref				Ref
one-5	337 593	25	7.4	(v.0-	xi.0)	0.82	(0.53-	one.26)		0.78	(0.51-	1.21)
half-dozen-25	619 062	93	xv.0	(12.3-	18.four)	1.36	(i.05-	one.78)	*	1.26	(0.96-	one.65)
26+	301 034	82	27.2	(21.9-	33.8)	i.eighty	(i.35-	2.42)	***	1.63	(1.21-	two.20)	**
P for trenda							0.05				0.10
Age at starting smoking in e'er smokers, years
Never	1 213 532	133	eleven.0	(9.2-	xiii.0)		Ref				Ref
26+	353 338	37	10.5	(7.six-	14.5)	1.00	(0.69-	1.44)		0.96	(0.66-	i.38)
16-25	991 233	165	16.6	(14.iii-	19.4)	one.twoscore	(one.11-	1.76)	**	i.28	(1.01-	1.62)	*
<16	58 881	19	32.3	(20.half-dozen-	50.6)	ii.31	(i.42-	3.75)	**	2.16	(1.33-	iii.l)	**
P for trenda							0.0069				0.0103
Quitting elapsing in former smokers, years
Daily smokers	one 229 548	187	15.two	(13.2-	17.half dozen)		Ref				Ref
<5	98 864	22	22.3	(14.7-	33.8)	1.22	(0.78-	1.91)		one.22	(0.78-	i.90)
≥5	124 624	26	20.9	(xiv.2-	30.6)	0.90	(0.59-	1.38)		0.91	(0.60-	1.36)
Never smokers	1 213 532	133	11.0	(9.2-	13.0)	0.73	(0.59-	0.91)	**	0.79	(0.63-	0.99)	*
P for trenda							0.lx				0.61

Exposures and categories	Person-years (Total: 2 961 315)	NPC events (due north = 399)	Outcome charge per unit of NPC per 100 000 person-years (95% CI)			Model ane (95% CI)				Model 2 (95% CI)
Never smokers	1 360 051	147	10.8	(9.2-	12.7)		Ref				Ref
Smoking status 1
E'er smokers	one 601 263	252	15.7	(13.9-	17.8)	1.44	(1.17-	one.76)	***	1.32	(one.07-	1.63)	**
Smoking status 2
Daily smokers	ane 250 684	190	15.2	(thirteen.2-	17.5)	i.49	(1.twenty-	1.85)	***	ane.37	(ane.10-	1.71)	**
Former smokers	345 257	60	17.4	(13.5-	22.four)	1.28	(0.94-	i.74)		1.19	(0.87-	ane.62)
Smoking amount in ever smokers, cigarettes/mean solar day
1-15	912 741	116	12.seven	(10.six-	12.2)	1.twenty	(0.94-	1.53)		i.eleven	(0.87-	i.43)
16+	496 559	105	21.1	(17.five-	25.6)	1.82	(1.42-	2.34)	****	1.67	(i.29-	ii.16)	***
P for trenda							0.0022				0.0028
Smoking duration in ever smokers, years
Never	1 213 532	133	eleven.0	(9.two-	13.0)		Ref				Ref
1-fifteen	572 694	43	7.5	(5.6-	ten.1)	0.83	(0.58-	1.18)		0.78	(0.55-	1.12)
16-35	429 234	88	20.five	(16.6-	25.iii)	one.72	(1.32-	2.26)	***	1.59	(1.xx-	2.09)	**
36+	280 254	72	25.7	(20.4-	32.4)	ane.66	(1.22-	two.27)	**	1.fifty	(1.09-	2.05)	*
P for trenda							0.nineteen				0.31
Smoking cumulative consumption in ever smokers, pack-years
Never	ane 213 532	133	11.0	(ix.2-	xiii.0)		Ref				Ref
1-5	337 593	25	vii.4	(5.0-	11.0)	0.82	(0.53-	one.26)		0.78	(0.51-	1.21)
6-25	619 062	93	xv.0	(12.3-	18.4)	1.36	(1.05-	1.78)	*	1.26	(0.96-	1.65)
26+	301 034	82	27.2	(21.nine-	33.8)	1.lxxx	(ane.35-	2.42)	***	1.63	(1.21-	2.20)	**
P for trenda							0.05				0.x
Age at starting smoking in ever smokers, years
Never	one 213 532	133	11.0	(9.2-	13.0)		Ref				Ref
26+	353 338	37	10.v	(7.6-	14.5)	1.00	(0.69-	1.44)		0.96	(0.66-	1.38)
xvi-25	991 233	165	sixteen.vi	(fourteen.iii-	19.4)	1.xl	(ane.xi-	1.76)	**	one.28	(one.01-	ane.62)	*
<16	58 881	19	32.3	(xx.half dozen-	50.half dozen)	two.31	(one.42-	3.75)	**	2.16	(1.33-	3.50)	**
P for trenda							0.0069				0.0103
Quitting duration in sometime smokers, years
Daily smokers	one 229 548	187	15.2	(thirteen.2-	17.half dozen)		Ref				Ref
<v	98 864	22	22.iii	(14.7-	33.8)	i.22	(0.78-	one.91)		1.22	(0.78-	1.90)
≥v	124 624	26	20.ix	(14.two-	xxx.vi)	0.xc	(0.59-	1.38)		0.91	(0.60-	1.36)
Never smokers	one 213 532	133	11.0	(9.2-	13.0)	0.73	(0.59-	0.91)	**	0.79	(0.63-	0.99)	*
P for trenda							0.lx				0.61

Model ane adjusted for age, Model ii adjusted for age and drinking status.

IPD, individual participant data; NPC, nasopharyngeal carcinoma; CI, confidence interval.

a

Tendency test in ever smokers, excluding never smokers; if trend tests in this table included never smokers, both would have yielded p < 0.05. Missing values for exposure were coded as carve up categories and included equally indicator variables in the models, except for in dose-response analyses.

*

P < 0.05;

**

P < 0.01;

***

P < 0.001;

****

P < 0.0001.

Table 2

Hazard ratios of NPC in male always smokers in the i-phase arroyo IPD meta-analysis of the combined cohort

Exposures and categories	Person-years (Total: two 961 315)	NPC events (north = 399)	Issue charge per unit of NPC per 100 000 person-years (95% CI)			Model 1 (95% CI)				Model 2 (95% CI)
Never smokers	1 360 051	147	10.viii	(9.2-	12.7)		Ref				Ref
Smoking status 1
Ever smokers	1 601 263	252	15.7	(13.9-	17.8)	1.44	(ane.17-	1.76)	***	1.32	(i.07-	i.63)	**
Smoking status ii
Daily smokers	ane 250 684	190	15.two	(xiii.2-	17.5)	i.49	(1.twenty-	1.85)	***	i.37	(i.10-	one.71)	**
Onetime smokers	345 257	60	17.4	(13.v-	22.four)	i.28	(0.94-	1.74)		1.19	(0.87-	1.62)
Smoking amount in always smokers, cigarettes/mean solar day
1-fifteen	912 741	116	12.7	(10.half-dozen-	12.2)	one.20	(0.94-	ane.53)		1.11	(0.87-	1.43)
16+	496 559	105	21.1	(17.5-	25.6)	1.82	(1.42-	two.34)	****	1.67	(i.29-	2.16)	***
P for trenda							0.0022				0.0028
Smoking elapsing in ever smokers, years
Never	1 213 532	133	11.0	(9.2-	13.0)		Ref				Ref
1-15	572 694	43	7.5	(5.6-	10.one)	0.83	(0.58-	1.xviii)		0.78	(0.55-	i.12)
16-35	429 234	88	20.5	(16.6-	25.3)	one.72	(1.32-	2.26)	***	1.59	(1.20-	2.09)	**
36+	280 254	72	25.7	(twenty.4-	32.iv)	1.66	(1.22-	two.27)	**	1.50	(1.09-	two.05)	*
P for tendencya							0.19				0.31
Smoking cumulative consumption in ever smokers, pack-years
Never	one 213 532	133	11.0	(ix.2-	xiii.0)		Ref				Ref
1-5	337 593	25	7.4	(5.0-	xi.0)	0.82	(0.53-	1.26)		0.78	(0.51-	1.21)
half-dozen-25	619 062	93	15.0	(12.iii-	18.four)	1.36	(ane.05-	1.78)	*	1.26	(0.96-	ane.65)
26+	301 034	82	27.two	(21.9-	33.8)	1.fourscore	(i.35-	2.42)	***	one.63	(ane.21-	2.twenty)	**
P for trenda							0.05				0.x
Age at starting smoking in ever smokers, years
Never	ane 213 532	133	11.0	(9.ii-	thirteen.0)		Ref				Ref
26+	353 338	37	10.5	(seven.6-	14.5)	1.00	(0.69-	i.44)		0.96	(0.66-	ane.38)
xvi-25	991 233	165	16.6	(fourteen.3-	xix.iv)	1.40	(ane.11-	1.76)	**	1.28	(1.01-	1.62)	*
<xvi	58 881	19	32.3	(20.6-	50.6)	2.31	(1.42-	3.75)	**	2.sixteen	(1.33-	3.50)	**
P for trenda							0.0069				0.0103
Quitting duration in former smokers, years
Daily smokers	one 229 548	187	15.2	(13.2-	17.6)		Ref				Ref
<5	98 864	22	22.3	(14.7-	33.8)	1.22	(0.78-	1.91)		ane.22	(0.78-	1.90)
≥5	124 624	26	20.nine	(xiv.2-	30.6)	0.90	(0.59-	1.38)		0.91	(0.60-	1.36)
Never smokers	1 213 532	133	xi.0	(nine.two-	xiii.0)	0.73	(0.59-	0.91)	**	0.79	(0.63-	0.99)	*
P for trenda							0.sixty				0.61

Exposures and categories	Person-years (Total: 2 961 315)	NPC events (n = 399)	Consequence rate of NPC per 100 000 person-years (95% CI)			Model 1 (95% CI)				Model two (95% CI)
Never smokers	1 360 051	147	10.viii	(ix.two-	12.7)		Ref				Ref
Smoking status one
Ever smokers	1 601 263	252	fifteen.7	(13.nine-	17.viii)	1.44	(1.17-	one.76)	***	1.32	(ane.07-	1.63)	**
Smoking status 2
Daily smokers	1 250 684	190	fifteen.2	(13.2-	17.five)	ane.49	(1.20-	1.85)	***	1.37	(i.10-	1.71)	**
Former smokers	345 257	threescore	17.4	(13.v-	22.4)	1.28	(0.94-	1.74)		1.19	(0.87-	1.62)
Smoking amount in ever smokers, cigarettes/solar day
1-15	912 741	116	12.7	(10.half dozen-	12.2)	1.twenty	(0.94-	1.53)		1.11	(0.87-	i.43)
16+	496 559	105	21.1	(17.five-	25.six)	1.82	(one.42-	ii.34)	****	1.67	(1.29-	ii.sixteen)	***
P for trenda							0.0022				0.0028
Smoking duration in ever smokers, years
Never	1 213 532	133	11.0	(9.2-	13.0)		Ref				Ref
1-xv	572 694	43	7.5	(5.6-	10.i)	0.83	(0.58-	1.18)		0.78	(0.55-	1.12)
16-35	429 234	88	20.five	(16.6-	25.iii)	1.72	(1.32-	2.26)	***	ane.59	(i.20-	2.09)	**
36+	280 254	72	25.7	(20.4-	32.4)	one.66	(1.22-	two.27)	**	i.50	(ane.09-	2.05)	*
P for tendencya							0.19				0.31
Smoking cumulative consumption in ever smokers, pack-years
Never	i 213 532	133	xi.0	(9.2-	13.0)		Ref				Ref
1-5	337 593	25	7.iv	(5.0-	11.0)	0.82	(0.53-	1.26)		0.78	(0.51-	one.21)
6-25	619 062	93	xv.0	(12.3-	18.4)	1.36	(1.05-	one.78)	*	i.26	(0.96-	1.65)
26+	301 034	82	27.ii	(21.9-	33.viii)	1.80	(ane.35-	ii.42)	***	1.63	(1.21-	2.20)	**
P for trenda							0.05				0.ten
Age at starting smoking in ever smokers, years
Never	ane 213 532	133	11.0	(9.2-	13.0)		Ref				Ref
26+	353 338	37	ten.5	(7.6-	xiv.5)	1.00	(0.69-	one.44)		0.96	(0.66-	1.38)
16-25	991 233	165	16.vi	(14.iii-	19.4)	1.xl	(ane.xi-	ane.76)	**	1.28	(1.01-	1.62)	*
<sixteen	58 881	19	32.three	(20.six-	50.six)	2.31	(i.42-	three.75)	**	2.16	(1.33-	3.50)	**
P for trenda							0.0069				0.0103
Quitting elapsing in one-time smokers, years
Daily smokers	1 229 548	187	15.2	(thirteen.2-	17.6)		Ref				Ref
<5	98 864	22	22.3	(14.7-	33.eight)	i.22	(0.78-	1.91)		i.22	(0.78-	1.90)
≥5	124 624	26	20.9	(xiv.two-	thirty.6)	0.xc	(0.59-	1.38)		0.91	(0.lx-	1.36)
Never smokers	1 213 532	133	eleven.0	(9.2-	13.0)	0.73	(0.59-	0.91)	**	0.79	(0.63-	0.99)	*
P for trenda							0.60				0.61

Model 1 adjusted for age, Model 2 adjusted for historic period and drinking status.

IPD, private participant data; NPC, nasopharyngeal carcinoma; CI, confidence interval.

a

Trend test in ever smokers, excluding never smokers; if trend tests in this table included never smokers, both would have yielded p < 0.05. Missing values for exposure were coded as dissever categories and included every bit indicator variables in the models, except for in dose-response analyses.

*

P < 0.05;

**

P < 0.01;

***

P < 0.001;

****

P < 0.0001.

Risks of NPC were higher in ever smokers (versus never) in four individual cohorts, including the Taiwan Cohort (adjusted Hour = 1.28, 95% CI = 0.64-2.53), Guangzhou Occupational Accomplice 1988 (two.54, one.00-vi.fifty), Taiwan MJ Cohort 1994 (ane.37, 0.98-1.91) and Guangzhou Biobank Accomplice 2003 (2.57, 0.74-8.98), and in the pooled interpretation (1.27, one.01-1.60, P=0.04). No heterogeneity was constitute in this meta-analysis (I ⁱⁱ = 7%, P _{heterogeneity} = 0.37) (Figure ii). These positive associations remained in daily smokers (versus never) ( Supplementary Figure S3, available equally Supplementary information at IJE online). However, no clear association was observed in erstwhile smokers (versus daily smokers) in each individual cohort or in the pooled analyses (adjusted 60 minutes = 0.84, 95% CI = 0.61-i.14, P=0.26). No heterogeneity was found (I ⁱⁱ = 0%, P _{heterogeneity} = 0·97) (Effigy three). Visual inspection of funnel plots showed no publication bias in our overall analyses (Figure 4; Supplementary Effigy S4, available as Supplementary data at IJE online).

Figure 2

Adjusted hazard ratios of nasopharyngeal carcinoma in male always smokers (daily smokers and former smokers combined) versus never smokers in individual cohort studies and two-phase approach individual participant data meta-analysis in random-effects model

Figure 2

Adjusted take chances ratios of nasopharyngeal carcinoma in male ever smokers (daily smokers and former smokers combined) versus never smokers in private cohort studies and two-phase approach individual participant data meta-analysis in random-furnishings model

Figure 3

Adjusted hazard ratios of nasopharyngeal carcinoma in male person erstwhile smokers (daily smokers and former smokers combined) versus daily smokers in individual cohort studies and two-phase approach individual participant information meta-assay in random-effects model

Figure 3

Adjusted hazard ratios of nasopharyngeal carcinoma in male former smokers (daily smokers and erstwhile smokers combined) versus daily smokers in individual cohort studies and 2-stage approach private participant information meta-analysis in random-effects model

Figure 4

Funnel plots of the risk of nasopharyngeal carcinoma (log-adjusted hazard ratios) associated with A: e'er smokers; B: former smokers (both versus never) in the 2-phase approach individual participant data meta-analysis (men just)

Figure 4

Funnel plots of the gamble of nasopharyngeal carcinoma (log-adjusted hazard ratios) associated with A: ever smokers; B: old smokers (both versus never) in the two-phase arroyo private participant information meta-assay (men only)

Discussion

This is the first IPD meta-analysis of prospective accomplice studies in endemic regions to evaluate the clan between smoking exposure and NPC with detailed information on smoking. We found smoking consistently associated with increased risk of NPC. Always smokers had 32% higher risks of NPC than never smokers. Smokers who consumed 16+ cigarettes per 24-hour interval had 67% college risks of NPC. Smokers who started smoking younger than age 16 had over twice the hazard of NPC compared with never smokers. Quitting was associated with a pocket-sized reduced risk of NPC in this cohort. This is the largest report to testify the harm of smoking and NPC, with dose-response relationships by dissimilar exposure indicators.

The findings from this IPD meta-analysis back up previous research demonstrating an increased risk of NPC in ever smokers (versus never). Xue et al.al. ⁴³ reported an increased risk of NPC (odds ratio = 1.38, 95% CI = 0.96-1.98, P=0.xviii) in an amass information-based meta-analysis of 399 975 participants with 328 NPC events including iii cohorts from endemic regions (Guangzhou, ⁵¹ Singapore ³⁷ and Taiwan ³⁸ ) and one cohort in a low-adventure region of NPC (U.s.a.). ³⁵ They also reported a college Hr of ane.63 (95% CI = i.38-1.92, P<0.01) based on 28 example-command studies. Long et al. ⁴⁴ updated the meta-assay including fofur contempo studies (three case-command ^29–31 and one cohort ³⁹ ) and showed that ever smokers (versus never) had a 56% higher risk of NPC, based on 17 case-control studies and four cohort studies. Whereas Long et al. ⁴⁴ reported a null clan based on two accomplice studies ^{37 , 38} (OR for e'er versus never smoking = i.11, 95% CI = 0.84-1.48, P=0.83), an increased hazard of NPC was observed in current smokers (2.19, i.02-iv.72) based on three cohort studies ^37–39 including our contempo study. ³⁹ Another accomplice study in 34 439 male person British doctors with four NPC deaths as well showed a positive clan for smoking. ³⁶

A dose-response effect for historic period at starting smoking was first observed in our written report. Participants who started smoking younger than 16 years showed the highest HR of 2.16. A relative take a chance (RR) of greater than ii means that the attributable fraction in the exposed is greater than 50% [(RR-one)/RR]. This indicates that in NPC patients who started smoking at a immature age, well-nigh half of the NPC cases can exist attributed to smoking. Friborg et al. reported a suggestive clan between age at smoking initiation and NPC (smokers started smoking at age <15 years: RR = 1.five, 95% CI = 0.viii-2.viii, P for tendency = 0.08). Our findings of increased risk of NPC associated with heavy and chronic smoking (college smoking amount, smoking duration and cumulative consumption in always smokers) are consistent with previous studies in Singapore, ³⁷ Taiwan ³⁸ and Guangzhou. ³⁹ We did not find dose-response relationships for smoking elapsing and cumulative consumption in ever smokers. Dose-response relationships were observed for smoking elapsing in Singapore (P=0.04) ³⁷ and for smoking cumulative consumption in Guangzhou (P=0.014), ³⁹ merely they both included never smokers in the trend exam, which would also have shown dose-response relationships in our analyses.

Tobacco has been classified as a group 1 carcinogen by the IARC since 1992. ⁵² As tobacco can cause laryngeal cancer ⁵³ and pharyngeal cancer, ⁵⁴ there is no plausible explanation why it cannot crusade cancer in the nasopharyngeal region, which is as well directly exposed to the carcinogens from smoking, and all were not associated with ionizing radiations exposure. ^55–57 The master reason for the limited show to support causation is probably because NPC is rare and individual cohort studies did not have sufficient number of NPC events.

There may exist several explanations for our findings of increased risk of NPC associated with smoking exposure in men. I possibility is that the association between smoking and NPC was mediated through Epstein-Barr virus (EBV) reactivation. ^{34 , 58 , 59} EBV is closely associated with the occurrence and evolution of NPC, and its reactivation is associated with smoking. Whereas one study in subjects with elevated IgA antibodies against EBV viral capsid antigen (VCA/IgA) found a zilch association between smoking and EBV, ^sixty several large studies in healthy subjects showed that both smoking ^{61 , 62} and cotinine ⁶³ were associated with higher seropositivity for several biomarkers of EBV reactivation and subsequently with college risk of NPC. ^{34 , 59} Another possibility is formaldehyde, a elective of cigarette fume which causes squamous cell carcinoma of the nasal cavities upon inhalation exposure of rats, and formaldehyde is considered a cause of nasopharyngeal cancer in humans by IARC. ⁶⁴ A study demonstrated a ten-fold higher level of the formaldehyde-Deoxyribonucleic acid adduct N6-hydroxymethyl deoxyadenosine in leukocytes of smokers than never smokers, suggesting its possible involvement in NPC in smokers. ⁶⁵ Moreover, tobacco smoke contains more than than 70 carcinogens ⁶⁶ and some of them may also contribute to the mechanism of how tobacco causes NPC.

By using the IPD meta-assay design, our study has the largest number of NPC events (n = 399) and of total participants (n = 334 935) in NPC-endemic regions and the world. With the IPD information, we have provided more reliable and robust results and improved the potentially important limitations of reviews based on published aggregated data. We used i- and two-stage approach meta-assay to evaluate the reliability of the results. ^fifty IPD immune us to conduct sensitivity and subgroup analyses by sexual activity, cohorts and smoking condition categories of each individual cohort, and used the same adjustment for potential confounders before the combined analysis. Compared with previous studies, we have enhanced generalizability by combining findings from all 6 eligible cohort studies across NPC endemic regions. ⁶⁷

We recognize the limitations of the short follow-upwards (<10 years), lack of detailed information on alcohol consumption, and missing data of smoking duration, age at starting smoking and quitting elapsing in one cohort. ⁴⁸ More NPC events would be available if all cohorts tin farther follow up and update the data. Express by the data nosotros nerveless, some other concern is confounding since our analyses accept just adapted for age and alcohol consumption, but non other potential confounders, such equally salted fish intake and EBV reactivation. Previous studies in Guangdong and Guangxi, People's republic of china, showed that associations between smoking and NPC did non alter substantially later adjusting for consumption of salted fish. ^{32 , 34} Our case-control study in Hong Kong, Prc, also reported similar association betwixt smoking and NPC with and without adjusting for salted fish intake (data non shown). ⁶⁸ Although our results may be influenced by EBV infection and activation, EBV may not be a confounder simply a mediator of the association between smoking and NPC. Nosotros did not collect data on reasons for quitting (whether stopped past pick or considering of disease). The protective effects of quitting cannot be assessed straightforwardly. ⁶⁹ Abeyance for v years or longer appeared to reduce NPC risk, but a larger dataset in hereafter research is needed for confirmation. As the nowadays analysis included Chinese men only, our findings may not be generalized to women and non-Chinese who are not in endemic regions. Future studies with detailed information on quitting and in women are recommended.

In decision, this first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational evidence that smoking increased NPC risk in men. NPC should be added to the 12–16 cancer sites known to exist tobacco-related cancers. Strong tobacco command policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions.

Information Availability

Due to upstanding restrictions protecting patient privacy, data may be available on request from the Guangzhou Biobank Accomplice Study Information Access Committee. Please contact the states at [gbcsdata@hku.hk] for fielding data accession requests. The data of the Guangzhou Occupational Accomplice and the Hong Kong Elderly Health Service Cohort Study underlying this article volition be shared on reasonable request to the corresponding writer, and the principal investigator Prof. Tai-Hing Lam [hrmrlth@hku.hk]. Information are from the Singapore Chinese Wellness Study, and the authors did non seek approval from the IRB to make the data publicly available. According to the Singapore Personal Data Protection Act, the authors could non release the information without approval from IRB. Researchers who meet the criteria for access to confidential data may contact the principal investigators of Singapore Chinese Health Study at Prof. Jian-Min Yuan [yuanj@upmc.edu] and Prof. Woon Puay Koh [woonpuay.koh@duke-nus.edu.sg] to seek approval from the National Academy of Singapore IRB. The Taiwan Cohort (conducted in 1984) data underlying this commodity will exist shared on reasonable request to the main investigator at Prof. Chen Chien-Jen [cjchen@ntu.edu.tw]. The data that support the findings of this study are available from MJ Health Inquiry Foundation, but restrictions employ to the availability of these data, which were used nether licence for the electric current written report and so are not publicly available. Data are nonetheless available from the authors upon reasonable request and with permission of MJ Health Inquiry Foundation.

Supplementary Data

Supplementary data are available at IJE online.

Funding

This study was funded by the Hong Kong RGC Area of Excellence Scheme (AoE/M-06/08), World Cancer Inquiry Fund Uk (WCRF United kingdom) and Wereld Kanker Onderzoek Fonds (WCRF NL), as part of the WCRF International grant programme (2011/460). This revision was supported past the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Section of Health and Human Services. The Guangzhou Biobank Accomplice Study was funded by the University of Hong Kong Foundation for Educational Development and Enquiry, Hong Kong, the Guangzhou Public Health Bureau and the Guangzhou Science and Engineering science Bureau, Guangzhou, China, and the University of Birmingham, United kingdom. The Guangzhou Occupational Cohort was funded by the Hong Kong Research Grants Council (HKU 466/96 M), Hong Kong Health Services Research Committee (531036), Guangdong Province Public Health Bureau 5 One Project (96–186), Guangzhou Municipal Science and Technology Commission (96-Z-65). The Hong Kong Elderly Health Service Cohort Written report was funded by the Wellness Services Enquiry Fund in Hong Kong (grant no. HSRF#S111016). The Singapore Chinese Health Written report was funded by National Institutes of Health grants RO1 CA55069, R35 CA53890, and R01 CA80205, from the National Cancer Institute, Bethesda, Md. The Taiwan Cohort conducted in 1984 was funded by DOH 75–0203-xviii and DOH 76–0203-17 from the Department of Health, Executive Yuan, Taipei, Taiwan. The Taiwan MJ Accomplice was supported in office past Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212–114004), MOST Clinical Trial Consortium for Stroke (MOST 109–2321-B-039–002), Prc Medical University Infirmary (DMR-109–231), Tseng-Lien Lin Foundation, Taichung, Taiwan.

Acknowledgements

The principal acknowledgments are to the participants who provided information for these studies and the research staff. We thank the Guangzhou Centre for Illness Control and Prevention (Professors G Z Lin, H Z Liu and M Wang), the Medical Insurance Assistants Bureau of Guangzhou, and the Guangzhou Municipal Public Security Bureau for profitable follow-up and record linkage. We likewise thank the Guangzhou Wellness and Happiness Clan for the Respectable Elders for convoking the subjects. We thank Dr Ye Guo-Xiong, Managing director of Guangzhou Public Health Bureau, adviser of the study, Guangzhou Public Security Bureau Population Information Centre and street police force stations, District Public Health Bureaux, Guangzhou Funeral Home and other staff of the Guangzhou Occupational Diseases Prevention and Treatment Center. We wish to thank the staff of the Elderly Health Service, Section of Wellness, particularly Shelley Chan, and the Infirmary Authority, the Government of Hong Kong Special Administrative Region, for their assistance in data collection and entry. We would likewise like to acknowledge the contribution of Dr P Y Leung, when at the Department of Wellness, in facilitating the cosmos of the cohort. We thank Siew-Hong Depression of the National University of Singapore for overseeing the fieldwork of the Singapore Chinese Health Report and Renwei Wang for the development and maintenance of the cohort study database. We too thank Mimi C Yu for being the founding and longstanding primary investigator of the Singapore Chinese Wellness Study. Nosotros give thanks Dr Elizabeth K Cahoon and Dr Lindsay K Morton for revising the manuscript.

Author Contributions

All the authors participated in individual cohort pattern, information collection and data cleaning. J.H.Fifty. conducted the combined statistical assay and drafted the manuscript under T.H.50.'southward and C.P.W.'s supervision. Z.Thou.Chiliad. re-analysed the information, conducted additionally analyses and revised the manuscript essentially based on reviewers' comments, and is the guarantor for the paper. All authors helped to typhoon the manuscript and revised information technology critically for of import intellectual content. All authors read and approved the last manuscript.

Conflict of interest

None alleged.

References

1

Ferlay

J

,

Ervik

M

,

Lam

F

et al.

Global Cancer Observatory: Cancer Today

.

Lyon, France

:

International Agency for Research on Cancer

,

2018

.

2

Tang

L-L

,

Chen

Westward-Q

,

Xue

W-Q

et al.

Global trends in incidence and mortality of nasopharyngeal carcinoma

.

Cancer Lett

2016

;

374

:

22

–

30

.

three

Bray

F

,

Ferlay

J

,

Soerjomataram

I

,

Siegel

RL

,

Torre

LA

,

Jemal

A.

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

.

CA Cancer J Clin

2018

;

68

:

394

–

424

.

4

Chang

ET

,

Adami

H-O.

The enigmatic epidemiology of nasopharyngeal carcinoma

.

Cancer Epidemiol Biomarkers Prev

2006

;

15

:

1765

–

77

.

5

Jia

W-H

,

Qin

H-D.

Not-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review

.

Semin Cancer Biol

2012

;

22

:

117

–

26

.

6

Mai

Z-M

,

Lin

J-H

,

Ip

DKM

,

Ho

S-Y

,

Chan

Y-H

,

Lam

T-H

. Epidemiology and Population Screening. Nasopharyngeal Carcinoma

.

Elsevier

,

2019

; pp.

65

–

84

.

7

Cancer IAfRo.

A Review of Man Carcinogens: Personal Habits and Indoor Combustions

.

Earth Health Arrangement

. Report No.: 928321322X. Geneva: WHO,

2012

.

viii

U.Due south. Department of Health and Human Services

.

The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon Full general

.

Atlanta, GA

:

U.Southward. Department of Health and Human Services

,

2014

.

nine

Shanmugaratnam

K

,

Tye

CY

,

Goh

EH

,

Chia

KB.

Etiological factors in nasopharyngeal carcinoma: a infirmary-based, retrospective, example-control, questionnaire report

.

IARC Sci Publ

1978

;

199

–

212

.

ten

Mabuchi

K

,

Bross

DS

,

Kessler

II.

Cigarette smoking and nasopharyngeal carcinoma

.

Cancer

1985

;

55

:

2874

–7

half dozen

.

11

Lin

TM

,

Chang

HJ

,

Chen

CJ

et al.

Take a chance factors for nasopharyngeal carcinoma

.

Anticancer Res

1986

;

six

:

791

–9

6

.

12

Yu

MC

,

Garabrant

DH

,

Huang

TB

,

Henderson

Exist.

Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, Red china

.

Int J Cancer

1990

;

45

:

1033

–iii

ix

.

xiii

Chen

CJ

,

Liang

KY

,

Chang

YS

et al.

Multiple gamble factors of nasopharyngeal carcinoma: Epstein-Barr virus, malarial infection, cigarette smoking and familial trend

.

Anticancer Res

1990

;

x

:

547

–

53

.

14

Sriamporn

S

,

Vatanasapt

V

,

Pisani

P

,

Yongchaiyudha

Southward

,

Rungpitarangsri

V.

Environmental adventure factors for nasopharyngeal carcinoma: a case-control study in northeastern Thailand

.

Cancer Epidemiol Biomarkers Prev

1992

;

i

:

345

–4

8

.

15

Nam

JM

,

McLaughlin

JK

,

Absorb

WJ.

Cigarette smoking, alcohol, and nasopharyngeal carcinoma: a case-control study amongst U.S. whites

.

J Natl Cancer Inst

1992

;

84

:

619

–

22

.

16

West

S

,

Hildesheim

A

,

Dosemeci

M.

Non-viral chance factors for nasopharyngeal carcinoma in the Philippines: results from a instance-control report

.

Int J Cancer

1993

;

55

:

722

–2

seven

.

17

Zhu

Chiliad

,

Levine

RS

,

Brann

EA

,

Gnepp

DR

,

Baum

MK.

A population-based case-command report of the relationship between cigarette smoking and nasopharyngeal cancer (United States)

.

Cancer Causes Control

1995

;

vi

:

507

–

12

.

18

Cheng

YJ

,

Hildesheim

A

,

Hsu

MM

et al.

Cigarette smoking, alcohol consumption and risk of nasopharyngeal carcinoma in Taiwan

.

Cancer Causes Control

1999

;

10

:

201

–0

7

.

xix

Armstrong

RW

,

Imrey

Atomic number 82

,

Lye

MS

,

Armstrong

MJ

,

Yu

MC

,

Sani

S.

Nasopharyngeal carcinoma in Malaysian Chinese: occupational exposures to particles, formaldehyde and heat

.

Int J Epidemiol

2000

;

29

:

991

–9

8

.

xx

Zou

J

,

Sun

Q

,

Akiba

Southward

et al.

A case-control report of nasopharyngeal carcinoma in the loftier groundwork radiation areas of Yangjiang, China

.

J Radiat Res

2000

;

41(Suppl

):

53

–

62

.

21

Chelleng

PK

,

Narain

G

,

Das

HK

,

Chetia

Grand

,

Mahanta

J.

Risk factors for cancer nasopharynx: a case-control study from Nagaland, Republic of india

.

Natl Med J India

2000

;

13

:

vi

–

eight

.

22

Yuan

JM

,

Wang

XL

,

Xiang

YB

,

Gao

YT

,

Ross

RK

,

Yu

MC.

Not-dietary risk factors for nasopharyngeal carcinoma in Shanghai, Cathay

.

Int J Cancer

2000

;

85

:

364

–6

9

.

23

Feng

BJ

,

Khyatti

M

,

Ben-Ayoub

W

et al.

Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa

.

Br J Cancer

2009

;

101

:

1207

–

12

.

24

Guo

X

,

Johnson

RC

,

Deng

H

et al.

Evaluation of nonviral adventure factors for nasopharyngeal carcinoma in a high-risk population of Southern Mainland china

.

Int J Cancer

2009

;

124

:

2942

–4

vii

.

25

Nesic

V

,

Sipetic

S

,

Vlajinac

H

,

Stosic-Divjak

Due south

,

Jesic

Due south.

Risk factors for the occurrence of undifferentiated carcinoma of nasopharyngeal type: a instance-command written report

.

Srp Arh Celok Lek

2010

;

138

:

6

–

10

.

26

Turkoz

FP

,

Celenkoglu

G

,

Dogu

GG

et al.

Take a chance factors of nasopharyngeal carcinoma in Turkey - an epidemiological survey of the Anatolian Social club of Medical Oncology

.

Asian Pac J Cancer Prev

2011

;

12

:

3017

–

21

.

27

Polesel

J

,

Franceschi

South

,

Talamini

R

et al.

Tobacco smoking, alcohol drinking, and the risk of unlike histological types of nasopharyngeal cancer in a depression-take a chance population

.

Oral Oncol

2011

;

47

:

541

–iv

5

.

28

Ji

X

,

Zhang

Due west

,

Xie

C

,

Wang

B

,

Zhang

Yard

,

Zhou

F.

Nasopharyngeal carcinoma chance by histologic type in central China: impact of smoking, booze and family history

.

Int J Cancer

2011

;

129

:

724

–

32

.

29

Fachiroh

J

,

Sangrajrang

S

,

Johansson

M

et al.

Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand

.

Cancer Causes Control

2012

;

23

:

1995

–

2002

.

30

Lye

MS

,

Visuvanathan

S

,

Chong

PP

,

Yap

YY

,

Lim

CC

,

Ban

EZ.

Homozygous wildtype of XPD K751Q polymorphism is associated with increased risk of nasopharyngeal carcinoma in Malaysian population

.

PLoS One

2015

;

x

:

e0130530

.

31

Xie

SH

,

Yu

IT

,

Tse

LA

,

Au

JS

,

Lau

JS.

Tobacco smoking, family history, and the risk of nasopharyngeal carcinoma: a case-referent study in Hong Kong Chinese

.

Cancer Causes Control

2015

;

26

:

913

–

21

.

32

Chang

ET

,

Liu

Z

,

Hildesheim

A

et al.

Agile and passive smoking and risk of nasopharyngeal carcinoma: a population-based case-control written report in Southern China

.

Am J Epidemiol

2017

;

185

:

1272

–

fourscore

.

33

Yong

SK

,

Ha

TC

,

Yeo

MC

,

Gaborieau

Five

,

McKay

JD

,

Wee

J.

Associations of lifestyle and diet with the risk of nasopharyngeal carcinoma in Singapore: a instance-control study

.

Mentum J Cancer

2017

;

36

:

3

.

34

Xu

F-H

,

Xiong

D

,

Xu

Y-F

et al.

An epidemiological and molecular study of the relationship betwixt smoking, risk of nasopharyngeal carcinoma, and Epstein–Barr virus activation

.

J Natl Cancer Inst

2012

;

104

:

1396

–

410

.

35

Chow

WH

,

McLaughlin

JK

,

Hrubec

Z

,

Nam

JM

,

Blot

WJ.

Tobacco use and nasopharyngeal carcinoma in a cohort of US Veterans

.

Int J Cancer

1993

;

55

:

538

–

forty

.

36

Doll

R

,

Peto

R

,

Boreham

J

,

Sutherland

I.

Mortality from cancer in relation to smoking: 50 years observations on British doctors

.

Br J Cancer

2005

;

92

:

426

–2

9

.

37

Friborg

JT

,

Yuan

JM

,

Wang

R

,

Koh

WP

,

Lee

HP

,

Yu

MC.

A prospective study of tobacco and alcohol use equally risk factors for pharyngeal carcinomas in Singapore Chinese

.

Cancer

2007

;

109

:

1183

–

91

.

38

Hsu

W-L

,

Chen

J-Y

,

Chien

Y-C

et al.

Independent issue of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-twelvemonth follow-upwardly study on nine,622 males without family history in Taiwan

.

Cancer Epidemiol Biomarkers Prev

2009

;

18

:

1218

–

26

.

39

Lin

J-H

,

Jiang

C-Q

,

Ho

South-Y

et al.

Smoking and nasopharyngeal carcinoma bloodshed: a cohort study of 101,823 adults in Guangzhou, Mainland china

.

BMC Cancer

2015

;

xv

:

906

.

twoscore

Marks

JE

,

Phillips

JL

,

Menck

HR.

The National Cancer Data Base study on the relationship of race and national origin to the histology of nasopharyngeal carcinoma

.

Cancer

1998

;

83

:

582

–viii

viii

.

41

Lee

AW

,

Lung

ML

,

Ng

WT.

Nasopharyngeal Carcinoma: From Etiology to Clinical Practise

. Cambridge, MA, United kingdom:

Bookish Printing

,

2019

.

42

Nicholls

J

,

Niedobitek

Chiliad

,

Histopathological Diagnosis of Nasopharyngeal Carcinoma: Looking beyond the Blue Book

. New York, NY:

Springer

,

2013

; pp.

ten

–

22

.

43

Xue

WQ

,

Qin

HD

,

Ruan

HL

,

Shugart

YY

,

Jia

WH.

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

:

325

–

38

.

44

Long

M

,

Fu

Z

,

Li

P

,

Nie

Z.

Cigarette smoking and the risk of nasopharyngeal carcinoma: a meta-analysis of epidemiological studies

.

BMJ Open

2017

;

7

:

e016582

.

45

Simmonds

Chiliad

,

Stewart

Chiliad

,

Stewart

L.

A decade of individual participant data meta-analyses: A review of electric current do

.

Contemp Clin Trials

2015

;

45

:

76

–

83

.

46

Wu

X

,

Tsai

SP

,

Tsao

CK

et al.

Cohort Contour: The Taiwan MJ Accomplice: one-half a million Chinese with repeated health surveillance data

.

Int J Epidemiol

2017

;

46

:

1744

–

1744g

.

47

Jiang

C

,

Thomas

GN

,

Lam

Thursday

et al.

Cohort Contour: The Guangzhou Biobank Cohort Written report, a Guangzhou-Hong Kong-Birmingham collaboration

.

Int J Epidemiol

2006

;

35

:

844

–

52

.

48

Schooling

CM

,

Chan

WM

,

Leung

SL

et al.

Accomplice Contour: Hong Kong Section of Wellness Elderly Health Service Cohort

.

Int J Epidemiol

2016

;

45

:

64

–

72

.

49

Stewart

50

,

Clarke

M

,

Rovers

Thousand

et al. ; PRISMA-IPD Development Group.

Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant information: the PRISMA-IPD Statement

.

2015

;

313

:

1657

–

65

.

50

Burke

DL

,

Ensor

J

,

Riley

RD.

Meta-analysis using private participant data: one-stage and 2-stage approaches, and why they may differ

.

Stat Med

2017

;

36

:

855

–

75

.

51

Zhang

W

,

Jiang

C

,

Hing

LT

et al.

A prospective cohort study on the comparison of run a risk of occupational grit exposure and smoking to decease [in Chinese]

.

Zhonghua Liu Xing Bing Xue Za Zhi

2004

;

25

:

748

–752. [CVOCROSSCVO]

52

IARC.Some Naturally Occurring Substances: Nutrient Items

and

Constituents

, Heterocyclic Effluvious Amines and Mycotoxins.

Lyon

:

International Bureau for Research on Cancer

,

1993

.

53

Pelucchi

C

,

Gallus

Southward

,

Garavello

W

,

Bosetti

C

,

La Vecchi

A.

Cancer take a chance associated with booze and tobacco utilise: focus on upper aero-digestive tract and liver

.

Alcohol Res Health

2006

;

29

:

193

–

98

. [CVOCROSSCVO]

54

Blot

WJ

,

McLaughlin

JK

,

Winn

DM

et al.

Smoking and drinking in relation to oral and pharyngeal cancer

.

Cancer Res

1988

;

48

:

3282

–8

7

.

55

Cahoon

EK

,

Preston

DL

,

Pierce

DA

et al.

Lung, laryngeal and other respiratory cancer incidence among Japanese atomic flop survivors: an updated analysis from 1958 through 2009

.

Radiat Res

2017

;

187

:

538

–

48

.

56

Zou

J

,

Dominicus

Q

,

Akiba

Southward

et al.

A case-control study of nasopharyngeal carcinoma in the high background radiation areas of Yangjiang

.

J Radiat Res

2000

;

41

:

53

–

S62

.

57

Sakata

R

,

Preston

DL

,

Brenner

AV

et al.

Radiation-related risk of cancers of the upper digestive tract among Japanese atomic bomb survivors

.

Radiat Res

2019

;

192

:

331

–

44

.

58

Hu

T

,

Lin

CY

,

Xie

SH

et al.

Smoking can increase nasopharyngeal carcinoma risk by repeatedly reactivating Epstein‐Barr Virus: an analysis of a prospective study in southern China

.

Cancer Med

2019

;

8

:

2561

–

71

.

59

Hsu

WL

,

Chien

YC

,

Huang

YT

et al. ; GEV-NPC Written report Group.

Cigarette smoking increases the risk of nasopharyngeal carcinoma through the elevated level of IgA antibiotic against Epstein‐Barr virus capsid antigen: a arbitration assay

.

Cancer Med

2020

;

nine

:

1867

–

76

.

lx

Chen

Y

,

Xu

Y

,

Zhao

West

et al.

Lack of association between cigarette smoking and Epstein Barr virus reactivation in the nasopharynx in people with elevated EBV IgA antibody titres

.

BMC Cancer

2018

;

18

:

190

.

61

He

Y-Q

,

Xue

W-Q

,

Xu

F-H

et al.

The human relationship between environmental factors and the profile of Epstein-Barr virus antibodies in the lytic and latent infection periods in healthy populations from endemic and non-endemic nasopharyngeal carcinoma areas in China

.

EBioMedicine

2018

;

30

:

184

–

91

.

62

He

Y-Q

,

Liao

Ten-Y

,

Xue

W-Q

et al.

Clan betwixt environmental factors and oral Epstein-Barr virus Dna Loads: a multicenter cross-sectional written report in Mainland china

.

J Infect Dis

2019

;

219

:

400

–0

9

.

63

Yang

Q-Y

,

He

Y-Q

,

Xue

West-Q

et al.

Association between serum cotinine level and serological markers of Epstein–Barr virus in good for you subjects in South China where nasopharyngeal carcinoma is owned

.

Front Oncol

2019

;

9

:

865

.

64

IARC.

Formaldehyde, 2-Butoxyethanol and 1-Tert-Butoxypropan-2-ol

.

Lyon,France

:

International Bureau for Research on Cancer

,

2006

.

65

Wang

M

,

Cheng

Thou

,

Balbo

South

,

Carmella

SG

,

Villalta

Pw

,

Hecht

SS.

Clear differences in levels of a formaldehyde-DNA adduct in leukocytes of smokers and nonsmokers

.

Cancer Res

2009

;

69

:

7170

–7

4

.

66

IARC.

Personal Habits and Indoor Combustions

.

Lyon

:

International Agency for Enquiry on Cancer

,

2012

.

67

Stewart

LA

,

Clarke

M.

Practical methodology of meta-analyses (overviews) using updated individual patient information. Cochrane Working Grouping

.

Stat Med

1995

;

14

:

2057

–

79

.

68

Mai

Z-Thousand

,

Lin

J-H

,

Ngan

RK-C

et al.

Solar ultraviolet radiation and vitamin D deficiency on Epstein-Barr Virus reactivation: observational and genetic evidence from a nasopharyngeal carcinoma-owned population

.

Open Forum Infect Dis

2020

;

7

:

ofaa426

.

69

Chen

Z

,

Peto

R

,

Zhou

M

et al.

Contrasting male and female trends in tobacco-attributed bloodshed in China: evidence from successive nationwide prospective cohort studies

.

Lancet

2015

;

386

:

1447

–

56

.

Author notes

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