IJC International Journal of Cancer
Lifetime risk of distinct upper aerodigestive tract cancers and consumption of alcohol, betel and cigarette Wan-Lun Hsu1, Yin-Chu Chien2, Chun-Ju Chiang3, Hwai-I Yang1,2, Pei-Jen Lou4,5, Cheng-Ping Wang4,5, Kelly J. Yu6, San-Lin You1,7, Li-Yu Wang8, Shu-Yuan Chen9, Czau-Siung Yang10 and Chien-Jen Chen1,3 1
Genomics Research Center, Academia Sinica, Taipei, Taiwan Molecular and Genomic Epidemiology Center, China Medical University Hospital, Taichung, Taiwan 3 Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan 4 Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan 5 Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan 6 Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, Bethesda, MD 7 Department of Healthcare Management, Yuanpei University, Hsinchu, Taiwan 8 Department of Medicine, Mackay Medical College, New Taipei city, Taiwan 9 Department of Public Health, Tzu-Chi University, Hualien, Taiwan 10 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan 2
Epidemiology
The cancer of upper aerodigestive tract (UADT) is a common cancers in the world. However, its lifetime risk by consumption of alcohol, betel and cigarettes remain to be elucidated. This study aimed to estimate lifetime risk of distinct UADT cancers and assess their associations with alcohol, betel and cigarette consumption. Three cohorts of 25,611 men were enrolled in 1982– 1992 in Taiwan. The history of alcohol, betel and cigarette consumption was enquired through questionnaire interview. Newly developed UADT cancers were ascertained through computerized linkage with national cancer registry profile. Lifetime (30–80 years old) risk and multivariate-adjusted hazard ratio (HRadj) of distinct UADT cancers by alcohol, betel and cigarette consumption were estimated. A total of 269 pathologically confirmed cases of UADT cancers were newly-diagnosed during 472,096 person-years of follow-up. The lifetime risk of UADT cancer was 9.42 and 1.65% for betel chewers and nonchewers, 3.22 and 1.21% for cigarette smokers and nonsmokers and 4.77 and 1.85% for alcohol drinkers and nondrinkers. The HRadj (95% confidence interval) of developing UADT cancer was 3.36 (2.51–4.49), 2.02 (1.43–2.84), 1.90 (1.46–2.49), respectively, for the consumption of betel, cigarette and alcohol. Alcohol, betel and cigarette had different effect on cancers at various anatomical sites of UADT. The cancer risk from the mouth, pharynx, esophagus to larynx increased for alcohol and cigarette consumption, but decreased for betel consumption. Alcohol, betel and cigarette consumption are independent risk predictors for distinct UADT cancers.
The cancers of upper aerodigestive tract (UADT) including the sites of oral cavity, pharynx, esophagus and larynx are common cancers among males in the world. Its incidence has declined recently in most countries including France, the United States and India.1,2 However, the annual age-adjusted cancer incidence rates for oral cavity, pharynx, larynx and Key words: betel quid chewing, cigarette smoking, alcohol drinking, cumulative lifetime incidence, UADT cancers Additional Supporting Information may be found in the online version of this article. Grant sponsor: Department of Health, Executive Yuan, Republic of China, Taiwan; Academia Sinica, Taiwan DOI: 10.1002/ijc.28791 History: Received 28 Oct 2013; Accepted 23 Jan 2014; Online 18 Feb 2014 Correspondence to: Prof. Chien-Jen Chen, Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan, Tel.: 1[886227899402], Fax: 1[886-2-27853208], E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 135, 1480–1486 (2014) V
esophagus in Taiwanese males were 11.86, 4.71, 3.50 and 6.59 per 100,000, respectively, in 1995; and steadily increased to 25.28, 12.67, 3.65 and 11.94 per 100,000, respectively, in 2009.3 Cancers of UADT have become an important public health issue in Taiwan in past decades. Numerous epidemiological evidences have shown that tobacco smoking and alcohol drinking are major risk factors for the development of UADT cancers,4–6 which may explain 73% of UADT cancers in Europe.7 In addition, large geographic variation in the incidence of UADT subsite cancers was observed in the world. This suggests other risk factors may play an important role in the carcinogenesis of UADT cancer as well. Betel nut/quid chewing is a common habit in Southeast Asia, and betel quid chewing prevalence is increasing in recent decades in Taiwan.8 There is different ingredient of betel quid in Taiwan and other countries. The betel quid in Taiwan is chewed without tobacco and often chewed with inflorescence of piper betel and lime, but most chewers have cigarette smoking habits.9 In a meta-analysis of nine case-control studies, the pooled odds ratio (95% CI) of
1481
Hsu et al.
What’s new? Betel quid chewing, alcohol consumption, and cigarette smoking are associated with an increased risk of upper aerodigestive tract (UADT) cancers, though lifetime risk associations have not been fully elucidated. The present study estimated lifetime risk of distinct UADT cancers in three male cohorts in Taiwan over a twenty-year period. The findings show that for alcohol and cigarette consumption the risk of cancer was higher at sites in the throat compared to the mouth, while an opposite pattern was observed for betel quid chewing. Cumulative UADT risk reached 17.2% for men who chewed more than 20 betel quids per day.
Material and Methods Study cohorts
Three community cohorts in Taiwan were used for the analysis of UADT cancer risk: Six-community Hypertension Intervention Project cohort15; Multiple Risk Factors for Multiple diseases cohort16,17; and Community-based Cancer Screening Project cohort.18 The characteristics of study cohorts and description are shown in Supporting Information Table S1 and Supporting Information materials. These study protocols and the informed consent procedure were reviewed and approved by the Institutional Review Board of the College of Public Health at National Taiwan University.
Additional information was collected on the types of alcohol beverage. Total consumption of pure ethanol in grams per day was calculated by multiplying the average frequency of alcohol consumption and the volume percentage of pure ethanol by beverage type. The cumulative exposure of cigarette smoke was defined in “pack-years” by multiplying the packs of cigarette smoked per day by the years of cigarettes smoking; the cumulative exposure of alcohol drinking was defined in “gram/day-years” by multiplying the ethanol grams drank per day by the years of alcohol drinking; and the cumulative exposure of betel quid chewing was defined in “quid/day-years” by multiplying the betel quids chewed per day by the years of betel quid chewing. Follow-up for vital status and ascertainment of upper-aerodigestive tract cancers
Newly developed UADT cancers and vital status were ascertained using the subjects’ national identification numbers by computerized linkage to the National Cancer Registry and the National Death Certification for the period between recruitment date and December 31, 2009. The definition of UADT cancers included (i) oral cavity (ICD-O codes C00 and C02-C06 except C02.4, C05.1 and C05.2), (ii) pharynx (ICD-O codes C01, C02.4, C05.1, C05.2, C09 and C12-C14), (iii) esophagus (ICD-O code C15) and (iv) larynx (ICD-O code C32). Participants affected with salivary gland (ICD-O codes C07 and C08), nasopharyngeal cancer (ICD-O code C11) and thyroid cancer (ICD-O code C73) were not included in the analysis because their etiology and histology are different from other UADT cancer sites. Statistical analysis
Data collection
At study entry, each study participant from three cohort studies was personally interviewed by well-trained research nurses using structured questionnaires. The information obtained from questionnaire interview included sociodemographic characteristics and information on consumption habits of betel quid chewing, cigarette smoking and alcohol drinking. Duration and quantity of three substance uses were also recorded. Betel quid chewing habit was defined as having chewed betel quids for at least 6 months, cigarette smoking habit was defined as having smoked at least one cigarette/day for at least 6 months and alcohol drinking habit was defined as having drunk alcohol regularly for at least 6 months. C 2014 UICC Int. J. Cancer: 135, 1480–1486 (2014) V
Nelson-Aalen method was used to estimate the cumulative lifetime risk (age 30–80 years old) of UADT and subsite cancers. For the calculation of UADT cancer incidence, the number of person-years at risk for each participant was calculated from the date of enrollment to the date of diagnosis of incident UADT cancer, the date of death or last date of linked data available from the national cancer registry (December 31, 2009), whichever came first. The adjusted HR (HRadj) of developing UADT cancer with 95% CIs were calculated using Cox proportional hazards models. All models included age at recruitment (continuous), educational levels (illiterate, primary school, high school and college), ethnicity (Fukkinese, Hakka and others), study cohort and potential
Epidemiology
developing oral cavity cancer was 3.50 (2.16–5.65) for betel quid chewing after adjustment for cigarette smoking.10 Several studies also reported that betel quid chewing is also associated with the risk of pharyngeal and esophageal cancers.11–13 One cohort study conducted in Taiwan reported the effect of betel quid chewing on cancer death. Compared with the never-smoking and never-chewing group, the hazard ratio (HR; 95% confidence interval, CI) was 12.52 (95% CI: 5.45–28.77) for oral cavity cancer, 5.64 (95% CI: 2.25–14.12) for esophageal cancer and 6.24 (95% CI: 1.04–37.44) for laryngeal cancer among betel quid chewers.14 However, most previous findings were derived from hospital-based case-control studies that studied one cancer at a time. In this study, we combined data from three communitybased long-term prospective studies, which included more than 25,000 males in Taiwan to estimate lifetime risk of UADT cancers and their associations with betel quid chewing, cigarette smoking and alcohol drinking.
1482
UADT cancers and consumption of alcohol, betel and cigarette
a steadily increasing risk of UADT cancers with increasing age (p for trend, 0.007). Hakka had a much lower risk of UADT cancer incidence compared to Fukkinese (HRadj, 0.45; 95% CI, 0.33–0.62). Higher educational level was associated with a lower risk of UADT cancer (p for trend, 0.016). Figure 1 shows the age-specific cumulative lifetime risk of UADT cancers, oral cavity cancer, pharynx cancer, esophageal
risk factors such as betel quid chewing, cigarette smoking and alcohol drinking. The dose-response relationship between risk of UADT cancers and various substance uses was tested for statistical significance using an ordinal variable in the model. Quantity, duration and cumulative exposure to various substance items were categorized into three groups. Three groups based on either approximately equal participant numbers or UADT cancer cases in the low and high consumption were established. Only male participants were included in this study because men were more frequently affected with UADT cancers than women, and the prevalence of cigarette smoking (1.7%), alcohol drinking (1.8%) and betel quid chewing (0.2%) was remarkably lower among female participants. There were eight UADT cases diagnosed before recruitment and excluded from this analysis. A total of 25,611 male participants are included in this analysis.
Results The incidence and HRadj with 95% CI for UADT cancers by sociodemographic characteristics at study entry are shown in Table 1. A total of 269 pathologically confirmed cases of UADT cancers were newly diagnosed during the follow-up of 472,096 person-years. The mean duration of follow-up was 18.4 years with a standard deviation of 6.1 years. The overall incidence rate was 57.0 per 100,000 person-years. There was
Figure 1. Lifetime risk of UADT cancers and subsites at various age.
Table 1. Incidence and HRadj with 95% CI of developing UADT cancer by age at recruitment, ethnicity and education UADT cancers
Person (years)
Case number
Incidence per 100,000 person (years)
HRadj (95% CI)1
5854 (22.9)
118049.9
51
43.2
1.00 (referent)
40–49
6299 (24.6)
126982.4
78
61.4
1.40 (0.98–2.00)
0.062
50–59
7753 (30.3)
143236.1
86
60.0
1.41 (0.99–1.99)
0.055
60
5705 (22.3)
83827.4
54
64.4
1.65 (1.12–2.42)
0.012
Total number of participants (%)
Lifetime risk of distinct upper aerodigestive tract cancers and consumption of alcohol, betel and cigarette Wan-Lun Hsu1, Yin-Chu Chien2, Chun-Ju Chiang3, Hwai-I Yang1,2, Pei-Jen Lou4,5, Cheng-Ping Wang4,5, Kelly J. Yu6, San-Lin You1,7, Li-Yu Wang8, Shu-Yuan Chen9, Czau-Siung Yang10 and Chien-Jen Chen1,3 1
Genomics Research Center, Academia Sinica, Taipei, Taiwan Molecular and Genomic Epidemiology Center, China Medical University Hospital, Taichung, Taiwan 3 Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan 4 Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan 5 Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan 6 Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, Bethesda, MD 7 Department of Healthcare Management, Yuanpei University, Hsinchu, Taiwan 8 Department of Medicine, Mackay Medical College, New Taipei city, Taiwan 9 Department of Public Health, Tzu-Chi University, Hualien, Taiwan 10 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan 2
Epidemiology
The cancer of upper aerodigestive tract (UADT) is a common cancers in the world. However, its lifetime risk by consumption of alcohol, betel and cigarettes remain to be elucidated. This study aimed to estimate lifetime risk of distinct UADT cancers and assess their associations with alcohol, betel and cigarette consumption. Three cohorts of 25,611 men were enrolled in 1982– 1992 in Taiwan. The history of alcohol, betel and cigarette consumption was enquired through questionnaire interview. Newly developed UADT cancers were ascertained through computerized linkage with national cancer registry profile. Lifetime (30–80 years old) risk and multivariate-adjusted hazard ratio (HRadj) of distinct UADT cancers by alcohol, betel and cigarette consumption were estimated. A total of 269 pathologically confirmed cases of UADT cancers were newly-diagnosed during 472,096 person-years of follow-up. The lifetime risk of UADT cancer was 9.42 and 1.65% for betel chewers and nonchewers, 3.22 and 1.21% for cigarette smokers and nonsmokers and 4.77 and 1.85% for alcohol drinkers and nondrinkers. The HRadj (95% confidence interval) of developing UADT cancer was 3.36 (2.51–4.49), 2.02 (1.43–2.84), 1.90 (1.46–2.49), respectively, for the consumption of betel, cigarette and alcohol. Alcohol, betel and cigarette had different effect on cancers at various anatomical sites of UADT. The cancer risk from the mouth, pharynx, esophagus to larynx increased for alcohol and cigarette consumption, but decreased for betel consumption. Alcohol, betel and cigarette consumption are independent risk predictors for distinct UADT cancers.
The cancers of upper aerodigestive tract (UADT) including the sites of oral cavity, pharynx, esophagus and larynx are common cancers among males in the world. Its incidence has declined recently in most countries including France, the United States and India.1,2 However, the annual age-adjusted cancer incidence rates for oral cavity, pharynx, larynx and Key words: betel quid chewing, cigarette smoking, alcohol drinking, cumulative lifetime incidence, UADT cancers Additional Supporting Information may be found in the online version of this article. Grant sponsor: Department of Health, Executive Yuan, Republic of China, Taiwan; Academia Sinica, Taiwan DOI: 10.1002/ijc.28791 History: Received 28 Oct 2013; Accepted 23 Jan 2014; Online 18 Feb 2014 Correspondence to: Prof. Chien-Jen Chen, Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan, Tel.: 1[886227899402], Fax: 1[886-2-27853208], E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 135, 1480–1486 (2014) V
esophagus in Taiwanese males were 11.86, 4.71, 3.50 and 6.59 per 100,000, respectively, in 1995; and steadily increased to 25.28, 12.67, 3.65 and 11.94 per 100,000, respectively, in 2009.3 Cancers of UADT have become an important public health issue in Taiwan in past decades. Numerous epidemiological evidences have shown that tobacco smoking and alcohol drinking are major risk factors for the development of UADT cancers,4–6 which may explain 73% of UADT cancers in Europe.7 In addition, large geographic variation in the incidence of UADT subsite cancers was observed in the world. This suggests other risk factors may play an important role in the carcinogenesis of UADT cancer as well. Betel nut/quid chewing is a common habit in Southeast Asia, and betel quid chewing prevalence is increasing in recent decades in Taiwan.8 There is different ingredient of betel quid in Taiwan and other countries. The betel quid in Taiwan is chewed without tobacco and often chewed with inflorescence of piper betel and lime, but most chewers have cigarette smoking habits.9 In a meta-analysis of nine case-control studies, the pooled odds ratio (95% CI) of
1481
Hsu et al.
What’s new? Betel quid chewing, alcohol consumption, and cigarette smoking are associated with an increased risk of upper aerodigestive tract (UADT) cancers, though lifetime risk associations have not been fully elucidated. The present study estimated lifetime risk of distinct UADT cancers in three male cohorts in Taiwan over a twenty-year period. The findings show that for alcohol and cigarette consumption the risk of cancer was higher at sites in the throat compared to the mouth, while an opposite pattern was observed for betel quid chewing. Cumulative UADT risk reached 17.2% for men who chewed more than 20 betel quids per day.
Material and Methods Study cohorts
Three community cohorts in Taiwan were used for the analysis of UADT cancer risk: Six-community Hypertension Intervention Project cohort15; Multiple Risk Factors for Multiple diseases cohort16,17; and Community-based Cancer Screening Project cohort.18 The characteristics of study cohorts and description are shown in Supporting Information Table S1 and Supporting Information materials. These study protocols and the informed consent procedure were reviewed and approved by the Institutional Review Board of the College of Public Health at National Taiwan University.
Additional information was collected on the types of alcohol beverage. Total consumption of pure ethanol in grams per day was calculated by multiplying the average frequency of alcohol consumption and the volume percentage of pure ethanol by beverage type. The cumulative exposure of cigarette smoke was defined in “pack-years” by multiplying the packs of cigarette smoked per day by the years of cigarettes smoking; the cumulative exposure of alcohol drinking was defined in “gram/day-years” by multiplying the ethanol grams drank per day by the years of alcohol drinking; and the cumulative exposure of betel quid chewing was defined in “quid/day-years” by multiplying the betel quids chewed per day by the years of betel quid chewing. Follow-up for vital status and ascertainment of upper-aerodigestive tract cancers
Newly developed UADT cancers and vital status were ascertained using the subjects’ national identification numbers by computerized linkage to the National Cancer Registry and the National Death Certification for the period between recruitment date and December 31, 2009. The definition of UADT cancers included (i) oral cavity (ICD-O codes C00 and C02-C06 except C02.4, C05.1 and C05.2), (ii) pharynx (ICD-O codes C01, C02.4, C05.1, C05.2, C09 and C12-C14), (iii) esophagus (ICD-O code C15) and (iv) larynx (ICD-O code C32). Participants affected with salivary gland (ICD-O codes C07 and C08), nasopharyngeal cancer (ICD-O code C11) and thyroid cancer (ICD-O code C73) were not included in the analysis because their etiology and histology are different from other UADT cancer sites. Statistical analysis
Data collection
At study entry, each study participant from three cohort studies was personally interviewed by well-trained research nurses using structured questionnaires. The information obtained from questionnaire interview included sociodemographic characteristics and information on consumption habits of betel quid chewing, cigarette smoking and alcohol drinking. Duration and quantity of three substance uses were also recorded. Betel quid chewing habit was defined as having chewed betel quids for at least 6 months, cigarette smoking habit was defined as having smoked at least one cigarette/day for at least 6 months and alcohol drinking habit was defined as having drunk alcohol regularly for at least 6 months. C 2014 UICC Int. J. Cancer: 135, 1480–1486 (2014) V
Nelson-Aalen method was used to estimate the cumulative lifetime risk (age 30–80 years old) of UADT and subsite cancers. For the calculation of UADT cancer incidence, the number of person-years at risk for each participant was calculated from the date of enrollment to the date of diagnosis of incident UADT cancer, the date of death or last date of linked data available from the national cancer registry (December 31, 2009), whichever came first. The adjusted HR (HRadj) of developing UADT cancer with 95% CIs were calculated using Cox proportional hazards models. All models included age at recruitment (continuous), educational levels (illiterate, primary school, high school and college), ethnicity (Fukkinese, Hakka and others), study cohort and potential
Epidemiology
developing oral cavity cancer was 3.50 (2.16–5.65) for betel quid chewing after adjustment for cigarette smoking.10 Several studies also reported that betel quid chewing is also associated with the risk of pharyngeal and esophageal cancers.11–13 One cohort study conducted in Taiwan reported the effect of betel quid chewing on cancer death. Compared with the never-smoking and never-chewing group, the hazard ratio (HR; 95% confidence interval, CI) was 12.52 (95% CI: 5.45–28.77) for oral cavity cancer, 5.64 (95% CI: 2.25–14.12) for esophageal cancer and 6.24 (95% CI: 1.04–37.44) for laryngeal cancer among betel quid chewers.14 However, most previous findings were derived from hospital-based case-control studies that studied one cancer at a time. In this study, we combined data from three communitybased long-term prospective studies, which included more than 25,000 males in Taiwan to estimate lifetime risk of UADT cancers and their associations with betel quid chewing, cigarette smoking and alcohol drinking.
1482
UADT cancers and consumption of alcohol, betel and cigarette
a steadily increasing risk of UADT cancers with increasing age (p for trend, 0.007). Hakka had a much lower risk of UADT cancer incidence compared to Fukkinese (HRadj, 0.45; 95% CI, 0.33–0.62). Higher educational level was associated with a lower risk of UADT cancer (p for trend, 0.016). Figure 1 shows the age-specific cumulative lifetime risk of UADT cancers, oral cavity cancer, pharynx cancer, esophageal
risk factors such as betel quid chewing, cigarette smoking and alcohol drinking. The dose-response relationship between risk of UADT cancers and various substance uses was tested for statistical significance using an ordinal variable in the model. Quantity, duration and cumulative exposure to various substance items were categorized into three groups. Three groups based on either approximately equal participant numbers or UADT cancer cases in the low and high consumption were established. Only male participants were included in this study because men were more frequently affected with UADT cancers than women, and the prevalence of cigarette smoking (1.7%), alcohol drinking (1.8%) and betel quid chewing (0.2%) was remarkably lower among female participants. There were eight UADT cases diagnosed before recruitment and excluded from this analysis. A total of 25,611 male participants are included in this analysis.
Results The incidence and HRadj with 95% CI for UADT cancers by sociodemographic characteristics at study entry are shown in Table 1. A total of 269 pathologically confirmed cases of UADT cancers were newly diagnosed during the follow-up of 472,096 person-years. The mean duration of follow-up was 18.4 years with a standard deviation of 6.1 years. The overall incidence rate was 57.0 per 100,000 person-years. There was
Figure 1. Lifetime risk of UADT cancers and subsites at various age.
Table 1. Incidence and HRadj with 95% CI of developing UADT cancer by age at recruitment, ethnicity and education UADT cancers
Person (years)
Case number
Incidence per 100,000 person (years)
HRadj (95% CI)1
5854 (22.9)
118049.9
51
43.2
1.00 (referent)
40–49
6299 (24.6)
126982.4
78
61.4
1.40 (0.98–2.00)
0.062
50–59
7753 (30.3)
143236.1
86
60.0
1.41 (0.99–1.99)
0.055
60
5705 (22.3)
83827.4
54
64.4
1.65 (1.12–2.42)
0.012
Total number of participants (%)
