Abstract
Objectives
We examined the association among cigarette smoking, smoking cessation and a broad range of cancer incidence and all cause and cause-specific mortality in a population-based cohort of adults of Chinese ethnicity in Singapore.
Methods
Subjects were 61,320 participants of the Singapore Chinese Health Study (44.5% men, aged 45–74 years, recruitment from 1993–1998) who were free of cancer at the baseline examination. Main outcomes-of-interest included cancer incidence, all cause and cause-specific mortality as of December 31, 2005.
Results
Cigarette smoking was positively associated with overall cancer incidence, including cancers at the following specific sites: head and neck region, upper gastrointestinal tract, hepatobiliary and pancreas cancer, lung, and bladder/renal pelvis cancer. Compared to never smokers, the relative risk (RR) (95% confidence interval [CI]) of cancer incidence (all cancer sites) among current smokers smoking >22 cigarettes/day was 1.9 (1.7–2.1), p-trend<0.0001. Similarly, cigarette smoking was associated with all cause and cause-specific mortality, including deaths due to cancer, ischemic heart disease, other heart diseases, and chronic obstructive pulmonary disease. Compared to never smokers, RR (95%CI) of all cause mortality among current smokers smoking >22 cigarettes/day was 1.8 (1.6–2.0), p-trend<0.0001. Also, relative to current smokers, ex-smokers experienced reduced cancer incidence and total mortality. The population attributable risk of smoking in men for cancer incidence as well as all-cause mortality was 23%, whereas in women it ranged from 4–5%.
Conclusions
Cigarette smoking is an important risk factor for cancer incidence and major causes of mortality in Chinese men and women of Singapore.
Keywords: Smoking, Smoking cessation, Cancer, Mortality, Population attributable risk, Chinese, Singapore
1. Introduction
Cigarette smoking is an important public health problem and a major cause of morbidity and mortality(1). Numerous epidemiologic studies in Western populations have reported a positive association between cigarette smoking and cancer, cardiovascular disease, chronic obstructive pulmonary disease (COPD), total and cause-specific mortality(2-26).
In contrast, relatively few prospective studies from Asia, including studies from China(27, 28) and East Asian and other countries(29-37) have examined morbidity and mortality in relation to smoking. Most of these reports exclusively studied men(27, 30-32, 37); among the few studies that included women(28, 29, 33-36), only two included women of Chinese ethnicity(28, 36). While previous Asian studies examined smoking in relation to coronary heart disease (CHD)(29-31), stroke incidence(29, 31, 33, 35) and cause-specific mortality(27, 28, 30, 32, 36), only two prospective studies examined cancer incidence(27, 34). Studies in Western populations have examined the effect of smoking cessation on morbidity and mortality(10-18, 26); in contrast, only one prospective Asian study examined the relationship between smoking cessation and cardiovascular mortality(33), but not other mortality causes or cancer incidence. In this context, we examined the association among cigarette smoking, smoking cessation and a broad range of cancer incidence and all cause and cause-specific mortality in a population-based cohort of adult Singaporeans of Chinese ethnicity, the Singapore Chinese Health Study.
2. Patients and methods
2.1. Study population
The design of the Singapore Chinese Health Study has been described previously(38). Briefly, the cohort was recruited between 1993 and 1998, drawn from permanent residents or citizens of Singapore who lived in government-built housing (86% of the Singapore population resided in such facilities during enrollment period). Men and women of Chinese ethnicity (restricting to the two major dialect groups, the Cantonese and the Hokkiens), aged 45–74 years, were eligible. A total of 63,257 persons (∼85% of eligible subjects) were enrolled. At recruitment, a face-to-face interview was conducted in the subject's home by a trained interviewer using a structured, scanner-readable questionnaire, which requested information on demographics, educational attainment, lifetime use of tobacco, current use of alcohol, current level of physical activity, medical history and family history of cancer. The questionnaire included a validated, semi-quantitative food frequency section listing 165 food items commonly consumed in the study population. The Singapore Food CompositionTable(38), which we developed in conjunction with this cohort study, allowed for the estimation of intake levels of approximately 100 nutritive/non-nutritive food components per study subject.
2.2. Exposure assessment
The study population was divided into never, former, and current smokers based on their choice of three possible responses to the following question, ‘Have you ever smoked at least 1 cigarette a day for 1 y or longer?’ Subjects who answered ‘no’ were classified as ‘non smokers, ’ those who answered ‘yes, but I quit smoking’ were classified as ‘former smokers, ’ and those answered ‘yes, and I currently smoke’ were classified as ‘current smokers. ’ There were six predefined categories of average number of cigarettes smoked/ day: ≤6 cigarettes, 7–12 cigarettes, 13–22 cigarettes, 23–32 cigarettes, 33–42 cigarettes, and ≥43 cigarettes. The number of years since quitting smoking for former smokers was categorised as: <1 year, 1–2 years, 3–4 years, 5–9 years, 10–14 years, 15–19 years, and ≥20 years. For the current analysis, based on sample size considerations, we categorised cigarette smoking status into four categories: non smoker, former smoker, current smoker with ≤22 cigarettes/ day, current smoker with >22 cigarettes/ day. Also, for former smokers, the number of years since quitting smoking was categorised as follows: <10 years, and 10 or more years.
Age was defined as the age in years at the time of baseline examination; education was categorised into no formal education, primary school, secondary school or above; alcohol intake was assessed as grams of daily ethanol consumption; body mass index (BMI) was calculated as weight (kilograms) divided by the square of height (metres); moderate physical activities included brisk walking, bowling, cycling on level ground, tai chi, or chi kung, and hours/week spent on such activities were categorised into none, ½ to 3 h/week, ≥4 h/week.
2.3. Cancer incidence and cause-specific mortality
We identified cancer cases through the population-based Singapore Cancer Registry which has been continuously included in the International Agency for Research on Cancer (IARC) serial publications on world-wide cancer incidence since 1968(39). Deaths were identified through record linkage with the Singapore Registry of Births and Deaths. In our recent follow-up telephone/in-person interview conducted between 1999 and 2004, among the 61,685 subjects (97.5%) that we had contact or follow-up information, either from themselves, their next-of-kin or death records, only 17 subjects (0.03%) have migrated out of Singapore. This suggests that emigration is negligible among the subjects in the cohort.
Of the 63,257 cohort participants, 1937 had a history of invasive cancer (except for nonmelanoma skin cancer) or in situ bladder cancer at recruitment, thus were excluded from the current analysis. As of December 31, 2005, among the 61,320 participants who were free of cancer at baseline, a total of 7982 had died and 5253 had developed either incident invasive cancer of any site or in-situ cancer of the bladder and cervix (for females only). Among the cancer cases, 4750 cases (90.4%) had histopathological diagnoses while the remaining 503 cases (9.6%) were diagnosed using clinical or radiological evidence. In addition, histological information on 4407 cancer diagnoses (83.9%) were verified via manual review of all pathology reports and 218 cases (4.2%) were verified via review of medical records by medically trained research staff.
2.4. Statistical analysis
Person-years for each cohort participant was counted from the date of interview to date of cancer diagnosis (for cancer morbidity analysis), or date of death, or December 31 2005, whichever occurred first. We examined two smoking-related exposures, assessed at the baseline examination: (1) categories of smoking status (non smoker [referent category], former smoker, current smoker with ≤22 cigarettes/ day, current smoker with >22 cigarettes/ day), and (2) categories related to smoking cessation (current smoker [referent category], <10 years since quitting, ≥10 years since quitting, never smoker). We were interested in two groups of outcomes: (1) cancer at all sites and site-specific cancer incidence (based on first diagnosed primary site of cancer categorised according to International Classification of Diseases, Tenth Revision [ICD-10] code), and (2) all cause and cause-specific mortality (based on underlying cause of death classification according to International Classification of Diseases, Ninth Revision [ICD-9] code from death certificates). The following cancer sites (ICD-10 code) were studied: all cancer sites (C00-C97), head and neck (C00.0-C14.8, C32.0-C32.9), upper gastrointestinal tract (oesophagus [C15.2-C15.9] and stomach [C16.0-C16.9]), colorectal cancer (colon [C18.0-C18.9] and rectum [C19]), hepatobiliary and pancreas cancer (liver and intrahepatic bile ducts[C22], gallbladder and other biliary tract [C23, 24] and pancreas [C25.0-C25.9]), lung (C34.0-C34.9), bladder and renal pelvis cancer (C65.0-C68.9), and breast cancer (women only) (C50). We counted only invasive cancers in defining incident cancer, except for bladder cancer (C67) and cervical cancer (C53), where in situ cancers were also included in the analysis. In the current analysis, we were interested in the global association between smoking and a broadly defined range of site-specific incident cancers. We initially performed separate analyses for liver (C22), pancreas (C25) and gallbladder/ other biliary tract (C23, 24) cancers. Since these sites showed similar positive association with smoking, we combined these categories into a single group, ‘hepatobiliary and pancreas cancer’, to obtain adequate sample size. Similarly, after separate analyses that showed similar associations, we chose to combine bladder (C67), and renal pelvis and other urinary organs (C65, C66, C68) into a single group, ‘bladder/renal pelvis cancer’. Breast cancer analyses are confined to women. There were very few bladder/renal pelvis cancer among women smokers (35 cases). Therefore, we presented results of both men and women combined. Mortality due to the following specific causes (ICD-9 code) were studied: cancer (140–208), ischemic heart disease (410–414), stroke (430–438), other heart diseases (391–398, 401, 402, 404, 415–417, 420–429), chronic obstructive pulmonary disease (COPD) (490–496), and liver cirrhosis (571). We used multivariable-adjusted proportional hazards models to estimate the relative risk (RR) and 95% confidence intervals (CI), controlling simultaneously for potential confounders, including age (years), gender (males, females), dialect group (Cantonese, Hokkien), year of recruitment, level of education (no formal education, primary school, secondary school or above), daily ethanol intake (grams), and h/week of moderate physical activity (none, ½ to 3 h/week, 4 h/week or more). Additional variables considered as potential confounders but not included in the final multivariable model were as follows: total calorie intake (kcal/day), total fruits (g/day), total vegetables (g/day), total red meats (g/day), dietary fibre (g/day), dietary cholesterol (mg/day), vitamin E (mg/day), weekly vitamin supplement use (yes, no), and among women, menopausal status (premenopausal, postmenopausal), and post-menopausal oestrogen use (current, former, never). We analysed cigarette smoking categories as an ordinal variable in multivariable models to examine trend in the association. We used cross-product interaction terms in regression models to test multiplicative interaction. We calculated the population attributable risk in relation to ever smoking using Levin's formula(40). All analyses were conducted using SAS version 9.2 (SAS Inc; Cary, NC). Statistical significance was defined as 2-sided p-value<0.05.
3. Results
Table 1 presents the baseline characteristics of the cohort by smoking status. Approximately 20% of all cohort participants (36% of men and 6% of women) reported smoking cigarettes at recruitment. Current smokers had lower levels of education and BMI, higher mean intake of alcohol, and were physically less active.
Table 1.
Selected baseline characteristics by smoking statusa
| Men (n=27,292) | Women (n=34,028) | |||||
|---|---|---|---|---|---|---|
| Never smoker | Former smoker | Current smoker | Never smoker | Former smoker | Current smoker | |
| No. of subjects | 11,521 (42.2%) | 5838 (21.4%) | 9933 (36.4%) | 31,062 (91.3%) | 842 (2.5%) | 2124 (6.2%) |
| Mean age, years | 55.3 | 59.0 | 56.7 | 55.7 | 63.1 | 60.8 |
| Highest education | ||||||
| No formal education | 859 (29.0%) | 602 (20.3%) | 1500 (50.7%) | 11881 (86.7%) | 471 (3.4%) | 1348 (9.8%) |
| Primary school | 4964 (35.6%) | 3294 (23.6%) | 5682 (40.8%) | 12324 (92.8%) | 301 (2.3%) | 658 (5.0%) |
| Secondary school or above | 5698 (54.8%) | 1942 (18.7%) | 2751 (26.5%) | 6857 (97.3%) | 70 (1.0%) | 118 (1.7%) |
| Alcohol intake frequency | ||||||
| Never | 8385 (44.8%) | 4151 (22.2%) | 6175 (33.0%) | 28362 (91.7%) | 741 (2.4%) | 1835 (5.9%) |
| Monthly | 1293 (44.3%) | 584 (20.0%) | 1040 (35.7%) | 1409 (89.4%) | 50 (3.2%) | 118 (7.5%) |
| Weekly | 1472 (37.8%) | 782 (20.1%) | 1643 (42.2%) | 991 (88.4%) | 34 (3.0%) | 96 (8.6%) |
| Daily | 371 (21.0%) | 321 (18.2%) | 1075 (60.8%) | 300 (76.5%) | 17 (4.3%) | 75 (19.1%) |
| Mean daily ethanol intake, g | 2.0 | 3.1 | 5.8 | 0.3 | 0.6 | 0.9 |
| Mean body mass index, kg/m2 | 23.3 | 23.3 | 22.5 | 23.3 | 23.4 | 22.7 |
| Hours/week of moderate physical activity | ||||||
| No | 8282 (40.2%) | 4201 (20.4%) | 8098 (39.4%) | 24694 (90.8%) | 660 (2.4%) | 1858 (6.8%) |
| ½ to 3 h/week | 2080 (49.6%) | 981 (23.4%) | 1133 (27.0%) | 4029 (93.3%) | 121 (2.8%) | 168 (3.9%) |
| 4 h/week or more | 1159 (46.1%) | 656 (26.1%) | 702 (27.9%) | 2339 (93.6%) | 61 (2.4%) | 98 (3.9%) |
Row percentages in parentheses are presented together with number of subjects in each cell, unless otherwise stated.
Table 2 presents the relation between categories of smoking status at baseline and cancer incidence. We observed a positive association between increasing smoking levels and risks of total cancer as well as cancer of the head and neck, upper gastrointestinal tract, hepatobiliary and pancreas, lung, and bladder/renal pelvis. Smoking was unrelated to the overall risk of colorectal cancer. A null association between smoking and breast cancer risk was noted in this study population. In a subsidiary analysis, women who began to smoke before 15 years of age had a relative risk of 1.7 (95% CI = 0.97–3.1) compared with never smokers.
Table 2.
Relation between smoking categories and cancer incidence
| Current smoker | |||||
|---|---|---|---|---|---|
| Cancer sites | Never smoker | Former smoker | ≤22 cigarettes/day | >22 cigarettes/day | p-trend |
| All cancers | |||||
| No. of cases, whole cohort (n=5253) | 2965 | 711 | 1272 | 305 | |
| No. of cases, men (n=2741) | 801 | 621 | 1034 | 285 | |
| No. of cases, women (n=2512) | 2164 | 90 | 238 | 20 | |
| Multivariable RR a, whole cohort | 1(Referent) | 1.2 (1.1–1.3) | 1.60 (1.5–1.7) | 1.9 (1.7–2.1) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 1.2 (1.1–1.4) | 1.70 (1.6–1.9) | 1.9 (1.7–2.2) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 1.3 (1.0–1.6) | 1.45 (1.3–1.7) | 2.1 (1.4–3.3) | <0.0001 |
| Head and neck cancer | |||||
| No. of cases, whole cohort (n=345) | 149 | 48 | 114 | 34 | |
| No. of cases, men (n=252) | 72 | 45 | 104 | 31 | |
| No. of cases, women (n=93) | 77 | 3 | 10 | 3 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.2 (0.85–1.7) | 2.1 (1.6–2.71) | 2.5 (1.6–3.7) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 1.1 (0.78–1.7) | 2.0 (1.5–2.76) | 2.3 (1.5–3.5) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 1.7 (0.54–5.6) | 2.1 (1.1–4.12) | 9.9 (3.1–32.0) | 0.0005 |
| Upper gastrointestinal tract cancer | |||||
| No. of cases, whole cohort (n=458) | 222 | 75 | 127 | 34 | |
| No. of cases, men (n=294) | 83 | 67 | 112 | 32 | |
| No. of cases, women (n=164) | 139 | 8 | 15 | 2 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.2 (0.88–1.6) | 1.5 (1.2–1.9) | 1.7 (1.2–2.5) | 0.0004 |
| Multivariable RR a, men | 1 (Referent) | 1.1 (0.82–1.6) | 1.6 (1.2–2.1) | 1.8 (1.2–2.7) | 0.0003 |
| Multivariable RR a, women | 1 (Referent) | 1.6 (0.78–3.3) | 1.1 (0.66–1.9) | 2.7 (0.67–11.01) | 0.26 |
| Colorectal cancer | |||||
| No. of cases, whole cohort (n=931) | 550 | 150 | 201 | 30 | |
| No. of cases, men (n=514) | 185 | 138 | 162 | 29 | |
| No. of cases, women (n=417) | 365 | 12 | 39 | 1 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.1 (0.92–1.4) | 1.2 (0.97–1.4) | 0.83 (0.56–1.2) | 0.46 |
| Multivariable RR a, men | 1 (Referent) | 1.2 (0.95–1.5) | 1.2 (0.96–1.5) | 0.87 (0.58–1.3) | 0.47 |
| Multivariable RR a, women | 1 (Referent) | 0.82 (0.46–1.5) | 1.2 (0.84–1.7) | 0.54 (0.08–3.9) | 0.61 |
| Hepatobiliary and pancreas cancer | |||||
| No. of cases, whole cohort (n=480) | 235 | 80 | 136 | 29 | |
| No. of cases, men (n=322) | 107 | 72 | 115 | 28 | |
| No. of cases, women (n=158) | 128 | 8 | 21 | 1 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.1 (0.85–1.5) | 1.5 (1.2–1.9) | 1.4 (0.92–2.1) | 0.002 |
| Multivariable RR a, men | 1 (Referent) | 1.1 (0.77–1.4) | 1.4 (1.1–1.8) | 1.3 (0.86–2.0) | 0.02 |
| Multivariable RR a, women | 1 (Referent) | 1.6 (0.79–3.4) | 1.8 (1.1–2.9) | 1.6 (0.22–11.5) | 0.009 |
| Lung cancer | |||||
| No. of cases, whole cohort (n=905) | 254 | 132 | 391 | 128 | |
| No. of cases, men (n=628) | 77 | 110 | 321 | 120 | |
| No. of cases, women (n=277) | 177 | 22 | 70 | 8 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 2.1 (1.6–2.6) | 4.8 (4.0–5.7) | 7.9 (6.2–10.0) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 2.0 (1.5–2.7) | 5.0 (3.9–6.4) | 7.9 (5.9–10.6) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 2.7 (1.7–4.3) | 4.3 (3.2–5.7) | 8.3 (4.0–17.1) | <0.0001 |
| Bladder/renal pelvis cancer | |||||
| No. of cases, whole cohort (n=146) | 61 | 33 | 40 | 12 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.5 (0.96–2.5) | 1.7 (1.1–2.7) | 2.7 (1.4–5.2) | 0.002 |
| Breast cancer (women only) | |||||
| No. of cases, women (n=534) | 491 | 14 | 28 | 1 | |
| Multivariable RR a, women | 1 (Referent) | 1.2 (0.68–2.0) | 0.97 (0.66–1.4) | 0.58 (0.08–4.1) | 0.87 |
Relative risk (95% confidence interval) estimated from a multivariable-adjusted proportional hazards model adjusted for age (years), gender (males, females), dialect group (Cantonese, Hokkien), year of recruitment, level of education (no formal education, primary school, secondary school or above), daily ethanol intake (g), and h/week of moderate physical activity (none, ½ to 3 h/week, 4 h/week or more).
In Table 3, we observed a positive association between increasing smoking categories and all cause mortality and the following cause-specific deaths: cancer, ischemic heart disease, and COPD. We also observed a positive association between smoking and other heart disease mortality, the RR estimates were similar to the results for ischemic heart disease (data not shown). A positive association between smoking and mortality due to liver cirrhosis was of borderline statistical significance (data not shown). Compared to never smokers (referent group), the RR (95% CI) of liver cirrhosis mortality (n=78) was 1.2 (0.60–2.4) among former smokers, 1.3 (0.70–2.5) among current smokers smoking ≤22cigarettes/day, and 2.0 (0.85–4.7) among current smokers smoking >22 cigarettes/day, p-trend=0.06. There was no overall association between smoking and stroke mortality.
Table 3.
Relation between smoking categories and mortality
| Current smoker | |||||
|---|---|---|---|---|---|
| Cause of death | Never smoker | Former smoker | ≤22 cigarettes/day | >22 cigarettes/day | p-trend |
| All causes | |||||
| No. of deaths, whole cohort (n=7982) | 3945 | 1340 | 2228 | 469 | |
| No. of deaths, men (n=4706) | 1325 | 1146 | 1802 | 433 | |
| No. of deaths, women (n=3276) | 2620 | 194 | 426 | 36 | |
| Multivariable RRa, whole cohort | 1(Referent) | 1.3 (1.2–1.4) | 1.7 (1.6–1.8) | 1.8 (1.6–2.0) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 1.3 (1.2–1.4) | 1.7 (1.6–1.8) | 1.7 (1.5–1.9) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 1.7 (1.4–1.9) | 1.6 (1.4–1.8) | 2.5 (1.8–3.5) | <0.0001 |
| Cancer | |||||
| No. of deaths, whole cohort (n=2710) | 1271 | 402 | 835 | 202 | |
| No. of deaths, men (n=1618) | 403 | 344 | 685 | 186 | |
| No. of deaths, women (n=1092) | 868 | 58 | 150 | 16 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.3 (1.2–1.5) | 2.1 (1.9–2.3) | 2.4 (2.0–2.8) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 1.3 (1.1–1.4) | 2.1 (1.9–2.4) | 2.3 (2.0–2.8) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 1.7 (1.3–2.3) | 1.9 (1.6–2.3) | 3.6 (2.2–5.9) | <0.0001 |
| Ischemic heart disease | |||||
| No. of deaths, whole cohort (n=1664) | 799 | 300 | 479 | 86 | |
| No. of deaths, men (n=1030) | 291 | 258 | 402 | 79 | |
| No. of deaths, women (n=634) | 508 | 42 | 77 | 7 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.3 (1.2–1.5) | 1.7 (1.5–1.9) | 1.6 (1.3–2.0) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 1.3 (1.1–1.6) | 1.8 (1.5–2.1) | 1.6 (1.2–2.0) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 1.7 (1.2–2.3) | 1.4 (1.1–1.8) | 2.4 (1.1–5.1) | 0.0002 |
| Stroke | |||||
| No. of deaths, whole cohort (n=832) | 476 | 136 | 193 | 27 | |
| No. of deaths, men (n=436) | 149 | 119 | 145 | 23 | |
| No. of deaths, women (n=396) | 327 | 17 | 48 | 4 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.1 (0.89–1.4) | 1.2 (1.0–1.4) | 0.86 (0.57–1.3) | 0.27 |
| Multivariable RR a, men | 1 (Referent) | 1.1 (0.85–1.4) | 1.1 (0.89–1.4) | 0.74 (0.47–1.2) | 0.93 |
| Multivariable RR a, women | 1 (Referent) | 1.0 (0.62–1.7) | 1.3 (0.98–1.8) | 2.1 (0.80–5.8) | 0.03 |
| Chronic obstructive pulmonary disease | |||||
| No. of deaths, whole cohort (n=378) | 85 | 97 | 162 | 34 | |
| No. of deaths, men (n=282) | 36 | 87 | 126 | 33 | |
| No. of deaths, women (n=96) | 49 | 10 | 36 | 1 | |
| Multivariable RR a, whole cohort | 1 (Referent) | 3.6 (2.6–5.0) | 4.9 (3.7–6.5) | 5.6 (3.6–8.6) | <0.0001 |
| Multivariable RR a, men | 1 (Referent) | 3.1 (2.1–4.6) | 4.1 (2.8–5.9) | 5.0 (3.1–8.0) | <0.0001 |
| Multivariable RR a, women | 1 (Referent) | 4.0 (2.0–8.1) | 6.6 (4.3–10.2) | 3.5 (0.49–25.6) | <0.0001 |
Relative risk (95% confidence interval) estimated from a multivariable-adjusted proportional hazards model adjusted for age (years), gender (males, females), dialect group (Cantonese, Hokkien), year of recruitment, level of education (no formal education, primary school, secondary school or above), daily ethanol intake (g), and h/week of moderate physical activity (none, ½ to 3 h/week, 4 h/week or more).
Table 4 presents the effect of smoking cessation on cancer incidence. For all cancers, we observed a statistically significant risk reduction for former smokers, and the risk reduction was dependent on the number of years of smoking cessation. Compared to current smokers, the RR (95% CI) for all cancers was 0.84 (0.75–0.94) for former smokers with <10 years and 0.67 (0.59–0.75) for former smokers with at least 10 years since smoking cessation. Similarly, a statistically significant, inverse associations was observed between the number of years since smoking cessation and the risk of developing cancer of the head and neck, upper gastrointestinal tract, hepatobiliary and pancreas, lung, and bladder/renal pelvis (Table 4).
Table 4.
Relation between smoking cessation and cancer incidence
| Years since quitting among former smokers | ||||
|---|---|---|---|---|
| Cancer site | Current smoker | <10 years | ≥10 years | Never smoker |
| All cancers | ||||
| No. of cases, whole cohort (n=5253) | 1577 | 356 | 355 | 2965 |
| Multivariable RRa, whole cohort | 1 (Referent) | 0.84 (0.75–0.94) | 0.67 (0.59–0.75) | 0.61 (0.57–0.66) |
| Head and neck cancer | ||||
| No. of cases, whole cohort (n=345) | 148 | 31 | 17 | 149 |
| Multivariable RR a, whole cohort | 1 (Referent) | 0.81 (0.55–1.2) | 0.37 (0.22–0.61) | 0.47 (0.36–0.61) |
| Upper gastrointestinal tract cancer | ||||
| No. of cases, whole cohort (n=458) | 161 | 38 | 37 | 222 |
| Multivariable RR a, whole cohort | 1 (Referent) | 0.87 (0.61–1.3) | 0.69 (0.48–1.0) | 0.66 (0.52–0.84) |
| Hepatobiliary and pancreas cancer | ||||
| No. of cases, whole cohort (n=480) | 165 | 31 | 49 | 235 |
| Multivariable RR a, whole cohort | 1 (Referent) | 0.67 (0.46–0.99) | 0.85 (0.62–1.2) | 0.69 (0.54–0.86) |
| Lung cancer | ||||
| No. of cases, whole cohort (n=905) | 519 | 88 | 44 | 254 |
| Multivariable RR a, whole cohort | 1 (Referent) | 0.59 (0.47–0.74) | 0.23 (0.17–0.32) | 0.20 (0.16–0.23) |
| Bladder/renal pelvis cancer | ||||
| No. of cases, whole cohort (n=146) | 52 | 21 | 12 | 61 |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.2 (0.75–2.1) | 0.52 (0.27–0.98) | 0.54 (0.36–0.82) |
Relative risk (95% confidence interval) estimated from a multivariable-adjusted proportional hazards model adjusted for age (years), gender (males, females), dialect group (Cantonese, Hokkien), year of recruitment, level of education (no formal education, primary school, secondary school or above), daily ethanol intake (g), and h/week of moderate physical activity (none, ½ to 3 h/week, 4 h/week or more).
Table 5 presents the effect of smoking cessation on all cause and selected cause-specific mortality. A statistically significant reduction in risk of all-cause mortality and cause-specific mortality was noted among former smokers. Compared with current smokers, the RR (95% CI) for all-cause mortality was 0.91 (0.84–0.99) for former smokers with <10 years since smoking cessation and 0.65 (0.60–0.71) for those who quit smoking at least 10 years.
Table 5.
Relation between smoking cessation and mortality
| Years since quitting among former smokers | ||||
|---|---|---|---|---|
| Cause of death | Current smoker | <10 years | ≥10 years | Never smoker |
| All causes | ||||
| No. of deaths, whole cohort (n=7982) | 2697 | 702 | 638 | 3945 |
| Multivariable RRa, whole cohort | 1 (Referent) | 0.91 (0.84–0.99) | 0.65 (0.60–0.71) | 0.59 (0.55–0.62) |
| Cancer | ||||
| No. of deaths, whole cohort (n=2710) | 1037 | 222 | 180 | 1271 |
| Multivariable RR a, whole cohort | 1 (Referent) | 0.77 (0.67–0.89) | 0.50 (0.42–0.58) | 0.47 (0.43–0.52) |
| Ischemic heart disease | ||||
| No. of deaths, whole cohort (n=1664) | 565 | 159 | 141 | 799 |
| Multivariable RR a, whole cohort | 1 (Referent) | 0.96 (0.80–1.1) | 0.66 (0.55–0.80) | 0.60 (0.53–0.67) |
| Chronic obstructive pulmonary disease | ||||
| No. of deaths, whole cohort (n=378) | 196 | 59 | 38 | 85 |
| Multivariable RR a, whole cohort | 1 (Referent) | 1.0 (0.75–1.3) | 0.50 (0.35–0.71) | 0.20 (0.15–0.27) |
Relative risk (95% confidence interval) estimated from a multivariable-adjusted proportional hazards model adjusted for age (years), gender (males, females), dialect group (Cantonese, Hokkien), year of recruitment, level of education (no formal education, primary school, secondary school or above), daily ethanol intake (g), and h/week of moderate physical activity (none, ½ to 3 h/week, 4 h/week or more).
Table 6 presents the population attributable risk of cancer incidence and cause-specific mortality in relation to ever smoking. Smoking accounted for more than one in five cancer cases as well as all-cause deaths in men whereas about 4–5% of cancer and death burdens were attributable to smoking in women.
Table 6.
Population attributable risk (PAR) of cancer morbidity and all cause and cause-specific mortality to cigarette smoking
| Relative risk (95% confidence interval) associated with ever smokinga | Population attributable risk associated with ever smoking | |||
|---|---|---|---|---|
| Men | Women | Men | Women | |
| Cancer morbidity | ||||
| All cancers | 1.5 (1.4–1.7) | 1.4 (1.3–1.6) | 23.0% | 3.6% |
| Head and neck cancer | 1.7 (1.3–2.3) | 2.4 (1.3–4.1) | 29.0% | 10.5% |
| Upper gastrointestinal tract cancer | 1.4 (1.1–1.9) | 1.3 (0.85–2.0) | 19.8% | 2.7% |
| Hepatobiliary and pancreatic cancer | 1.2 (0.97–1.6) | 1.7 (1.2–2.6) | 11.9% | 6.1% |
| Lung cancer | 4.1 (3.2–5.2) | 4.0 (3.1–5.1) | 63.8% | 20.5% |
| Bladder/renal pelvis cancer | 1.8 (1.2–2.8) | 1.3 (0.48–3.3) | 32.5% | 2.2% |
| Mortality | ||||
| All causes | 1.5 (1.4–1.6) | 1.7 (1.5–1.8) | 22.6% | 5.3% |
| Cancer | 1.8 (1.6–2.0) | 1.9 (1.7–2.2) | 30.8% | 7.4% |
| Ischemic heart disease | 1.6 (1.4–1.8) | 1.5 (1.2–1.8) | 24.3% | 4.3% |
| Chronic obstructive pulmonary disease | 3.8 (2.6–5.3) | 5.7 (3.8–8.6) | 61.3% | 29.2% |
Relative risk (95% confidence interval) estimated from a multivariable-adjusted proportional hazards model adjusted for age (years), dialect group (Cantonese, Hokkien), year of recruitment, level of education (no formal education, primary school, secondary school or above), daily ethanol intake (g), and h/week of moderate physical activity (none, ½ to 3 h/week, 4 h/week or more).
4. Discussion
In a large population-based cohort of adult Chinese Singaporeans, cigarette smoking was positively associated with risk of developing any cancer as well as certain specific cancer sites including head and neck, upper gastrointestinal tract, hepatobiliary and pancreas, lung, and bladder/renal pelvis. Similarly, cigarette smoking also was associated with all-cause and cause-specific mortality including deaths due to cancer, ischemic heart disease, other heart diseases, and COPD. Smoking cessation was associated with statistically significant reduction in risk of smoking-related cancers and smoking related causes of death. Overall, smoking accounted for one in four cancer cases and deaths in men and <5% of cancer and death burdens in women of the study population.
Prevalence of smoking was historically extremely low among Asian women(41-43), and most previous Asian studies examining smoking included only men(27, 30-32, 37). The well documented increase in prevalence of cigarette smoking in women in the newly industrialised Asian countries(44), including Singapore, is postulated to be related, at least in part, to the westernisation(45, 46) in lifestyles of those Asian populations. While smoking prevalence has declined in many western developed countries, it remains high among men in newly industrialised Asian countries and its prevalence is increasing among women (44). Smoking related lung cancer is the third most frequent cancer among women in Singapore(47). While the age-standardised incidence rate of lung cancer in men has fallen from 60 per 100,000 person-years in 1980 to 45 per 100,000 person-years in 2002, it has remained stable in women at approximately 16 per 100,000 person-years over the last two decades(47). Our data highlights the potential enormous impact of smoking on population health of this continent.
Our results of an overall positive association between cancer incidence and smoking is consistent with previous prospective studies from Asia(27, 34) and agrees with recent reports from the US Surgeon General(1, 48) and the International Agency for Research on Cancer(44) on the health impact of smoking.
In the current study, cigarette smoking was unrelated to colorectal cancer overall. In a concurrent, separate report, we described in further details the relationship between cigarette smoking and colorectal cancer by smoking intensity and duration, stratified by sub-site and stage of the disease. We noted that smoking was associated with a statistically significant, 50% increase in risk of rectal cancer, but was unrelated to risk of colon cancer (Tsong et al., submitted). Some(34, 49-51) but not all(52-54) prior studies have reported a lack of association between smoking and colorectal cancer. Other studies have examined cofactors such as subject's metabolic genotype in tobacco carcinogen metabolism(55, 56) and tumour characteristics(55, 57) and found smoking to be associated with subgroups defined by these cofactors.
We noted no overall association between cigarette smoking and breast cancer in Singapore Chinese women. However, there was a hint that women who began smoking at a young age (≤14 years) might be at risk of breast cancer. This observation is consistent with a recent report that smoking initiation at younger age (adolescence and early adulthood) is associated with increased risk of breast cancer, but that smoking was not associated with breast cancer after first child birth(58). Most studies(59-68), including a pooled analysis of 53 epidemiologic studies(68), reported no association between smoking and female breast cancer although some prior studies have noted a positive association(69-73). Recent reports from the US Surgeon General(1, 48) and the International Agency for Research on Cancer(44) concluded that there is no evidence of an association between smoking and breast cancer among women(1, 44, 48).
Our findings of an overall positive association between smoking and all cause and cause-specific mortality other than stroke are consistent with previous studies from Asia(27, 74) and the US Surgeon General's report(1). In the present study, current smoking was not associated with stroke mortality, a finding consistent with many(29, 32, 75, 76), but not all(27, 31, 33, 37, 77, 78), previous studies from Asia. Our findings on stroke mortality are contrary to the US Surgeon General's report(1) which concluded that smoking is positively related to stroke risk, particularly ischemic stroke and subarachnoid haemorrhage. The US report was predominantly based on studies from Western populations(2, 18-26); only two studies from Asian populations were included(31, 78). One explanation for the observed lack of association may be the reported heterogeneous nature of the association between smoking and stroke subtypes, including a potential lack of association with intracerebral haemorrhage(79) and embolic brain infarction(80).
The main strengths of the current study include its large sample size, good representation of women, its population-based and prospective follow-up nature, and the high percentage of cancer cases that were diagnosed histopathologically. The nationwide cancer registry has been in place since 1968 and has been shown to be comprehensive in its recording of cancer cases(81). Thus, cancer case ascertainment can be assumed to be complete. However, although women represent 55% of this cohort, only 8.7% (n=2965) were ever smokers and most women were light smokers (i.e. under one pack/day). The relatively small number of cancer death cases in women smokers prevented an in-depth analysis of smoking in this gender subgroup. Despite these limitations, our data suggest that female smokers were equally at risk for cancer and other major causes of death from chronic diseases as men.
In conclusion, in a large population-based cohort of Chinese men and women in Singapore, cigarette smoking was positively associated with cancer incidence in multiple sites, and with all cause and cause-specific mortality. Smoking cessation, as opposed to continuation of smoking, was associated with reduction in cancer incidence and all cause and cause-specific mortality.
Acknowledgments
Guarantor statement: ‘The guarantor, AS, accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish’.
Contributors: All authors contributed to the intellectual development of this paper. AS and MCY had the original idea for the study. AS analysed the data, wrote the first draft paper, and is the guarantor. MCY, JMY provided statistical expertise and critical corrections to the manuscript. MCY, JMY, WPK, HPL provided critical corrections to the manuscript. MCY is the Principal Investigator of the Singapore Chinese Health Study.
Ethical Approval: This study followed the recommendations of the Declaration of Helsinki and was approved by the institutional review boards at the University of Minnesota, Minneapolis and the National University of Singapore, Singapore. Written, informed consent was obtained from all participants.
Details of funding: Supported by National Institutes of Health grants RO1 CA55069, R35 CA53890, and R01 CA80205, from the National Cancer Institute, Bethesda, MD.
Independence of researchers from funding source: The funding agencies had no role in the research presented in the paper and the researchers were fully independent in pursuing this research.
We thank Ms. Siew-Hong Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study, and Ms. Kazuko Arakawa of the University of Southern California for the development and management of the cohort study database. We also thank the Singapore Cancer Registry for assistance with the identification of cancer outcomes.
Footnotes
Conflict of interest statement: None declared.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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