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Smoking causes death in many ways, but the rate of risk reduction after quitting, compared to continuing to smoke, is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer.
To assess the relation between cigarette smoking and smoking cessation on total and cause-specific mortality in women.
Prospective observational study of 104,519 female participants in the Nurses’ Health Study followed from 1980 to 2004.
Hazard ratios for total mortality, further categorized into vascular and respiratory diseases, cancers and other causes.
A total of 12483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. Compared to never smokers, current smokers had an increased risk of total mortality (hazard ratio = 2.81, 95% confidence interval (CI) = 2.68–2.95) and all major cause-specific mortality evaluated. The hazard ratio for cancers classified by the 2004 Surgeon General’s report to be smoking-related was 7.25 (CI:6.43–8.18) and for other cancers, 1.58 (CI:1.45–1.73). The hazard ratio for colorectal cancer was 1.63 (CI:1.29–2.05) for current smokers and 1.23 (CI:1.02–1.49) for former smokers, compared to never smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation for total mortality (P=0.003), respiratory disease mortality (P=0.001), and all smoking-caused cancer mortality (P=0.001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different timeframes for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.
Most of the excess risk of vascular mortality due to smoking can be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation has a dramatic impact on risk of respiratory disease, lung cancer, and other smoking-caused cancer deaths and little effect on other cause-specific mortality. These data suggest that smoking increases the risk of colorectal cancer mortality but not ovarian cancer mortality.
Tobacco use remains the leading preventable cause of death in the United States.1 Globally, approximately 5 million premature deaths were attributable to smoking in 2000.2 The World Health Organization projects by 2030 that tobacco-attributable deaths will annually account for 3 million deaths in industrialized countries and 7 million in developing countries.3 The hazards of smoking have been documented over the past 55 years, providing sufficient evidence of a causal relationship between smoking and many types of death.
After 12 years of follow-up in the Nurses’ Health Study, Kawachi et al. described the extent of the increase in risk of total and cause-specific mortality (vascular disease, cancer including and excluding lung cancer, and external causes of death) associated with current smoking and early age at smoking initiation compared to never smokers, as well as the decrease in risk associated with smoking cessation compared to continuing smokers.4 We have continued to follow these women over time. Utilizing 22 years of follow-up, we are now able to characterize the relationship of smoking to other causes of death, including respiratory diseases and cancers.
The Nurses’ Health Study (NHS) cohort was established in 1976 when 121,700 female US registered nurses 30 to 55 years of age residing in 11 states completed a mailed questionnaire. Participants provided detailed information about medical history and risk factors for cancer, heart disease, and other diseases.5 Since 1976, this information has been updated and extended on biennial follow-up questionnaires. This study was approved by the Committee on the Use of Human Subjects in Research at the Brigham and Women’s Hospital (Boston, Mass); completion of the self-administered questionnaire was considered to imply informed consent.
On the initial 1976 questionnaire, participants reported whether they currently smoked or had ever smoked in the past and the age at which they started smoking. Current smokers reported the number of cigarettes smoked per day, and past smokers reported their age at which they stopped smoking and the number of cigarettes smoked per day before quitting. On each subsequent biennial questionnaire, participants reported whether they currently smoked cigarettes, and at the start of each 2-year follow-up cycle, were reclassified by smoking status (never, past, or current), by quantity of cigarettes smoked and duration among current smokers, and by time since quitting among former smokers. For the analysis on current smoking, we classified current smokers into categories of 1–14, 15–24, 25–34 and ≥ 35 cigarettes smoked per day and categories of age at starting: ≤ 17, 18–21, 22–25, and 26+ years. For the smoking cessation analysis, we classified past smokers into categories of years since quitting: <5, 5 to <10, 10 to <15, 15 to <20, and 20+ years.
Our main outcome was death from all causes, occurring after the 1980 questionnaire was returned but before June 1, 2004. Deaths were grouped into 6 broad categories: (1) vascular diseases; (2) respiratory diseases; (3) lung cancer; (4) all smoking-caused cancers (cancers denoted by the 2004 Surgeon General’s report to be caused by smoking6) including those of the lip, mouth, pharynx, esophagus, larynx, pancreas, bladder and kidney, cervix, stomach, trachea and lung, and acute myeloid leukemia; (5) other cancers; and (6) other causes. Vascular deaths were further categorized into deaths due to coronary heart disease and cerebrovascular disease. Respiratory deaths were further categorized into those due to chronic obstructive pulmonary disease (COPD), as well as a broader group, COPD2, which included confirmed COPD as well as unspecified diseases of the respiratory system (this grouping may include some participants with COPD who were not diagnosed).
Deaths were usually reported by families, and deaths among non-respondents were identified by searching the National Death Index.7 We ascertained the cause of death and sought the pertinent medical records. Study physicians reviewed these records and the death certificate to classify individual causes of death. Only 6.1% of deaths were determined by death certificate information only.
Person-years of follow-up accrued from the date of return of the 1980 questionnaire until either the date of death or the end of follow-up (1 June 2004), whichever came first. We started follow-up in 1980 since alcohol use and physical activity were not ascertained until this follow-up cycle. Person-time for each 2-year follow-up period was equal to the number of months between the return of successive questionnaires. Women did not contribute person-time in follow-up cycles in which they were missing smoking data.
We evaluated the effect of cigarettes smoked per day, age at starting smoking, and time since quitting smoking on total and cause-specific mortality. We also present data on pack-years of smoking in a supplementary table, if readers are interested. We also chose to evaluate cancers not classified by the 2004 Surgeon General’s report to be smoking-related if more than 300 cancer-specific deaths were available. Lastly, we evaluated birth cohort effects in our population by evaluating the hazard ratios for those born between 1920–1929 and 1930–1939, excluding deaths before age 56. We used never smokers as the reference group for the analyses evaluating the hazard ratios (HRs) for cigarettes smoked per day and age at initiation among current smokers, and current smokers as the reference group for the analysis evaluating the HRs for time since quitting among former smokers.8 For all analyses, we used Cox proportional hazard models conditioned on age in months and follow-up cycle. All multivariate models included history of hypertension, diabetes, and high cholesterol levels, body mass index, change in weight from age 18 to baseline, alcohol intake (categories of non-drinkers and drinkers of 0.1–4.9, 5.0–14.9, and 15.0+ grams/day), physical activity (quintiles based on intensity level and a metabolic equivalent task (MET) value calculated from the specific activity engaged in most frequently (1980–1984) and MET hours/week (1986–2000), previous use of oral contraceptives (never-, past-, current-user), postmenopausal estrogen therapy (never-, past-, current-user) and menopausal status, and parental history of myocardial infarction before age 65 years. We also additionally adjusted for servings of beef, pork, or lamb, servings of processed meat, total calcium and folate intake, and duration of aspirin use when evaluating the relation between smoking and colorectal cancer mortality. All variables except for height were updated biennially until diagnosis of non-fatal disease. Tests for linear trend were calculated excluding the reference category and using the midpoint of the categories for cigarettes smoked per day and years since quitting, and the reported age at which the participant started smoking, using the Wald test. The exposed attributable fraction was calculated using the hazard ratios for current or former smokers compared to never smokers.
For all analyses, we excluded participants with a prior history of cancer (other than non-melanoma skin cancer), vascular disease, or respiratory disease before baseline. We also excluded those participants (n=1,872) who had smoked but did not provide their age at smoking initiation. There were 104,519 participants included in the analyses of number of cigarettes smoked per day and smoking cessation, and 79,172 participants included in the analyses of age at start of smoking, as that included only current and never smokers. All analyses were conducted using SAS software, version 9 (SAS Institute Inc, Cary, NC). All P values were based on 2-sided tests and were considered statistically significant at P≤.05.
Non-fatal diseases that occur during follow-up may affect subsequent smoking and act as an intermediate variable between smoking and mortality. For example, a person experiencing a non-fatal myocardial infarction may reduce their smoking or quit smoking altogether,8, 9 and this myocardial infarction (partly induced by smoking) may increase her risk of death. The extent of this type of confounding was evaluated in our first report on smoking and coronary heart disease mortality by performing the G-computational algorithm,10, 11 and the risk estimates were identical to the crude estimates of risk. In the analyses presented here, we attempted to address the problem of confounding by non-fatal diseases by stopping the updating of smoking and all covariates for those participants developing any of the following non-fatal diseases: vascular disease, cancer, or respiratory disease. We used the covariate information provided in the period prior to diagnosis of the non-fatal disease in all subsequent follow-up periods for these participants.
A total of 12483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. There were 2,957 vascular deaths with 1,385 deaths due to coronary heart disease and 734 due to cerebrovascular disease, 759 respiratory deaths with 163 due to COPD; 1237 lung cancer deaths, 2104 smoking-caused cancer deaths (including lung cancer), 3805 deaths due to other cancers, and 2858 deaths due to other causes. Age standardized characteristics at baseline are presented by smoking status (see Table 1). In 1980, 28% of participants were current smokers, 26% were past smokers, and 46% were never smokers. In 2002, only 8% of those alive were current smokers. Current smokers had less increase in weight since age 18, slightly less hypertension and a lower BMI, more alcohol use ≥ 15g/d, and less vigorous weekly exercise than former or never smokers.
Compared to never smokers, current smokers had an increased risk of dying from any major cause during follow-up. (see Table 2). Risks increased significantly with number of cigarettes smoked per day for all major causes (except for cerebrovascular deaths Ptrend = 0.08) and with increasing pack-years of smoking (see Supplementary Table 1). The strongest associations for the category of ≥35 cigarettes smoked per day were for COPD and lung cancer (HR=114.5, CI: 42.8–307 and HR=39.9, CI: 30.1–52.8). Multivariate-adjusted risk estimates for current smoking for cancers included in the all smoking-caused cancers group (in addition to lung cancer) are as follows: acute myeloid leukemia (N=202, HR=1.72, CI: 1.15–2.58); bladder and kidney (N=184, HR=2.97, CI: 2.00–4.42); cervix (N=29, HR=10.18, CI: 3.46–29.9); esophagus (N=44, HR=7.03, CI: 2.96–16.69); lip and mouth (N=30, HR=4.72, CI: 1.84–12.13); pharynx (N=23, HR=6.01, CI: 1.75–20.7); pancreas (N=383, HR=1.84, CI: 1.39–2.43); and stomach (N=108, HR=1.59, CI: 0.96–2.64). Only 9 deaths were due to laryngeal cancer, all among current smokers.
We explored the relation between smoking and mortality for cancer sites with more than 300 deaths and for those sites not previously studied in this cohort. There were 578 colorectal cancer deaths, 467 ovarian cancer deaths, and 1138 breast cancer deaths; however, a recent Nurses’ Health Study analysis found no relation between current smoking and breast cancer survival among those with breast cancer (RR=1.00, 95% CI: 0.83–1.19).12 Current smokers had a 63% increase in the risk of colorectal cancer mortality (95% CI: 1.29–2.05) and a slightly elevated risk of ovarian cancer (HR=1.20, 95% CI: 0.92–1.56) compared to never smokers, but a significant trend for cigarettes smoked per day for colorectal and ovarian cancer mortality was not observed. A significant trend for pack-years of smoking for colorectal mortality was observed (P = 0.004). Overall, approximately 64% of all deaths among current smokers were attributable to cigarette smoking; specifically, 69% of vascular deaths, 90% of respiratory deaths, 95% of lung cancer deaths, 86% of lung and other smoking-caused cancer deaths, 37% of other cancer deaths, and 47% of other deaths were attributable to current cigarette smoking.
The hazard ratio for total mortality for current smokers who started smoking at ≤ 17 years was 2.93 (CI: 2.70–3.18)-, 22% higher than for those starting at or after 26 years (HR=2.40) (see Table 3). For vascular disease and its sub-groups, the hazard ratios for age at starting smoking did not change significantly with increasing age (P= 0.84), while a significant trend was observed with increasing age for respiratory disease (P = 0.001), lung cancer (P < 0.001), and smoking-caused cancer mortality (P = 0.001).
The hazards for total mortality in both birth cohorts were similar, but as the mean age at smoking initiation was 19.9 and 19.3 years of age for those born in the 1920s and 1930s, respectively, we did not expect to observe differences by birth cohort.
We observed a significant 13% reduction in the risk of all-cause mortality within the first five years of quitting smoking compared to continuing to smoke, and the excess risk decreased to the level of a never smoker 20 years after quitting (See Table 4 and Figure 1), with some causes taking more or less time. Significant trends were observed with increasing years since quitting for all major cause-specific outcomes. A more rapid decline in risk after quitting smoking compared to continuing to smoke was observed in the first 5 years for vascular diseases compared to other causes. Much of the excess risk for these causes of death were realized within the first 5 years for coronary heart disease and cerebrovascular disease. In the first 5 years of quitting smoking, 61% and 42% of the full potential benefit of quitting occurred, when compared to long-term (i.e. ≥20 years) quitters. For death due to respiratory disease, an 18% reduction in risk of death was observed 5–10 years after quitting smoking, with the risk reaching that of a never-smoker’s risk after 20 years. This time frame for risk reduction was similar to that observed for COPD. For lung cancer mortality, a significant 21% reduction in risk was observed within the first 5 years compared to continuing smokers, but the excess risk did not disappear for 25 years. Past smokers with 20–25 years of cessation had an 86% reduction in risk of lung cancer mortality compared to current smokers (CI: 0.09–0.20) while those with 25+ years of cessation had a 91% reduction in risk (CI: 0.07–0.11). When including the other smoking-caused cancers, the excess risk approached a never-smoker’s risk more than 20 years after quitting smoking. Although the test for trend was not significant, quitting for more than 20 years was associated with a significant 30% reduction in colorectal cancer mortality (95% CI: 0.53–0.93), compared to continuing to smoke. Approximately 28% of all deaths among past smokers were attributable to cigarette smoking; specifically, 24% of vascular deaths, 75% of respiratory deaths, 81% of lung cancer deaths, 57% of lung and other smoking-caused cancer deaths, 8% of other cancer deaths, and 21% of other deaths were attributable to former cigarette smoking.
This report adds to the growing evidence on the relationship between smoking and mortality.13, 14 The original report from the Nurses’ Health Study on smoking and cause-specific mortality included 2,847 deaths and evaluated 6 mortality-specific outcomes: total mortality, total cardiovascular diseases, total cancer, total cancer excluding lung cancer, and external causes of injury. This updated report on smoking and mortality in the Nurses’ Health Study cohort includes an additional 16 years of follow-up, 12,483 deaths, and additional estimates for coronary heart disease, cerebrovascular disease, respiratory disease, COPD, lung cancer, smoking-caused cancers, colorectal cancer, ovarian cancer, and other causes. Since smoking behavior changes over time, updating participants’ smoking status every 2 years enables more accurate evaluation of the detrimental effects from long-term smoking and the risk reduction over time from sustained cessation. The 9,636 additional deaths that have accrued over time also allow for better precision in estimating the extent of risks associated with smoking and smoking cessation on causes of death previously studied.
As expected, smoking increased the risk of dying from all major cause-specific mortality, with hazard ratios 8 to 14 times higher for lung cancer mortality and COPD mortality compared to total mortality. The increase in the HR with increasing cigarettes smoked per day varied by outcome. An increasing trend was less pronounced for deaths due to vascular disease, suggesting that the first few cigarettes account for most of the increased risk; in contrast, an increase in the number of cigarettes smoked per day substantially increased risk for respiratory death.
Cohort studies consistently support an increased risk associated with current smoking on colorectal cancer risk, but only after accounting for an induction period of 30–40 years.15 Our mortality estimates are higher for current smoking and similar for former smoking compared to those from the American Cancer Society Cancer Prevention Study II, which reported HRs of 1.41 (95% CI: 1.26–1.58) and 1.22 (95% CI: 1.09–1.37) for current and past smoking status among women.16 The 2004 Surgeon General’s report concludes that the evidence is suggestive but not sufficient to infer a causal relationship between smoking and colorectal cancer,6 mainly because of the possibility that the higher death rates from colorectal cancer may be due to less screening in smokers and a later stage of disease at diagnosis. However, we observed only modest differences in colorectal cancer screening in our cohort. In 1992, 5% of smokers reported screening by sigmoidoscopy and 31% by the stool occult blood test in the past two years, versus 10% and 42%, respectively, for past smokers, and 8% and 38% for never smokers. There was a small difference in the percentage of never smokers compared to past and current smokers who had an advanced stage of colorectal cancer at diagnosis. It is unlikely that these small differences in screening and stage at diagnosis explain the smoking and colorectal cancer mortality relation.
The 2004 Surgeon General’s report also concluded that the evidence was inadequate to infer a causal relationship between smoking and ovarian cancer.6 Although we observed a positive but non-significant relation between current smoking and ovarian cancer morality, we found no significant trend with increasing cigarettes smoked per day, pack-years of smoking, and age starting smoking, nor an association between smoking cessation and ovarian cancer mortality, even after 20 years of quitting. Previous studies suggest an increased risk of ovarian cancer incidence associated with current smoking for mucinous epithelial tumors.17, 18
Smoking cessation was beneficial for each cause-specific mortality outcome examined. Unlike the Cancer Prevention Study I, which did not update smoking status during follow-up and found that the risks associated with lung cancer and COPD mortality remained even after 20 years, we observed a monotonic decrease in risk compared to current smokers with increasing years of smoking cessation, with risks equivalent to that of never smokers after 25 years.19 By stopping the updating of covariates after diagnosis, we minimize the bias due to symptom-induced smoking cessation or reducing smoking levels (the “ill quitter” effect). Inability of other studies to update smoking exposure over time or utilize smoking information just before diagnoses may obscure the harms of continuing smoking and the benefits of cessation, because current smokers may quit smoking over time and some past smokers may resume smoking.
In the British Doctors Study, men born in the 1920s likely had more intense early cigarette exposure than earlier birth cohorts, and coupled with improvements in treatment, an estimated two-thirds of those persistent smokers were likely to die from smoking.20 We did not see differences in early cigarette exposure between those born between 1920–1929 and 1930–1939, translating into similar hazards for total mortality in both groups; however, youth are starting to smoke at younger ages. One nationwide survey reported that 13% of eighth grade students first smoked by age 11,21 and 22% of all high school students report themselves as current smokers.22 It is likely that deaths attributable to smoking will increase over time unless there is a substantial increase in cessation.
In summary, our findings indicate that 64% of deaths in current smokers and 28% of deaths in past smokers are attributable to smoking. Quitting reduces the excess mortality rates for all major causes of death examined: most of the excess risk of vascular mortality due to smoking can be eliminated rapidly upon cessation and within 20 years for lung diseases, where the damaging effects of smoking are greatest. Early age at initiation increases mortality risk, so implementing and maintaining school tobacco prevention programs, in addition to enforcing youth access laws, are key preventive strategies.23, 24 Effectively communicating risks to smokers and helping them quit successfully should be an integral part of public health programs.
Funding/Support: The project described was supported by grant R25CA098566 and T32CA09001 from the National Institutes of Health, the Association of Schools of Public Health, and the Legacy Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute of the National Institutes of Health.
Role of the Sponsor: The funding source had no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval or the manuscript.
Financial Disclosures: None reported.
Author Contributions: Drs. Kenfield and Colditz had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.Study concept and design: Kenfield, Stampfer, Rosner, and Colditz.
Acquisition of data: Kenfield, Stampfer, Colditz.
Analysis and interpretation of data: Kenfield, Stampfer, Rosner, and Colditz.
Drafting of the manuscript: Kenfield.
Critical revision of the manuscript for important intellectual content: Kenfield, Stampfer, Rosner, and Colditz.
Statistical analysis: Kenfield and Rosner.
Obtained funding: Stampfer and Colditz.
Administrative, technical, or material support: Colditz.
Study supervision: Stampfer and Colditz.
Additional Contributions: We thank the participants and staff of the Nurses’ Health Study for their valuable contributions. Special thanks to Weiliang Qiu for his graphical expertise.
Weiliang Qiu, PhD
Affiliation: Harvard Medical School and Brigham and Women’s Hospital
No compensation received