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Lung Cancer Risk Reduction After Smoking Cessation: Observations From a Prospective Cohort of Women

J.O. Ebbert, P. Yang, C.M. Vachon, R.A. Vierkant, J.R. Cerhan, A.R. Folsom, T.A. Sellers

From the Nicotine Research Center, Division of Community Internal Medicine, Mayo Clinic Cancer Center, Rochester; and University of Minnesota, Division of Epidemiology, Minneapolis, MN.

Address reprint requests to: Ping Yang, MD, PhD, Department of Health Sciences and Cancer Center at Mayo Clinic/Foundation, 200 First St. SW, Rochester, MN 55905; email: yang.ping{at}mayo.edu.

	ABSTRACT

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Purpose: We conducted this study because the duration of excess lung cancer risk among former smokers has been inconsistently reported, doubt has been raised regarding the population impact of smoking cessation, and differential risk reduction by histologic cell type after smoking cessation needs to be confirmed.

Methods: The Iowa Women’s Health Study is a prospective cohort study of 41,836 Iowa women aged 55 to 69 years. In 1986, mailed questionnaires were used to collect detailed smoking history. Age-adjusted lung cancer incidence through 1999 was analyzed according to years of smoking abstinence. Relative risks were estimated using Cox regression analysis.

Results: There were 37,078 women in the analytic cohort. Compared with the never smokers, former smokers had an elevated lung cancer risk (relative risk, 6.6; 95% confidence interval, 5.0 to 8.7) up to 30 years after smoking cessation for all former smokers. However, a beneficial effect of smoking cessation was observed among recent and distant former smokers. The risk of adenocarcinoma remained elevated up to 30 years for both former heavier and former lighter smokers.

Conclusion: The risk for lung cancer is increased for both current and former smokers compared with never smokers and declines for former smokers with increasing duration of abstinence. The decline in excess lung cancer risk among former smokers is prolonged compared with other studies, especially for adenocarcinoma and for heavy smokers, suggesting that more emphasis should be placed on smoking prevention and lung cancer chemoprevention.

	INTRODUCTION

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LUNG CANCER risk among female former smokers has been shown to decrease with increasing duration of smoking abstinence.¹ Case-control and cohort studies have observed a 50% or greater lung cancer risk reduction in the first decade of smoking abstinence for female former smokers compared with current smokers.^1–7 However, the time that needs to pass before the risk of lung cancer among former smokers reaches that of never smokers is less clear. Case-control study data have indicated that excess lung cancer risk persists beyond 10 to 15 years of smoking abstinence and that this risk may decline more quickly for lighter than for heavier smokers.^2,3,8 Data from cohort studies have indicated both that the lung cancer risk decreases to the level of never smokers by 15 years⁷ and that excess risk persists beyond 16 years for heavier smokers.^1,9

The inconsistent results in the duration of lung cancer risk after smoking cessation may be partially explained by differing rates of risk reduction by histologic cell type. Previous studies have shown a steady decline in risk for small cell and squamous cell carcinoma but not for adenocarcinoma with increasing duration of abstinence.^10,11 A meta-analysis found that smoking cessation is associated with a greater risk reduction for small cell and squamous cell lung cancer than for adenocarcinoma.¹² More prospective cohort studies are needed to define the duration of excess lung cancer risk among female former smokers and to determine how lung cancer risk decreases with duration of abstinence by histologic cell type.

Evidence exists indicating that the population effect of smoking cessation is less than previously expected. Although decreased lung cancer incidence and mortality has been repeatedly observed in studies of former smokers using conventional case-control¹ and cohort^6,7,9,13,14 study designs, much of the observational data are based on individuals who were already former smokers at the time these studies were initiated. Although randomized, controlled trials theoretically provide the best data regarding the population effect of smoking cessation, negligible and even increased lung cancer mortality associated with smoking cessation have been observed in these studies.^15–19 Results from natural experiments^20,21 have indicated that rates of lung cancer death do not significantly decline in a population experiencing substantial declines in smoking prevalence. These results have obfuscated the benefit of smoking cessation. Cohort studies assessing the effect of recent and distant smoking cessation on lung cancer risk may add to the body of evidence supporting the effort to aggressively treat all current smokers at the individual and population levels.

We examined lung cancer risk among former smokers in a large prospective cohort of women to estimate the duration of excess lung cancer risk, to determine risk reduction by histologic cell type, and to assess the effect of smoking cessation. Our cohort study provides additional evidence on smoking cessation and lung cancer among women.

	METHODS

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Study Population and Data Collection
The Iowa Women’s Health Study (IWHS) is a prospective cohort study of risk factors for cancer and chronic diseases in women aged 55 to 69 years.^22,23 In January 1986, a questionnaire was mailed to 99,826 women randomly selected from a list of women with a valid Iowa driver’s license in 1985. The 41,836 respondents (42.7% response rate) form the cohort under observation. The cohort was 98% Caucasian, and 65% lived in towns of fewer than 10,000 inhabitants. Compared with nonrespondents, respondents were on average 2 months younger and more likely to live in rural areas. The nonrespondents have been demonstrated to have higher mortality rates from smoking-related diseases than the respondents.²⁴

Self-reported items on the baseline questionnaire included reproductive history, height, self-measured body circumferences, weight, education, and physical activity. The survey also included a food frequency questionnaire.²⁵ Data collected for cigarette smoking history included age at initiation, average packs per day, and age at cessation.

Baseline Exclusions and Cohort Follow-Up
At study baseline, we excluded women with previous cancers other than nonmelanoma skin cancer (n = 3,830). We also excluded cases with missing smoking histories (n = 928). This left a cohort at risk for incident lung cancer of 37,078 women. Follow-up questionnaires were mailed in 1987, 1989, 1992, and 1997 to update smoking status, address changes, and vital status. However, among women who remained eligible at the time of follow-up questionnaire distribution, the response rates were significantly different across the baseline-defined subgroups of smokers. The response rates were 78%, 84%, and 85% for the 1992 questionnaire (P < .001) and 74%, 80%, and 81% (P < .001) for the 1997 questionnaire for current, former, and never smokers at baseline, respectively. To avoid potential bias introduced by differential reporting across exposure groups, smoking-related variables were analyzed based on the baseline questionnaire.

Incident lung cancer cases occurring from 1986 through 1999 were identified through the Iowa Cancer Registry, which is part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.²⁶ The Iowa Cancer Registry uses Iowa death certificate data and the National Death Index as part of its data collection and verification procedure. A computer match was performed annually between the list of cohort members and the records of Iowans with incident cancer in the registry.

Data regarding the diagnosis were abstracted by registry personnel from medical records and pathology reports according to SEER protocol²⁷ and were coded according to International Classification of Diseases for Oncology, second edition (ICD-O-2).²⁸ Lung cancer (ICD-O-2: 34.0 to 34.9) was categorized as adenocarcinoma (8140 to 8380, 8481, 8480), squamous cell carcinoma (8050 to 8076), small cell carcinoma (8041 to 8045), or other/unspecified (8000, 8010, 8012, 8020, 8021, 8430, 8560, 9680, and 9691) cell types using ICD-O-2 morphology codes.

Statistical Methods
The length of follow-up for each individual in the study was calculated as the time from completion of the baseline questionnaire until date of lung cancer diagnosis, date of death, or date of move from Iowa. If none of these occurred, the woman was assumed to be alive and living in Iowa through December 31, 1999. As of December 31, 1999, 625 (1.7%) were diagnosed with lung cancer; 4,755 (12.8%) died in Iowa; 85 (0.2%) died outside of Iowa; 1,741 (4.7%) moved out of Iowa; and 29,872 (80.6%) were alive and living in Iowa.

Each individual was classified according to smoking status: current (smoked at least 100 cigarettes in lifetime and currently smoking), former (smoked at least 100 cigarettes in lifetime and currently not smoking), and never (smoked fewer than 100 cigarettes in lifetime and currently not smoking). Former smokers were further classified according to years of smoking abstinence and pack-years of smoking (pack-years = total years of smoking multiplied by cigarette packs smoked per day).

Comparisons of the smoking-related characteristics of participants who developed various histologic cell types were performed with analysis of variance (ANOVA) and ² tests. For most analyses, squamous cell and small cell carcinomas were combined into one group because of sparse data. Multivariate Cox proportional hazards regression was used to calculate rate ratios representing relative risks (RRs) and 95% confidence intervals (CIs). Two sets of Cox regression analyses were performed: one comparing former smokers with never smokers (referent group) and one comparing former smokers with current smokers (referent group). For all Cox models, lung cancer incidence was modeled as a function of age.²⁹ Each model included the following potential confounding variables as covariates: physical activity level, education, body-mass index (BMI), waist circumference, alcohol, and fruit consumption.^30–32 Tests for trend of lung cancer risk by increasing years of abstinence were performed by ordering the categorical variable and including it in the model as a linear effect.

To assess the effect of smoking cessation during the follow-up period, we evaluated the changing patterns of lung cancer risk with respect to duration of abstinence before study baseline and incidence trends during follow-up. Three groups of smokers were examined in relation to never smokers: 1) distant former smokers, who stopped smoking more than 5 years before study baseline; 2) recent former smokers, who stopped smoking within 5 years of baseline; and 3) all baseline current smokers. All statistical tests were two-sided, and all analyses were carried out using the SAS (SAS Institute, Inc, Cary, NC) and Splus (Mathsoft, Inc, Seattle, WA) software systems.

	RESULTS

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Through 14 years and 470,111 person-years of follow-up, there were 625 lung cancer cases (250 adenocarcinoma, 121 small cell carcinoma, 119 squamous cell carcinoma, and 135 other/unspecified cell types) identified in the cohort at risk. Between 1986 and 1999, lung cancer incidence was 133 per 100,000 in the IWHS cohort and 170 per 100,000 in all women of Iowa in comparable age groups based on SEER data.

Comparing lung cancer cases with noncases among all subjects, the baseline mean ages were similar (Table 1). Among former smokers, lung cancer cases initiated smoking at a younger age, achieved smoking abstinence later in life, smoked a higher mean number of cigarettes per day, and had more years of cigarette use on average (compared with noncases; P < .001). Adenocarcinoma was the most common histologic cell type and accounted for 40% of all diagnosed lung cancers: 70% of the lung cancers among never smokers, 41% among the former smokers, and 32% among current smokers. Adenocarcinoma was the most common lung cancer cell type for all former smokers in the first, second, and third decade of time since smoking cessation. The relative frequency of adenocarcinoma of all lung cancer increased from 34% (35 of 103) in the first decade to 72% (13 of 18) in the third decade of smoking abstinence.

To evaluate the effect of smoking cessation on lung cancer during the 14-year follow-up, we compared RRs between two intervals; years 1 to 7 and years 8 to 14 after baseline (Table 3). A suggestive decline in relative risk (from 18.4 to 15.4; 16.3%) was observed among baseline current smokers, but a more profound effect of smoking cessation was observed among former smokers, particularly for recent former smokers. Differences in lung cancer risk reduction of recent former smokers and distant former smokers compared with current smokers are shown in Fig 1.

View larger version (20K): [in this window] [in a new window]   Fig 1. Relative risk of lung cancer among former smokers compared with current smokers, Iowa Women’s Health Study, 1986–1999. Age-adjusted risk estimates; relative risks (RRs) are 3-year moving averages.

	DISCUSSION

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Another possible explanation for the increased duration of risk could be that the former smokers relapsed to smoking. Only four lung cancer cases who were former smokers relapsed between baseline and lung cancer diagnosis. Excluding these subjects did not significantly change the results, confirming that smoking relapse is not influencing the observed prolonged duration of lung cancer risk. Furthermore, among the lung cancer cases, there were 70 current smokers at baseline who became abstinent during follow-up. We considered these former smokers as current smokers in the analysis and may, therefore, underestimate the lung cancer risk among former smokers.

Controversies exist with regard to the population effect of smoking cessation on lung cancer risk,^13,20,21,34 which appears to be dependent on study design and population. Conventional case-control¹ and cohort^6,7,9,13,14 studies have unequivocally observed decreased lung cancer burden with smoking cessation. However, negligible and even increased lung cancer mortality from smoking cessation has been observed from randomized controlled trials^15–17 and population- or community-based trials¹⁸ as well as from natural experiments.^20,21 In a natural experiment,^20,21 a population of smokers is considered an intervention group, a portion of which becomes smoking abstinent during the follow-up period, and never smokers are considered a control group. If a significant number of current smokers at baseline undergo smoking abstinence during the follow-up period, then one would observe the RR of current smokers to never smokers to converge toward unity.

We attempted to assess the population effect in our cohort by analyzing the follow-up data to assess whether baseline current smokers were achieving smoking abstinence during follow-up. Twenty-nine percent of the baseline current smokers who had sufficient data to answer the follow-up questionnaire in 1992 quit smoking. To correlate the rate of smoking cessation with the reduction of lung cancer risk in baseline current smokers relative to never smokers, we compared the RRs between 1986 and 1992 and 1993 and 1999 (Table 3). Although not statistically significant, we observed a 16% RR reduction in lung cancer. The discrepancy between the decline in smoking prevalence among baseline current smokers and the decline in lung cancer risk in this cohort could be explained by the following: 1) an overestimation of smoking cessation resulting from the increased likelihood of nonrespondents being continuing smokers and of quitters relapsing to smoking on later follow-up; 2) an underestimation of risk reduction resulting from the aging of the cohort; 3) baseline current smokers who quit during follow-up because of medical illness³⁵; 4) a follow-up time that was too short to observe the lung cancer risk reduction; and 5) limited lung cancer risk reduction because cohort subjects quit smoking during follow-up, creating a pool of recent quitters.

Previous research has shown that lung cancer risk reduction with smoking cessation is more consistent in squamous cell and small cell than with adenocarcinoma,^10,11 which we observed in this cohort. There was a nonsignificantly lower risk for adenocarcinoma but a significantly lower risk of squamous cell and small cell among former heavier smokers compared with current heavier smokers in the first 10 years of smoking abstinence. This observation is consistent with the theory that the smoking-induced pathologic changes leading to an increased risk for lung cancer are not reversed after smoking cessation to the same degree for adenocarcinoma as they are for squamous cell and small cell lung cancer.

We did not observe a consistent inverse relationship between the risk for adenocarcinoma in former smokers compared with never smokers with time since smoking cessation. This finding may be an artifact caused by the few number of cases of adenocarcinoma diagnosed in the third decade of smoking abstinence or may be influenced by other factors for adenocarcinoma among former female smokers, such as the consumption of filtered or "low tar" cigarettes. Researchers have postulated that one of the chief factors accounting for the persistently increased risk of adenocarcinoma of the lung after smoking cessation is the use of filters, which may result in deeper inhalation and prolonged breath holding to compensate for lower nicotine yields.^36–38 Deep inhalation may deposit smoke particles in the periphery of the lung, where most adenocarcinomas arise. In a study using nine population-based cancer registries, the rates of squamous cell carcinoma and adenocarcinoma along the airways corresponded closely with the deposition pattern of large and small smoke particles, with the smaller smoke particles distributing predominantly to the periphery.³⁹ Because adenocarcinoma tends to arise in the peripheral lung tissue, the clinical diagnosis may be delayed because they are less likely to cause airway obstruction and clinical symptoms such as hemoptysis.⁴⁰ Furthermore, the mean volume doubling time of adenocarcinoma is twice that of squamous cell carcinoma,⁴¹ and these tumors are more likely to arise in a smoking-induced diseased lung.⁴⁰ All of these factors may contribute to the prolonged duration of lung adenocarcinoma risk and the inconsistent risk decline after smoking cessation.

One of the potential limitations of this study relates to the lack of data on environmental tobacco smoke (ETS) exposure. This may result in an underestimation of the RR of lung cancer caused by tobacco smoke inasmuch as IWHS participants without a smoking history but with significant ETS have been classified as never smokers. This effect is likely to be small relative to the effect of mainstream smoke.

Another potential limitation relates to the differences between the responders and nonresponders in the cohort with regard to their smoking histories,²⁴ also known as the "healthy responders" effect.⁴² This phenomenon is reflected by an elevated disease risk in the early years of a prospective cohort study, which decreases with increasing duration of follow-up. During the first 5 years of follow-up in the IWHS cohort, Bisgard et al²⁴ reported a 40% higher lung cancer rate among nonresponders than among responders. During our 14 years of follow-up, lung cancer incidence was 28% lower (133 v 170 per 100,000) in the cohort than among Iowa women in the same age range. This effect should not change the internal validity of the study but could potentially influence the generalizability of our findings to other populations. In addition, our RR estimates of lung cancer risk using the entire cohort of women (N = 41,836) were similar to those of the analytic cohort after baseline exclusions, indicating that these exclusions did not bias our results by creating an artificially healthy cohort of women at baseline.

We confirm the declining risk of lung cancer among former smokers compared with never smokers in a cohort of older Midwestern females, but we observed that this excess lung cancer risk persisted up to 30 years. Health care providers need to continue to be aggressive about diagnosing and treating tobacco use disorders at all ages because the weight of all evidence indicates that smoking cessation decreases lung cancer risk. However, more resources may need to be focused on prevention of smoking initiation and chemoprevention of lung cancer because former smokers have significantly prolonged elevated risk of lung cancer after smoking cessation.

	ACKNOWLEDGMENTS

 
We thank Susan Ernst for her technical assistance with the manuscript.

	NOTES

 
Supported in part by grants CA92049, CA80127, CA84354, CA39741 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

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Submitted May 20, 2002; accepted November 13, 2002.

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