Lung Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI]

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Lung Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at or call 1-800-4-CANCER.

Lung Cancer Prevention

Summary of Evidence

Note: Separate PDQ summaries on Lung Cancer Screening; Small Cell Lung Cancer Treatment; Non-Small Cell Lung Cancer Treatment; and Prevention and Cessation of Cigarette Smoking: Control of Tobacco Use are also available.

Smoking Avoidance

Based on solid evidence, cigarette smoking causes lung cancer and therefore, smoking avoidance would result in decreased mortality from primary lung cancers.

Description of the Evidence

  • Study Design: Evidence obtained from a randomized controlled trial.
  • Internal Validity: Good.
  • Consistency: Good.
  • Magnitude of Effects on Health Outcomes: Decreased risk, large magnitude.
  • External Validity: Good.

Smoking Cessation

Based on solid evidence, long-term sustained smoking cessation results in decreased incidence of lung cancer and of second primary lung tumors.

Description of the Evidence

  • Study Design: Evidence obtained from case-control and cohort studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • Magnitude of Effects on Health Outcomes: Decreased risk, moderate magnitude.
  • External Validity: Good.

Beta Carotene

Based on solid evidence, high-intensity smokers who take pharmacological doses of beta carotene have an increased lung cancer incidence and mortality that is associated with taking the supplement.

Description of the Evidence

  • Study Design: Evidence obtained from randomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Good.
  • Magnitude of Effects on Health Outcomes: Increased risk, small magnitude.
  • External Validity: Good.

Radon Exposure

Based on solid evidence, exposure to radon increases lung cancer incidence and mortality.

Description of the Evidence

  • Study Design: Evidence obtained from case-control and cohort studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • Magnitude of Effects on Health Outcomes: Increased risk that follows a dose-response gradient, with small increases in risk for levels experienced in most at-risk homes.
  • External Validity: Fair.

Vitamin E/Tocopherol

Based on solid evidence, taking vitamin E supplements does not affect the risk of lung cancer.

Description of the Evidence

  • Study Design: Evidence obtained from four randomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Fair.
  • Magnitude of Effects on Health Outcomes: Strong evidence of no association.
  • External Validity: Good.


Incidence and Mortality

Lung cancer has a tremendous impact on U.S. mortality, with an estimated 221,130 new cases and 156,940 deaths in 2011 in men and women combined.[1] Lung cancer incidence and mortality rates increased markedly throughout most of the last century, first in men and then in women. The trends in lung cancer incidence and mortality rates have closely mirrored historical patterns of smoking prevalence, after accounting for an appropriate latency period. Because of historical differences in smoking prevalence between men and women, lung cancer rates in men have been consistently declining since 1990. The incidence rate in men declined from a high of 102.1 cases per 100,000 in 1984 to 71.8 cases in 2007. Consistent declines in women have not been seen.[1,2] In the United States, it is estimated that lung cancer will account for about 14% of new cancer cases and about 27% of all cancer deaths in 2011. Lung cancer is the leading cause of cancer deaths in both men and women. In 2011, it is estimated that 71,340 deaths will occur among U.S. women due to lung cancer, compared with 39,520 deaths due to breast cancer.[1]

Cigarette Smoking is the Primary Risk Factor

The epidemic of lung cancer in the 20th century was primarily due to increases in cigarette smoking, the predominant cause of lung cancer. The threefold variation in lung cancer mortality rates across the United States more or less parallels long-standing state-specific differences in the prevalence of cigarette smoking. For example, average annual age-adjusted lung cancer death rates for 1996 to 2000 were highest in Kentucky (78 per 100,000) where 31% were current smokers in 2001; whereas the lung cancer death rates were lowest in Utah (26 per 100,000), which had the lowest prevalence of cigarette smoking (13%).[3]

Surgical treatment or radiation therapy is the treatment of choice for early stages of cancer. Unfortunately, initial success with these modalities is overshadowed by the potential for long-term development of second primary tumors.[4] Therefore, new approaches for controlling lung cancer are being developed, including prevention strategies, such as cancer chemoprevention.

The Biology of Carcinogenesis

Understanding the biology of carcinogenesis is crucial to the development of effective chemoprevention . Two basic concepts supporting the chemoprevention approach are the multistep nature of carcinogenesis and the diffuse field-wide carcinogenic process. Epithelial cancers in the lung appear to develop in a predictable series of steps extending over years. Epithelial carcinogenesis is conceptually divided into three phases: initiation, promotion, and progression. This process has been inferred from human studies identifying clinical-histological premalignant lesions (e.g., metaplasia and dysplasia). The concept of field carcinogenesis is that multiple independent neoplastic lesions occurring within the lung can result from repeated exposure to carcinogens, primarily tobacco. Patients developing cancers of the aerodigestive tract secondary to cigarette smoke also are likely to have multiple premalignant lesions of independent origin within the carcinogen-exposed field. The concepts of multistep and field carcinogenesis provide a model for prevention studies.[5]


1. American Cancer Society.: Cancer Facts and Figures 2011. Atlanta, Ga: American Cancer Society, 2011. Also available online. Last accessed July 27, 2011.
2. Edwards BK, Brown ML, Wingo PA, et al.: Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 97 (19): 1407-27, 2005.
3. Weir HK, Thun MJ, Hankey BF, et al.: Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 95 (17): 1276-99, 2003.
4. Lippman SM, Hong WK: Not yet standard: retinoids versus second primary tumors. J Clin Oncol 11 (7): 1204-7, 1993.
5. Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin Oncol 12 (4): 851-73, 1994.

Evidence of Benefit

Smoking Cessation

The most important risk factor for lung cancer (and for many other cancers) is tobacco use.[1,2,3] Epidemiologic data have established that cigarette smoking is the predominant cause of lung cancer. This causative link has been widely recognized since the 1960s, when national reports in Great Britain and the United States brought the cancer risk of smoking prominently to the public's attention.[2] The percentages of lung cancers estimated to be caused by tobacco smoking in males and females are 90% and 78%, respectively. Cigar and pipe smoking also have been associated independently in case-control and cohort studies with increased lung cancer risk.[4,5] The cigar risks are of particular concern because of the recent increase in cigar use in the United States.[6]

Secondhand Tobacco Smoke

Secondhand tobacco smoke is also an established cause of lung cancer.[7] Secondhand smoke has the same components as inhaled mainstream smoke, though in lower absolute concentrations, between 1% and 10%, depending on the constituent. Carcinogenic compounds in tobacco smoke include the polynuclear aromatic hydrocarbons (PAHs), including the classical carcinogen benzo[a]pyrene (BaP), and the nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Elevated biomarkers of tobacco exposure, including urinary cotinine, urinary NNK metabolites, and carcinogen-protein adducts, are seen in passive smokers.[8,9,10]

The development of lung cancer is the culmination of multistep carcinogenesis. Genetic damage caused by chronic exposure to carcinogens (e.g., those in cigarette smoke) is the driving force behind the multistep process. Evidence of genetic damage is the association of cigarette smoking with the formation of the DNA adducts in human lung tissue. An unequivocal link between tobacco smoke and lung carcinogenesis has been established by molecular data.[11,12]

Other Environmental Causes of Lung Cancer

Several environmental exposures other than tobacco smoke are causally associated with lung cancer, but the proportion of the lung cancer burden due to these exposures is small compared with cigarette smoking. Many lung carcinogens have been identified in studies of high occupational exposures. Considered in total, occupational exposures have been estimated to account for approximately 10% of lung cancers.[13] These carcinogens include asbestos, radon, tar and soot (source of polycyclic aromatic hydrocarbons), arsenic, chromium, and nickel. For many of these workplace carcinogens, cigarette smoking interacts to synergistically increase the risk.[14] In developed countries, workplace exposures to these agents have largely been controlled.


Using epidemiologic evidence from uranium miners, the lifetime relative risk (RR) for residing in a home with U.S. Environmental Protection Agency action radon level of 4 pCi/L is estimated to be about 1.4 for smokers and 2.0 for nonsmokers.[15] The authors also estimated that 10% of all lung cancer deaths and 30% of lung cancer deaths in lifetime nonsmokers are attributable to indoor exposure to radon. Meta-analysis and pooled analyses of case-control studies of lung cancer and indoor radon exposure provide similar estimations of risk.[16,17]

Air pollution

Whereas early evidence from case-control and cohort studies was found wanting, more recently the evidence has solidified to the extent that it points toward a genuine association between air pollution and lung cancer.[18] In particular, two prospective cohort studies provide evidence to suggest that air pollution is weakly associated with the risk of lung cancer. In an extended follow-up of a study of six U.S. cities, the adjusted RR of lung cancer mortality for each 10 µg/m3 increase in concentration of fine-particulate was 1.27 (95% confidence interval [CI], 0.96–1.69).[19] Using data from the American Cancer Society's Cancer Prevention Study II, it was observed that compared with the least polluted areas, residence in areas with high sulfate concentrations was associated with an increased risk of lung cancer (adjusted RR = 1.4; 95% CI, 1.1–1.7) after adjustment for occupational exposures and the factors mentioned above.[20] In a subsequent update to this report, the risk of lung cancer was observed to increase 14% for each 10 µg/m3 increase in concentration of fine particles.[21]

Diet and Physical Activity

The results of case-control and prospective cohort studies show that individuals with high dietary intake of fruits or vegetables have a lower risk of lung cancer than those with low fruit or vegetable intake.[22] Evidence from cohort studies published since 2000 reinforces this notion.[23,24,25,26,27] In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a strong protective association was observed with fruit, but not vegetable, consumption.[28] A stronger protective association was observed for fruit compared with vegetable consumption in a pooled analysis of seven cohort studies.[29] While the focus has been on fruit and vegetable consumption and micronutrients, a wide range of dietary and anthropometric factors have been investigated. The results of a meta-analysis showed alcohol drinking in the highest consumption categories was associated with an increased risk of lung cancer.[30] Anthropometric measures have also been studied, indicating a tendency for leaner persons to have increased lung cancer risk relative to those with greater body mass index (BMI).[31,32] The overall evidence for physical activity has been mixed, but several studies have reported that more physically active individuals have a lower risk of lung cancer than those who are more sedentary,[33,34,35] even after adjustment for cigarette smoking.

Studies of modifiable lifestyle factors other than cigarette smoking have yielded intriguing findings, but the fact that these characteristics differ in smokers versus nonsmokers makes it challenging to separate the influence of these factors from the concomitant effects of smoking. At present, when considering the relationships between lung cancer and factors such as dietary habits, alcohol drinking, BMI, and physical activity, cigarette smoking cannot be dismissed as a possible explanation.

Smoking Prevention and Cessation

Substantial harm to the public health accrues from addiction to cigarette smoking. Compared with nonsmokers, smokers exhibit a dose-dependent increase in the risk of developing malignancies of the lung, head and neck, bladder, esophagus, kidney, pancreas, stomach, and cervix.[36,37] Conversely, substantial benefits accrue to the public health from smoking cessation. (Refer to the PDQ summary on Prevention and Cessation of Cigarette Smoking: Control of Tobacco Use for more information.) Avoidance of tobacco use is the most effective measure to prevent lung cancer. Evidence suggests that the preventive effect of smoking cessation depends upon the duration and intensity of prior smoking and upon time since cessation. Compared with persistent smokers, a 30% to 50% reduction in lung cancer mortality risk has been noted after 10 years of cessation.[1,37,38,39] One powerful indicator of the benefit of reduced tobacco consumption (due to both decreases in smoking initiation and increases in smoking cessation) is the decline in overall age-adjusted lung cancer mortality among men since the mid-1980s, which is consistent with reductions in smoking prevalence among men since the 1950s.[40] Declines in female lung cancer mortality now also are evident at ages younger than 60 years,[41] resulting in a decline in the overall lung cancer mortality rates among women. Gender differences in time trends for lung cancer are a reflection of (1) the later adoption of cigarette smoking and, (2) the later reduction in smoking prevalence among women compared to men.

Nicotine dependence exposes smokers in a dose-dependent fashion to carcinogenic and genotoxic elements that cause lung cancer.[38] Overcoming nicotine dependence is often extremely difficult. The Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research [AHCPR]) developed a set of clinical smoking-cessation guidelines for helping nicotine-dependent patients and healthcare providers.[39] The six major elements of the guidelines include:[38]

1.Clinicians must document the tobacco-use status of every patient.
2.Every patient using tobacco should be offered one or more of the effective smoking cessation treatments that are available.
3.Every patient using tobacco should be provided with at least one of the effective brief cessation interventions that are available.
4.More intense interventions are more effective than less intense interventions in producing long-term tobacco abstinence, reflecting the dose-response relationship between the intervention and its outcome.
5.One or more of the three treatment elements identified as being particularly effective should be included in smoking-cessation treatment:
1.Nicotine-replacement (e.g., nicotine patches and gum).
2.Social support from clinician in the form of encouragement and assistance.
3.Skills training/problem solving (cessation/abstinence techniques).
6.To be effective, health care systems must make institutional changes resulting in systematic identification of tobacco users and intervention with these patients at every visit.

Pharmacotherapies for smoking cessation, including nicotine replacement therapies (gum, patch, spray, lozenge, and inhaler) and antidepressant therapy (e.g., bupropion), result in statistically significant increases in smoking cessation rates compared with placebo. Since the AHCPR guidelines were published, additional evidence of the effectiveness of such pharmacotherapies for smoking cessation has been published.[42,43,44] The choice of therapy should be individualized based on a number of factors, including past experience, preference, and potential agent side effects.

In addition to individually focused cessation efforts, a number of efforts at the community, state, and national level have been credited with reducing the prevalence of smoking. These include: reducing minors' access to tobacco products, disseminating effective school-based prevention curricula together with media strategies, raising the cost of tobacco products, using tobacco excise taxes to fund community-level interventions including mass media, providing proven quitting strategies through health care organizations, and adopting smoke-free laws and policies.[41,45]

The Community Intervention Trial for Smoking Cessation (COMMIT) was a National Cancer Institute (NCI)-funded large-scale trial to assess a combination of community-based interventions designed to help smokers to quit smoking. COMMIT involved 11 matched pairs of communities in North America, which were randomly assigned to an arm offering an active community-wide intervention or a control arm (no active intervention).[46] The 4-year intervention included community psychology principles implemented through existing media channels, major community organizations, and social institutions capable of influencing smoking behavior in large groups of people. The interventions were implemented in each community through a local community board that provided oversight and management of COMMIT activities.

The results showed no reduction in the mean quit rate of heavy-smokers in the intervention communities compared with the control communities (18.0% vs. 18.7%, P = .68), but among light-to-moderate smokers the intervention communities did have slightly higher quit rates than the control communities (30.6% vs. 27.5%, P = .004).[47,48]

Although a measurable benefit was demonstrated for light-to-moderate smokers, the lack of benefit among heavy smokers indicates the community-based strategy alone was insufficient to have a marked impact on heavy smokers. A better strategy is needed to prevent initial smoking behavior and to treat highly dependent smokers.


Studies have examined whether it is possible to prevent cancer development in the lung and other aerodigestive tract sites using chemopreventive agents. Chemoprevention is defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy. Chemoprevention studies include efforts to control carcinogenic stages and risks in a population ranging from healthy individuals with no known risk factors to persons at high risk of developing cancer, such as patients cured of an initial cancer who are at elevated risk of developing another primary cancer.[49,50]

Chemoprevention is not yet established in standard clinical practice, but there is intensive study of this strategy for cancer prevention in the lung and other epithelial sites. Such studies have served to develop both human models for the study of chemoprevention and specific chemopreventive regimens.

The field-cancerization hypothesis in upper aerodigestive tract malignancy, which predicts diffuse epithelial injury as the result of inhaled carcinogens, has guided the development of these studies. Clinical evidence for field carcinogenesis is found in the occurrence of premalignant lesions and multiple primary tumors.[51,52] Molecular studies provide further evidence for multistep and field carcinogenesis in the lung.[11,12,50]

Reversal of Premalignancy

A chemoprevention trial using isotretinoin also employed histologic studies of bronchoscopic biopsies to examine the intermediate endpoint of squamous metaplasia.[53] This study included randomization to isotretinoin or placebo groups to confirm the activity reported in the earlier uncontrolled trial. A similar reduction in the extent of squamous metaplasia in 35 isotretinoin-treated patients (54.3%) and 34 placebo-treated patients (58.8%) was reported, indicating that isotretinoin at the given dose-schedule (1 mg/kg/day) had no impact on reversal of squamous metaplasia.

A similar conclusion was reached in a randomized trial of etretinate for the reversal of metaplasia read from sputum samples.[54] Of the 138 participants in this study who completed 6 months of treatment with etretinate (25 mg/day) or placebo, 32.4% of the 71 etretinate-treated patients and 29.8% of the 67 placebo-treated patients had improvement in sputum atypia.

In a placebo-controlled randomized lung cancer chemoprevention trial of beta carotene (50 mg/day) plus retinol (25,000 IU every other day) in approximately 750 U.S. male asbestos workers,[55] no difference was observed between the two study arms in the primary endpoint of prevalence of sputum atypia at a median intervention period of 58 months.

These trials have established that retinoids have minimal or no effect on metaplasia, but the response of metaplasia to smoking cessation and its spontaneous variability indicate that metaplasia may be one of the earliest stages in the carcinogenic process. Retinoids have shown activity in later stages of the carcinogenic process, and it is, therefore, possible that they are active in later stages of lung premalignancy.

Prevention of Second Primary Tumors

Other clinical evidence of field carcinogenesis is the occurrence of multiple primary tumors. High-dose retinyl palmitate (300,000 IU/day) was given (versus no treatment) in an adjuvant phase III trial following resection of stage I non-small cell lung cancer.[56] Although the improvement in disease-free survival for the retinyl palmitate group was not statistically significant, the retinyl palmitate group did show a statistically significant improvement in terms of time to new primary cancers within the aerodigestive field.

The lifetime risk of second primary tumors following early-stage lung cancer is 20% to 30%. This high rate allows second primary tumor chemoprevention trials to have smaller sample sizes than primary prevention trials.[49,51,56,57] A phase III trial to study the efficacy of low-dose isotretinoin (30 mg/day) to prevent second primary tumors following early-stage (I) non-small cell lung cancer is being conducted through the Oncology Intergroup involving all NCI Cooperative Oncology Groups. In this randomized, double-blind, placebo-controlled trial, 1,166 participants received 3 years of intervention (n = 589) or placebo (n = 577) and an additional 4 years of follow-up. The primary endpoint was time-to-second primary tumor (SPT), with secondary endpoints time to recurrence and overall survival. Compliance was 60% in the isotretinoin arm and 75% in the placebo arm. After a median follow-up of 3.5 years, no statistically significant differences were observed between the trial arms with respect to SPT (Cox model hazard ratio [HR] = 1.08; 95% CI, 0.78–1.49), recurrence (HR = 0.99; 95% CI, 0.76–1.29), or survival (HR = 1.07; 95% CI, 0.84–1.35). A secondary analysis of treatment-by-smoking interaction suggested that isotretinoin was harmful in current smokers and beneficial in nonsmokers. Statistically significant treatment-related toxic effects included cheilitis, skin dryness, conjunctivitis, and arthralgia.[57]

A European multicenter study, the Euroscan trial, is also studying the efficacy of chemoprevention following head and neck or lung cancer.[51] The Euroscan study consists of two parallel trials, one for each organ site, and is using a 2 x 2 factorial design to study the efficacy of retinyl palmitate and the antioxidant N-acetyl-cysteine.

Primary Chemoprevention

Two primary chemoprevention trials in lung cancer have studied individuals at increased risk for the development of lung cancer as the result of smoking or asbestos exposure.

Results of the NCI Alpha-Tocopherol Beta Carotene (ATBC) trial were first published in 1994.[58] This trial included 29,133 Finnish chronic male smokers aged 50 to 69 years in a 2 x 2 factorial design of alpha-tocopherol (50 mg/day) and beta carotene (20 mg/day). Subjects were randomly assigned to one of four groups: beta carotene alone, alpha-tocopherol alone, beta carotene plus alpha-tocopherol, or placebo for 5 to 8 years. Subjects receiving beta carotene (alone or with alpha-tocopherol) had a higher incidence of lung cancer (RR = 1.18; 95% CI, 1.03–1.36) and higher total mortality (RR = 1.08; 95% CI, 1.01–1.16). This effect appeared to be associated with heavier smoking (one or more packs/day) and alcohol intake (at least one drink/day).[59] Supplementation with alpha-tocopherol produced no overall effect on lung cancer (RR = 0.99; 95% CI, 0.87–1.13). Another study, using 600 IU of Vitamin E every other day, showed no effect on lung cancer in women.[60]

In 1996, the results of the U.S. Beta Carotene and Retinol Efficacy Trial (CARET) were published.[61] This multicenter trial involved 18,314 smokers, former smokers, and asbestos-exposed workers who were randomly assigned to beta carotene (at a higher dose than the ATBC, 30 mg/day) plus retinyl palmitate (25,000 IU/day) or placebo. The primary endpoint was lung cancer incidence. The trial was terminated early by the Data Monitoring Committee and NCI because its results confirmed the ATBC finding of a harmful effect of beta carotene over that of placebo, which increased lung cancer incidence (RR = 1.28; 95% CI, 1.04–1.57) and total mortality (RR = 1.17; 95% CI, 1.03–1.33). In a follow-up study of CARET participants after the intervention discontinued, these effects attenuated for a period of time. After 6 years of postintervention follow-up, the postintervention RR for lung cancer incidence was 1.12 (95% CI, 0.97–1.31) and for total mortality was 1.08 (95% CI, 0.99–1.71). During the postintervention phase a larger RR among women, rather than men, emerged for both outcomes in subgroup analyses; the reason for this observation, if it is reliable, is not known.[62]

Subgroup analyses from the CARET study suggested an association of excess lung cancer incidence in the active intervention group with the highest quartile of alcohol intake (especially large-cell histology).[63]

The overall findings from the ATBC [58,59] and CARET [61,63] studies, which include over 47,000 subjects, suggest that pharmacological doses of beta carotene increase lung cancer risk in relatively high-intensity smokers. The mechanism of this adverse effect is not known. Lung cancer risks were not increased in subsets of moderate-intensity smokers (less than a pack per day) in the ATBC study, or in former smokers in the CARET study. There is no evidence from other studies (including the Physicians' Health Study discussed below) [64] that beta carotene supplementation increases lung cancer risk in nonsmokers. Both studies found that higher baseline plasma beta carotene levels were associated with lower lung cancer rates (even after beta carotene supplementation). This finding is consistent with epidemiologic data which show that high intake of beta carotene-rich foods and high beta carotene plasma levels are associated with reduced lung cancer risk. A recent prospective cohort study of European men who smoked found an inverse relationship between fruit intake and lung cancer mortality, but the association was limited to heavy smokers.[65] Similarly, in a recent analysis of baseline questionnaire data from ATBC,[25] consumption of fruits and vegetables high in carotenoids (including those other than beta carotene) was associated with a lower risk of developing lung cancer during the 14 years of follow-up. These positive epidemiologic findings and the analysis of ATBC questionnaires, together with the adverse intervention results, suggest that the beneficial outcomes associated with high beta carotene plasma levels may be due to increased dietary intake of fruits and vegetables. These findings show the importance of randomized, prospective studies to confirm epidemiologic studies.

Multiple-Site Primary Prevention Trials

In the United States, the Physicians' Health Study was designed to study the effects of beta carotene and aspirin in cancer and cardiovascular disease. The study is a randomized, double-blind, placebo-controlled trial begun in 1982 involving 22,071 male physicians aged 40 to 84 years. The Physicians' Health Study, published in May 1996 with an average intervention and follow-up of 12 years, found no effect of beta carotene on overall risk of cancer (RR = 0.98) or of lung cancer among current (11% of study population) or former (39% of study population) smokers.[64]

In the Women's Health Study approximately 40,000 female health professionals were randomly assigned to 50 mg beta carotene on alternate days or placebo. After a median of 2.1 years of beta carotene treatment and 2 additional years of follow-up, there was no evidence that beta carotene protected against lung cancer, as there were more lung cancer cases observed in the beta carotene (n = 30) than placebo (n = 21) group.[66]

Randomized trials among cardiovascular disease patients have now accrued enough follow-up to report results for lung cancer. The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) is a randomized placebo-controlled trial to test antioxidant vitamin supplementation with vitamin E, vitamin C, and beta carotene among 20,536 United Kingdom adults with coronary disease, other occlusive arterial disease, or diabetes. The trial began recruitment in 1994, and as of the 2001 follow-up the results showed a slightly higher rate of lung cancer in the vitamin group compared with the placebo group (1.6% vs. 1.4%).[67] The Heart Outcomes Prevention Evaluation (HOPE) trial began in 1993 and continued follow-up as the HOPE-The Ongoing Outcomes (HOPE-TOO) through 2003. In this randomized placebo-controlled trial, patients 55 years or older with vascular disease or diabetes were assigned to 400 IU vitamin E or placebo. With a median follow-up of 7 years, the group randomly assigned to vitamin E had a significantly lower lung cancer incidence rate (1.4%) than the placebo group (2.0%) (RR = 0.72; 95% CI, 0.53–0.98).[68]

The protective association between vitamin E supplements and lung cancer in the HOPE-TOO study needs to be interpreted in the context of evidence from other randomized trials. In the ATBC study, supplementation with alpha-tocopherol produced no overall effect on lung cancer (RR = 0.99; 95% CI, 0.87–1.13). In the Women's Health Study of 40,000 female health professionals, using 600 IU of vitamin E every other day showed no evidence of protection against lung cancer in women (RR = 1.09; 95% CI, 0.83–1.44).[60] Looking at the vitamin E results for ATBC, HPS, and HOPE-TOO studies combined, the summary odds ratio was 0.97 (95% CI, 0.87–1.08),[68] and adding the results from the Women's Health Study to this would bring the association even closer to the null. The combined evidence for vitamin E supplementation thus continues to be consistent with no effect on lung cancer risk.


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