- Email: [email protected]
Prevention of Lung Cancer*
Prevention of Lung Cancer* Summary of Published Evidence Michael J. Kelley, MD; and Douglas C. McCrory, MD, MHS
Study objectives: To describe empiric research related to lung cancer prevention strategies, including chemoprevention aimed at reducing lung cancer incidence and various smoking avoidance and cessation interventions aimed at reducing smoking rates. Design, setting, and participants: Systematic searches of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies. For chemoprevention studies, we considered only randomized controlled trials (RCTs) with lung cancer incidence as an end point. For studies of smoking avoidance or cessation, we selected systematic reviews and meta-analyses, and searched for individual RCTs only where high-quality and current reviews and meta-analyses were not available. Measurement and results: Chemoprevention of lung cancer has been studied in five RCTs of primary prevention, no RCTs of secondary prevention, and five RCTs of tertiary prevention. None of these trials has shown evidence for efficacy of any agents tested, including retinol (vitamin A), -carotene, N-acetylcysteine, and selenium. There is a great deal of evidence about a wide variety of clinicianbased and community-based efforts at smoking avoidance or cessation. Certain approaches have been shown to be effective (eg, mass media public education campaigns, direct restrictions on smoking, clinician-based approaches ranging from brief clinician advice to more in-depth sessions, and “life-skills training” in schools). Some approaches have intermediate or short-term effectiveness (ie, youth access restrictions and school-based interventions), and others have been shown to be ineffective (ie, acupuncture and provider education) or have been insufficiently studied (ie, provider feedback). Conclusions: There are no agents that have been proven to be effective for preventing lung cancer. Several clinician-based and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention. (CHEST 2003; 123:50S–59S) Key words: carotenoids; chemoprevention; health education; lung neoplasms; primary prevention; smoking cessation; vitamin A Abbreviations: ATBC ⫽ ␣-Tocopherol -Carotene Lung Cancer Prevention Study; CARET ⫽ -Carotene and Retinol Efficacy Trial; CI ⫽ confidence interval; NSCLC ⫽ non-small cell lung cancer; RCT ⫽ randomized controlled trial; RR ⫽ relative risk
smoking is causally associated with the C igarette development of cancer of the lung, which is the leading cause of cancer mortality in the United States and worldwide. More Americans die of lung cancer each year than breast, prostate, and colon cancer combined.1 The battle to decrease lung cancer mortality has been waged on the following four fronts: (1) treatment of disease; (2) early detection; (3) chemoprevention; and (4) smoking avoidance and cessation. This article will focus on the latter two fronts. Chemoprevention is the use of specific natural or synthetic chemical agents to inhibit the development of *From the Department of Medicine, Duke University Medical Center, Durham, NC. This research was supported by a contract from the American College of Chest Physicians. Correspondence to: Michael J. Kelley, MD, Hematology/Oncology (111G), Durham VAMC, 508 Fulton St, Durham NC 27705; e-mail: [email protected] 50S
invasive cancer by blocking the DNA damage that initiates carcinogenesis or by reversing or arresting the progression of premalignant cells.2 Chemoprevention strategies can be applied to the prevention of lung cancer in those persons with known risk factors (primary chemoprevention), those persons with disease precursors (secondary chemoprevention), or those persons with a prior cancer that had been treated with curative intent (tertiary chemoprevention). As a strong and prevalent risk factor for lung cancer, tobacco smoking has been the target for the prevention of lung cancer and other smoking-related diseases.
Materials and Methods We searched for phase III studies of putative chemopreventive agents used for primary, secondary, or tertiary prevention in which the primary end point was lung cancer incidence. We Lung Cancer Guidelines
conducted computerized searches of the MEDLINE bibliographic database from 1966 to July 2001, the HealthStar database, and the Cochrane Library. We searched using the terms lung neoplasm, prevention and control and smoking, prevention and control, along with terms to identify randomized controlled trials (RCTs), systematic reviews, meta-analyses, and practice guidelines. In addition, we searched the reference lists of included studies, practice guidelines, systematic reviews, and metaanalyses. For chemoprevention studies, we considered only RCTs with lung cancer incidence as an end point. For studies of smoking avoidance or cessation, we selected systematic reviews and meta-analyses, and we searched for individual RCTs only where high-quality and current reviews and meta-analyses were not available.
Results Primary Chemoprevention Interventions Risk factors for the development of lung cancer include smoking cigarettes or other tobacco products, asbestos exposure, and radon exposure. Eight publications3–10 describing five RCTs of primary prevention aimed at reducing lung cancer incidence in subjects with one or more of these risk factors were identified (Table 1). Four of the studies targeted high-risk groups, while the Physicians’ Health Study6 targeted a group with lower than average risk of lung cancer. Although none of the interventions was shown to be effective at preventing lung cancer, the results were consistent in showing that -carotene, rather than reducing lung cancer incidence, was associated with increased lung cancer incidence. Statistically significant increases in lung cancer incidence in smokers receiving -carotene supplements were shown in the ␣-Tocopherol, -Carotene (ATBC) Lung Cancer Prevention Study3–5 and the -Carotene and Retinol Efficacy Trial (CARET).8,9 A similar trend was observed in a small study comparing -carotene and retinol (vitamin A) in asbestos workers,7 although the difference was not statistically significant. A closer examination of these studies is instructive for the design of future studies. The ATBC trial3–5 examined the effect of ␣-tocopherol (vitamin E) and -carotene on the incidence of lung cancer in 29,133 Finnish male smokers using a 2 ⫻ 2 factorial design. The selection of these agents was based almost exclusively on epidemiologic studies linking a vegetable-rich diet (high in -carotene and vitamin E) with a decrease in the risk of lung cancer.11 carotene and vitamin E have antioxidant properties in vitro. Subjects were recruited from 1985 to 1993 and took supplements (ie, ␣-tocopherol, 50 mg/d, and -carotene, 20 mg/d) for 5 to 8 years (mean, 6.1 years) for a total follow-up of 169,751 subject-years. No effect of ␣-tocopherol (vitamin E) on lung cancer incidence was observed (relative risk [RR], 0.98; www.chestjournal.org
95% confidence interval [CI], 0.86 to 1.12). However, in the -carotene arms, the RR of lung cancer incidence was 1.18 (95% CI, 1.03 to 1.36). This effect was most pronounced in those who persons who smoked ⱖ 20 cigarettes a day and in those with higher alcohol intake.5 The CARET study8,9 was a large two-arm study that was designed to compare the effects of a combination of -carotene and retinol to those of placebo on lung cancer incidence in subjects who were at high risk for the development of lung cancer. The rationale for the study was based on the results of observational epidemiologic studies that had demonstrated a statistically significantly decreased RR of lung cancer between the extreme quintiles or quartiles of dietary intake and serum levels of -carotene and vitamin A.11–13 In addition, vitamin A analogs were demonstrated to have potential utility in preventing cancer in animal models. A pilot study14 of 1,029 high-risk subjects (ie, those persons with ⱖ 20 pack-years of cigarette smoking who were currently smoking or had quit within the previous 6 years) demonstrated the safety and tolerability of carotene, 50 mg daily, retinol, 25,000 IU daily, and the combination of the two. The completed study enrolled a total of 18,314 subjects, including current and former smokers of both sexes and male asbestos workers (ie, those persons who had worked with asbestos at least 15 years prior to study enrollment who had evidence of asbestosis on chest radiogram), with a total of 73,135 person-years of follow-up and a mean length of follow-up of 4.0 years. The active intervention was continued throughout this period of time. A planned interim analysis demonstrated a statistically significantly increased RR for the development of lung cancer (RR, 1.28; 95% CI, 1.04 to 1.57), death from any cause (RR, 1.17; 95% CI, 1.03 to 1.33), and death from lung cancer (RR, 1.46; 95% CI, 1.07 to 2.00), resulting in early termination of the active intervention arm. It has been suggested15,16 that higher concentrations of -carotene resulting from supplementation may have pro-oxidant effects, inducing DNA damage and membrane instability. The Physicians’ Health Study6 was a randomized, double-blind, placebo-controlled trial of aspirin (325 mg every other day) and -carotene (50 mg every other day) conducted using a 2 ⫻ 2 factorial design among 22,071 male physicians in the United States. Only 11% of participants were current smokers and 39% were former smokers at study entry. The study began in 1982, and the aspirin arms were terminated in 1988 when a significant reduction in first myocardial infarction incidence was noted. The primary end points were cardiovascular disease and cancer incidence. An analysis of the cancer incidence in patients in the -carotene arms at the end of the CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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Table 1—RCTs Examining the Effect of Primary Chemoprevention Interventions on Lung Cancer Incidence* Study/Year ATBC3–5/1994
CARET8,9/1996
No. 29,133
18,314
Population Male smokers (Finland)
Smokers (64%); former smokers (34%); asbestos workers; age 45– 74 yr; men and women (except only male asbestos workers)
Intervention ␣-tocopherol, 50 mg/ d, ⫾ -carotene
Placebo ⫾ -carotene -carotene, 20 mg/ d, ⫾ ␣-tocopherol Placebo ⫾ ␣-tocopherol -carotene, 30 mg/d, and retinol 25,000 IU/d
End Point
Result
Lung cancer incidence
444 cases
0.98 (0.86–1.12)
450 cases 482 cases
1 1.18 (1.03–1.36)
Lung cancer incidence
Placebo Physicians’ Health Study6/2000
Women’s Health Study10/1999
Western 1998
Australia7/
22,071
39,876
1,024
Male physicians (US); 11% smokers
-carotene, 50 mg, ⫾ ASA, 325 mg every other day
Lung cancer incidence
Female health professionals; 45 yr of age
Placebo ⫾ ASA, 325 mg every other day -carotene, 50 All cancer mg, ⫾ ASA, 325 mg incidence every other day Placebo ⫾ ASA, 325 mg every other day -carotene, 50 Cancer deaths mg, ⫾ ASA, 325 mg every other day Placebo ⫾ ASA, 325 mg every other day -carotene, 50 mg Lung cancer qod, ⫾ ASA ⫾ incidence vitamin E
Asbestos workers
Placebo ⫾ ASA ⫾ vitamin E -carotene, 50 mg qod, ⫾ ASA ⫾ vitamin E Placebo ⫾ ASA ⫾ vitamin E -carotene, 50 mg qod, ⫾ ASA ⫾ vitamin E Placebo ⫾ ASA ⫾ vitamin E Retinol, 25,000 IU/d
-carotene, 30 mg/d Retinol, 25,000 IU/d -carotene, 30 mg/d Retinol, 25,000 IU/d -carotene, 30 mg/d
RR (95% CI)
412 cases 1 5.92/1,000 1.28 (1.04–1.57) person-yr
4.62/1,000 1 person-yr 85 cases 0.9 (0.7–1.2)
Comments Blinded; statistically significant increase in lung cancer incidence seen in the smokers receiving carotene
Blinded; statistically significant increase in relative risk of lung cancer in those receiving -carotene alone or in combination with retinol
Blinded; cancer incidence in the -carotene arms showed no difference in the incidence of total cancers, lung cancer, or any other cancer. No information on effect ASA as on lung cancer incidence
93 cases 1,314 cases
1.0 (0.9–1.0)
1,353 cases 414
1.0 (0.9–1.2)
Lung cancer incidence
1.43 (0.82–2.49)†
Blinded; -carotene arm terminated early due to results of ATBC and CARET studies, limiting ability of study to detect effect of -carotene on lung cancer incidence
406 30 cases
21 All cancer incidence
378
1.03 (0.89–1.18)
369 Cancer deaths
31
1.11 (0.67–1.85)
28 Lung cancer incidence
Mesothelioma incidence All-cause mortality
4 cases
0.66 (0.19–2.32)
6 cases 3 cases
0.24 (0.07–0.86)
12 cases 21 cases
0.56 (0.33–0.95)
No placebo; not blinded; 56 subjects crossed over (most from retinol group); no difference in lung cancer incidence, but malignant mesothelioma was significantly lower in the retinol group compared with the -carotene group
37 cases
*ASA ⫽ acetylsalicylic acid; ⫾ ⫽ with or without; qod ⫽ every other day. †Investigators in the Women’s Health Study employed a Cox proportional hazard model to calculate RR for lung cancer associated with -carotene vs placebo and reported that the results were not statistically significant. However, they did not report the actual values obtained for RR and 95% CI. The values given here were calculated by the authors of this article using the Cochran-Mantel-Haenszel 2 using the number of lung cancer cases and total number of patients in each treatment group. More precise methods would require data not published, such as individual patient data or person-years at risk for each treatment group. 52S
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study in 1995 showed no significant difference in the incidence of total cancers, lung cancer, or any other cancer. The study has not been analyzed for an effect of aspirin on lung cancer incidence.17 The Women’s Health Study10 randomized nearly 40,000 women who were at least 45 years of age in a 2 ⫻ 2 ⫻ 2 factorial design to measure the effect of -carotene, aspirin, and vitamin E on cancer and cardiovascular disease incidence. Thirteen percent of enrolled women were current smokers. Following the publication of other studies, the -carotene arm was closed. After supplementation for 2.1 years with -carotene and an additional median follow-up of 2.0 years (median total follow-up, 4.1 years), there was no difference in cancer incidence or death with respect to -carotene supplementation. There were 30 cases of lung cancer in the -carotene arms and 21 cases in the placebo arms (RR, 1.42; 95% CI, 0.88 to 2.49), a result that is not statistically significant. The early termination of the study limits the ability to detect a significant effect of the -carotene supplementation on lung cancer incidence or death from lung cancer. A South African study7 of 1,024 asbestos workers (92% male) randomly assigned subjects in equal proportions to either -carotene (30 mg/d) or retinol (25,000 IU/d) from 1990 to 1995. Twenty-one percent of participants were current smokers, and 52% were former smokers. After a median intervention and follow-up time of 4.5 years, no difference in lung cancer incidence was found (RR, 0.66; 95% CI, 0.19 to 2.32), although the small number of lung cancers (10) severely limited the power of this statement. The incidence of malignant mesothelioma was statistically significantly lower in the retinol group compared to the -carotene group (RR, 0.24; 95% CI, 0.07 to 0.86). No ongoing large-scale RCTs for the primary prevention of lung cancer in high-risk individuals were identified. The recently begun Selenium and Vitamin E Cancer Prevention Trial18 will examine the effect of selenium and vitamin E on lung cancer incidence as a secondary end point in low-risk men. Secondary Chemoprevention Interventions Persons with identifiable precursor lesions are appropriate for possible secondary prevention interventions. In lung cancer, there appears to be an orderly histologic progression of changes in the epithelium of the large airways from normal epithelium to metaplasia, increasing degrees of dysplasia, carcinoma in situ, and invasive squamous cell cancer.19 These histologic changes are more pronounced in the proximal than in the distal airways and are more common with increased cigarette www.chestjournal.org
usage, reaching their maximum in the airways uninvolved with lung cancer in patients who died of lung cancer.20,21 In addition, the frequency of carcinoma in situ increases with the number of cigarettes smoked per day and is highest in patients who died of lung cancer.22,23 Bronchial epithelial histologic changes can be identified in directed or blind endobronchial biopsy samples and as atypia in sputum samples. In the periphery of the lung, atypical adenomatous hyperplasia has been proposed as a precursor lesion of invasive adenocarcinoma,19 the most common histologic subtype of non-small cell lung cancer (NSCLC).24 Angiogenic squamous hyperplasia is a recognized lesion that also may be a malignant precursor.25 Neither of these latter morphologic lesions is frequently identified in nonsurgical biopsy specimens. We identified no RCTs of secondary prevention in subjects who had been selected for the presence of precursor lesions that used lung cancer incidence as an end point. At least five small randomized studies of secondary chemoprevention have been performed with retinoids, -carotene plus retinol, and the combination of vitamin B12 and folate administered for up to 6 months.26 However, all of these studies used either bronchial epithelial metaplasia or sputum atypia as a surrogate end point. None used lung cancer incidence as a primary or secondary end point. Tertiary Chemoprevention Interventions Patients with a previous incidence of cancer of the upper aerodigestive tract (ie, lung, head and neck, and esophagus) have the highest rate of development of lung cancer of any population. Patients who have undergone resection for early-stage NSCLC develop a second primary lung cancer at a rate of approximately 2% per subject per year.27 This population has been used to test chemoprevention strategies in five RCTs28 –32 that had primary end points of second primary cancer (of the lung) [Table 2]. Each of these studies was limited by the use of a clinicopathologic definition of the term second primary cancer. Molecular genetic analysis can assess more definitively the clonality of metachronous tumors of the upper aerodigestive tract.33 Two of the smallest studies suggest beneficial effects for retinoids (ie, oral isotretinoin)28 and retinyl palmitate29 in reducing second primary cancer incidence. The study by Hong et al28 was designed with a primary end point of primary tumor recurrence, and the observation of a reduction in second primary tumors was a secondary analysis. The interpretation of these studies from the perspective of lung cancer prevention is further complicated by the CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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Table 2—RCTs Examining the Effect of Tertiary Chemoprevention Interventions on Lung Cancer Incidence (Second Primary Tumor)* Study/Year
No.
Population
MD Anderson Cancer Center28/ 1990
103
Head and neck cancer
Istituto Nazionale Tumori29/1993
307
Stage I NSCLC status postresection
Lippman et al30/ 2001
1,166
Stage I NSCLC status postresection
EUROSCAN31/ 2000
2,592
Stage I–III head and neck cancer (60%) and lung (40%) cancer
Yale Study32/2001
264
Early-stage head and neck cancer
Intervention
End Point
Isotretinoin, 50–100 mg/m2/ d ⫻ 12 mo
Second primary tumor
Placebo Retinol palmitate, 300,000 IU/d ⫻ 12 mo
Any second primary cancer
Placebo Retinol palmitate, 300,000 UADTC second IU/d ⫻ 12 mo primary tumor Placebo Retinol palmitate, 300,000 Lung cancer IU/d ⫻ 12 mo incidence Placebo Isotretinoin, 30 mg/d ⫻ 3 yr All second primary tumor incidence Placebo Retinyl palmitate, 300,000 IU/d ⫻ 1 yr, then 150,000 IU/d ⫻ 1 yr
NAC, 600 mg/d ⫻ 2 yr Retinyl palmitate (as above) plus NAC (as above) Placebo -carotene, 50 mg/d
Placebo -carotene, 50 mg/d
Placebo -carotene, 50 mg/d Placebo
All second primary tumor incidence
Result
RR (95% CI) or p Value
Comments
2 cases
0.0005
Small study, but suggested beneficial effects from oral isotretinoin
12 cases 18 cases
0.09†
Small study, but suggested retinyl palmitate reduced second primary cancer incidence
29 cases 13 cases
0.045†
25 cases 11 21 4.2%/yr
3.9%/yr 54 cases
p value not reported 1.08 (0.78–1.42) Large study; showed no effect of isotretinoin on incidence of second primary cancers 0.174†
Large study; showed no effect of retinyl palmitate and/or Nacetylcysteine on second primary cancer incidence
61 cases 61
Lung cancer incidence
32 13 cases
9 Head and neck 33 cancer, recurrent or second primary 34 Second primary 17 tumor 14 cases
1.44 (0.62–3.39) Underpowered; stopped early due to results from other studies, but showed trend toward increase in lung cancer incidence in patients treated with carotene 0.9 (0.56–1.45)
1.20 (0.59–2.45)
*NAC ⫽ N-acetylcysteine; UADTC ⫽ urinary, airways, and digestive tract cancer. †By log rank test.
fact that a fraction of second primary tumors were of the head and neck. Furthermore, the results of subsequent large trials that were undertaken to confirm these results do not support this effect for isotretinoin30 or retinyl palmitate and/or N-acetylcysteine.31 A trial of -carotene (50 mg/d) vs placebo in patients with prior cancer of the head and neck was stopped early after the results of the ATBC and CARET studies were available.32 Similar to the primary prevention trials of -carotene, this trial showed a nonsignificant trend toward increased lung cancer incidence in patients who were treated with -carotene. A randomized trial of selenium in patients who 54S
had undergone resection for early-stage NSCLC was recently begun in North America.34 The basis for this study, as well as that for the ongoing Selenium and Vitamin E Cancer Prevention Trial18 mentioned earlier, includes observational studies showing lower serum levels of selenium in lung cancer patients compared with control subjects, antioxidant properties of selenium as essential cofactor for glutathione peroxidase, decreased cancer incidence following selenium supplementation in Linxian, China,35 and decreased lung cancer incidence in an RCT of selenium supplementation to prevent skin cancer.36 Tin miners in the Yunnan province of China have a high incidence of lung cancer (ie, ⬎ 1% per year). A Lung Cancer Guidelines
small (n ⫽ 40) blinded feasibility study37 in this population demonstrated that selenium supplementation with malt cakes was well-tolerated, increased serum and tissue levels of selenium, increased glutathione peroxidase levels, decreased lipid peroxide levels, and improved DNA repair in response to ultraviolet or benzo-a-pyrene damage. This population continues to be studied. Smoking Prevention (Primary Smoking Prevention) and Cessation (Secondary Smoking Prevention) An overwhelming body of evidence links cigarette smoking to lung cancer in a causative relationship. The cessation of smoking results in a slow decline in the risk of cancer development, but this risk remains elevated compared to never-smokers ⬎ 15 years after smoking cessation.38 The relative benefit of smoking cessation appears to be greater for those persons with shorter smoking histories.38,39 Thus, the prevention of smoking initiation among nonsmokers and the encouragement of smoking cessation among smokers lead to a decline in lung cancer incidence and mortality, which recently has been seen in states instituting aggressive antismoking campaigns. Statewide comprehensive tobacco control programs, which typically involve some mix of public education, print media campaigns, prevention of youth access to tobacco, restriction of advertising, creation of smokefree environments, work site antismoking programs, health professional training on cessation techniques, and school-based smoking prevention curricula including a “life-skills training” approach, have had the most success. A distinguishing feature of these comprehensive tobacco control programs is their focus on changing smoking behavior through strategies that alter the social environment where smoking occurs. Successful school-based programs have included interventions that teach social reinforcement (ie, dealing with peer pressure), social norms (ie, increasing self-esteem), and developmental orientation (ie, development of decision making and interpersonal skills).40 To determine whether community-based or clinician-based smoking prevention interventions are effective in reducing smoking, we sought to identify existing systematic reviews and meta-analyses to summarize an enormous body of literature. The following two major efforts have covered most of the available evidence on these topics: the US Public Health Service Tobacco Use and Dependence Clinical Practice Guideline41 and the Task Force on Community Preventive Services.42 Evidence for the effectiveness of clinician-based interventions has been described by the Tobacco Use and Dependence Clinical Practice Guideline panel, staff, and www.chestjournal.org
consortium representatives in two reports, the first published by Agency for Health Care Research and Quality in 1996,43 and the second, an update, by the US Department of Health and Human Services in 2000.41,44 The Task Force on Community Preventive Services focused on interventions intended to achieve tobacco use prevention and control in the general population but excluded interventions that targeted only high-risk individuals (eg, cessation interventions for smokers with coronary artery disease, cessation programs conducted entirely in hospital settings, or interventions to reduce exposure to environmental tobacco smoke in homes with asthmatic children). This task force reviewed interventions at the health-care system level (eg, provider education or provider performance feedback), but not interventions delivered by clinicians to patients in a clinical setting. Table 3 identifies, for each topic covered, the most up-to-date and complete systematic review. We describe the conclusions reached, the number of studies cited, and the quality of the supporting evidence according to the scale used by the Task Force on Community Preventive Services42 (ie, “strong,” “sufficient,” or “insufficient”). The systematic reviews, in turn, identify the individual studies cited and, in the case of Hopkins et al,42 provide detailed descriptions of each study in an appendix.
Discussion The relative rarity of lung cancer incidence in chemoprevention studies has limited the number of agents tested in definitive RCTs due to the cost and prolonged duration of studies. There are goodquality clinical studies demonstrating that the administration of -carotene alone or in combination with retinol to smokers increases the incidence of, and deaths from, lung cancer, and one study has shown that the administration of vitamin E to smokers has no effect on lung cancer incidence. In two adequately powered studies, no effect on second primary tumor incidence (primarily but not exclusively lung cancer) was observed with retinoids (ie, retinyl palmitate and isotretinoin), and in one study, no effect was seen with the administration of Nacetylcysteine. A trial of selenium supplementation to prevent second lung cancers is ongoing. There is a great deal of evidence about a wide variety of clinician-based and community-based efforts at smoking avoidance or cessation. Certain approaches have been shown to be effective (eg, mass media public education campaigns, direct restrictions on smoking, clinician-based approaches ranging from brief clinician advice to more in-depth CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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Table 3—Clinician-Based and Community-Based Interventions to Reduce Tobacco Exposure* Topic School-based interventions
Community interventions Education to reduce ETS in the home Workplace smoking cessation programs Statewide comprehensive tobacco control programs Mass media/public education Campaigns (brief recurring message) Cessation series
Existing Systematic Review/Year
Many experimental and quasi-experimental evaluations suggest that some programs resulted in a significant short-term reduction in smoking, delay in initiation, or change in attitudes toward tobacco use. Programs that used a “social influences” model tended to be the most effective, especially when enhanced by an extensive community-based education program. Long-term effects on deterrence of youth smoking are less certain. The recent Hutchinson Smoking Prevention Project,46 a randomized trial testing the social influences approach, found no longterm effect of an early school-based intervention (grades 3–10). Only one rigorously designed trial47 has shown an effect: a “life-skills training” approach with ongoing school consultation aimed at reducing tobacco, alcohol, and illegal drug use showed a positive effect on longterm smoking deterrence.
Hopkins et al42/2001
Ineffective in reducing infant ETS exposure (1 qualifying study, evidence is insufficient) Effective in increasing tobacco use cessation and reducing consumption of tobacco products. Inconsistent results (52 studies)
Eriksen and Gottlieb48/ 1998 Bibeau et al49/1988 Wakefield and Chaloupka50/2000
Hopkins et al42/2001 Hopkins et al42/2001
Advertising restrictions
None
Youth access restrictions
Lantz et al45/2000
Tobacco excise taxes; increasing unit price for tobacco products
Hopkins et al42/2001
Direct restrictions on smoking
Hopkins et al42/2001
Clinician-based approaches Identifying tobacco users
Assessment of willingness to quit
Advice to quit smoking Intensity of clinical interventions
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Summary/Conclusions
Lantz et al /2000 45
Eriksen and Gottlieb48/ 1998 Fiore et al44/2000
Inconsistent evidence of reducing teenage smoking prevalence (5 programs)
Effective in increasing tobacco use cessation and reducing consumption of tobacco products (15 studies, strong evidence) Inconsistent results and inadequate comparison groups (9 studies, evidence insufficient) Noted as “in progress” by the Task Force on Community Preventive Services. To be covered in future publication Can lead to a general reduction in illegal sales of cigarettes to minors; whether this will translate into reduced and sustained reductions in youth tobacco use is uncertain Effective in reducing tobacco use prevalence and consumption among both adolescents and young adults (8 studies, strong evidence). Increases tobacco use cessation and reduces consumption (17 studies, strong evidence) Effective in reducing exposure to ETS in workplace (9 studies, strong evidence) Effective in reducing cigarette consumption at work (9 studies); ineffective at increasing tobacco use cessation (14 studies) Implementing clinic systems designed to increase the assessment and documentation of tobacco use status markedly increases the rate at which clinicians intervene with their patients who smoke (9 studies, strong evidence); results in higher rates of smoking cessation (3 studies, sufficient evidence) Little consistent evidence that motivation to quit is useful for treatment matching. Tailored interventions based on specialized assessment (eg, stages of change) do not consistently produce higher long-term quit rates than nontailored interventions of equal intensity (sufficient evidence) Brief physician advice significantly increases long-term smoking abstinence rates (7 studies, strong evidence) Clinician-to-smoker advice delivered on four or more occasions is especially effective in increasing abstinence rates. Greater session length for clinician advice to quit was associated with greater abstinence rates from 3 to 90 min (35 studies, strong evidence)
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Table 3—Continued* Topic
Existing Systematic Review/Year
Type of clinician
Treatment delivered by a variety of clinician types increases abstinence rates (29 studies, strong evidence). Treatments delivered by multiple types of clinicians are more effective than interventions delivered by a single type of clinician (37 studies, sufficient evidence) Proactive telephone counseling, group counseling, and individual counseling formats are effective in increasing abstinence rates (58 studies, strong evidence). Use of multiple formats increases abstinence rates (54 studies, strong evidence) Three types of counseling and behavioral therapies result in higher abstinence rates: (1) practical counseling (problem solving skills/skills training); (2) social support as part of treatment; and (3) helping smokers obtain social support outside of treatment (62 studies, sufficient evidence) Aversive smoking interventions (rapid smoking, rapid puffing) increase abstinence rates (38 studies—sufficient evidence) No difference in abstinence rates (5 studies—insufficient evidence) Pharmacotherapy is effective in smoking cessation: bupropion SR (2 studies, strong evidence); nicotine gum (13 studies, strong evidence); nicotine inhaler (4 studies, strong evidence); nicotine nasal spray (3 studies, strong evidence); nicotine patch (27 studies, strong evidence); clonidine (5 studies); nortriptyline (2 studies, sufficient evidence); combination treatment (3 studies, sufficient evidence) Antidepressants other than bupropion SR and nortriptyline (no studies, insufficient evidence) Anxiolytics/benzodiazepines/beta-blockers (few studies, insufficient evidence) Silver acetate (2 studies, insufficient evidence) Mecamylamine (2 studies, insufficient evidence) Reduces the likelihood of relapse (multiple studies, strong evidence)
Format of psychosocial treatments
Type of counseling and behavioral therapies
Acupuncture Pharmacotherapy
Health-care system level interventions Provider reminder systems Provider education
Summary/Conclusions
Hopkins et al42/2001
Reminder plus education (multicomponent interventions) Provider feedback Reducing patient out-ofpocket cost for effective cessation therapies Patient telephone support
Increase provider delivery of advice to quit to tobacco-using patients (7 studies, sufficient evidence) Few studies evaluated effect on patient tobacco use cessation; inconsistent results on provider delivery of advice to quit (16 studies, insufficient evidence) Increase both provider delivery of advice to quit and patient tobacco use cessation (20 studies, strong evidence)
No studies assessed effect on provider delivery of advice to quit or patient tobacco use cessation (3 studies, insufficient evidence) Increases both use of effective therapy and patient tobacco use cessation (5 studies, sufficient evidence)
Increases tobacco use cessation when implemented with other interventions (32 studies, strong evidence)
*Includes interventions aimed at reducing environmental tobacco smoke exposure, decreasing tobacco use initiation, and increasing tobacco use cessation. ETS ⫽ environmental tobacco smoke.
sessions, and “life-skills training” in schools). Some approaches have intermediate or short-term effectiveness (ie, youth access restrictions, school-based interventions), and others have been shown to be ineffective (ie, acupuncture and provider education) or have been insufficiently studied (ie, provider feedback). Thus, although there has been little progress in chemoprevention, several clinician-based www.chestjournal.org
and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention. References 1 Greenlee RT, Hill-Harmon MB, Murray T, et al. Cancer statistics, 2001. CA Cancer J Clin 2001; 51:15–36 CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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2 Kelloff GJ, Sigman CC, Greenwald P. Cancer chemoprevention: progress and promise. Eur J Cancer 1999; 35:1755–1762 3 The ATBC Cancer Prevention Study Group. The alphatocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann Epidemiol 1994; 4:1–10 4 The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330:1029 –1035 5 Albanes D, Heinonen OP, Taylor PR, et al. AlphaTocopherol, and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996; 88:1560 –1570 6 Cook NR, Le IM, Manson JE, et al. Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians’ Health Study (United States). Cancer Causes Control 2000; 11:617– 626 7 de Klerk NH, Musk AW, Ambrosini GL, et al. Vitamin A, and cancer prevention: II. Comparison of the effects of retinol and beta-carotene. Int J Cancer 1998; 75:362–367 8 Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334:1150 – 1155 9 Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996; 88:1550 –1559 10 Lee IM, Cook NR, Manson JE, et al. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study. J Natl Cancer Inst 1999; 91:2102–2106 11 Peto R, Doll R, Buckley JD, et al. Can dietary beta-carotene materially reduce human cancer rates? Nature 1981; 290: 201–208 12 Steinmetz KA, Potter JD. Vegetables, fruit, and cancer: II. Mechanisms. Cancer Causes Control 1991; 2:427– 442 13 Omenn GS. What accounts for the association of vegetables and fruits with lower incidence of cancers and coronary heart disease? Ann Epidemiol 1995; 5:333–335 14 Goodman GE, Omenn GS, Thornquist MD, et al. The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers. Cancer Epidemiol Biomarkers Prev 1993; 2:389 – 396 15 Patrick L. Beta-carotene: the controversy continues. Altern Med Rev 2000; 5:530 –545 16 Lowe GM, Booth LA, Young AJ, et al. Lycopene and beta-carotene protect against oxidative damage in HT29 cells at low concentrations but rapidly lose this capacity at higher doses. Free Radic Res 1999; 30:141–151 17 Sturmer T, Glynn RJ, Lee IM, et al. Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study. Ann Intern Med 1998; 128:713–720 18 Klein EA, Thompson IM, Lippman SM, et al. SELECT the next prostate cancer prevention trial: Selenium and Vitamin E Cancer Prevention Trial. J Urol 2001; 166:1311–1315 19 Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol 2001; 54:257–271 20 Auerbach O, Gere JB, Forman JB, et al. Changes in the bronchial epithelium in relation to smoking and cancer of the lung. N Engl J Med 1957; 256:97–104 21 Auerbach O, Stout AP, Hammond EC, et al. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 1961; 265:253–267 58S
22 Jay SJ, Wehr K, Nicholson DP, et al. Diagnostic sensitivity and specificity of pulmonary cytology: comparison of techniques used in conjunction with flexible fiberoptic bronchoscopy. Acta Cytol 1980; 24:304 –312 23 Mao L, Lee JS, Kurie JM, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 1997; 89:857– 862 24 Devesa SS, Shaw GL, Blot WJ. Changing patterns of lung cancer incidence by histological type. Cancer Epidemiol Biomarkers Prev 1991; 1:29 –34 25 Keith RL, Miller YE, Gemmill RM, et al. Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer. Clin Cancer Res 2000; 6:1616 –1625 26 Khuri FR, Lippman SM. Lung cancer chemoprevention. Semin Surg Oncol 2000; 18:100 –105 27 Rosa UW, Prolla JC, Gastal Ed. Cytology in diagnosis of cancer affecting the lung: results in 1,000 consecutive patients. Chest 1973; 63:203–207 28 Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990; 323:795– 801 29 Pastorino U, Infante M, Maioli M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993; 11:1216 –1222 30 Lippman SM, Lee JJ, Karp DD, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 2001; 93:605– 618 31 van Zandwijk N, Dalesio O, Pastorino U, et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer: for the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 2000; 92:977–986 32 Mayne ST, Cartmel B, Baum M, et al. Randomized trial of supplemental beta-carotene to prevent second head and neck cancer. Cancer Res 2001; 61:1457–1463 33 Yang HK, Linnoila RI, Conrad NK, et al. TP53, and RAS mutations in metachronous tumors from patients with cancer of the upper aerodigestive tract. Int J Cancer 1995; 64:229 – 233 34 National Cancer Institute. Phase III randomized chemoprevention study of selenium in participant swith previously resected stage I non-small cell lung cancer (summary last modified September 2001); protocol IDs E-5597, NCI-P000176. Available at: http://www.cancer.gov/cancer_information/pdq/doc_cit.aspx?citationid⫽200_19869. Accessed December 16, 2002 35 Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/ mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993; 85:1483–1492 36 Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial; Nutritional Prevention of Cancer Study Group. JAMA 1996; 276:1957–1963 37 Hilton LW. The Robert Tiffany Lectureship: vital signs at the millennium; becoming more than we are. Cancer Nurs 1999; 22:6 –16 38 Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst 1993; 85:457– 464 39 Sobue T, Yamaguchi N, Suzuki T, et al. Lung cancer incidence rate for male ex-smokers according to age at cessation of smoking. Jpn J Cancer Res 1993; 84:601– 607 Lung Cancer Guidelines
40 Bruvold WH. A meta-analysis of adolescent smoking prevention programs. Am J Public Health 1993; 83:872– 880 41 The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives. A clinical practice guideline for treating tobacco use and dependence: a US Public Health Service report. JAMA 2000; 283:3244 – 3254 42 Hopkins DP, Briss PA, Ricard CJ, et al. Reviews of evidence regarding interventions to reduce tobacco use and exposure to environmental tobacco smoke. Am J Prev Med 2001; 20:16 – 66 43 Fiore MC, Bailey WC, Cohen SJ, et al. Smoking cessation: clinical practice guideline No. 18. Agency for Health Care Policy and Research Publication No. 96-0692. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1996 44 Fiore MC, Bailey WC, Cohen SJ, et al. Treating tobacco use and dependence. Agency for Health Care Policy and Research Publication No. 00-0032. Rockville, MD: US Department of
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Health and Human Services, Public Health Service, 2000. 45 Lantz PM, Jacobson PD, Warner KE, et al. Investing in youth tobacco control: a review of smoking prevention and control strategies. Tob Control 2000; 9:47– 63 46 Peterson AV Jr, Kealey KA, Mann SL, et al. Hutchinson Smoking Prevention Project: long-term randomized trial in school-based tobacco use prevention–results on smoking. J Natl Cancer Inst 2000; 92:1979 –1991 47 Botvin GJ, Baker E, Dusenbury L, et al. Long-term follow-up results of a randomized drug abuse prevention trial in a white middle class population. JAMA 1995; 273:1106 –1112 48 Eriksen MP, Gottlieb NH. A review of the health impact of smoking control at the workplace. Am J Health Promot 1998; 13:83–104 49 Bibeau DL, Mullen KD, McLeroy KR, et al. Evaluations of workplace smoking cessation programs: a critique. Am J Prev Med 1988; 4:87–95 50 Wakefield M, Chaloupka F. Effectiveness of comprehensive tobacco control programmes in reducing teenage smoking in the USA. Tob Control 2000; 9:177–186
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Study objectives: To describe empiric research related to lung cancer prevention strategies, including chemoprevention aimed at reducing lung cancer incidence and various smoking avoidance and cessation interventions aimed at reducing smoking rates. Design, setting, and participants: Systematic searches of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies. For chemoprevention studies, we considered only randomized controlled trials (RCTs) with lung cancer incidence as an end point. For studies of smoking avoidance or cessation, we selected systematic reviews and meta-analyses, and searched for individual RCTs only where high-quality and current reviews and meta-analyses were not available. Measurement and results: Chemoprevention of lung cancer has been studied in five RCTs of primary prevention, no RCTs of secondary prevention, and five RCTs of tertiary prevention. None of these trials has shown evidence for efficacy of any agents tested, including retinol (vitamin A), -carotene, N-acetylcysteine, and selenium. There is a great deal of evidence about a wide variety of clinicianbased and community-based efforts at smoking avoidance or cessation. Certain approaches have been shown to be effective (eg, mass media public education campaigns, direct restrictions on smoking, clinician-based approaches ranging from brief clinician advice to more in-depth sessions, and “life-skills training” in schools). Some approaches have intermediate or short-term effectiveness (ie, youth access restrictions and school-based interventions), and others have been shown to be ineffective (ie, acupuncture and provider education) or have been insufficiently studied (ie, provider feedback). Conclusions: There are no agents that have been proven to be effective for preventing lung cancer. Several clinician-based and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention. (CHEST 2003; 123:50S–59S) Key words: carotenoids; chemoprevention; health education; lung neoplasms; primary prevention; smoking cessation; vitamin A Abbreviations: ATBC ⫽ ␣-Tocopherol -Carotene Lung Cancer Prevention Study; CARET ⫽ -Carotene and Retinol Efficacy Trial; CI ⫽ confidence interval; NSCLC ⫽ non-small cell lung cancer; RCT ⫽ randomized controlled trial; RR ⫽ relative risk
smoking is causally associated with the C igarette development of cancer of the lung, which is the leading cause of cancer mortality in the United States and worldwide. More Americans die of lung cancer each year than breast, prostate, and colon cancer combined.1 The battle to decrease lung cancer mortality has been waged on the following four fronts: (1) treatment of disease; (2) early detection; (3) chemoprevention; and (4) smoking avoidance and cessation. This article will focus on the latter two fronts. Chemoprevention is the use of specific natural or synthetic chemical agents to inhibit the development of *From the Department of Medicine, Duke University Medical Center, Durham, NC. This research was supported by a contract from the American College of Chest Physicians. Correspondence to: Michael J. Kelley, MD, Hematology/Oncology (111G), Durham VAMC, 508 Fulton St, Durham NC 27705; e-mail: [email protected] 50S
invasive cancer by blocking the DNA damage that initiates carcinogenesis or by reversing or arresting the progression of premalignant cells.2 Chemoprevention strategies can be applied to the prevention of lung cancer in those persons with known risk factors (primary chemoprevention), those persons with disease precursors (secondary chemoprevention), or those persons with a prior cancer that had been treated with curative intent (tertiary chemoprevention). As a strong and prevalent risk factor for lung cancer, tobacco smoking has been the target for the prevention of lung cancer and other smoking-related diseases.
Materials and Methods We searched for phase III studies of putative chemopreventive agents used for primary, secondary, or tertiary prevention in which the primary end point was lung cancer incidence. We Lung Cancer Guidelines
conducted computerized searches of the MEDLINE bibliographic database from 1966 to July 2001, the HealthStar database, and the Cochrane Library. We searched using the terms lung neoplasm, prevention and control and smoking, prevention and control, along with terms to identify randomized controlled trials (RCTs), systematic reviews, meta-analyses, and practice guidelines. In addition, we searched the reference lists of included studies, practice guidelines, systematic reviews, and metaanalyses. For chemoprevention studies, we considered only RCTs with lung cancer incidence as an end point. For studies of smoking avoidance or cessation, we selected systematic reviews and meta-analyses, and we searched for individual RCTs only where high-quality and current reviews and meta-analyses were not available.
Results Primary Chemoprevention Interventions Risk factors for the development of lung cancer include smoking cigarettes or other tobacco products, asbestos exposure, and radon exposure. Eight publications3–10 describing five RCTs of primary prevention aimed at reducing lung cancer incidence in subjects with one or more of these risk factors were identified (Table 1). Four of the studies targeted high-risk groups, while the Physicians’ Health Study6 targeted a group with lower than average risk of lung cancer. Although none of the interventions was shown to be effective at preventing lung cancer, the results were consistent in showing that -carotene, rather than reducing lung cancer incidence, was associated with increased lung cancer incidence. Statistically significant increases in lung cancer incidence in smokers receiving -carotene supplements were shown in the ␣-Tocopherol, -Carotene (ATBC) Lung Cancer Prevention Study3–5 and the -Carotene and Retinol Efficacy Trial (CARET).8,9 A similar trend was observed in a small study comparing -carotene and retinol (vitamin A) in asbestos workers,7 although the difference was not statistically significant. A closer examination of these studies is instructive for the design of future studies. The ATBC trial3–5 examined the effect of ␣-tocopherol (vitamin E) and -carotene on the incidence of lung cancer in 29,133 Finnish male smokers using a 2 ⫻ 2 factorial design. The selection of these agents was based almost exclusively on epidemiologic studies linking a vegetable-rich diet (high in -carotene and vitamin E) with a decrease in the risk of lung cancer.11 carotene and vitamin E have antioxidant properties in vitro. Subjects were recruited from 1985 to 1993 and took supplements (ie, ␣-tocopherol, 50 mg/d, and -carotene, 20 mg/d) for 5 to 8 years (mean, 6.1 years) for a total follow-up of 169,751 subject-years. No effect of ␣-tocopherol (vitamin E) on lung cancer incidence was observed (relative risk [RR], 0.98; www.chestjournal.org
95% confidence interval [CI], 0.86 to 1.12). However, in the -carotene arms, the RR of lung cancer incidence was 1.18 (95% CI, 1.03 to 1.36). This effect was most pronounced in those who persons who smoked ⱖ 20 cigarettes a day and in those with higher alcohol intake.5 The CARET study8,9 was a large two-arm study that was designed to compare the effects of a combination of -carotene and retinol to those of placebo on lung cancer incidence in subjects who were at high risk for the development of lung cancer. The rationale for the study was based on the results of observational epidemiologic studies that had demonstrated a statistically significantly decreased RR of lung cancer between the extreme quintiles or quartiles of dietary intake and serum levels of -carotene and vitamin A.11–13 In addition, vitamin A analogs were demonstrated to have potential utility in preventing cancer in animal models. A pilot study14 of 1,029 high-risk subjects (ie, those persons with ⱖ 20 pack-years of cigarette smoking who were currently smoking or had quit within the previous 6 years) demonstrated the safety and tolerability of carotene, 50 mg daily, retinol, 25,000 IU daily, and the combination of the two. The completed study enrolled a total of 18,314 subjects, including current and former smokers of both sexes and male asbestos workers (ie, those persons who had worked with asbestos at least 15 years prior to study enrollment who had evidence of asbestosis on chest radiogram), with a total of 73,135 person-years of follow-up and a mean length of follow-up of 4.0 years. The active intervention was continued throughout this period of time. A planned interim analysis demonstrated a statistically significantly increased RR for the development of lung cancer (RR, 1.28; 95% CI, 1.04 to 1.57), death from any cause (RR, 1.17; 95% CI, 1.03 to 1.33), and death from lung cancer (RR, 1.46; 95% CI, 1.07 to 2.00), resulting in early termination of the active intervention arm. It has been suggested15,16 that higher concentrations of -carotene resulting from supplementation may have pro-oxidant effects, inducing DNA damage and membrane instability. The Physicians’ Health Study6 was a randomized, double-blind, placebo-controlled trial of aspirin (325 mg every other day) and -carotene (50 mg every other day) conducted using a 2 ⫻ 2 factorial design among 22,071 male physicians in the United States. Only 11% of participants were current smokers and 39% were former smokers at study entry. The study began in 1982, and the aspirin arms were terminated in 1988 when a significant reduction in first myocardial infarction incidence was noted. The primary end points were cardiovascular disease and cancer incidence. An analysis of the cancer incidence in patients in the -carotene arms at the end of the CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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Table 1—RCTs Examining the Effect of Primary Chemoprevention Interventions on Lung Cancer Incidence* Study/Year ATBC3–5/1994
CARET8,9/1996
No. 29,133
18,314
Population Male smokers (Finland)
Smokers (64%); former smokers (34%); asbestos workers; age 45– 74 yr; men and women (except only male asbestos workers)
Intervention ␣-tocopherol, 50 mg/ d, ⫾ -carotene
Placebo ⫾ -carotene -carotene, 20 mg/ d, ⫾ ␣-tocopherol Placebo ⫾ ␣-tocopherol -carotene, 30 mg/d, and retinol 25,000 IU/d
End Point
Result
Lung cancer incidence
444 cases
0.98 (0.86–1.12)
450 cases 482 cases
1 1.18 (1.03–1.36)
Lung cancer incidence
Placebo Physicians’ Health Study6/2000
Women’s Health Study10/1999
Western 1998
Australia7/
22,071
39,876
1,024
Male physicians (US); 11% smokers
-carotene, 50 mg, ⫾ ASA, 325 mg every other day
Lung cancer incidence
Female health professionals; 45 yr of age
Placebo ⫾ ASA, 325 mg every other day -carotene, 50 All cancer mg, ⫾ ASA, 325 mg incidence every other day Placebo ⫾ ASA, 325 mg every other day -carotene, 50 Cancer deaths mg, ⫾ ASA, 325 mg every other day Placebo ⫾ ASA, 325 mg every other day -carotene, 50 mg Lung cancer qod, ⫾ ASA ⫾ incidence vitamin E
Asbestos workers
Placebo ⫾ ASA ⫾ vitamin E -carotene, 50 mg qod, ⫾ ASA ⫾ vitamin E Placebo ⫾ ASA ⫾ vitamin E -carotene, 50 mg qod, ⫾ ASA ⫾ vitamin E Placebo ⫾ ASA ⫾ vitamin E Retinol, 25,000 IU/d
-carotene, 30 mg/d Retinol, 25,000 IU/d -carotene, 30 mg/d Retinol, 25,000 IU/d -carotene, 30 mg/d
RR (95% CI)
412 cases 1 5.92/1,000 1.28 (1.04–1.57) person-yr
4.62/1,000 1 person-yr 85 cases 0.9 (0.7–1.2)
Comments Blinded; statistically significant increase in lung cancer incidence seen in the smokers receiving carotene
Blinded; statistically significant increase in relative risk of lung cancer in those receiving -carotene alone or in combination with retinol
Blinded; cancer incidence in the -carotene arms showed no difference in the incidence of total cancers, lung cancer, or any other cancer. No information on effect ASA as on lung cancer incidence
93 cases 1,314 cases
1.0 (0.9–1.0)
1,353 cases 414
1.0 (0.9–1.2)
Lung cancer incidence
1.43 (0.82–2.49)†
Blinded; -carotene arm terminated early due to results of ATBC and CARET studies, limiting ability of study to detect effect of -carotene on lung cancer incidence
406 30 cases
21 All cancer incidence
378
1.03 (0.89–1.18)
369 Cancer deaths
31
1.11 (0.67–1.85)
28 Lung cancer incidence
Mesothelioma incidence All-cause mortality
4 cases
0.66 (0.19–2.32)
6 cases 3 cases
0.24 (0.07–0.86)
12 cases 21 cases
0.56 (0.33–0.95)
No placebo; not blinded; 56 subjects crossed over (most from retinol group); no difference in lung cancer incidence, but malignant mesothelioma was significantly lower in the retinol group compared with the -carotene group
37 cases
*ASA ⫽ acetylsalicylic acid; ⫾ ⫽ with or without; qod ⫽ every other day. †Investigators in the Women’s Health Study employed a Cox proportional hazard model to calculate RR for lung cancer associated with -carotene vs placebo and reported that the results were not statistically significant. However, they did not report the actual values obtained for RR and 95% CI. The values given here were calculated by the authors of this article using the Cochran-Mantel-Haenszel 2 using the number of lung cancer cases and total number of patients in each treatment group. More precise methods would require data not published, such as individual patient data or person-years at risk for each treatment group. 52S
Lung Cancer Guidelines
study in 1995 showed no significant difference in the incidence of total cancers, lung cancer, or any other cancer. The study has not been analyzed for an effect of aspirin on lung cancer incidence.17 The Women’s Health Study10 randomized nearly 40,000 women who were at least 45 years of age in a 2 ⫻ 2 ⫻ 2 factorial design to measure the effect of -carotene, aspirin, and vitamin E on cancer and cardiovascular disease incidence. Thirteen percent of enrolled women were current smokers. Following the publication of other studies, the -carotene arm was closed. After supplementation for 2.1 years with -carotene and an additional median follow-up of 2.0 years (median total follow-up, 4.1 years), there was no difference in cancer incidence or death with respect to -carotene supplementation. There were 30 cases of lung cancer in the -carotene arms and 21 cases in the placebo arms (RR, 1.42; 95% CI, 0.88 to 2.49), a result that is not statistically significant. The early termination of the study limits the ability to detect a significant effect of the -carotene supplementation on lung cancer incidence or death from lung cancer. A South African study7 of 1,024 asbestos workers (92% male) randomly assigned subjects in equal proportions to either -carotene (30 mg/d) or retinol (25,000 IU/d) from 1990 to 1995. Twenty-one percent of participants were current smokers, and 52% were former smokers. After a median intervention and follow-up time of 4.5 years, no difference in lung cancer incidence was found (RR, 0.66; 95% CI, 0.19 to 2.32), although the small number of lung cancers (10) severely limited the power of this statement. The incidence of malignant mesothelioma was statistically significantly lower in the retinol group compared to the -carotene group (RR, 0.24; 95% CI, 0.07 to 0.86). No ongoing large-scale RCTs for the primary prevention of lung cancer in high-risk individuals were identified. The recently begun Selenium and Vitamin E Cancer Prevention Trial18 will examine the effect of selenium and vitamin E on lung cancer incidence as a secondary end point in low-risk men. Secondary Chemoprevention Interventions Persons with identifiable precursor lesions are appropriate for possible secondary prevention interventions. In lung cancer, there appears to be an orderly histologic progression of changes in the epithelium of the large airways from normal epithelium to metaplasia, increasing degrees of dysplasia, carcinoma in situ, and invasive squamous cell cancer.19 These histologic changes are more pronounced in the proximal than in the distal airways and are more common with increased cigarette www.chestjournal.org
usage, reaching their maximum in the airways uninvolved with lung cancer in patients who died of lung cancer.20,21 In addition, the frequency of carcinoma in situ increases with the number of cigarettes smoked per day and is highest in patients who died of lung cancer.22,23 Bronchial epithelial histologic changes can be identified in directed or blind endobronchial biopsy samples and as atypia in sputum samples. In the periphery of the lung, atypical adenomatous hyperplasia has been proposed as a precursor lesion of invasive adenocarcinoma,19 the most common histologic subtype of non-small cell lung cancer (NSCLC).24 Angiogenic squamous hyperplasia is a recognized lesion that also may be a malignant precursor.25 Neither of these latter morphologic lesions is frequently identified in nonsurgical biopsy specimens. We identified no RCTs of secondary prevention in subjects who had been selected for the presence of precursor lesions that used lung cancer incidence as an end point. At least five small randomized studies of secondary chemoprevention have been performed with retinoids, -carotene plus retinol, and the combination of vitamin B12 and folate administered for up to 6 months.26 However, all of these studies used either bronchial epithelial metaplasia or sputum atypia as a surrogate end point. None used lung cancer incidence as a primary or secondary end point. Tertiary Chemoprevention Interventions Patients with a previous incidence of cancer of the upper aerodigestive tract (ie, lung, head and neck, and esophagus) have the highest rate of development of lung cancer of any population. Patients who have undergone resection for early-stage NSCLC develop a second primary lung cancer at a rate of approximately 2% per subject per year.27 This population has been used to test chemoprevention strategies in five RCTs28 –32 that had primary end points of second primary cancer (of the lung) [Table 2]. Each of these studies was limited by the use of a clinicopathologic definition of the term second primary cancer. Molecular genetic analysis can assess more definitively the clonality of metachronous tumors of the upper aerodigestive tract.33 Two of the smallest studies suggest beneficial effects for retinoids (ie, oral isotretinoin)28 and retinyl palmitate29 in reducing second primary cancer incidence. The study by Hong et al28 was designed with a primary end point of primary tumor recurrence, and the observation of a reduction in second primary tumors was a secondary analysis. The interpretation of these studies from the perspective of lung cancer prevention is further complicated by the CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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Table 2—RCTs Examining the Effect of Tertiary Chemoprevention Interventions on Lung Cancer Incidence (Second Primary Tumor)* Study/Year
No.
Population
MD Anderson Cancer Center28/ 1990
103
Head and neck cancer
Istituto Nazionale Tumori29/1993
307
Stage I NSCLC status postresection
Lippman et al30/ 2001
1,166
Stage I NSCLC status postresection
EUROSCAN31/ 2000
2,592
Stage I–III head and neck cancer (60%) and lung (40%) cancer
Yale Study32/2001
264
Early-stage head and neck cancer
Intervention
End Point
Isotretinoin, 50–100 mg/m2/ d ⫻ 12 mo
Second primary tumor
Placebo Retinol palmitate, 300,000 IU/d ⫻ 12 mo
Any second primary cancer
Placebo Retinol palmitate, 300,000 UADTC second IU/d ⫻ 12 mo primary tumor Placebo Retinol palmitate, 300,000 Lung cancer IU/d ⫻ 12 mo incidence Placebo Isotretinoin, 30 mg/d ⫻ 3 yr All second primary tumor incidence Placebo Retinyl palmitate, 300,000 IU/d ⫻ 1 yr, then 150,000 IU/d ⫻ 1 yr
NAC, 600 mg/d ⫻ 2 yr Retinyl palmitate (as above) plus NAC (as above) Placebo -carotene, 50 mg/d
Placebo -carotene, 50 mg/d
Placebo -carotene, 50 mg/d Placebo
All second primary tumor incidence
Result
RR (95% CI) or p Value
Comments
2 cases
0.0005
Small study, but suggested beneficial effects from oral isotretinoin
12 cases 18 cases
0.09†
Small study, but suggested retinyl palmitate reduced second primary cancer incidence
29 cases 13 cases
0.045†
25 cases 11 21 4.2%/yr
3.9%/yr 54 cases
p value not reported 1.08 (0.78–1.42) Large study; showed no effect of isotretinoin on incidence of second primary cancers 0.174†
Large study; showed no effect of retinyl palmitate and/or Nacetylcysteine on second primary cancer incidence
61 cases 61
Lung cancer incidence
32 13 cases
9 Head and neck 33 cancer, recurrent or second primary 34 Second primary 17 tumor 14 cases
1.44 (0.62–3.39) Underpowered; stopped early due to results from other studies, but showed trend toward increase in lung cancer incidence in patients treated with carotene 0.9 (0.56–1.45)
1.20 (0.59–2.45)
*NAC ⫽ N-acetylcysteine; UADTC ⫽ urinary, airways, and digestive tract cancer. †By log rank test.
fact that a fraction of second primary tumors were of the head and neck. Furthermore, the results of subsequent large trials that were undertaken to confirm these results do not support this effect for isotretinoin30 or retinyl palmitate and/or N-acetylcysteine.31 A trial of -carotene (50 mg/d) vs placebo in patients with prior cancer of the head and neck was stopped early after the results of the ATBC and CARET studies were available.32 Similar to the primary prevention trials of -carotene, this trial showed a nonsignificant trend toward increased lung cancer incidence in patients who were treated with -carotene. A randomized trial of selenium in patients who 54S
had undergone resection for early-stage NSCLC was recently begun in North America.34 The basis for this study, as well as that for the ongoing Selenium and Vitamin E Cancer Prevention Trial18 mentioned earlier, includes observational studies showing lower serum levels of selenium in lung cancer patients compared with control subjects, antioxidant properties of selenium as essential cofactor for glutathione peroxidase, decreased cancer incidence following selenium supplementation in Linxian, China,35 and decreased lung cancer incidence in an RCT of selenium supplementation to prevent skin cancer.36 Tin miners in the Yunnan province of China have a high incidence of lung cancer (ie, ⬎ 1% per year). A Lung Cancer Guidelines
small (n ⫽ 40) blinded feasibility study37 in this population demonstrated that selenium supplementation with malt cakes was well-tolerated, increased serum and tissue levels of selenium, increased glutathione peroxidase levels, decreased lipid peroxide levels, and improved DNA repair in response to ultraviolet or benzo-a-pyrene damage. This population continues to be studied. Smoking Prevention (Primary Smoking Prevention) and Cessation (Secondary Smoking Prevention) An overwhelming body of evidence links cigarette smoking to lung cancer in a causative relationship. The cessation of smoking results in a slow decline in the risk of cancer development, but this risk remains elevated compared to never-smokers ⬎ 15 years after smoking cessation.38 The relative benefit of smoking cessation appears to be greater for those persons with shorter smoking histories.38,39 Thus, the prevention of smoking initiation among nonsmokers and the encouragement of smoking cessation among smokers lead to a decline in lung cancer incidence and mortality, which recently has been seen in states instituting aggressive antismoking campaigns. Statewide comprehensive tobacco control programs, which typically involve some mix of public education, print media campaigns, prevention of youth access to tobacco, restriction of advertising, creation of smokefree environments, work site antismoking programs, health professional training on cessation techniques, and school-based smoking prevention curricula including a “life-skills training” approach, have had the most success. A distinguishing feature of these comprehensive tobacco control programs is their focus on changing smoking behavior through strategies that alter the social environment where smoking occurs. Successful school-based programs have included interventions that teach social reinforcement (ie, dealing with peer pressure), social norms (ie, increasing self-esteem), and developmental orientation (ie, development of decision making and interpersonal skills).40 To determine whether community-based or clinician-based smoking prevention interventions are effective in reducing smoking, we sought to identify existing systematic reviews and meta-analyses to summarize an enormous body of literature. The following two major efforts have covered most of the available evidence on these topics: the US Public Health Service Tobacco Use and Dependence Clinical Practice Guideline41 and the Task Force on Community Preventive Services.42 Evidence for the effectiveness of clinician-based interventions has been described by the Tobacco Use and Dependence Clinical Practice Guideline panel, staff, and www.chestjournal.org
consortium representatives in two reports, the first published by Agency for Health Care Research and Quality in 1996,43 and the second, an update, by the US Department of Health and Human Services in 2000.41,44 The Task Force on Community Preventive Services focused on interventions intended to achieve tobacco use prevention and control in the general population but excluded interventions that targeted only high-risk individuals (eg, cessation interventions for smokers with coronary artery disease, cessation programs conducted entirely in hospital settings, or interventions to reduce exposure to environmental tobacco smoke in homes with asthmatic children). This task force reviewed interventions at the health-care system level (eg, provider education or provider performance feedback), but not interventions delivered by clinicians to patients in a clinical setting. Table 3 identifies, for each topic covered, the most up-to-date and complete systematic review. We describe the conclusions reached, the number of studies cited, and the quality of the supporting evidence according to the scale used by the Task Force on Community Preventive Services42 (ie, “strong,” “sufficient,” or “insufficient”). The systematic reviews, in turn, identify the individual studies cited and, in the case of Hopkins et al,42 provide detailed descriptions of each study in an appendix.
Discussion The relative rarity of lung cancer incidence in chemoprevention studies has limited the number of agents tested in definitive RCTs due to the cost and prolonged duration of studies. There are goodquality clinical studies demonstrating that the administration of -carotene alone or in combination with retinol to smokers increases the incidence of, and deaths from, lung cancer, and one study has shown that the administration of vitamin E to smokers has no effect on lung cancer incidence. In two adequately powered studies, no effect on second primary tumor incidence (primarily but not exclusively lung cancer) was observed with retinoids (ie, retinyl palmitate and isotretinoin), and in one study, no effect was seen with the administration of Nacetylcysteine. A trial of selenium supplementation to prevent second lung cancers is ongoing. There is a great deal of evidence about a wide variety of clinician-based and community-based efforts at smoking avoidance or cessation. Certain approaches have been shown to be effective (eg, mass media public education campaigns, direct restrictions on smoking, clinician-based approaches ranging from brief clinician advice to more in-depth CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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Table 3—Clinician-Based and Community-Based Interventions to Reduce Tobacco Exposure* Topic School-based interventions
Community interventions Education to reduce ETS in the home Workplace smoking cessation programs Statewide comprehensive tobacco control programs Mass media/public education Campaigns (brief recurring message) Cessation series
Existing Systematic Review/Year
Many experimental and quasi-experimental evaluations suggest that some programs resulted in a significant short-term reduction in smoking, delay in initiation, or change in attitudes toward tobacco use. Programs that used a “social influences” model tended to be the most effective, especially when enhanced by an extensive community-based education program. Long-term effects on deterrence of youth smoking are less certain. The recent Hutchinson Smoking Prevention Project,46 a randomized trial testing the social influences approach, found no longterm effect of an early school-based intervention (grades 3–10). Only one rigorously designed trial47 has shown an effect: a “life-skills training” approach with ongoing school consultation aimed at reducing tobacco, alcohol, and illegal drug use showed a positive effect on longterm smoking deterrence.
Hopkins et al42/2001
Ineffective in reducing infant ETS exposure (1 qualifying study, evidence is insufficient) Effective in increasing tobacco use cessation and reducing consumption of tobacco products. Inconsistent results (52 studies)
Eriksen and Gottlieb48/ 1998 Bibeau et al49/1988 Wakefield and Chaloupka50/2000
Hopkins et al42/2001 Hopkins et al42/2001
Advertising restrictions
None
Youth access restrictions
Lantz et al45/2000
Tobacco excise taxes; increasing unit price for tobacco products
Hopkins et al42/2001
Direct restrictions on smoking
Hopkins et al42/2001
Clinician-based approaches Identifying tobacco users
Assessment of willingness to quit
Advice to quit smoking Intensity of clinical interventions
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Summary/Conclusions
Lantz et al /2000 45
Eriksen and Gottlieb48/ 1998 Fiore et al44/2000
Inconsistent evidence of reducing teenage smoking prevalence (5 programs)
Effective in increasing tobacco use cessation and reducing consumption of tobacco products (15 studies, strong evidence) Inconsistent results and inadequate comparison groups (9 studies, evidence insufficient) Noted as “in progress” by the Task Force on Community Preventive Services. To be covered in future publication Can lead to a general reduction in illegal sales of cigarettes to minors; whether this will translate into reduced and sustained reductions in youth tobacco use is uncertain Effective in reducing tobacco use prevalence and consumption among both adolescents and young adults (8 studies, strong evidence). Increases tobacco use cessation and reduces consumption (17 studies, strong evidence) Effective in reducing exposure to ETS in workplace (9 studies, strong evidence) Effective in reducing cigarette consumption at work (9 studies); ineffective at increasing tobacco use cessation (14 studies) Implementing clinic systems designed to increase the assessment and documentation of tobacco use status markedly increases the rate at which clinicians intervene with their patients who smoke (9 studies, strong evidence); results in higher rates of smoking cessation (3 studies, sufficient evidence) Little consistent evidence that motivation to quit is useful for treatment matching. Tailored interventions based on specialized assessment (eg, stages of change) do not consistently produce higher long-term quit rates than nontailored interventions of equal intensity (sufficient evidence) Brief physician advice significantly increases long-term smoking abstinence rates (7 studies, strong evidence) Clinician-to-smoker advice delivered on four or more occasions is especially effective in increasing abstinence rates. Greater session length for clinician advice to quit was associated with greater abstinence rates from 3 to 90 min (35 studies, strong evidence)
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Table 3—Continued* Topic
Existing Systematic Review/Year
Type of clinician
Treatment delivered by a variety of clinician types increases abstinence rates (29 studies, strong evidence). Treatments delivered by multiple types of clinicians are more effective than interventions delivered by a single type of clinician (37 studies, sufficient evidence) Proactive telephone counseling, group counseling, and individual counseling formats are effective in increasing abstinence rates (58 studies, strong evidence). Use of multiple formats increases abstinence rates (54 studies, strong evidence) Three types of counseling and behavioral therapies result in higher abstinence rates: (1) practical counseling (problem solving skills/skills training); (2) social support as part of treatment; and (3) helping smokers obtain social support outside of treatment (62 studies, sufficient evidence) Aversive smoking interventions (rapid smoking, rapid puffing) increase abstinence rates (38 studies—sufficient evidence) No difference in abstinence rates (5 studies—insufficient evidence) Pharmacotherapy is effective in smoking cessation: bupropion SR (2 studies, strong evidence); nicotine gum (13 studies, strong evidence); nicotine inhaler (4 studies, strong evidence); nicotine nasal spray (3 studies, strong evidence); nicotine patch (27 studies, strong evidence); clonidine (5 studies); nortriptyline (2 studies, sufficient evidence); combination treatment (3 studies, sufficient evidence) Antidepressants other than bupropion SR and nortriptyline (no studies, insufficient evidence) Anxiolytics/benzodiazepines/beta-blockers (few studies, insufficient evidence) Silver acetate (2 studies, insufficient evidence) Mecamylamine (2 studies, insufficient evidence) Reduces the likelihood of relapse (multiple studies, strong evidence)
Format of psychosocial treatments
Type of counseling and behavioral therapies
Acupuncture Pharmacotherapy
Health-care system level interventions Provider reminder systems Provider education
Summary/Conclusions
Hopkins et al42/2001
Reminder plus education (multicomponent interventions) Provider feedback Reducing patient out-ofpocket cost for effective cessation therapies Patient telephone support
Increase provider delivery of advice to quit to tobacco-using patients (7 studies, sufficient evidence) Few studies evaluated effect on patient tobacco use cessation; inconsistent results on provider delivery of advice to quit (16 studies, insufficient evidence) Increase both provider delivery of advice to quit and patient tobacco use cessation (20 studies, strong evidence)
No studies assessed effect on provider delivery of advice to quit or patient tobacco use cessation (3 studies, insufficient evidence) Increases both use of effective therapy and patient tobacco use cessation (5 studies, sufficient evidence)
Increases tobacco use cessation when implemented with other interventions (32 studies, strong evidence)
*Includes interventions aimed at reducing environmental tobacco smoke exposure, decreasing tobacco use initiation, and increasing tobacco use cessation. ETS ⫽ environmental tobacco smoke.
sessions, and “life-skills training” in schools). Some approaches have intermediate or short-term effectiveness (ie, youth access restrictions, school-based interventions), and others have been shown to be ineffective (ie, acupuncture and provider education) or have been insufficiently studied (ie, provider feedback). Thus, although there has been little progress in chemoprevention, several clinician-based www.chestjournal.org
and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention. References 1 Greenlee RT, Hill-Harmon MB, Murray T, et al. Cancer statistics, 2001. CA Cancer J Clin 2001; 51:15–36 CHEST / 123 / 1 / JANUARY, 2003 SUPPLEMENT
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