Prevention Of Lung Cancer
Prevention of lung cancer : summary of published evidenceMichael J. Kelley 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), [beta]-carotene, N-acetylcysteine, and selenium. 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 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.
Key words: carotenoids; chemoprevention; health education; lung neoplasms; primary prevention; smoking cessation; vitamin A
Abbreviations: ATBC = [alpha]-Tocopherol [beta]-Carotene Lung Cancer Prevention Study; CARET = [beta]-Carotene and Retinol Efficacy Trial; CI = confidence interval; NSCLC = non-small cell lung cancer; RCT = randomized controlled trial; RR = relative risk
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Cigarette smoking is causally associated with the 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 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 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 meta-analyses.
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 publications (3-10) 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 Study (6) 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 [beta]-carotene, rather than reducing lung cancer incidence, was associated with increased lung cancer incidence. Statistically significant increases in lung cancer incidence in smokers receiving [beta]-carotene supplements were shown in the [alpha]-Tocopherol, [beta]-Carotene (ATBC) Lung Cancer Prevention Study (3-5) and the [beta]-Carotene and Retinol Efficacy Trial (CARET). (8,9) A similar trend was observed in a small study comparing [beta]-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 trial (3-5) examined the effect of a-tocopherol (vitamin E) and [beta]-carotene on the incidence of lung cancer in 29,133 Finnish male smokers using a 2 x 2 factorial design. The selection of these agents was based almost exclusively on epidemiologic studies linking a vegetable-rich diet (high in [beta]-carotene and vitamin E) with a decrease in the risk of lung cancer, (11) [beta]-carotene and vitamin E have antioxidant properties in vitro. Subjects were recruited from 1985 to 1993 and took supplements (ie, [alpha]-tocopherol, 50 mg/d, and [beta]-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 a-tocopherol (vitamin E) on lung cancer incidence was observed (relative risk [RR], 0.98; 95% confidence interval [CI], 0.86 to 1.12). However, in the [beta]-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 [greater than or equal to] 20 cigarettes a day and in those with higher alcohol intake. (5)
The CARET study (8,9) was a large two-arm study that was designed to compare the effects of a combination of [beta]-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 [beta]-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 study (14) of 1,029 high-risk subjects (ie, those persons with [greater than or equal to] 20 pack-years of cigarette smoking who were currently smoking or had quit within the previous 6 years) demonstrated the safety and tolerability of [beta]-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 suggested (15,16) that higher concentrations of [beta]-carotene resulting from supplementation may have pro-oxidant effects, inducing DNA damage and membrane instability.
The Physicians' Health Study (6) was a randomized, double-blind, placebo-controlled trial of aspirin (325 mg every other day) and [beta]-carotene (50 mg every other day) conducted using a 2 x 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 [beta]-carotene arms at the end of the 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 Study (10) randomized nearly 40,000 women who were at least 45 years of age in a 2 x 2 x 2 factorial design to measure the effect of [beta]-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 [beta]-carotene arm was closed. After supplementation for 2.1 years with [beta]-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 [beta]-carotene supplementation. There were 30 cases of lung cancer in the [beta]-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 [beta]-carotene supplementation on lung cancer incidence or death from lung cancer.
A South African study (7) of 1,024 asbestos workers (92% male) randomly assigned subjects in equal proportions to either [beta]-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 [beta]-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 Trial (18) 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 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, [beta]-carotene plus retinol, and the combination of vitamin [B.sub.12] 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 RCTs (28-32) 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 palmitate (29) in reducing second primary cancer incidence. The study by Hong et al (28) 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 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 isotretinoin (30) or retinyl palmitate and/or N-acetylcysteine. (31) A trial of [beta]-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 [beta]-carotene, this trial showed a nonsignificant trend toward increased lung cancer incidence in patients who were treated with [beta]-carotene.
A randomized trial of selenium in patients who 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 Trial (18) 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 small (n = 40) blinded feasibility study (37) 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 smoke-free 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 Guideline (41) 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 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 Services (42) (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 good-quality clinical studies demonstrating that the administration of [beta]-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 N-acetylcysteine. 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 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 and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention.
Table 1--RCTs Examining the Effect of Primary Chemoprevention
Interventions on Lung Cancer Incidence *
Study/Year No. Population
ATBC (3-5)/1994 29,133 Male smokers (Finland)
CARET (8,9)/1996 18,314 Smokers (64%); former smokers
(34%); asbestos workers; age
45-74 yr; men and women
(except only male asbestos
workers)
Physicians' Health 22,071 Male physicians
Study (6)/2000 (US); 11% smokers
Women's Health 39,876 Female health
Study (10)/1999 professionals; 45 yr of age
Western Australia 1,024 Asbestos workers
(7)/1998
Study/Year Intervention End Point Result
ATBC (3-5)/1994 [alpha]-tocopherol, Lung cancer 444 cases
50 mg/d, [+ or -] incidence
[beta]-carotene
Placebo [+ or -] 450 cases
[beta]-carotene
[beta]-carotene, 482 cases
20 mg/d, [+ or -]
[alpha]-tocopherol
Placebo [+ or -] 412 cases
[alpha]-tocopherol
CARET (8,9)/1996 [beta]-carotene, Lung cancer 5.92/1,000
30 mg/d, and incidence person-yr
retinol 25,000
IU/d
Placebo 4.62/1,000
person-yr
Physicians' Health [beta]-carotene, 50 Lung cancer 85 cases
Study (6)/2000 mg, [+ or -] ASA, incidence
325 mg every other
day
Placebo [+ or -] 93 cases
ASA, 325 mg every
other day
[beta]-carotene, 50 All cancer 1,314 cases
mg, [+ or -] ASA, incidence
325 mg every other
day
Placebo [+ or -] 1,353 cases
ASA, 325 mg every
other day
[beta]-carotene, 50 Cancer 414
mg, [+ or -] ASA, deaths
325 mg every other
day
Placebo [+ or -] 406
ASA, 325 mg every
other day
Women's Health [beta]-carotene, Lung cancer 30 cases
Study (10)/1999 50 mg qod, incidence
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA 21
[+ or -] vitamin E
[beta]-carotene, All cancer 378
50 mg qod, incidence
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA 369
[+ or -] vitamin E
[beta]-carotene, Cancer 31
50 mg qod, deaths
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA 28
[+ or -] vitamin E
Western Australia Retinol, 25,000 IU/d Lung cancer 4 cases
(7)/1998 incidence
[beta]-carotene, 6 cases
30 mg/d
Retinol, 25,000 IU/d Mesothelioma 3 cases
incidence
[beta]-carotene, 12 cases
30 mg/d
Retinol, 25,000 IU/d All-cause 21 cases
mortality
[beta]-carotene, 37 cases
30 mg/d
Study/Year Intervention RR (95% CI)
ATBC (3-5)/1994 [alpha]-tocopherol, 0.98 (0.86-1.12)
50 mg/d, [+ or -]
[beta]-carotene
Placebo [+ or -] 1
[beta]-carotene
[beta]-carotene, 1.18 (1.03-1.36)
20 mg/d, [+ or -]
[alpha]-tocopherol
Placebo [+ or -] 1
[alpha]-tocopherol
CARET (8,9)/1996 [beta]-carotene, 1.28 (1.04-1.57)
30 mg/d, and
retinol 25,000
IU/d
Placebo 1
Physicians' Health [beta]-carotene, 50 0.9 (0.7-1.2)
Study (6)/2000 mg, [+ or -] ASA,
325 mg every other
day
Placebo [+ or -]
ASA, 325 mg every
other day
[beta]-carotene, 50 1.0 (0.9-1.0)
mg, [+ or -] ASA,
325 mg every other
day
Placebo [+ or -]
ASA, 325 mg every
other day
[beta]-carotene, 50 1.0 (0.9-1.2)
mg, [+ or -] ASA,
325 mg every other
day
Placebo [+ or -]
ASA, 325 mg every
other day
Women's Health [beta]-carotene, 1.43 (0.82-2.49)
Study (10)/1999 50 mg qod, ([dagger])
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA
[+ or -] vitamin E
[beta]-carotene, 1.03 (0.89-1.18)
50 mg qod,
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA
[+ or -] vitamin E
[beta]-carotene, 1.11 (0.67-1.85)
50 mg qod,
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA
[+ or -] vitamin E
Western Australia Retinol, 25,000 IU/d 0.66 (0.19-2.32)
(7)/1998 [beta]-carotene,
30 mg/d
Retinol, 25,000 IU/d 0.24 (0.07-0.86)
[beta]-carotene,
30 mg/d
Retinol, 25,000 IU/d 0.56 (0.33-0.95)
[beta]-carotene,
30 mg/d
Study/Year Intervention Comments
ATBC (3-5)/1994 [alpha]-tocopherol, Blinded; statistically
50 mg/d, [+ or -] significant increase in
[beta]-carotene lung cancer incidence
seen in the smokers
receiving [beta]-carotene
Placebo [+ or -]
[beta]-carotene
[beta]-carotene,
20 mg/d, [+ or -]
[alpha]-tocopherol
Placebo [+ or -]
[alpha]-tocopherol
CARET (8,9)/1996 [beta]-carotene, Blinded; statistically
30 mg/d, and significant increase in
retinol 25,000 relative risk of lung
IU/d cancer in those receiving
[beta]-carotene alone or
in combination with
retinol
Placebo
Physicians' Health [beta]-carotene, 50 Blinded; cancer incidence
Study (6)/2000 mg, [+ or -] ASA, in the [beta]-carotene
325 mg every other arms showed no difference
day in the incidence of
total cancers, lung
cancer, or any other
cancer. No information
on effect ASA as on lung
cancer incidence
Placebo [+ or -]
ASA, 325 mg every
other day
[beta]-carotene, 50
mg, [+ or -] ASA,
325 mg every other
day
Placebo [+ or -]
ASA, 325 mg every
other day
[beta]-carotene, 50 Lung cancer incidence
mg, [+ or -] ASA,
325 mg every other
day
Placebo [+ or -]
ASA, 325 mg every
other day
Women's Health [beta]-carotene, Blinded; [beta]-carotene
Study (10)/1999 50 mg qod, arm terminated early due
[+ or -] ASA to results of ATBC and
[+ or -] vitamin E CARET studies, limiting
ability of study to
detect effect of [beta]-
carotene on lung cancer
incidence
Placebo [+ or -] ASA
[+ or -] vitamin E
[beta]-carotene,
50 mg qod,
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA
[+ or -] vitamin E
[beta]-carotene,
50 mg qod,
[+ or -] ASA
[+ or -] vitamin E
Placebo [+ or -] ASA
[+ or -] vitamin E
Western Australia Retinol, 25,000 IU/d No placebo; not blinded;
(7)/1998 56 subjects crossed over
(most from retinol
group); no difference in
lung cancer incidence,
but malignant mesothe-
lioma was significantly
lower in the retinol
group compared with the
[beta]-carotene group
[beta]-carotene,
30 mg/d
Retinol, 25,000 IU/d
[beta]-carotene,
30 mg/d
Retinol, 25,000 IU/d
[beta]-carotene,
30 mg/d
* ASA = acetylsalicylic acid; [+ or -] = with or without; qod = every
other day.
([dagger]) Investigators in the Women's Health Study employed a Cox
proportional hazard model to calculate RR for lung cancer associated
with [beta]-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 [chi square] 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.
Table 2--RCTs Examining the Effect of Tertiary Chemoprevention
Interventions on Lung Cancer Incidence (Second Primary Tumor) *
Study/Year No. Population
MD Anderson 103 Head and neck
Cancer Center cancer
(28)/1990
Istituto Nazionale 307 Stage I NSCLC
Tumori (29)/1993 status post-resection
Lippman et al (30)/ 1,166 Stage I NSCLC
2001 status post-resection
EUROSCAN (31)/ 2,592 Stage I-III head
2000 and neck cancer (60%)
and lung (40%) cancer
Yale Study (32)/2001 264 Early-stage head
and neck cancer
Study/Year Intervention End Point
MD Anderson Isotretinoin, 50-100 Second primary
Cancer Center mg/[m.sup.2]/d x 12 mo tumor
(28)/1990
Placebo
Istituto Nazionale Retinol palmitate, Any second
Tumori (29)/1993 300,000 IU/d x 12 mo primary cancer
Placebo
Retinol palmitate, UADTC second
300,000 IU/d x 12 mo primary tumor
Placebo
Retinol palmitate, Lung cancer
300,000 IU/d x 12 mo incidence
Placebo
Lippman et al (30)/ Isotretinoin, 30 mg/d x All second
2001 3 yr primary tumor
incidence
Placebo
EUROSCAN (31)/ Retinyl palmitate, All second
2000 300,000 IU/d x 1 yr, primary tumor
then 150,000 IU/d x incidence
1 yr
NAC, 600 mg/d x 2 yr
Retinyl palmitate
(as above) plus NAC
(as above)
Placebo
Yale Study (32)/2001 [beta]-carotene, 50 mg/d Lung cancer
incidence
Placebo
[beta]-carotene, 50 mg/d Head and neck
cancer,
recurrent or
second primary
Placebo
[beta]-carotene, 50 mg/d Second primary
tumor
Placebo
Study/Year Intervention Result
MD Anderson Isotretinoin, 50-100 2 cases
Cancer Center mg/[m.sup.2]/d x 12 mo
(28)/1990
Placebo 12 cases
Istituto Nazionale Retinol palmitate, 18 cases
Tumori (29)/1993 300,000 IU/d x 12 mo
Placebo 29 cases
Retinol palmitate, 13 cases
300,000 IU/d x 12 mo
Placebo 25 cases
Retinol palmitate, 11
300,000 IU/d x 12 mo
Placebo 21
Lippman et al (30)/ Isotretinoin, 30 mg/d x 4.2%/yr
2001 3 yr
Placebo 3.9%/yr
EUROSCAN (31)/ Retinyl palmitate, 54 cases
2000 300,000 IU/d x 1 yr,
then 150,000 IU/d x
1 yr
NAC, 600 mg/d x 2 yr 61 cases
Retinyl palmitate 61
(as above) plus NAC
(as above)
Placebo 32
Yale Study (32)/2001 [beta]-carotene, 50 mg/d 13 cases
Placebo 9
[beta]-carotene, 50 mg/d 33
Placebo 34
[beta]-carotene, 50 mg/d 17
Placebo 14 cases
RR (95% CI)
Study/Year Intervention or p Value
MD Anderson Isotretinoin, 50-100 0.0005
Cancer Center mg/[m.sup.2]/d x 12 mo
(28)/1990
Placebo
Istituto Nazionale Retinol palmitate, 0.09 ([dagger])
Tumori (29)/1993 300,000 IU/d x 12 mo
Placebo
Retinol palmitate, 0.045 ([dagger])
300,000 IU/d x 12 mo
Placebo
Retinol palmitate, p value not
300,000 IU/d x 12 mo reported
Placebo
Lippman et al (30)/ Isotretinoin, 30 mg/d x 1.08 (0.78-1.42)
2001 3 yr
Placebo
EUROSCAN (31)/ Retinyl palmitate, 0.174 ([dagger])
2000 300,000 IU/d x 1 yr,
then 150,000 IU/d x
1 yr
NAC, 600 mg/d x 2 yr
Retinyl palmitate
(as above) plus NAC
(as above)
Placebo
Yale Study (32)/2001 [beta]-carotene, 50 mg/d 1.44 (0.62-3.39)
Placebo
[beta]-carotene, 50 mg/d 0.9 (0.56-1.45)
Placebo
[beta]-carotene, 50 mg/d 1.20 (0.59-2.45)
Placebo
Study/Year Intervention Comments
MD Anderson Isotretinoin, 50-100 Small study, but
Cancer Center mg/[m.sup.2]/d x 12 mo suggested
(28)/1990 beneficial
effects from oral
isotretinoin
Placebo
Istituto Nazionale Retinol palmitate, Small study, but
Tumori (29)/1993 300,000 IU/d x 12 mo suggested retinyl
palmitate reduced
second primary
cancer incidence
Placebo
Retinol palmitate,
300,000 IU/d x 12 mo
Placebo
Retinol palmitate,
300,000 IU/d x 12 mo
Placebo
Lippman et al (30)/ Isotretinoin, 30 mg/d x Large study; showed
2001 3 yr no effect of
isotretinoin on
incidence of second
primary cancers
Placebo
EUROSCAN (31)/ Retinyl palmitate, Large study; showed
2000 300,000 IU/d x 1 yr, no effect of
then 150,000 IU/d x retinyl palmitate
1 yr and/or N-acetyl-
cysteine on
second primary
cancer incidence
NAC, 600 mg/d x 2 yr
Retinyl palmitate
(as above) plus NAC
(as above)
Placebo
Yale Study (32)/2001 [beta]-carotene, 50 mg/d Underpowered; stopped
early due to
results from other
studies, but showed
trend toward
increase in lung
cancer incidence
in patients treated
with [beta]-
carotene
Placebo
[beta]-carotene, 50 mg/d
Placebo
[beta]-carotene, 50 mg/d
Placebo
* NAC = N-acetylcysteine; UADTC = urinary, airways, and digestive
tract cancer.
([dagger]) By log rank test.
Table 3--Clinician-Based and Community-Based Interventions to Reduce
Tobacco Exposure *
Existing
Systematic
Topic Review/Year Summary/Conclusions
School-based Lantz et al Many experimental and quasi-
interventions (45)/2000 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
long-term effect of an
early school-based
intervention (grades 3-10).
Only one rigorously designed
trial (47) 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
long-term smoking deterrence.
Community inter-
ventions
Education to Hopkins et al Ineffective in reducing infant
reduce ETS (42)/2001 ETS exposure (1 qualifying
in the home study, evidence is
insufficient)
Workplace smoking Eriksen and Effective in increasing tobacco
cessation Gottlieb use cessation and reducing
programs (48)/1998 consumption of tobacco
Bibeau et al products. Inconsistent
(49)/1988 results (52 studies)
Statewide Wakefield and Inconsistent evidence of
comprehensive Chaloupka reducing teenage smoking
tobacco control (50)/2000 prevalence (5 programs)
programs
Mass media/public
education
Campaigns (brief Hopkins et al Effective in increasing tobacco
recurring (42)/2001 use cessation and reducing
message) consumption of tobacco
products (15 studies, strong
evidence)
Cessation series Hopkins et al Inconsistent results and
(42)/2001 inadequate comparison groups
(9 studies, evidence
insufficient)
Advertising None Noted as "in progress" by the
restrictions Task Force on Community
Preventive Services. To be
covered in future publication
Youth access Lantz et al Can lead to a general reduction
restrictions (45)/2000 in illegal sales of
cigarettes to minors; whether
this will translate into
reduced and sustained
reductions in youth tobacco
use is uncertain
Tobacco excise Hopkins et al Effective in reducing tobacco
taxes; increasing (42)/2001 use prevalence and consumption
unit price for among both adolescents and
tobacco products young adults (8 studies,
strong evidence). Increases
tobacco use cessation and
reduces consumption (17
studies, strong evidence)
Direct restrictions Hopkins et al Effective in reducing exposure
on smoking (42)/2001 to ETS in workplace (9
studies, strong evidence)
Eriksen and Effective in reducing cigarette
Gottlieb consumption at work (9
(48)/1998 studies); ineffective at
increasing tobacco use
cessation (14 studies)
Clinician-based Fiore et al
approaches (44)/2000
Identifying Implementing clinic systems
tobacco users 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)
Assessment of Little consistent evidence that
willingness to motivation to quit is useful
quit 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)
Advice to quit Brief physician advice
smoking significantly increases
long-term smoking abstinence
rates (7 studies, strong
evidence)
Intensity of Clinician-to-smoker advice
clinical delivered on four or more
interventions 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)
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)
Format of Proactive telephone counseling,
psychosocial group counseling, and
treatments individual counseling formats
are effective in increasing
abstinence rates (58 studies,
strong evidence). Use of
multiple formats increases
abstinence rates (54 studies,
strong evidence)
Type of counseling Three types of counseling and
and behavioral behavioral therapies result
therapies 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)
Acupuncture No difference in abstinence
Pharmacotherapy 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)
Health-care Hopkins et al
system level (42)/2001
interventions
Provider reminder Increase provider delivery of
systems advice to quit to tobacco-
using patients (7 studies,
sufficient evidence)
Provider education Few studies evaluated effect on
patient tobacco use cessation;
inconsistent results on
provider delivery of advice
to quit (16 studies,
insufficient evidence)
Reminder plus Increase both provider delivery
education of advice to quit and patient
(multicomponent tobacco use cessation (20
interventions) studies, strong evidence)
Provider feedback No studies assessed effect on
provider delivery of advice
to quit or patient tobacco
use cessation (3 studies,
insufficient evidence)
Reducing patient Increases both use of effective
out-of-pocket therapy and patient tobacco
cost for use cessation (5 studies,
effective sufficient evidence)
cessation
therapies
Patient telephone Increases tobacco use cessation
support 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.
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* 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: kelleym@duke.edu
COPYRIGHT 2003 American College of Chest Physicians
COPYRIGHT 2003 Gale Group
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