Lung cancer prevention

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.