Epidemiology

Gender In the United States, the estimated number of new lung cancer cases for 2005 was 93,010 for men and 79,560 for women. Although the incidence of lung cancer had been rising in women, the rate of increase has begun to slow recently. The incidence is decreasing in men.

Age The age at which lung cancer patients are diagnosed varies widely, but the median age at diagnosis is approximately 70 years.

Race In the United States, the highest incidence of lung cancer in men and women is found in African-Americans (117.2/100,000 for men and 54.5/100,000 for women) followed by Caucasians (77.9/100,000 for men and 51.3/100,000 for women).

Geography There are geographic variations in the incidence of lung cancer, with the highest rates worldwide observed in North America and Eastern Europe; in the United States, the highest rates are found in northern urban areas and along the southern coast from Texas to Florida.

Survival The overall 5-year survival rate for lung cancer is 15%, of which there has been a 1% improvement each decade for the past 30 years.

Etiology and risk factors

Cigarette smoking Approximately 87% of all cases of lung cancer are related to cigarette smoking. There is a relatively strong dose-response relationship between cigarette smoking and the development of this cancer. The greater the number of cigarettes smoked on a daily basis and the greater the number of years of smoking, the greater is the risk of lung cancer. An individual who smokes one pack of cigarettes daily has a 20-fold increased risk of lung cancer compared to a nonsmoker.

The overall incidence of cigarette smoking decreased from 1974 through 1992. Smoking cessation decreases the risk of lung cancer, but a significant decrease in risk does not occur until approximately 5 years after stopping, and the risk remains higher in former smokers than in nonsmokers for at least 25 years. The benefit of smoking cessation is greater if it occurs at a younger age.

Smoking cessation is difficult. Recent data have suggested that a variety of hereditary factors increase the risk of addiction to nicotine among some individuals. Nevertheless, millions of former smokers have quit successfully. Smoking cessation programs that address both physical withdrawal from nicotine and psychological dependence appear to be more effective than either of these approaches alone. In addition, continued efforts are needed to prevent adolescents and preadolescents from beginning to smoke or to encourage them to quit after a brief period of experimentation.

Several cancer centers have recently reported that more than half of their patients with newly diagnosed lung cancer are former smokers, having quit more than 1 year before diagnosis. Healthy ex-smokers represent a large group of individuals who may benefit from effective tools for early detection and/or chemoprevention of lung cancer.

Secondhand smoke Not only is smoking risky for those who smoke, but it also poses a hazard to nonsmokers who either live or work with smokers. It is estimated that approximately 3,000 lung cancer deaths per year in the United States are due to secondhand smoke. Individuals who live in a household with a smoker have a 30% increase in the incidence of lung cancer compared to nonsmokers who do not live in such an environment.

Asbestos exposure is another risk factor for lung cancer. Cigarette smokers who are exposed to asbestos develop lung cancer at an extremely high rate. There is a 90-fold increase compared with unexposed individuals. Exposure to asbestos is also a major risk factor for the development of mesothelioma (see discussion of this cancer in the following chapter).

Radioactive dust and radon exposure Uranium miners who have been exposed to radioactive dust and radon gas also have an increased incidence of lung cancer. Although there has been some controversy about the risk posed by exposure to residential radon gas, a study conducted in Sweden showed an increased incidence of lung cancer in individuals who were exposed to a high level of radon in their homes.

Screening and prevention

Screening

Currently, screening for lung cancer among asymptomatic individuals at elevated risk due to smoking history or occupational exposures is not recommended. An unfortunate result of this policy is that most patients present in advanced stage, and cure rates have improved little over the past 30 years. Only 7% of NSCLC patients are diagnosed in stage IA.

Three randomized screening trials conducted in the United States in the 1970s failed to show a reduction in lung cancer mortality among the smokers who were screened by sputum cytology and chest x-ray for lung cancer. Despite the fact that these American trials were not designed to evaluate chest x-ray as a screening tool, the results led most experts to conclude that screening for lung cancer was not worthwhile. In addition, most investigators recommended that research efforts and resources be allocated to the prevention of lung cancer. A more recent, randomized, prospective trial from Czechoslovakia showed that screening with a chest x-ray increased the diagnosis of early-stage lung cancer but failed to reduce the mortality from lung cancer.

The potential to screen for lung cancer has received renewed interest due to the superior performance of low-dose helical CT compared with chest radiography in detecting small lesions. Although there is insufficient evidence to establish policy related to routine screening for lung cancer with spiral CT, there is a growing trend toward promoting screening with this new technology to individuals at increased risk for lung cancer.

Numerous studies are currently under way to evaluate chest CT scan for lung cancer screening. Several recent reports from Japan, Germany, and the United States have documented the ability of low-dose spiral CT scans to detect lung cancer at an early stage. In some recent trials, more than 80% of lung cancers detected by screening were diagnosed in stage I.

Kaneko screened male smokers > 50 years of age. Of the 15 cancers detected by CT scan, only 4 were seen on chest x-ray; 14 of the 15 cancers were stage I, with an average diameter of 1.6 cm. Ohmatsu found 35 lung cancers (0.37% detection rate) with 9,452 CT scans. Of these cancers, 27 were stage IA. These patients had a 3-year survival rate of 83%.

The International Early Lung Cancer Action Project (I-ELCAP, http://www.ielcap.org/professionals.htm) is a single-arm prospective study that has accrued more than 35,000 study subjects in 30 sites and documented that a high percentage of lung cancers are detected in stage I, a stage in which long-term survival can reasonably be anticipated in more than 60% of patients. These studies provide early evidence to suggest that CT lung cancer population screening has the potential to reduce lung cancer mortality in the near future.

Henschke et al have reported encouraging results from ELCAP of screening with spiral CT scan. Included in the initial report were 1,000 symptom-free volunteers, aged 60 years or older, with at least 10 pack-years of cigarette smoking and no previous cancer who were medically fit to undergo thoracic surgery. Noncalcified pulmonary nodules were detected in 233 participants (23% [95% confidence interval (CI): 21–26]) by low-dose CT at baseline, compared with 68 (7% [95% CI: 5–9]) by chest radiography. Lung cancer was detected by CT in 27 patients (2.7% [95% CI: 1.8–3.8]) and by chest radiography in 7 patients (0.7% [95% CI: 0.3–1.3]).

Of the 27 CT-detected cancers, 26 were resectable. Stage I cancers were diagnosed in 23 of 27 patients (85%) by CT and 4 of 7 patients (57%) by chest radiography. In addition, low-dose CT detected four more nonparenchymal cases of lung cancer: two with endobronchial lesions and two in the mediastinum. These cases show an added benefit of low-dose CT over chest radiography, although the data were not included in the analysis. (The study primarily focused on malignant disease in noncalcified pulmonary nodules detected by low-dose CT or radiography.) It remains to be seen, however, whether lung cancer screening with low-dose spiral CT will reduce the lung cancer mortality of the study population or only improve the 5-year survival rate of the patients diagnosed with lung cancer.

Based on growing evidence that spiral CT may truly provide for a successful early detection strategy, the National Cancer Institute (NCI) launched the National Lung Screening Trial (NLST, http://www.nci.nih.gov/NLST) in September 2002. NLST has accrued 50,000 current and former smokers (aged 55–74) into a prospective trial, randomizing participants to receive annual spiral CT or annual chest x-rays. Survival data will not be available for a number of years.

The efficacy of lung cancer screening is also being evaluated as part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Men and women were randomized to receive annual chest x-ray vs usual care. Eligibility was not based on risk of lung cancer, because given the large size of the study (> 100,000 participants), it was expected that there would be appreciable numbers of current and former smokers among the participants.

The lack of demonstrated benefit for the older screening approaches should not be misinterpreted as nihilism about the early detection of patients with lung cancer. Individuals at risk (current and former smokers) who present with symptoms consistent with lung cancer deserve appropriate evaluation. The lack of resolution of radiographic abnormalities on a chest x-ray obtained after the completion of empiric antibiotic therapy for pneumonia should prompt further evaluation for possible lung cancer.

Chemoprevention

The concept of field carcinogenesis was originally developed for the aerodigestive tract in the early 1950s. Reducing the exposure of the epithelial mucosa to carcinogens, predominately cigarette smoke, has the greatest impact on reducing the incidence of cancer in high-risk individuals.

The Finnish Alpha-Tocopherol Beta Carotene Study evaluated 29,133 male smokers over 5 to 8 years and there was an 18% increased incidence of lung cancer in the group taking beta-carotene. Other chemopreventative agents studied include aspirin, retinyl palmitate, etretinate, isotretinoin, 4-hydroxyphenyl retinamide, anethole dithiolethione, and N-acetylcysteine. There has been no clear benefit of beta carotene identified in any of the studies.

Second primary lung tumors develop at a rate of 1%–3% annually for the first 5 years following resection of stage I NSCLC. The retinoid 13-cis-retinoic acid (isotretinoin [Accutane]) has reduced the incidence of second primary cancer in head and neck cancer patients in one small randomized trial.

The intergroup randomized trial that assessed the ability of 13-cis-retinoic acid to prevent the occurrence of a second primary cancer in patients with completely resected stage I NSCLC showed no impact of treatment on the incidence of second primary tumors. Furthermore, patients who continued to smoke and who received isotretinoin had a higher risk of recurrence of the index cancer. The early findings have demonstrated a higher-than-expected recurrence rate in patients with early-stage lung cancer who received 13-cis-retinoic acid and continued to smoke. Also, there was no reduction in second primary tumors in the 13-cis-retinoic acid-treated group. Trials using cyclooxygenase-2 (COX-2) inhibition are yet to be reported in former and current smokers. Tyrosine kinase inhibition is currently being studied to reverse bronchial premalignant lesions and Ki-67 levels in the Lung Cancer Biomarkers Chemoprevention Consortium trial.

Selenium as L-selenomethionine has been shown to inhibit cell growth, induce apoptosis in vitro, and retard carcinogenesis at higher dose levels in animal models. Epidemiologic data suggest an inverse relationship between selenium intake and lung cancer.

In a study by Clark et al designed to determine the effects of selenium on the incidence of basal or squamous cell carcinomas, nutritional supplementation with this agent showed no consequences on the incidence of skin cancer; however, secondary analyses revealed that it was associated with significantly fewer cases of lung cancer.

A phase III intergroup selenium prevention trial has been designed to follow the lung cancer isotretinoin prevention trial. To reduce the incidence of second primary tumors, this double-blind design is randomizing patients by a 2:1 ratio to receive either selenomethionine (200 µg/d) vs placebo daily for 48 months. Patients will be monitored for safety, development of second primary tumors, and recurrence.

Educational programs Although the information from the intergroup randomized chemoprevention study is being collected, it is important to continue educational efforts to prevent adolescents from starting to smoke cigarettes and to advocate smoking cessation in active smokers. Some experts believe that educational programs must begin during childhood, probably between the ages of 6 and 10 years. Targeting children and young adults is a significant priority of any lung cancer reduction program.

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