Screening and Prevention
Screening
Prior to 2011, screening for lung cancer among asymptomatic individuals at elevated risk because of smoking history or occupational exposures was not recommended. An unfortunate result of this policy was that most patients present at an advanced stage, and cure rates have improved little over the past 30 years. Only 7% of NSCLC patients received a diagnosis at 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 radiography for lung cancer. Despite the fact that these American trials were not designed to evaluate chest radiography 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 recent, randomized, prospective trial from Czechoslovakia showed that screening with chest radiography 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 because of the superior performance of low-dose helical computed tomography (CT) compared with chest radiography in detecting small lesions.
Numerous studies are ongoing 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 (Radiology 1996) screened male smokers older than 50 years. Of the 15 cancers detected by CT scan, only 4 were seen on chest radiography; 14 of the 15 cancers were stage I, with an average diameter of 1.6 cm. Ohmatsu (ASCO 1999) 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 I-ELCAP (International Early Lung Cancer Action Project) is a single-arm prospective study that has accrued more than 35,000 study subjects from 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 screening in populations at high risk for lung cancer has the potential to reduce lung cancer mortality in the near future.
In a controversial article from I-ELCAP, Henschke et al presented the results of their low-dose CT screening trial in 31,567 high-risk participants. CT was performed every 7 to 18 months. Lung cancer was found in 484 (1.5%), of whom 412 (85%) had stage I cancer, with an 88% 10-year survival rate estimated in that cohort. Noncalcified pulmonary nodules were detected in 233 participants (23%; 95% 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 with diagnosed lung cancer. In response to the I-ELCAP results, Bach et al reviewed the collective results of three prospective, concurrently run, randomized screening trials in 3,246 high-risk patients. They found no reduction in lung cancer deaths or advanced cancer in the screened groups.
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) in September 2002. NLST has accrued 53,500 current and former smokers (aged 55 to 74) into a prospective trial, randomizing participants to receive annual spiral CT or annual chest radiography. In October 2010, the data safety monitoring board announced that there was a 20.3% reduction in lung cancer mortality and a 7% reduction in all-cause mortality in those screened with low-dose CT. Concerns have been raised about the fact that more than 20% of patients are found to have abnormalities and the cost of screening this patient population could be as much as $38,000 per year of life gained. The number of people needed to be screened with low-dose CT to prevent one lung cancer–related death was 320 in the NLST.
The increased use of CT scanning in the United States, currently more than 62 million scans per year, has significantly increased the exposure to radiation in the population and may be a future health issue. The exposure to radiation from two or three CT scans in an adult is similar to that experienced by survivors of atomic bombs dropped on Japan in 1945. The risks associated with exposure to radiation are highest in children. Because of potential harm from overdiagnosis and the risk of radiation-induced cancers, this important study is the first step toward a targeted cost-effective public policy of encouraging the use of CT screening in populations in which the risk-reward ratio is most advantageous.
The efficacy of lung cancer screening is also being evaluated as part of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Men and women were randomized to receive annual chest radiography or 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.
Biomarkers, proteomic evaluations, and circulating endothelial cells are currently under intensive investigation within and outside the Early Detection Research Network.
Updated guidelines in 2011 from the National Comprehensive Cancer Network (NCCN) in the United States recommend annual low-dose CT screening for those at high risk; they recommend no routine screening for moderate- or low-risk individuals. High risk was defined by the NCCN as age 55 to 74 years with a 30 pack-year history of smoking and, if no longer smoking, smoking cessation within the past 15 years; or a 20 pack-year history of smoking with one additional risk factor (other than secondhand smoke exposure). Similar guidelines were also issued in 2012 by the American Society of Clinical Oncology (ASCO), the American Association for Thoracic Surgery, and the American College of Physicians.
Expert groups are in agreement that patient counseling of the risks and benefits of screening; the development of a registry to collect data on follow-up testing, smoking behavior, radiation exposure, and patient experience; the development of quality metrics for CT interpretation, similar to quality control for mammography; and emphasis on the importance of smoking cessation are all integral components of a screening strategy.
The lack of demonstrated benefit for the earlier radiographic screening approaches should not be misinterpreted as nihilism about the early detection of lung cancer. Individuals at risk (current and former smokers) who present with symptoms consistent with lung cancer deserve appropriate evaluation. A lack of resolution of abnormalities on a chest radiograph 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 was conducted to determine whether certain vitamin supplements would prevent cancer. It evaluated 29,133 male smokers over 5 to 8 years and found there was an 18% increase in the incidence of lung cancer in the group taking beta-carotene. Other chemopreventive agents studied in a phase III fashion include retinol(Drug information on retinol), aspirin(Drug information on aspirin), retinyl palmitate, etretinate, isotretinoin(Drug information on isotretinoin), α-tocopherol, 4-hydroxyphenyl retinamide, anethole dithiolethione, and N-acetylcysteine. None of them showed any preventive benefit.
Second primary lung tumors develop at a rate of 1% to 3% annually for the first 5 years following resection of stage I NSCLC. 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. Also, there was no reduction in second primary tumors in the 13-cis-retinoic acid–treated group. Trials using cyclooxygenase 2 inhibition in former and current smokers are yet to be reported. 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(Drug information on selenium) intake and lung cancer.
A study (Clark et al: JAMA 1996) designed to determine the effects of selenium on the incidence of basal or squamous cell carcinomas showed that nutritional supplementation with this agent had 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 was designed to follow the lung cancer isotretinoin prevention trial. To reduce the incidence of second primary tumors, this double-blind design randomized patients by a 2:1 ratio to receive either selenomethionine (200 μg/d) or placebo daily for 48 months. Patients were monitored for safety, development of second primary tumors, and recurrence. At a planned interim analysis, there was a trend toward a lower incidence of second primary cancers in patients receiving placebo compared with selenium. Second primary tumor (lung/overall) incidence was 1.36/3.66 per 100 person years for placebo vs 1.91/4.11 for selenium (P = .150). The study was discontinued because of futility.
Educational programs
Given that results from the Intergroup study and other chemoprevention studies to date have been disappointing, it is important to continue educational efforts to prevent adolescents from smoking 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.
Smoking cessation is more likely to be successful when a combination of behavioral and pharmacologic interventions are offered. A simple five-step algorithm called the 5 A's that includes the elements of brief counseling for office practice is effective for increased abstinence rates. This system encourages clinicians to ask patients about their smoking status, advise smokers to quit, assess their readiness to quit, assist them with their smoking cessation effort, and arrange for follow-up visits or contact. First-line drug therapy for smokers includes nicotine(Drug information on nicotine) replacement therapy, bupropion, or varenicline(Drug information on varenicline). A meta-analysis of 36 randomized trials of bupropion monotherapy found that bupropion nearly doubles the likelihood of smoking cessation, compared with placebo. The most common side effects of bupropion include insomnia, agitation, dry mouth, and headache, while seizures are a rare (0.1% of patients) but serious side effect.
Another meta-analysis found that varenicline increased the odds of quitting three-fold compared with placebo and produced a quit rate of 33% at 6-month follow-up. Three randomized trials have also suggested that varenicline is superior to bupropion for rate of short-term smoking cessation and may be superior for long-term cessation; however, long-term cessation data are more equivocal. Varenicline may increase the risk of neuropsychiatric and cardiovascular side effects, and patients should be monitored closely while taking it.
