When the National Lung Screening Trial (NLST) launched in the U.S. in 2002, neither American nor European medical organizations endorsed specific lung cancer screening guidelines. Furthermore, the existing strategies missed crucial lung cancer diagnoses because the disease can be asymptomatic until the advanced stages.
Management Summary
Challenge: With 1.6 million fatalities per year, lung cancer is the leading cause of cancer-related deaths worldwide. However, reliable screening programs for early detection have been lacking.
Solution: Low-dose CT (LDCT) screening can help reduce lung cancer mortality by up to 20 percent. This is according to a large clinical trial which enrolled around 53,000 heavy smokers in the U.S.
Result: Annual LDCT screening is now recommended and reimbursed in the U.S. for patients between 55 and 80 years of age who have a long history of heavy smoking. In Europe and other countries, where further screening trials are underway, there is an ongoing debate on how to implement lung cancer screening without multiplying false-positive results and costs of follow-up care. False-positive results are test results that are positive even though the patient does not have the disease – a fact which is discovered through further diagnostic workup.
Study Shows Reduction in Mortality
Lung cancer is typically diagnosed in the advanced stages, when surgical cure is not an option. The NLST set out to investigate whether lung cancer screening with low-dose computed tomography (LDCT) could tackle the problem. This study of more than 53,000 men and women with a history of heavy smoking showed that annual LDCT screening is an irreplaceable component in fighting lung cancer. Participants screened with LDCT had a 20 percent lower risk of dying from lung cancer than patients in a control group that was given standard chest X-rays. This reduction in mortality is likely due to earlier tumor detection and treatment.
Notably, the death rate from other causes was also lower in the LDCT arm. “The important message here is that CT screening itself did not promote early morbidity or mortality. Participants were not exposed to downstream complications they could have died from,” says Denise Aberle, MD, Professor of Radiology at UCLA Medical Center in Los Angeles, and one of the principal investigators on the NLST. David Naidich, MD, Professor of Radiology at New York University School of Medicine, who served on the oversight committee of the study, agrees that the trial eliminated concerns that the risks of annual LDCT scans might outweigh the benefits. With modern CT scanners, the radiation exposure involved would be small, he says.
“We identified more early-stage lung cancers in the LDCT arm, but found fewer late-stage cancers, which means we saw a true stage shift.”
The National Lung Screening Trial – Key Facts
The National Lung Screening Trial (NLST) was launched in 2002. It randomly assigned around 53,000 current or former heavy smokers to receive either low-dose computed tomography or chest X-rays for three annual screens. Eligible male and female participants in the study were aged between 55 and 74 years and had a history of at least 30 pack-years (i.e. 30 years of smoking one pack per day), and, if former smokers, had quit within the past 15 years. Patients were enrolled at 33 medical centers across the U.S. All of the multi-detector CT scanners deployed were at least four-slice systems.
Screening exams were labeled as “positive” if a lung nodule 4 mm in diameter or larger was observed on CT scans, or if a “suspicious” nodule or mass was detected on radiographs. The rate of adherence to screening was over 90 percent, though with a portion of lung cancer cases diagnosed only in the post-screening phase. About 6 years after the first enrollment, patients in the LDCT group showed 20 percent lower mortality from lung cancer compared with the radiography arm (likely due to earlier treatment) and a 6.7 percent relative decrease in death from other causes.8
Translating Research into Routine Care
Meanwhile, the U.S. Preventive Services Task Force (USPSTF), which issues the country’s screening guidelines, has recommended that people who fall within the NLST patient population and who are aged between 55 and 80 should receive annual lung cancer screenings.1 The procedure is now covered by the country’s private and government insurers for older people with a long history of heavy smoking.2 This could have an important impact on healthcare delivery and the use of CT screening in the U.S. Given the USPSTF recommendations and reimbursement coverage, this could result in up to 8 million additional LDCT screens each year.3
The NLST results also caught the interest of medical organizations in Europe, Aberle and Naidich say. Aberle explains that a lung cancer screening trial called NELSON, which is taking place in the Netherlands and Belgium, will combine its results with the Danish Lung Cancer Screening Trial (DLCST) to include about 22,000 patients total. In China, where lung cancer has been increasing rapidly in the past few decades, at least one LDCT cancer screening trial of 3,000 participants is underway in Shanghai.4 Other countries can benefit by running their own trials in order to find the best approach to lung cancer screening, Aberle says.
Challenges in LDCT Screening
However, important issues remain unresolved. As the authors of the NLST report point out, many of the centers involved in the trial are recognized for their expertise in cancer diagnosis and treatment, leaving open the question as to whether community facilities would perform equally well. Likewise, the European Society of Radiology and the European Respiratory Society have issued a white paper recommending the use of LDCT screening only at certified multidisciplinary centers that can ensure standardized operating procedures and offer long-term clinical follow-up that includes smoking cessation programs.5
In 2014, a group of Swiss experts cautioned that, before implementing large-scale LDCT screening in clinical routine, the population to be screened and the possible psychological consequences of taking part in such programs as well as guidelines on a workup of indeterminate screening results would have to be clearly defined.6 A recent cost-effectiveness study stated that, within the U.S. health system, each quality-adjusted life year gained through LDCT screening could carry additional costs (compared to no screening) of US$81,000. However, estimates vary widely.7
Another major issue is how to convince high-risk patients, particularly those from underprivileged communities, to seek lung cancer screening. These populations suffer disproportionately from lung cancer because they often present with very advanced disease. Aberle suggests that university medical centers could do a better job of community engagement by providing resources and local training to the community healthcare workers who serve these populations. It is unreasonable to expect that such high-risk patients will leave their communities to travel to major academic centers for screening and care. Models for community engagement and outreach, where healthcare is incorporated into the community, must be implemented.
What Happens Next
At the same time, it seems likely that people beyond the parameters of the original NLST study population could also benefit from well-planned lung cancer screening programs. “A lot of people get lung cancer who do not satisfy the NLST eligibility criteria,” states Aberle. She points out that the NLST criteria apply to less than 30 percent of people who are diagnosed with lung cancer in the U.S. One approach to expanding screening eligibility, she says, could be to build risk prediction models that take into account patients’ exposure to known respiratory carcinogens, air pollution, underlying lung disease, and family history of lung cancer.
Lung cancer screening in connection with other forms of screening and counseling is very attractive. LDCT works for lung cancer screening because it can detect even very small nodules within the aerated lung. Furthermore, other smoking-related diseases are detectable with lung screening. Coronary artery calcium assessment has been shown to provide a personalized estimation of the risk of heart attack or death from coronary artery disease. Due to the high contrast between calcium and soft tissues, coronary artery calcium can be evaluated on lung screening to improve risk prediction for cardiovascular events.
Similarly, emphysema is a smoking-related condition that is readily identified on LDCT screening and independently contributes to the risk of lung cancer in individual patients. Finally, the incorporation of smoking cessation counseling and medications into the screening process will significantly reduce tobacco-related diseases. The NLST results should be viewed as just the beginning of our understanding of screening and preventive services for tobacco-related diseases.
About the Author
Kathleen Raven has covered lung cancer clinical trials for Biopharm Insight, consumer health for Reuters Health, and biomedical news for Nature Medicine. She is a freelance writer based in New Haven, Connecticut, USA.
