National Lung Screening Trial: Questions and Answers
NLST Primary Findings
What is the NLST?
The National Lung Screening Trial (NLST) is a lung cancer screening trial sponsored by the National Cancer Institute (NCI) and conducted by the American College of Radiology Imaging Network (ACRIN) and the Lung Screening Study group.
Launched in 2002, NLST compared two ways of detecting lung cancer: low-dose helical (spiral) computed tomography (CT) and standard chest X-ray, for their effects on lung cancer death rates in a high-risk population. Both chest X-rays and helical CT scans have been used as a means to find lung cancer early, but the effects of these screening techniques on lung cancer mortality rates had not been determined definitively. Over a 21 month period, 53,454 current or former heavy smokers ages 55 to 74 joined the NLST at study centers across the United States.
What was the primary result of the NLST?
The NLST researchers found approximately 15 percent to 20 percent fewer lung cancer deaths among trial participants screened with low-dose helical CT relative to chest X-ray. This finding was highly significant from a statistical viewpoint, meaning it was due not to chance but rather to screening with helical CT. The 15 percent to 20 percent lower lung cancer death rate is equivalent to approximately three fewer deaths per 1,000 people screened in the CT group compared to the chest X-ray group over an average of 6.5 years of follow-up in the trial (17.6 per 1,000 versus 20.7 per 1,000).
Were there any other important findings from this study?
An additional finding, which was not the main endpoint of the trial's design, showed that all-cause mortality (deaths due to any factor, including lung cancer) was 6.7 percent lower in those screened with low-dose helical CT relative to those screened with chest X-ray. This difference was largely due to the decrease in lung cancer mortality. If lung cancer deaths were excluded, the differences in all causes of mortality between low-dose helical CT and chest X-ray were not statistically significant.
What did the study find about false-positive results?
A positive screening result was defined as one in which a nodule or other finding was observed that was potentially related to lung cancer. On average, over all three screening rounds, 24.2 percent of the low-dose helical CTs were positive and 6.9 percent of the chest X-rays were positive and led to a diagnostic evaluation. Among people who had multiple annual screens (up to three screens) 39.1 percent had at least one positive screen in the CT arm and 16.0 percent had at least one positive screen in the chest X-ray arm. Diagnostic evaluation most frequently consisted of further imaging, and invasive procedures were rare.
Across the three rounds, when a positive screening result was obtained, 96.4 percent of the low-dose helical CT tests and 94.5 percent of the chest X-ray exams were false-positive, meaning that the observed finding was not due to lung cancer. These percentages varied little by round. The vast majority of false-positive results were probably due to the detection of benign lymph nodes or granulomata, which are non-cancerous inflamed tissue masses. The fact that these false-positive results were not cancer was usually confirmed noninvasively by the lack of change in the finding on follow-up CTs.
What was the absolute reduction in lung cancer risk in the NLST?
Please see the attached ‘Patient and Physician Guide’ for a discussion of absolute risk reduction.
Implications of NLST Findings
Is it OK to keep smoking because there is a screening test that has benefit?
No. Tobacco is one of the strongest cancer-causing agents. Tobacco use causes many different types of cancers, including lung cancer, as well as chronic lung diseases and cardiovascular diseases. The damage caused by smoking is cumulative and the longer a person smokes, the higher the risk of disease. By quitting smoking, the ongoing damage decreases. If you smoke, the most important thing you can do to decrease your risk of dying of a number of conditions, including lung cancer, is to stop smoking. CT screening decreases your risk of dying only for lung cancer, not other conditions. While it is never too late to quit smoking, the sooner a person quits the better. Finally, many participants in the trial died of lung cancer despite receiving CT screening.
- Cigarette, cigar, and pipe smoking all increase the risk of lung cancer. Tobacco smoking causes about 9 out of 10 cases of lung cancer in men and about 8 out of 10 cases of lung cancer in women.
- Studies have shown that smoking low tar or low nicotine cigarettes does not lower the risk of lung cancer.
- Studies also show that the risk of lung cancer from smoking cigarettes increases with the number of cigarettes smoked per day and the number of years smoked. People who smoke have about 20 times the risk of lung cancer compared to those who do not smoke.
Quitting smoking is hard, but there are many proven treatments that can help. NCI has information about stopping smoking at http://smokefree.gov or the Smoking Quitline at 1-877-44U-QUIT (1-877-448-7848). At that phone number, NCI smoking cessation counselors can give help quitting smoking and provide answers to smoking-related questions in English or Spanish, Monday through Friday, from 8:00 a.m. to 8:00 p.m., Eastern time.
Should all smokers have low-dose helical CT to screen for lung cancer and/or other diseases?
Not necessarily. The NLST participants were a very specific population of men and women ages 55 to 74 who were heavy smokers. They had a smoking history of at least 30 pack-years but no signs or symptoms of lung cancer at the beginning of the trial. Pack-years are calculated by multiplying the average number of packs of cigarettes smoked per day by the number of years a person has smoked. It should also be noted that the population enrolled in this study, while ethnically representative of the high-risk U.S. population of smokers, was a highly motivated and primarily urban group, and these results may not fully translate to other populations.
Men and women in a similar age group and with a similar smoking history should be aware that not all lung cancers found with screening will be early stage. A screening CT looks for initial signs of disease in healthy people while a diagnostic CT is done after a person has a sign or symptom of disease.
What resources are available to physicians who evaluate lung nodules found via a CT scan?
For physicians and other practitioners, the Fleischner Society (http://www.fleischner.org ), an international medical society for thoracic radiology, has established guidelines for diagnosing indeterminate lung nodules. Other professional organizations have developed guidelines for evaluating many other types of lung nodules.
What do the USPSTF lung cancer screening recommendations issued December 31, 2013 mean for lung screening?
The vast amount of data generated by NLST, some of which is still being studied, will greatly inform the development of clinical guidelines and policy recommendations. Those recommendations, however, are decisions that are being made by other organizations such as the U.S. Preventive Services Task Force (USPSTF).
The USPSTF issued draft recommendations in July 2013 for public comment and, based on that feedback, issued final recommendations, which can be found at http://www.uspreventiveservicestaskforce.org/uspstf13/lungcan/lungcanfinalrs.htm. The USPSTF now recommends annual screening for lung cancer with low-dose CT in people 55 through 80 years old with a 30 or more pack year history of smoking who are currently smoking or have quit within the past 15 years. They advise that screening should be discontinued once the individual has not smoked for 15 years or develops a health problem significantly limiting either life expectancy or ability or willingness to undergo curative lung surgery. They give lung cancer screening with low-dose CT a grade B recommendation. The grade of B denotes that the USPSTF has high certainty that the net benefit is moderate; or has moderate certainty that the net benefit is moderate to substantial.
The list of preventive services that have a rating of A or B from the USPSTF that are relevant for implementing the Affordable Care Act can be found at http://www.uspreventiveservicestaskforce.org/uspstf/uspsabrecs.htm. For more information about the Affordable Care Act and preventive services, go to https://www.healthcare.gov/what-are-my-preventive-care-benefits.
The USPSTF referenced modeling work done by NCI-sponsored CISNET researchers. What is CISNET and what did the modeling reports show?
In part, in order to inform other organizations such as the USPSTF, the Cancer Intervention and Surveillance Modeling Network (CISNET) developed a technical report that used five independent models and estimated the long term harms and benefits from a program of screening as experienced by people born in the U.S. in 1950 over their lifetime. This contrasts with the NLST screening trial, which for reasons of cost and efficiency, included heavy smokers age 55-74 at study entry who had three annual lung cancer screening exams. The year 1950 was chosen for the CISNET models because people born at this time are the same age as participants in the mid-range of those who enrolled in the NLST. The five models were calibrated to the NLST results and predicted lung cancer outcomes consistent with the trial observations. The researchers evaluated over 500 scenarios of annual or less frequent screening; for ages to start screening between 45 and 60 as well as ages to stop screening between 75 and 85; for a range of minimum smoking exposure (measured in pack-years); and the maximum time since quitting. CISNET models identified consensus strategies that were efficient, preventing the greatest number of lung cancer deaths for the screening exams required. The report can be found at http://www.uspreventiveservicestaskforce.org/uspstf13/lungcan/lungcanmodeling.htm.
Specifically, the investigators focused on 26 screening scenarios that started screening at age 50, 55 or 60 and stopped screening at age 80 or 85. Among these 26 programs, screening every three years reduced lung cancer mortality by 5 percent to 6 percent, compared to screening every two years that reduced mortality by seven percent to 10 percent, and annual screening that offered reductions between 11 percent and 21 percent.
The CISNET findings support a range of possible scenarios with competing tradeoffs of benefits and harms. For example, annual lung cancer screening of people with at least 30 pack-years of smoking and a maximum of 15 years since quitting who were between the ages of 55 and 80 offers one reasonable tradeoff between benefits and harms. Compar-able scenarios with a later starting age of 60 but increasing the maximum years since quitting (to 25 years) offer an alternative with a comparable tradeoff of benefits and harms. Extending eligibility to individuals with fewer pack-years, although still efficient among some of the scenarios considered, led to additional benefits but more corresponding harms.
The primary difference between the modeling findings and the initial NLST study findings is that, instead of the age group of 55-74 that was eligible for the trial deriving greatest benefit, the CISNET modeling shows that an age group of 55 to 80 of heavy smokers would benefit most from annual lung screening. However, the benefits of screening individuals at older ages is dependent on their underlying health status and the presence of illnesses that could increase the complication rates of a diagnostic evaluation and management of abnormalities identified by screening (such as heart disease, etc.).
CISNET models cannot determine which CT screening scenarios are “best”. They can, however, provide valuable tools to project the results of the trial to different scenarios over the course of a lifetime, and given calculations of harms and benefits, show which ones provide the greatest benefits for a specified level of harm.
Are there radiation exposure risks associated with repeat CT scans?
The radiation exposures from the screening done in the NLST will be modeled to see how low-dose CT scans change a person's risk for cancer over the remainder of his or her life, but these analyses are complex, require a number of assumptions, and will take a while to conduct.
Previous studies show that there can be an increased lifetime risk of cancer due to ionizing radiation exposure. It is important to recognize that the benefit of potentially finding a treatable cancer in current or former heavy smokers, ages 55 to 74, using helical CT appear to outweigh the radiation exposure risks of the procedure.
For comparison purposes, a standard low-dose helical CT scan as used in the NLST delivers a small amount of radiation to several organs in the body, primarily the lung (4 mGy, or milligrays, which is a measure of absorbed radiation dose) and the breast (4 mGy) but also the red bone marrow, stomach, liver and pancreas (each about 1 mGy). By comparison, a standard screening mammogram results in a similar radiation exposure to both breasts (about 4 mGy) but the doses to all other organs are negligible (less than 0.1 mGy). The total whole body effective dose that is ultimately delivered via a CT scan is calculated as a weighted average of the dose to each organ and is therefore higher for a lung CT scan, about 1.5 mGy, compared to 0.7 mGy for a mammogram. As a final comparison, a chest X-ray delivers only about 0.05 to 0.1 mGy.
Does screening with chest X-rays reduce lung cancer mortality?
No. Some NLST sites were also involved in a separate trial, the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, or PLCO. The PLCO, started in 1992, looked at chest X-rays for lung cancer screening in half of its 155,000 participants. The other half received usual care from their health care providers and served as the control group. A special analysis of about 30,000 PLCO participants, who were similar in age and smoking history to the population of NLST participants, showed no lung cancer mortality benefit for those who got chest X-rays. A full analysis of the PLCO trial was published in 2012; it also showed no lung cancer mortality benefit for participants in the chest X-ray part of the trial.
What additional questions will be answered as a result of the NLST?
The NLST results published in 2011 in the New England Journal of Medicine (and updated in Cancer on Nov. 15, 2013) are the primary findings. However, data from the NLST continue to be analyzed by NLST investigators and other researchers. Some important questions that are currently being addressed, or will be addressed in the future using NLST data, are as follows:
- What medical resources are utilized when CT screening tests or chest X-ray tests are positive in individuals at high risk of lung cancer?
- What is the overall cost-effectiveness of CT screening in the most commonly accepted health services research metric: dollars per quality-adjusted life year? This result was published in the New England Journal of Medicine on November 12, 2014.
- How does lung cancer screening affect an individual's quality of life overall, when the screening test is positive, and when the test determines that there is a lung cancer?
- How does lung cancer screening influence smoking behaviors and beliefs, both short-term and long-term?
- What early biomarkers for lung cancer in a group at high risk for lung cancer can be validated in the associated biospecimen archive (blood, sputum, urine)? Other information, such as germline (inherited) mutations that might predict increased risk of lung cancer, or somatic (non-heritable) mutations in the archived lung cancer specimens associated with outcomes from the cancer, may also be obtained.
- To what extent does low-dose CT detect slow-growing, non-life threatening lung tumors (“overdiagnosis”)?
A list of additional publications that utilize the NLST data can be found at https://biometry.nci.nih.gov/cdas/nlst/pubs_projects/browse/publications.
Background about the Trial
Why was this study needed?
Lung cancers, the vast majority of which are caused by cigarette smoking, are the leading cause of cancer-related deaths in the United States. This disease is expected to claim 159,480 lives in 2013. Lung cancer kills more people than cancers of the breast, prostate, and colon combined. There are more than 94 million current and former smokers in the United States, many of whom are at high risk of lung cancer.
Most lung cancers are detected when they cause symptoms. By the time lung cancer is diagnosed, the disease has often already spread outside the lung. Therefore, researchers have sought to develop methods to screen for lung cancer before symptoms become evident. Helical CT, a technology introduced in the 1990s, can detect tumors well under 1 centimeter (cm), or 0.4 inches in size, whereas chest X-rays detect tumors about 1 cm to 2 cm (0.4 to 0.8 inches) in size. It is sometimes hypothesized that the smaller the tumor, the higher the chance of long-term survival. However, in other randomized trials, chest X-ray screening has not been found to reduce deaths from lung cancer, even though it does increase the detection of small tumors. The NLST, with a large number of participants in a randomized trial, was able to provide the evidence needed to determine whether low-dose helical CT scans are better than chest X-rays in helping to reduce a person's chances of dying from lung cancer.
How do lung screening tests work?
A chest X-ray produces a picture of the organs within a person's chest. Throughout the procedure, the person stands with the chest pressed to a photographic plate, hands on hips and elbows pushed forward. During a single, sub-second breath-hold, a beam of X-rays passes through the person's chest to the photographic plate, which creates an image. When processed, the image is a two-dimensional picture of the lungs.
Low-dose helical CT uses X-rays to scan the entire chest in about 7 to 15 seconds during a single, large breath-hold. The CT scanner rotates around the person, who is lying still on a table as the table passes through the center of the scanner. A computer creates images from the X-ray information coming from the scanner and then assembles these images into a series of two-dimensional slices of the lung at very small intervals so that increased details within the organs in the chest can be identified.
In the NLST, four different brands of machines were used: GE Healthcare (5 models); Philips Healthcare (3 models); Siemens Healthcare (4 models); and Toshiba (2 models).
What happened during the study?
- Participants talked with NLST staff about the study and their eligibility was determined.
- Participants read and signed a consent form that explained the NLST in detail, including risks and benefits.
- Participants were assigned by chance (randomly assigned) to have either chest X-rays or CT scans, and were offered the same test each year for three years.
- Expert radiologists reviewed the chest X-ray or CT scan. Test results were mailed to the participants and to their doctors, who determined if follow-up tests were needed.
- Participants were asked to update information about their health periodically, for up to seven years.
- Some NLST screening centers collected blood, urine, or sputum (phlegm) specimens from participants for future lung cancer studies. Specimens of lung cancer and normal lung tissue that were removed during surgery were also collected from some of the participants. These specimens, also known as biospecimens, will be used for future research to look for biomarkers that may someday help doctors better screen for, and diagnose, lung cancer.
- During the trial, participants who were current smokers were encouraged to quit, and if they wished, were referred to smoking cessation resources. Participants did not have to quit smoking to take part in the study.
What happened if screening result was positive?
For participants with positive screening tests (a positive test means that it revealed an abnormality that might be cancer), the study centers notified the participants and their primary care doctors. Depending on the type of abnormality seen on the screening exam, recommendations for additional diagnostic evaluation were made. The names of diagnostic and cancer experts were provided on request, but decisions regarding further evaluation were made by participants and their doctors. Any tests performed to follow up on a positive screening result could have been performed at the study center if the participants and their doctors so chose.
Who paid for the testing?
- People participating in the trial were screened free of charge with either low-dose helical CT or chest X-ray.
- Costs for any diagnostic evaluation or treatment for lung cancer or other medical conditions were charged to the participants in the same way as if they were not part of the trial. A participant's medical insurance plan paid for diagnosis and treatment according to the plan's policies. Participants who had no insurance were referred to local community resources to receive needed evaluations.
- In addition to the low-dose helical CT scans and chest X-rays that all of the centers performed, some NLST centers also collected samples of blood, urine, or sputum for future lung cancer studies. These procedures were performed without charge.
About Screening for Lung Cancer
What are some of the possible risks of screening for lung cancer?
Recent studies indicate that 20 percent to 60 percent of screening CT scans of current and former smokers will show abnormalities. Most of these abnormalities are not lung cancer; they are false-positives. However, these abnormalities − scars from smoking, areas of inflammation, or other noncancerous conditions − can mimic lung cancer on scans and may require additional testing. These tests may cause anxiety for the participant or may lead to unnecessary biopsies or surgery.
Lung biopsy, a potentially risky procedure, involves the removal of a small amount of tissue, either through a scope fed down the windpipe (called bronchoscopy) or with a needle through the chest wall (called percutaneous lung biopsy). Though they happen infrequently, possible complications from biopsies include partial collapse of the lung, bleeding, infection, pain, and discomfort.
Depending on the size and location of the abnormality detected, chest surgery to obtain a larger biopsy specimen may be required. The two most common surgical procedures are thoracoscopy and thoracotomy. Thoracoscopy involves making three small incisions in the chest, using one opening to introduce a small camera and the others to introduce surgical instruments. Thoracotomy is major surgery that produces one large incision and typically is more painful, requires a longer recovery period, and is more dangerous in people with lung or heart conditions, which tend to be common in current or former smokers.
In addition, studies suggest that both CT and X-ray screening for lung cancer may detect small tumors that would never become life threatening. This phenomenon, called overdiagnosis (see definitions below), puts some screening recipients at risk from unnecessary diagnostic biopsies or additional surgeries as well as unnecessary treatments for cancer, such as chemotherapy or radiation therapy.
On Dec. 9, 2013, in JAMA Internal Medicine (doi:10.1001/jamainternmed.2013.12738), NLST authors and others issued a finding on overdiagnosis based on detailed analysis of the primary NLST findings. In particular, they focused on the fact that screening can detect slow-growing tumors that otherwise may not cause clinical symptoms, leading to overdiagnosis. Overdiagnosis cases represent one potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment.
The authors calculated two measures of overdiagnosis: the probability that a lung cancer detected by screening with low-dose CT is an overdiagnosis, defined as the excess lung cancers detected by low-dose CT divided by all lung cancers detected by screening in the low-dose CT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent one death from lung cancer.
In reporting their results from follow-up of 1089 lung cancers in the low-dose CT arm and 969 in the chest X-ray arm of the NLST, they found the following:
- The probability was 18.5 percent that any lung cancer detected by screening with low-dose CT was an overdiagnosis
- 22.5 percent probability that a non–small cell lung cancer, the most common form of the disease, detected by low-dose CT was an overdiagnosis
- The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent one death from lung cancer was 1.38
The authors concluded that a bit more than 18 percent of all lung cancers detected by low-dose CT in the NLST appeared to be indolent, and that overdiagnosis should be considered when describing the risks of low-dose CT screening for lung cancer. However, the authors also point out that these figures are likely to change as follow-up continues, and therefore may represent an upper bound on the estimates of overdiagnosis.
Why is mortality the measure of the effectiveness of a screening test? Why not case survival?
Mortality refers to the number of deaths from the disease within the whole population screened. Case survival refers only to the number of people with the disease remaining alive at a certain point in time after diagnosis.
Changes in lung cancer mortality rates (rates of death from lung cancer) are the accepted measure of screening effectiveness. The major reason that case survival cannot be used when determining the effectiveness of screening is that it does not take into account specific biases that affect its measurement. These biases are lead-time, length, and overdiagnosis bias.
Screening tests are performed in ostensibly healthy people who do not have symptoms of cancer. If the screening detects a cancer, the time of diagnosis is advanced (made earlier). The time between a screening diagnosis and death will be longer just because of early diagnosis, even if the screen does not ultimately change the time of death. This is called lead-time bias
Secondly, studies of other types of cancer show that screening tends to detect more slowly growing cancers and may not be helpful with very fast-growing tumors. This is called length bias. Screen-detected cancers may be less aggressive and slower-growing cancers than the cancers picked up by symptoms, which would make screening appear to prolong life, when in fact it is simply picking up the less lethal cancers. An extreme of this tendency is overdiagnosis bias, in which the tumor detected by screening has the pathologic features of malignancy but grows so slowly that it may never cause death.
Case survival measurements cannot adjust for lead-time, length, and overdiagnosis biases and may overestimate the benefit of screening. Showing a decrease in lung cancer deaths in those who are screened versus those who are not screened (or those receiving a different kind of screening test) through a randomized trial provides definitive evidence of screening benefit and circumvents the biases of lead time, length and overdiagnosis.
Definition of Terms
- Lead-time bias: Lung cancer-specific survival is measured from the time of diagnosis (Dx) of lung cancer to the time of death. If a lung cancer is screen-detected before symptoms (Sx), then the lead time in diagnosis equals the length of time between screening detection and when the first signs/symptoms would have appeared. Even if early treatment had no benefit, the survival of screened persons would be longer simply by the addition of the lead time. To be beneficial, screening tests should detect disease before signs or symptoms occur and must lead to decreased mortality.
- Length bias refers to the tendency of the screening test to detect cancers that take longer to become symptomatic; therefore, the more indolent, slower-growing cancers. Not all cancers have the same behavior: some are very aggressive, while some grow more slowly. The cancers that grow slowly are easier to detect because they have a longer pre-symptomatic period of time when they are detectable. Thus, the screening test detects more slowly growing cancers. The survival in patients with screen-detected cancers is longer in part because the screened cancers are more indolent. The improved survival cannot be accurately attributed to the early treatment.
- Overdiagnosis bias is an extreme form of length bias in which the screening test detects a lung cancer that is not lethal—it behaves like a benign process and does not result in the death of the individual. This benign process, sometimes called pseudodisease, is a cancer you die with and not from. It looks like cancer both to the naked eye and under the microscope, but it does not have the potential to kill. When a screening test detects such a cancer, it appears to have been treated successfully, making the screening test look effective when in fact, the test detected something non-lethal.
- Survival refers to the number of people remaining alive at a certain point in time relative to diagnosis. For example, a 5-year survival rate of 60 percent means that 60 percent of people will be alive five years from diagnosis. Survival is the most important measure used to compare different methods of treatment to one another. People with the same disease and severity of disease are treated with different agents (or in different ways); their survival is measured to determine which treatment is associated with longer survival.
- Mortality refers to the number of deaths from the disease within the population screened:
# Individuals screened overall
- Case fatality rate refers to the number of deaths from the disease within the population having the disease:
# Individuals with lung cancer
Case fatality rate cannot be used to measure screening effectiveness because it does not account for screening biases.
- Cure: Most commonly defined as survival to 5 years. This is an imprecise term that is highly confusing to the lay public. It is frequently misinterpreted as meaning permanently cancer-free.