National Lung Screening Trial: Questions and Answers
- What is the National Lung Screening Trial (NLST)? The NLST, a cancer screening clinical trial, compared the effects of two ways of detecting lung cancer − low-dose helical CT and standard chest X-ray – on lung cancer mortality rates. Both chest X-rays and CT scans have been used in efforts to find lung cancer early; this study examined the consequences of the screening methods on large, randomized populations of heavy smokers ages 55 to 74, using death from lung cancer as the primary end point. (Question 1)
- What was the primary result of the trial? NLST researchers found 20 percent fewer lung cancer deaths among trial participants screened with CT. (Question 3)
- 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. Conversely, if a person quits smoking, much of the damage is reversible over time. (Question 7)
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 distinguishes the initial results, reported in November 2010, from the publication of the primary results in June 2011?
The NLST Data and Safety Monitoring Board (DSMB), a group of independent experts, determined in October 2010 that sufficient data were available for the first time for the DSMB to ascertain that the study could provide a statistically significant answer to the study's primary objective and that the group receiving low-dose helical CT scans had a benefit. The conclusions were conveyed in a letter to the NCI director, in which the DSMB recommended that this information be made public. NCI concurred with the recommendation and reported the initial results on November 4, 2010. The 2010 results pertained only to screening positivity, lung cancer mortality, and all-cause mortality. On June 29, 2011, the primary results were published online in the New England Journal of Medicine and represented a more comprehensive accounting of the mortality benefit for low-dose helical CT in addition to providing detail on diagnostic procedures performed and resulting lung cancers that were diagnosed.
What was the primary result of the NLST?
The NLST researchers found 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.
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. 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.
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. They should also be aware that at this time, reimbursement for screening CT scans is not provided by most insurance carriers. The current estimated Medicare reimbursement rate for a non-contrast helical diagnostic CT of the lung is $300 but varies by geographic location. A diagnostic CT is done after a person has a sign or symptom of disease, while a screening CT looks for initial signs of disease in healthy people.
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 organizations have developed guidelines for many other types of lung nodules.
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 three low-dose CT scans changed a person's risk for cancer over the remainder of his or her life, but that analysis 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 low-dose CT used for screening in the NLST delivers a much lower dose of radiation than a regular diagnostic CT. Additionally, 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 and has 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. Independent of the NLST, investigators from the lung component of the PLCO will report their full set of findings in the near future.
What do NLST participants do now?
In the NLST, participants received three screening tests after they were randomly assigned to either the CT or chest X-ray arm: one screen at the time of enrollment and then two more annually. All of the participants finished receiving NLST screening tests by the end of 2007 and have been under the care of their personal health care providers rather than study personnel.
Participants were sent a letter in November 2010 with the initial study results. It was recommended that those who received chest X-rays talk with their health care providers about having low-dose helical CT scans. Because it is not known if having more than three low-dose helical CT scans has any benefit, those who received helical CT scans in the NLST were advised to talk to their personal health care providers about lung cancer screening, including the possibility of having additional helical CT scans. Reimbursement for screening CT scans is not provided by most insurance carriers.
Data from the NLST will continue to be analyzed by the NLST investigators. Additional publications will be forthcoming and results will appear at http://www.cancer.gov/clinicaltrials/noteworthy-trials/nlst/updates. NCI is committed to guarding the identity of all participants in the trial. The availability of data from the study will be governed by the informed consent documents signed by the participants and by requirements of law.
Will screening recommendations for lung cancer change based on these results?
As with all cancer clinical trials, the NLST provided answers to a set of very specific questions related to a specific population. Whether those answers can be used to provide general recommendations for the entire population must be the subject of future analysis and study. The vast amount of data generated by NLST, much of which is still being studied, will greatly inform the development of clinical guidelines and policy recommendations. Those, however, are decisions that will ultimately be made by other organizations.
What additional questions will be answered as a result of the NLST?
The NLST results in the June 29, 2011, online issue of the New England Journal of Medicine are the primary findings. Many more analyses will be done to try to answer questions such as:
- 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?
- 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.
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 156,940 lives in 2011. 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 already spread outside the lung in 15 percent to 30 percent of cases. 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 did two different trials address the question of benefit from lung cancer screening?
The International Early Lung Cancer Action Project (I-ELCAP) conducted a non-randomized study that used CT screening to detect early lung cancer. Its results, which were reported in 2006, suggested that CT screening might be beneficial. However, because the I-ELCAP study was not a randomized trial and did not use the endpoint of lung cancer mortality, many clinical investigators waited until the NLST results were available so that the utility of this screening approach could be determined definitively. Another non-randomized study of CT screening, which was published in 2007, failed to demonstrate the benefits inferred from the I-ELCAP trial. These conflicting results underscored the importance of NLST and its randomized trial design.
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.
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.
For a press release related to the NLST primary results, please go to http://www.cancer.gov/newscenter/pressreleases/2011/NLSTprimaryNEJM.
For a Fact Sheet on the NLST, please go to http://www.cancer.gov/newscenter/pressreleases/2011/NLSTFastFacts.
For more information on lung cancer and screening, please go to http://www.cancer.gov/cancertopics/types/lung.
Copies of the DSMB and NLST participant letters can be found on the NLST site at http://www.cancer.gov/clinicaltrials/noteworthy-trials/nlst.
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