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What is NLST? What is NLST?
Why is this study needed?
What have previous studies found?
How do these tests work?
How long will the trial last?
What happened during the study?
What were the possible benefits for participants in NLST?
What are some of the possible risks of screening for lung cancer?
Why can't five-year survival rates be used as a measure of lung cancer screening success?
What is the appropriate measure of screening effectiveness?
How do you monitor safety for participants?
How is participant privacy protected?
How were participants' doctors involved?
What happened if lung cancer was found during the study?
Who paid for the testing?
The National Lung Screening Trial (NLST) is a lung cancer screening trial sponsored by the National Cancer Institute (NCI). Screening means testing people to detect a disease before it causes symptoms.
Launched in 2002, NLST is comparing two ways of detecting lung cancer: spiral computed tomography (CT) and standard chest X-ray. Both chest X-rays and spiral CT scans have been used to find lung cancer early. So far, neither test has been shown to reduce a person's chance of dying from lung cancer. This trial aims to determine whether one test is better than the other in helping to reduce deaths from this disease.
By February 2004, more than 53,000 current or former smokers had joined NLST at more than 30 study sites across the country. The trial, now closed to further enrollment, is collecting and analyzing data, and will examine the risks and benefits of spiral CT scans compared to chest X-rays.
This trial is a randomized clinical trial - the "gold standard" of research studies - and should be large enough to determine whether there is a 20 percent or greater decrease in lung cancer mortality among those screened by using spiral CT compared to chest X-ray.
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Lung cancer, which is most frequently caused by cigarette smoking, is the leading cause of cancer-related deaths in the United States. It is expected to claim 159,390 lives in 2009. Lung cancer kills more people than cancers of the breast, prostate, colon, and pancreas combined. There are more than 90 million current and former smokers in the United States, many of whom are at higher risk of lung cancer.
Currently, 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. Spiral CT, a technology introduced in the 1990s, can pick up tumors well under 1 centimeter (cm) in size, while chest X-rays detect tumors about 1 to 2 cm (0.4 to 0.8 inches) in size. Conventional wisdom suggests that the smaller the tumor, the more likely the chance of long-term survival. However, in randomized trials, X-ray screening has not been found to help reduce deaths from lung cancer, even though it does increase the detection of small tumors. NLST, because of the large number of individuals participating and because it is a randomized trial, should be able to provide the evidence needed to determine whether spiral CT scans are better than chest X-rays in helping to reduce a person's chances of dying from lung cancer.
Several additional important questions being addressed in NLST include
- What are all of the causes of death in groups who are screened for lung cancer?
- At what stage is lung cancer diagnosed when screened?
- How well does the screening test detect early lung cancer and all lung cancers?
- What follow-up medical tests are used when CT screening tests or chest x-ray screening tests are positive in high-risk people?
- How cost effective is lung cancer screening?
- How does lung cancer screening affect quality of life for those who test positive?
- How does lung cancer screening influence smoking behavior and beliefs?
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Some studies have shown that spiral CT detects smaller abnormalities than chest x-rays. However, smaller cancers are not always "early" cancers, and we do not know if detecting these small abnormalities and treating them will reduce lung cancer deaths. To address this question, it is necessary to conduct a randomized clinical trial such as NLST.
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A chest X-ray produces a picture of the organs within the chest. Throughout the procedure, the participant stands with the chest pressed to a photographic plate, hands on hips and elbows pushed forward. During a single, large breath-hold, a short beam of X-rays passes through the participant's chest to the photographic plate, which then creates an image on the film. When processed, the film produces a two-dimensional picture of the lungs.
In NLST, spiral CT, also called helical CT, uses X-rays to scan the entire chest in about 12 to 20 seconds during a single, large breath-hold. The CT scanner rotates around the participant, 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 three-dimensional model of the lungs.
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The study opened for enrollment in September 2002 and closed in February 2004. The researchers enrolled the 50,000 people needed for the trial in less than 18 months. When people entered the trial, they were randomly assigned (by chance) to receive either a spiral CT scan or a chest X-ray. They then had the same screening procedure again at one and two years after their first scan. Researchers contact participants at least yearly to monitor their health.
If there is strong evidence that one form of screening for lung cancer saves more lives than the other, the trial could end early.
NLST researchers originally projected that the information on deaths occurring through the second half of 2008 would be sufficient for the trial to reach a definitive conclusion. However, because it takes, on average, 18 months to learn of a death, collect a death certificate, and verify the cause of death (lung cancer or another cause), data from deaths occurring in 2008 may not be available until 2010.
In addition, as a precautionary measure, NLST researchers decided to proceed with collecting data on events (deaths, etc.) occurring through the end of 2009. If they waited until 2010, as originally planned, to make a decision on collecting data from 2009, they would have a harder time obtaining the information than if the data were collected with standard procedures in real time.
These data will be accumulated over 18 months and, as they become available, will provide additional contributions to analyses occurring in 2010 and, if needed, in 2011. It is important to note that the regular interim analyses will continue to be conducted, and a conclusive result could be reached before 2011.
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- Participants talked with NLST staff about the study and their eligibility was determined.
- Participants read and signed a consent form that explained NLST in detail. (A Guide to Understanding Informed Consent describes how clinical trial participants are protected during the course of a study.)
- Participants were assigned by chance (randomly assigned) to have either chest X-rays or CT scans, and received the same test each year for three years.
- Expert radiologists reviewed the chest X-ray or CT scan.
- Test results were mailed to the participant and his/her doctor, who determined if follow-up tests were needed.
- Participants were asked to update information about their health periodically, for up to eight 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 resected during surgery have also been collected for some of the patients. 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, if participants want to quit smoking, they are referred to smoking cessation resources. But they did not have to quit to take part in the study.
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All participants received a free lung cancer screening exam each year for three years. It was also possible that if lung cancer was detected, it may have been caught at an early stage. Early detection of lung cancer may help prevent symptoms eventually caused by the cancer, result in milder treatment with fewer side effects, and/or prolong life, but scientists don't know for certain that these things will happen. Data gathered from NLST will help to clarify some of these uncertainties. Smoking cessation information and/or assistance was also offered to participants.
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Recent studies indicate that 25 percent to 60 percent, or more, of screening CT scans of smokers and former smokers will show abnormalities. Most of these abnormalities are not lung cancer. 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 biopsy 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 (called thoracotomy or thoracic surgery) to obtain a larger biopsy specimen may be required. Thoracotomy is major surgery that removes substantial amounts of lung tissue. The procedure can damage nerves in the chest, and is more dangerous in people with underlying 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, puts some screening recipients at risk from unnecessary biopsies or surgeries as well as unnecessary treatments for cancer, such as chemotherapy or radiation therapy.
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Survival refers to the number of people who are alive at a certain point in time relative to when they were diagnosed. A screening test that detects cancers before symptoms develop improves "survival" if only because the cancer is found earlier - even if the patient still dies on the same day they would have had they not been tested. Therefore, survival is not an acceptable measure of how good a screening test is.
Consider exactly how a five-year survival rate is figured. It is a fraction. Imagine 1,000 people diagnosed with lung cancer five years ago. If 150 are alive today, the five-year survival is 150/1000, or 15 percent. Even if a screening test increases the five-year survival to 90 percent, it is entirely possible that none of the patients with screened-detected lung cancer will live even an extra day. This is why the only way to correctly measure the effectiveness of a lung cancer screening test is to measure mortality, which is the number of deaths from lung cancer in each group screened. Mortality is calculated by dividing the number of patients in each group who died from lung cancer by the number in each group who were screened.
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Change in lung cancer mortality (deaths from lung cancer) is the accepted measure of screening effectiveness. Where screening is concerned, the survival from the time of diagnosis misrepresents the benefit because it is confounded by several biases peculiar to screening:
- Lead-time bias: Lung-cancer-specific survival is measured from the time of diagnosis of lung cancer to the time of death. If a lung cancer is screen-detected before symptoms, 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 is 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.
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- Length bias refers to the tendency of the screening test to detect cancers that take longer to become symptomatic; that is, the more indolent, slow-growing cancers. Not all cancers have the same behavior: some are very aggressive, whereas some grow more slowly. The cancers that grow slowly are easier to detect because they have a longer presymptomatic period when they are detectable. Thus, the screening test detects more slow-growing cancers than fast-growing cancers. Patients with screen-detected cancers survive longer in part because the screened cancers are more indolent, but the improved survival cannot be accurately attributed to the early treatment.
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- Overdiagnosis bias is an extreme form of length bias in which the screening test detects a lung cancer that is not lethal - that is, a cancer that behaves like a benign process and does not result in the death of the individual. This benign process, sometimes called pseudo-disease, is a tumor one dies 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 tumor that is then removed, it appears to have been treated successfully, making the screening test look effective when, in fact, the test detected something nonlethal.
There are other biases that render survival an ineffective measure of screening benefit, but lead-time, length, and overdiagnosis bias are the most important and are widely appreciated. It is for this reason that lung cancer-specific mortality (the number of deaths among those screened) has remained a highly valid measure of screening benefit; it circumvents these biases. It is important to note that "case fatality rate" cannot be used as a measure of screening effectiveness because this measurement does not eliminate these biases. Case fatality rate refers to number of deaths occurring among those with lung cancer. As such, case fatality rate includes the very slow growing cancers (length bias) and benign-behaving cancers (overdiagnosis bias) detected by screening, in which outcomes are expected to be very good. Case fatality rates misrepresent screening benefit by making screen-detected lung cancer appear to result in better outcomes, when, in fact, the overall death rates in the screened population (mortality rate) may not improve.
A DEFINITION OF TERMS:
Survival refers to the number of people remaining alive at a certain point in time relative to diagnosis. For example, a five-year survival 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:
| # Deaths |
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| # Individuals screened overall | Case fatality rate refers to the number of deaths from the disease within the population having the disease:
| # Deaths |
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| # 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 disease-free survival to five years. This is an imprecise term that can be highly confusing to the public. It is frequently misinterpreted as meaning permanently cancer-free.
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An independent Data and Safety Monitoring Board meets bi-annually and makes recommendations on trial design and progress based on careful review of all data across the entire trial. The NLST data have been analyzed each year, beginning in 2006. If there are statistically significant differences in outcomes between the chest x-ray and CT groups, the trial may be stopped. Each NLST site also has an Independent Review Board that must review and approve all materials and actions for NLST participants.
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The informed consent document that participants reviewed prior to their enrollment in the study contains a statement on confidentiality telling the extent to which access to an individual's medical information will be restricted. (For links to material about the ways in which clinical trial participants are protected before and during the conduct of a study, see Protecting Participants in Clinical Trials.)
This confidentiality statement specifies any groups or organizations that may have access to a participant's records for quality assurance and data analysis (such as the National Cancer Institute, the Food and Drug Administration, or other trial sponsor).
The privacy of research participants' medical records are protected by law under national standards set to protect the privacy of personal health information, administered by the U.S. Department of Health and Human Services.
For specific information about NLST's informed consent document, contact one of the sites. Use the NLST Screening Centers map to find and contact a participating cancer center near you. Or call the National Cancer Institute's Cancer Information Service toll-free, Monday through Friday, 9 a.m. to 4:30 p.m., at 1-800-4-CANCER (1-800-422-6237). Information is available in English or Spanish. The number for callers with TTY equipment is 1-800-332-8615.
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All participant test results were mailed to that participant and her/his doctor. If the screening detected something (see below), the participant and doctor were notified so they could review medical options.
Some NLST Screening Centers may have collected blood, urine, or sputum (phlegm) for future lung cancer studies. Follow-up information about these tests was given to participants and their doctor.
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For participants with positive screening tests, meaning the screening test revealed an abnormality that might be cancer, the study centers notified the participants and their primary care doctors and encouraged a consultation with a cancer expert. Names of 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.
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- People participating in the trial were screened free of charge with either spiral 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.
- If the participant had no insurance, aid may have been available at the local level to pay for biopsies and treatment.
- In addition to the spiral 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. (See the list of NLST Screening Centers for more details.) These procedures were performed without charge.
- People were not paid and did not receive other compensation for participation in this study.
- Questions about cost can be addressed by staff at the NLST centers.
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