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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 happens during the study?
What are the possible benefits of participating 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 are participants' doctors involved?
What happens if lung cancer is found during the study?
Who pays 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 chest X-rays nor spiral CT scans have been shown to reduce a person's chance of dying from lung cancer. This study will aim to show if either test is better at reducing deaths from this disease.
By February 2004, nearly 50,000 current or former smokers had joined NLST at more than 30 study sites across the country. The trial, now closed to further enrollment, is slated to collect and analyze data for eight years, and will examine the risks and benefits of spiral CT scans compared to chest X-rays.
This trial is a randomized, controlled study--the "gold standard" of research studies--and is large enough to determine if there is a 20 percent or greater drop in lung cancer mortality from 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 more than 162,400 lives in 2006. 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 high risk for lung cancer.
Currently, when lung cancer is detected, the disease has already spread outside the lung in 15 percent to 30 percent of cases. Spiral CT, a technology introduced in the 1990s, can pick up tumors well under one 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 survival. But no scientific evidence to date has shown that screening or early detection of lung cancer actually saves lives. NLST, because of the large number of individuals participating and because it is a randomized, controlled trial, will be able to provide the evidence needed to determine whether spiral CT scans are better than chest X-rays at reducing 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 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, if it tests positive and up until diagnosis?
- How does lung cancer screening influence smoking behavior and beliefs?
- Can blood, urine, or sputum (phlegm) predict lung cancer in high risk groups?
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Some studies have shown that spiral CT detects smaller abnormalities than chest x-ray. 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, controlled clinical trial as we are doing in 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.
Spiral CT, also called helical CT, uses X-rays to scan the entire chest in about 15 to 25 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 for the trial study in less than eighteen months. When people entered the study, they were randomized--assigned by chance--to receive either a spiral CT scan or a chest X-ray. They will have the same screening procedure again one and two years later. Until 2009, researchers will 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.
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- Participants talk with NLST staff about the study and determine eligibility.
- Participants read and sign a consent form that explains NLST in detail. (A Guide to Understanding Informed Consent describes how clinical trial participants are protected during the course of a study.)
- Participants are assigned by chance (randomized) to have either chest X-rays or CT scans, and will receive the same test each year for three years.
- Expert radiologists review the chest X-ray or CT scan.
- Test results are mailed to the participant and his/her doctor, who determines if follow-up tests are needed.
- Participants are asked to update information about their health periodically, for up to eight years.
- Some NLST Screening Centers collect blood, urine or sputum (phlegm) for future lung cancer studies.
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All participants receive a free lung cancer screening exam each year for three years. It is also possible that if lung cancer is detected, it may be caught at an early stage. Early detection of lung cancer may reduce symptoms from cancer, result in milder treatment with fewer side effects, or prolong life, but scientists don't know these things will happen for sure. Data gathered from NLST will help to clarify some of these uncertainties.
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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 upon 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 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.
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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.
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, while 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. The survival in patients with screen-detected cancers is longer in part because the screened cancers are more indolent, but 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 - 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 pseudodisease, 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, 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 significant and are widely appreciated. It is for this reason that lung-cancer-specific mortality (the number of deaths among those screened) has remained the single most 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:
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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 is highly confusing to the lay 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 will be analyzed each year, beginning in 2006. If there are significant differences in outcomes between the chest x-ray and CT groups the trial design might be changed or the trial may end early. Each NLST site also has an Independent Review Board which must review and approve all materials and actions for NLST participants.
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The informed consent document that participants review 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 are mailed to that participant and her/his doctor. If the screening detects something (see below), the participant and doctor will be notified so that they can review medical options.
Some NLST Screening Centers may ask to collect your blood, urine or sputum (phlegm) for future lung cancer studies. Follow-up information about these tests will be provided to participants and their doctor.
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For participants with positive screening tests, meaning that the screening test reveals an abnormality that might be cancer, the study centers will notify the participants and their primary care doctors and encourage a consultation with a cancer expert. Names of cancer experts will be provided upon request, but decisions regarding further evaluation will be made by participants and their doctors. Any tests performed to follow up on a positive screening result may be performed at the study center, if participants and their doctors so choose.
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People participating in the trial are 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 are charged to the participants in the same way as if they were not part of the trial. A participant's medical insurance plan will pay for diagnosis and treatment according to the plan's policies.
If the participant has no insurance, aid may be available at the local level to pay for biopsies and treatment.
In addition to the spiral CT scans and chest X-rays that all the centers do, some NLST centers also collect samples of blood, urine or sputum for future lung cancer studies. (See the list of NLST Screening Centers for more details.) These tests are done without charge.
People are not paid or receive other compensation for participation in this study.
Questions about cost can be addressed by staff at the NLST Screening Centers.
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