Key Points What is the National Lung Screening Trial? The National Lung Screening Trial (NLST), a cancer screening clinical trial, 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. (Question 1) Why is this study needed? Lung cancer, which is caused most frequently 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 an estimated 91.5 million current and former smokers in the United States, all of whom are at higher risk of lung cancer. (Question 2) How does spiral CT work? 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. Throughout the procedure, the participant lies still on a table. The table and patient pass through the CT scanner, which is shaped like a donut with a large hole. The scanner rotates around the participant, and a computer creates images from the scan, assembling them into a three-dimensional model of the lungs. (Question 4)

1. What is the National Lung Screening Trial?

   The National Lung Screening Trial (NLST), a cancer screening clinical trial, 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, however, neither chest X-rays nor spiral CT scans have been shown to reduce a person's chance of dying from lung cancer. This study aims to determine whether one test is better than the other in helping to reducing deaths from this disease. The trial, slated to survey participants through 2010, also will examine the risks and benefits of spiral CT scans compared to chest X-rays. By February 2004, NLST had enrolled approximately 53,000 current or former smokers at more than 30 study sites throughout the United States. The trial is now closed to further enrollment. The study is funded by the National Cancer Institute (NCI).

   This trial is a randomized, controlled study--the "gold standard" of research studies--and should be large enough to determine whether there is a 20 percent or greater drop in lung cancer mortality among those screened by from using spiral CT compared to chest X-ray.

2. Why is this study needed?

   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 an estimated 91.5 million current and former smokers in the United States, all 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 in size, while chest X-rays can detect tumors about 1 to 2 centimeters (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 number of individuals participating and because it is a randomized, controlled 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 in those who tests positive?
   • How does lung cancer screening influence smoking behavior and beliefs?
   
   

3. Why is this study needed if observational studies have shown that spiral CT can improve the survival of people with lung cancer?

   Some studies have shown that spiral CT detects smaller abnormalities than chest X-rays. However, smaller cancers are not always "early" cancers, and scientists do not know if detecting these small abnormalities, and then treating them, will reduce lung cancer deaths. To address this question, it is necessary to conduct a randomized, controlled trial such as NLST.

   An observational lung cancer screening study, published in The Lancet in 1999, provided researchers with important information that assisted in the design of NLST: how often spiral CT screening tests are positive and what percentage of those positive tests actually turn out to be cancer. However, the observational results did not provide information about whether or not spiral CT screening helped lower the number of deaths from lung cancer. The data do not yet exist to know whether either spiral CT or chest X-ray is a beneficial screening test for lung cancer.

   In addition, international observational study results have helped answer a variety of questions about imaging-based screening for lung cancer. However, without a control arm that does not receive the screening test of interest, it is not possible to determine whether CT screening helps lower lung cancer death rates in screened populations. Survival statistics alone are misleading because screening tests should detect cancers before the development of signs or symptoms. As such,, even if screening does not help prevent or delay the time of death, it would be expected to help improve survival simply by advancing (making earlier) the time of diagnosis.

   Furthermore, researchers cannot compare results of observational studies with historical epidemiologic data on mortality. Such comparisons are not valid because they introduce biases. For example, observational data on hormone replacement therapy in postmenopausal women showed striking cardiovascular health and other benefits, but the results of the Women's Health Initiative (WHI) demonstrated increases in heart disease and stroke with hormone therapy. Ultimately, the WHI trial was stopped because the risks were considered too great for the women who were receiving hormone replacement therapy. Because the question about the mortality benefit from lung cancer screening must be answered, NCI funded NLST. Similarly, many European scientific groups are developing randomized trials similar to NLST.

4. How does spiral CT work?

   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. Throughout the procedure, the participant lies still on a table. The table and patient pass through the CT scanner, which is shaped like a donut with a large hole. The scanner rotates around the participant and a computer creates images from the scan, assembling them into a three-dimensional model of the lungs.

5. How is spiral CT used in hospitals now?

   Virtually all hospitals and free-standing radiology facilities in the United States have a spiral CT machine. These machines are routinely used for staging lung and other cancers -- that is, determining how advanced the cancer is after diagnosis. Some hospitals perform spiral CT scans as a new way to find early lung cancer in smokers and former smokers.

6. What were the possible benefits for participants of this trial?

   All participants received a free lung cancer screening exam. 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 clarify some of these uncertainties. Smoking cessation information and/or assistance was also offered to participants.

7. What are some of the possible risks of screening for lung cancer?

   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.

   To ensure patient safety, 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. Each NLST site also has an Institutional Review Board (IRB) that must review and approve all materials and actions for NLST participants.

8. What will happen during the study?

   When people entered the study, starting in 2002, 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, by phone or mail, at least yearly to monitor their health.

   Some NLST centers collected blood, urine, or sputum (phlegm) specimens from participants. 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 will be referred to smoking cessation resources. But they did not have to quit to take part in the study.

9. How long will the trial last?

   NLST researchers originally projected that the information obtained on deaths that occurred 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 its cause (lung cancer or other 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.

10. What is a randomized, controlled trial?

    A randomized, controlled trial is the most reliable method of determining what medical interventions work best and are safest. Participants are assigned by chance -- that is, randomly assigned -- to one of two (or more) groups, with one group receiving one intervention and the other group receiving another. One of the groups serves as a comparison group, or control, for the other.

    In a randomized trial, the goal is to determine whether there are differences in outcomes between the two groups at the end of the study. The process of randomization aims to evenly distribute between the study groups all characteristics of the participants, such as health histories, that can influence outcome other than the interventions being studied.

    If each group includes similar participants, then any differences seen in outcome between the two groups can be attributed to the intervention. In this screening study, participants will have an equal chance of being assigned to a group that is screened with spiral CT or to a group that is screened with chest X-ray.

11. Who was eligible to join NLST?

    The trial is now closed to further enrollment. Current or former smokers who had smoked heavily or for many years and were between 55 and 74 years of age were eligible for this study. The choice to focus on individuals with this smoking history was made for scientific reasons. That is, the goal was to evaluate lung cancer screening in current or former smokers who had an increased risk of developing lung cancer and who might benefit from early disease detection. All potential participants were asked a series of questions to ensure that they were eligible to participate.

    All potential participants had to be in general good health, without a history of lung cancer, and, in the five years prior to their enrollment, not have been treated for, or had evidence of, any cancer other than non-melanoma skin cancer or most in situ cancers (participants must not have had bladder cancer in situ or transitional cell cancer in situ in the past five years). Potential participants also could not be enrolled in any other cancer screening or cancer prevention trial and could not have had a CT scan of the chest or lungs within the prior 18 months of their enrollment.

12. Have current and former smokers participated in studies like this before?

    To determine the willingness of participants to join a study like NLST, NCI launched a small trial, called the Lung Screening Study, in late 2000 to recruit 3,000 current and former smokers. Within two months, all necessary participants agreed to join the study and be assigned by chance to receive either a spiral CT scan or a chest X-ray. The success of this study's recruitment led NCI to undertake NLST, which should be large enough to answer the important public health question of whether one of these methods of lung cancer screening is better than the other in helping to reduce deaths from the disease. Results from the Lung Screening Study were presented at a scientific meeting in Orlando, Fla., in June 2009 and showed that lung cancer screening with low-dose CT results in a high rate (33 percent after two screenings) of false positives (indicating cancer is present when it is not) and extensive follow-up testing.

13. What happened if lung cancer was found during the study?

    For participants with positive screening tests, meaning that the screening test reveals an abnormality that might be cancer, the study centers notified the participants and their primary care physicians and encouraged a consultation with a cancer expert. Guidelines for the diagnostic evaluation of positive screening tests had been determined by the NLST investigators based on current best practices and were included in the screening results given to participants and their health care providers. Names of cancer experts were provided upon request, but decisions regarding further evaluation were made by participants and their physicians. Tests needed to follow up on a positive screening result may have been performed at the study center, if participants and their physicians chose this option.

14. Did participating in NLST cost anything?

    People participating in the trial were screened free of charge with either spiral CT or chest X-ray. However, 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 company paid for diagnosis and treatment according to their plans' policies. If the participant had no insurance, the availability of aid was explored at the local level to pay for biopsies and treatment.

15. How can one get more information about lung cancer or NLST?

    People can call NCI's Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) for information about the trial in English or Spanish. The number for callers with TTY equipment is 1-800-332-8615.

    A National Lung Screening Trial press release can be found at http://www.cancer.gov/newscenter/nlst.

    Read an interview with NLST scientists, view a video news release on the launch of the trial, and find photos, stills, audio clips, and other materials related to NLST at http://newscenter.cancer.gov/newscenter/benchmarks-vol2-issue9.

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