Key Points What is the National Lung Screening Trial? The National Lung Screening Trial (NLST), a cancer screening clinical trial, will compare 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 most frequently caused by cigarette smoking, is the leading cause of cancer-related deaths in the United States. It is expected to claim nearly 162,460 lives in 2006. 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 high risk for lung cancer. (Question 2) How does spiral CT work? 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 3-D model of the lungs. (Question 4) How is spiral CT used in hospitals now? More than half of the hospitals in the United States own 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. Recently some hospitals have begun performing spiral CT scans as a new way to find early lung cancer in smokers and former smokers. (Question 5)

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 show if either test is better at reducing deaths from this disease. The trial, slated to last until 2009, also will examine the risks and benefits of spiral CT scans compared to chest X-rays. By February 2004, NLST had enrolled over 50,000 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.

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.

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 nearly 162,460 lives in 2006. 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 high risk for 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?

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-ray. 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 the NLST.

An observational lung cancer screening study, published in Lancet in 1999, provided researchers with important information that assisted in the design of the NLST: how often spiral CT screening tests are positive; and what percentage of those positive tests actually turn out to be cancers. However, the observational results did not provide information on whether spiral CT screening lowered 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.

International observational study results, recently reported in the literature, will help 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 lowers death rates in screened populations. Survival statistics alone are misleading because screening tests should detect cancers prior to the development of signs or symptoms. As such, screening would be expected to improve survival, even if it does not prevent or delay the time of death, simply by advancing (making earlier) the time of diagnosis.

Additionally, researchers cannot compare results of an observational trial with historical epidemiologic data on mortality. Such comparisons are not valid because they introduce biases. For example, observational data on hormone replacement therapy showed a striking benefit to women, 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 too great in the women who were receiving hormone replacement therapy. Because the mortality benefit question must be answered, the NCI has funded the NLST. Similarly, many European scientific groups are developing randomized trials in the fashion of the NLST.

4. How does spiral CT work?

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 3-D model of the lungs.

5. How is spiral CT used in hospitals now?

About 60 percent of the hospitals in the United States own 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. Recently some hospitals have begun performing spiral CT scans as a new way to find early lung cancer in smokers and former smokers.

6. What were the possible benefits of participating in this trial?

All participants receive a free lung cancer screening exam. 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 for sure that these things will happen. Data gathered from NLST will help to clarify some of these uncertainties.

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 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.

To insure 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 Independent Review Board which must review and approve all materials and actions for NLST participants.

8. How long will the trial last? What will happen during the study?

When people entered the study, starting in 2002, they were randomized - assigned by chance - to receive either a spiral CT scan or a chest X-ray. They had the same screening procedure again one and two years after their first scan. Unless an annual, external review panel finds compelling evidence of benefit or harm in 2007 or 2008, the study will conclude in 2009. Until that time, researchers will contact participants, by phone or mail, at least yearly to monitor their health.

Some NLST centers will collect blood, urine, or sputum (phlegm). Specimens of lung cancer and normal lung tissue that have been resected during surgery will also be collected in some of the patients. These samples will be used for future research to test biomarkers that may someday help doctors better diagnose lung cancer. During the trial, if participants want to quit smoking, they will be referred to smoking cessation resources. But they do not have to quit to take part in the study.

9. What is a randomized, controlled study?

A randomized, controlled trial is the most reliable method of determining what medical interventions work best and are safest. Participants are assigned by chance––randomized––to one of two groups, where one group receives one intervention and the other group receives another. One of the groups serves as a comparison group, or "control," for the other.

In a randomized trial, the goal is to determine if 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.

10. Who was eligible to join NLST?

The trial is now closed to further enrollment. Current or former smokers, who have smoked heavily or for many years and are between 55 and 74 years of age, were eligible for this study. All potential participants were asked a series of questions to ensure that they were eligible to participate. For scientific reasons, these screening tests will be evaluated in current or former smokers who have a high risk of developing lung cancer and who may benefit from early disease detection.

All potential participants were to be in general good health, without a history of lung cancer, and in the 5 years prior to their enrollment, not have been treated for, or had evidence of, any cancer, other than nonmelanoma 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 5 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.

11. 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, to recruit 3,000 current and former smokers in late 2000. Within two months, all the necessary participants agreed to join the study and to 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 will be large enough to answer the important public health question of whether lung cancer screening with either of these two methods reduces deaths from the disease.

12. What happens if lung cancer is 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 will notify the participants and their primary care physicians and encourage a consultation with a cancer expert. Guidelines for the diagnostic evaluation of positive screening tests have been determined by the NLST investigators based on current best practices and will be included in the screening results given to participants and their health care providers. Names of cancer experts will be provided upon request, but decisions regarding further evaluation will be made by participants and their physicians. Tests needed to follow up on a positive screening result may be performed at the study center, if participants and their physicians so choose.

13. Will participating in NLST cost anything?

People participating in the trial will be 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 will be charged to the participants in the same way as if they were not part of the trial. A participant's medical insurance 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.

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

People can call the NCI'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) 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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