Credit: Teresa Winslow (artist), for NCI

People with a history of smoking have a high risk of lung cancer – a disease with a five-year relative survival rate (for smokers and non-smokers combined) of only 15.8 percent.  Previous attempts at developing a test to find lung cancer early, when it is easier to treat, have not been able to demonstrate a decrease in mortality rates. Now, a study sponsored by the National Cancer Institute (NCI) has determined that low-dose helical computed tomography (CT) scans can reduce lung cancer mortality for current and former heavy smokers.  In the nation-wide study, which included over 53,000 participants, researchers found 20 percent fewer lung cancer deaths among those who were screened with low-dose helical CT (also known as spiral CT) compared with those who were screened with chest X-rays. In addition, deaths from all-causes (including lung cancer) were seven percent lower in those who received the low-dose helical CT scans.

“This is the first time that we have seen clear evidence of a significant reduction in mortality with a lung screening test in a randomized controlled trial.  The fact that low-dose helical CT provides a decided benefit will be a result that will have implications for the screening and management of lung cancer for many years to come,” said Christine Berg, M.D., NLST project officer for the NCI, in a press release.

In September 2002, the NCI launched the largest lung cancer screening study ever conducted.  The National Lung Screening Trial, or NLST, compared the effects of two lung cancer screening procedures, low dose helical CT and chest X-ray, in reducing mortality in current and former heavy smokers aged 55 to 74. Unlike previous trials, the NLST was a randomized control trial, the gold standard in clinical trials. Participants were randomly assigned to one of two comparable groups – chest X-ray or helical CT – and received three annual screenings based on their assigned technology.  The groups were followed for at least five years beyond the final screening. (Read an article in this publication from the launch of the trial in 2002)

“The results of this trial provide objective evidence of the benefits of low-dose helical CT screening in an older, high-risk population and suggest that if low-dose helical CT screening is implemented responsibly, and individuals with abnormalities are judiciously followed, we have the potential to save thousands of lives,” said Denise Aberle, M.D., NLST national principal investigator for ACRIN, in an NCI press release.  “However, given the high association between lung cancer and cigarette smoking, the trial investigators reemphasize that the single best way to prevent lung cancer deaths is to never start smoking, and if already smoking, to quit permanently.”

Low dose helical CT, which was introduced in the 1990’s, uses computer-controlled X-rays to scan the entire chest in about 7-15 seconds during a single, 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.

(Figure A:) Conventional CT scan. (Figure B:) Spiral CT scan. Credit: NCI Cancer Imaging Program

A computer creates images from the X-ray information coming from the scanner and assembles these images into a series of two-dimensional slices of the lung at very small intervals so that increased details within the organs of the chest can be identified.  Virtually all hospitals and free-standing radiology facilities in the United States now have a helical CT machine, which are routinely used for diagnostics. While some facilities do perform helical CT scans for the purpose of screening for lung cancer, such practice has not been previously supported by evidence and is not currently covered by most insurance providers.

Screening with CT scans comes with its own risks.  Radiation exposure from repeated CT scans can lead to illness, including cancer, and people who get false-positive results may be subjected to unnecessary surgical procedures.   It’s important to note that most abnormalities detected with CT screening are not cancer, even in people who are at high risk.

There are over 94 million current and former smokers in the United States who are at high risk for lung cancer.  In 2010, it is estimated that 222,520 people will be diagnosed with, and 157,300 will die from lung cancer, the leading cause of cancer death in the United States.

More information about the new results of the NLST is available in National Lung Screening Trial – Initial results: Questions and Answers and Fast Facts on NLST.  For more information on lung cancer and screening, please visit our Lung Cancer Homepage.

NLST logo

In September 2002, the National Cancer Institute (NCI) launched the largest lung cancer screening study ever undertaken. Called the National Lung Screening Trial (NLST), the study is seeking 50,000 current and former smokers to determine if screening people with either spiral computerized tomography (CT) or chest X-ray before they have symptoms can reduce deaths from lung cancer.

Spiral CT, a technology introduced in the 1990s, uses X-rays to scan the entire chest in about 15 to 25 seconds. A computer creates images from the scan, assembling them into a 3-dimensional model of the lungs. More than half of the hospitals in the United States own a spiral CT machine and routinely use them 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. However, no scientific evidence to date has shown that screening or early detection of lung cancer with either spiral CT or chest X-rays actually saves lives.

BenchMarks talked with the co-directors of NLST to get an overview of the study and what can be learned from it.

John K. Gohagan, Ph.D., FACE, is chief of the Early Detection Research Group in NCI’s Division of Cancer Prevention. He is also in charge of a NCI-funded research network that has been conducting for several years a lung screening study called the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Many PLCO sites will be participating in NLST.

Denise R. Aberle, M.D., is professor and chief of thoracic imaging, vice-chair of research, department of radiological sciences, David Geffen School of Medicine at the University of California Los Angeles. She is a leading investigator of the American College of Imaging Network (ACRIN), the NCI-funded research network that conducts a broad spectrum of multi-institutional clinical trails in diagnostic imaging related to cancer.

What is the purpose of the NLST?

Dr. Gohagan: Lung cancer kills more Americans than any other single cancer. There is currently no consensus on screening procedures for lung cancer. The NLST will compare two lung cancer screening tests: low dose spiral CT and chest X-ray, to determine which is better at lowering lung cancer deaths. Several trials have been conducted in the past to determine the effectiveness of chest X-rays and sputum cytology in reducing lung cancer mortality. The results of these trials were inconclusive; however, the earlier trials were relatively small. There is currently a much larger trial, PLCO, which is investigating the use of chest X-ray versus usual care for lung cancer. With the introduction of spiral CT as a potential screening tool, its effectiveness relative to potential harm needs to be proven.

Most people would assume spiral CT is better than chest X-ray because it’s more modern technology. Is there any evidence to support this?

Dr. Aberle: Spiral CT is a more modern technology, certainly as a potential screening test for lung cancer. We know that spiral CT can detect smaller lung abnormalities, including cancers, than chest X-ray. Finding and treating these smaller abnormalities may reduce lung cancer deaths. But it may not. It could turn out that screening with spiral CT will result in more intrusive diagnostic and therapeutic procedures without reducing lung cancer deaths. The answer to this question is the goal of NLST.

How will you know if either screening method is actually saving lives?

Dr. Gohagan: The NLST is a randomized control trial. Randomized controlled trials are the gold standard in clinical trials for determining differences between screening or treatment effects. In the NLST, participants will be randomly assigned to one of two arms, the chest X-ray arm or the spiral CT arm, essentially creating equivalent populations. The chest X-ray arm will receive three annual chest X-ray screenings, while the spiral CT arm will receive three annual spiral CT screenings. Both groups will be carefully followed by NLST medical staff for up to five years beyond the final screen. The number of lung cancer deaths and other outcomes in the two groups will be monitored year by year. This study design will allow us to determine whether spiral CT is more effective than chest X-ray, and by how much.

Why was a 20 percent difference chosen as the endpoint?

Dr. Aberle: With any trial, there is a balance between the number of participants that will need to be studied and the magnitude of the difference you want to determine. The smaller the expected difference between two tests, the larger the number of participants you must follow in order to see that difference. The early lung cancer screening trials were designed to detect a 50 percent difference between the groups under investigation. Some investigators today have predicted differences of 50 percent or more in mortality between the spiral CT and chest-X-ray screening arms. NCI experts in early detection trials and expert consultants from around the nation and abroad have concluded that a meaningful difference could be as small as 20 percent. A 20 percent difference will require that we enroll 50,000 participants. The trial has been designed so that if the difference between the two study arms is greater than 20 percent, NLST can be stopped early by its independent data safety and monitoring board.

Why is this trial important?

Dr. Gohagan: Lung cancer is a major public health concern in the United States. In the absence of a proven screening test, medical practitioners are faced with a serious quandary over how best to manage the large number of Americans, especially current and former heavy smokers, who have a high lifetime risk of lung cancer. This trial will have considerable implications for public health policy. If spiral CT is more effective than chest X-ray, medical practitioners and the public will want to make use of it in their battle against lung cancer. If it is not more effective, or if its use contributes to even greater medical morbidity and mortality, the public, medical practitioners and insurers will want to know that.

What will happen if a suspicious lesion is found during screening?

Dr. Gohagan: Participants and their personal physicians will be notified within three weeks of the screening exam of the results and the need for follow up. NLST medical staff may offer state-of-the-science guidance on appropriate follow-up options and may assist in referring interested participants to specialists; in all instances they will follow the participant until they are assured that appropriate follow up has occurred. Medical records documenting the follow-up diagnoses and any treatments will be collected and abstracted for the participant’s file. NLST staff will maintain regular contact with all living participants for the duration of the trial.

Recent studies indicate that 25 percent to 60 percent, or more, of people who undergo spiral CT screening are expected to have some abnormality show up on their scans. What is the typical scenario of what happens after a lesion is found?

Dr. Aberle: Data from current observational trials indicate that spiral CT detects many more lung abnormalities than chest X-ray. However, the majority of positive screens on spiral CT are benign, and most are less than 1 centimeter in size. In this size range, there are few tests sufficiently reliable to distinguish between lung cancers and non-cancerous lesions, such as scars or inflammation. Different diagnostic tests will apply to participants with positive spiral CT screens depending upon the size and other characteristics of the abnormality detected.

Pea-size or smaller nodules that are too small to reliably biopsy will likely be followed over time to evaluate for any suspicious changes that might indicate cancer, such as slow growth. Larger lung abnormalities, the size of a dime or bigger, can be more easily approached by percutaneous biopsy, or evaluated with more sophisticated tests, such as contrast-enhanced CT densitometry or positron emission tomography (PET) scans, technologies that more accurately distinguish benign and malignant lesions. In some cases, larger lesions may be referred directly for surgical biopsy.

Investigational studies are currently using advanced image processing software on CT scans to measure subtle changes in nodule volumes over short time intervals. These are very promising techniques because over a time interval of one to two months you can determine whether a very small nodule is growing and is likely or not to be a cancer. These tools will be useful in the future, because they might further reduce the time interval between first detection of cancer and treatment, but in reality they are not yet sufficiently robust that they can be applied on a massive scale.

What other information will NLST provide?

Dr. Aberle: The NLST will give us an important opportunity to explore the effects of screening on smoking behaviors and the psychological consequences of screening-not only the emotional effects of the screening process itself, but also the impact of a positive screening test on the individual. Some of the sites will also collect data to analyze the differential cost implications of the two screening methods.

These are particularly important questions because there will be a large group of individuals who will have positive screening tests for ultimately benign lesions, but in whom additional diagnostic tests will be indicated. Those individuals will be subjected to additional imaging studies, the possibility of biopsies, or even surgery. It’s important that we measure the psychological consequences and the costs of these screening tests on the population being screened, not just those in whom lung cancer is found.

Finally, some of the NLST sites will collect samples of blood, urine, and sputum from participants in both arms at the times of the screening examinations.

How will blood, urine, and sputum samples be used?

Dr. Aberle: All of these individuals will have been very well characterized with respect to their smoking histories, lung-related diseases, other risk factors for lung cancer, family histories, etc. We will also have their imaging data as we follow them through time. As we learn more about the molecular genetics of lung cancer, such as which markers may be helpful in predicting cancer or which markers are associated with different stages or cancer behaviors, the specimens will be important for testing these potential markers. We may find that blood tests or urine tests are an important way of defining people who would benefit from lung cancer screening. The biomarkers may be important screening tests themselves.

Why is NCI, as opposed to some other entity, doing this study?

Dr. Gohagan: This is a very large clinical trial that probably no other single entity in this country could support. The National Cancer Institute is a federal agency created and commissioned by the U.S. Congress to reduce cancer morbidity and death in America. One of NCI’s missions is to determine which early detection procedures are effective in reaching these goals.

While the funding for this $200 million trial comes primarily from the NCI, the American Cancer Society is contributing some funding for specific activities that will help make the trial successful.

Animation/Video

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Text Transcript

Announcer: Tom Whitherspoon holds onto wonderful memories of a 45-year marriage. His wife died last year of lung cancer. They both were heavy smokers and now Tom is concerned about his own health.

Mr. Whitherspoon: “At the end, to watch her as I sat there holding her hand, gasping for breath as she died. I mean, it’s not an experience I ever want to go through again.”

Announcer: Tom Whitherspoon and many researchers hope that finding cancerous tumors before they cause symptoms will benefit people by lowering deaths from lung cancer. But when it comes to lung cancer, doctors aren’t sure earlier detection makes treatment more successful.

Dr. Gohagan: “Spiral CT is a new technology which has been shown to detect small lesions in the lungs, smaller than you can find with a chest X-ray, but we don’t know whether finding these lesions and treating them will actually lead to benefit for people. We don’t know if a spiral CT is better than an X-ray.”

Announcer: To find out if either test will reduce deaths from lung cancer, NCI is looking for 50,000 volunteers for a landmark 8-year study. The National Lung Screening Trial, or NLST, will be the biggest lung cancer screening study ever undertaken. Half of the participants will be screened by chest X-ray, the other half by Spiral CT. All will be randomly assigned.

Dr. Aberle: “At this time, there’s no effective screening test for lung cancer, and yet it’s the largest cause of cancer deaths in this country. I think many people don’t understand the magnitude of the epidemic of lung cancer.”

Announcer: The NCI trial will also look at the benefits and the risks of screening. Those risks exist because abnormalities seen on screening tests must be followed up by additional invasive tests that have risks of their own, just to determine whether or not the screening abnormalities are really cancer.

Dr. Gohagan: “Screening tests that turn out to be positive are followed up by diagnostic procedures and some of those procedures have risks associated with them.”

Announcer: The stakes are high for the estimated 90 million current and former smokers in the United States who are at higher risk for lung cancer. Today, more Americans die of lung cancer than from prostate, breast, colon, and pancreatic cancers combined.

Dr. Aberle: “The hope is that this trial will lead to saving thousands of lives of people in this country.”

Announcer: Male and female smokers and former smokers, age 55 to 74, may join NLST. Screening for participants is free of charge.

For more information about the clinical trial, call toll-free 1-800-4-CANCER.

This is Tom Hendrick reporting.

Audio Clips

1. John K. Gohagan, Ph.D., NCI’s Division of Cancer Prevention, discusses whether or not spiral CT could reduce the number of deaths from lung cancer.

   ( Audio – Length: 00:14 )

   Text Transcript

   John K. Gohagan, Ph.D., NCI’s Division of Cancer Prevention, discusses whether or not spiral CT could reduce the number of deaths from lung cancer.
   Dr. Gohagan: Spiral CT is a new technology which has been shown to detect small lesions in the lungs, smaller than you can find with an X-ray, but we don’t know whether finding these lesions and treating them will actually lead to benefit for people. We don’t know if a spiral CT is better than an X-ray.

2. Denise R. Aberle, M.D., University of California Los Angeles, discusses the need for an effective screening test.

   ( Audio – Length: 00:12 )

   Text Transcript

   Denise R. Aberle, M.D., University of California Los Angeles, discusses the need for an effective screening test.
   Dr. Aberle: At this time there’s no effective screening test for lung cancer, and yet it’s the largest cause of cancer deaths in this country. I think many people don’t understand the magnitude of the epidemic of lung cancer.

3. Dr. Gohagan discusses the need for follow-up tests after screening.

   ( Audio – Length: 00:07 )

   Text Transcript

   Dr. Gohagan discusses the need for follow-up tests after screening.
   Dr. Gohagan: Screening tests that turn out to be positive are followed up by diagnostic procedures, and some those procedures have risks associated with them.

4. Dr. Aberle talks about how this trial could possibly save thousands of lives.

   ( Audio – Length: 00:07 )

   Text Transcript

   Dr. Aberle talks about how this trial could possibly save thousands of lives.
   Dr. Aberle: The hope is that this trial will lead to saving thousands of lives of people this country.

Photos/Stills

1. Conventional Lung X-Ray

2. National Lung Screening Trial (NLST) logo