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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.

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