The American College of Radiology Imaging Network (ACRIN)( www.acrin.org ) continues to apply its National Cancer Institute (NCI) funding toward the development, implementation, and analysis of multidisciplinary, multicenter trials of diagnostic imaging and image-guided treatment technologies. The overarching goal of ACRIN is to develop information from its trials that will improve the length and quality of lives of cancer patients and allay the concerns of individuals who fear they might have cancer but actually do not.

ACRIN’s largest and most complex trial is the National Lung Screening Trial (NLST), which is also among the most prominent trials in the entire NCI clinical trials portfolio. NLST is a collaboration of ACRIN and NCI’s Lung Screening Study (LSS). Initiated in 2002, the NLST recruited 30 institutions across the United States to accrue 50,000 asymptomatic, high-risk subjects into a randomized trial to determine whether annual chest radiography or low-dose CT scanning could reduce the death rate from lung cancer. To be eligible, subjects had to be long-term smokers between the ages of 55 and 74.

The rationale for the NLST was straightforward. Although a number of observational studies have suggested a benefit to screening CT in terms of survival (the average number of years individuals survive from the time they are diagnosed), such studies are prone to specific biases associated with observational screening studies. These biases uniformly give a more positive view of screening performance than is actually the case. Given the cost of annual screening for the large population of smokers at higher risk for lung cancer, and given that there is a high false-positive rate in many individuals who previously have had granuloma-producing diseases—leading to prolonged, sometimes invasive follow-up regimens—NCI felt it was essential to conduct the NLST to ensure that CT lung cancer screening was both beneficial and cost-effective before recommending annual screening be implemented in the United States.

TRIAL DESIGN

The NLST obviates the biases of observational studies with its randomized controlled design, so that the primary end point, rather than survival, is lung cancer-specific mortality (the death rate, or number of people who die per 1,000 population per year). This is really what we need to know before implementing population-based lung cancer screening—whether either chest ray or CT actually reduces the death rate from this most malignant cancer.

Upon agreeing to participate in the NLST, subjects were randomly assigned to either chest radiography or CT scanning and received their initial screening examination. Each subject receives repeat screening, employing the same technology, at 1 and 2 years following the initial screening. Subjects will be followed for up to 6 years. The 50,000 subjects are estimated to allow detection of a 20% reduction in lung cancer mortality with 90% certainty.

However, the ACRIN component of the NLST has been designed to do much more. Led by trial principal investigator Denise Aberle, MD, of UCLA and ACRIN Network Statistician Constantine Gatsonis, PhD, of Brown University, the NLST includes such secondary end points as:

  • The impact of screening examinations on subject quality of life;
  • The effect of screening on promoting smoking cessation;
  • If there is a benefit to screening in mortality reduction, a calculation of the financial cost for each year of life saved.

In addition, the ACRIN component of the NLST is producing two extremely valuable archives beyond the data essential to determining the critical primary and secondary end points. One of these is an image archive. Every screening image devolving from subjects accrued by ACRIN is being stored in an electronic archive in ACRIN Headquarters (the Philadelphia Research Offices of the American College of Radiology). Given that ACRIN accrued nearly 19,000 of the subjects, this means that by the end of the trial ACRIN will have an archive of nearly 60,000 CT scans and 60,000 chest radiographs that can be correlated with definitive information on whether the subject had lung cancer and his or her outcome. This archive is available for public use and should prove particularly valuable for the development of computer-aided detection algorithms, as well as further research on the imaging manifestations of lung cancer.

Ten thousand of ACRIN’s subjects also are donating blood, urine, and sputum specimens at each screening. These specimens are being stored as a resource for future research on whether there are genetic markers that identify individuals to be at even higher risk for the development of lung cancer (ie, genetic biomarkers). Up to 90,000 such specimens will be available to lung cancer researchers by 2009, when the study is scheduled to undergo its final analysis.

Between now and 2009, there is much remaining to be done. The last of the follow-up screening will occur over the next 18 months. Subjects are undergoing periodic medical chart review and direct communication to determine their health status and whether they have developed lung cancer. There will be several interim analyses over the next 4 years to determine whether the principal question of the efficacy of screening in reducing the lung cancer death rate can be answered earlier. This would be the case if there were a larger than expected beneficial effect to screening.

The NLST may well prove to be among the most significant trials ever to be conducted in medical imaging. Given the rigorousness of the trial design, a positive result would likely legitimize lung cancer screening, increase the numbers of individuals seeking screening, and perhaps engender payor reimbursement for this procedure.

Bruce J. Hillman, MD, is the Theodore E. Keats Professor of Radiology, University of Virginia, Charlottesville, Va, and Chair, American College of Radiology Imaging Network (ACRIN).