NLST Trial Halted; Low-dose CT Scans Reduce Lung Cancer Deaths

Former and heavy smokers screened for lung cancer with low-dose helical CT are less likely to die of lung cancer than those screened with standard chest X-rays, according to initial results of the National Lung Screening Trial (NLST) released yesterday. Sponsored by the National Cancer Institute (NCI) and the largest randomized study of lung cancer screening in a high-risk population to date, the trial compared the effects of lung cancer screening with CT and X-ray on lung cancer mortality. It revealed 20% fewer lung cancer deaths among trial participants screened with low-dose helical CT. In progress since 2002, the trial was halted this week after the trial’s independent oversight committee reached the conclusion that the data had provided a statistically convincing affirmative answer to the study’s primary question: Can CT screening reduce mortality associated with smoking? The trial entailed the enrollment, by the American College of Radiology Imaging Network (ACRIN) and the Lung Screening Study group, of 53,456 current and former heavy smokers ages 55 to 74 into the National Lung Screening Trial (NLST) at 33 sites across the United States. Starting in August 2002, subjects remained in the trial for a 20-month period and were randomly assigned to receive three annual screens with either low-dose helical CT or a standard chest X-ray. All CT scanners were certified for use in the trial, meeting NLST protocol requirements and ACR guidelines. Multi-detector (ie, at least four detectors) scanners were used to ensure that subjects’ entire chest could be scanned in a single maximal breath hold and to achieve good spatial resolution. All NLST acquisitions utilized a low radiation exposure protocol consistent with lung cancer screening protocols in use at the time the study began and defined as a protocol to minimize patient radiation exposure while maintaining the performance of CT for the detection of lung nodules. Participants submitted to screening tests at enrollment as well as at the end of their first and second years on the trial and were subsequently followed for up to another five years. All deaths were documented, with special attention paid to the verification of lung cancer as a cause. An ancillary finding showed that all-cause mortality (deaths due to any factor, including lung cancer) was 7% lower in those screened with low-dose helical CT than in those screened with chest X-ray. Approximately 25% of deaths in the NLST were due to lung cancer, while other deaths were due to factors such as cardiovascular disease. Further analysis of this aspect of the findings is pending.A Rich Biological Specimen BaseIn addition to collecting detailed information about the imaging screens and other clinical information, 15 NLST ACRIN sites collected and banked specimens of blood, sputum, and urine. Tissue of trial participants’ lung cancer was also collected across most sites. These specimens will provide a rich resource to validate molecular markers that may complement imaging to detect early lung cancer. "The NLST ACRIN biospecimens were collected at the time of each of the three screening exams,” stated Denise R. Aberle, MD, national principal investigator for NLST ACRIN, site co-principal investigator for the UCLA NLST team and an ACRIN deputy chair. Aberle, who is also a member of the UCLA Jonsson Comprehensive Cancer Center, professor of radiology and bioengineering and vice chair for research in radiology at UCLA, said this upon the release of the study: “There is major potential from these specimens to identify panels of genetic, protein, and other molecular biomarkers of early lung cancer that can ultimately be translated into clinical practice.” A decision to announce the initial NLST findings was made after the trial’s independent data and safety monitoring board (DSMB) notified NCI Director Harold Varmus, MD, that the accumulated data had been found to now provide a “statistically convincing” answer to the study’s primary question. At the time of the DSMB’s final meeting on October 20, 2010, a total of 354 deaths from lung cancer had occurred among participants in the CT arm of the study, while a significantly larger 442 lung cancer deaths had occurred among those in the chest X-ray group. The DSMB concluded that the 20.3% reduction in lung cancer mortality among subjects evaluated using CT met the standard for statistical significance and recommended ending the study. According to Constantine Gatsonis, PhD, director of the ACRIN Biostatistics and Data Management Center, and professor of medical science and director of the Center for Statistical Sciences at Brown University, “Progress towards the primary endpoint of the study—ie, mortality due to lung cancer--was monitored by the DSMB on the basis of regular reports produced by the biostatistics group of the study. When the evidence for a reduction of mortality in the CT arm became overwhelming—statistically significant—the DSMB decided to recommend stopping the trial. In making the decision, the DSMB also took into consideration that there was no evidence of unforeseen screening effects that warranted acting contrary to the trial's pre-specified monitoring plan.” Gatsonis also noted that the results of the study may impact practice patterns, with physicians carefully considering the results before deciding on a course of action given the absence of lung cancer screening guidelines. He also predicted that the study will be used as a “rich body of knowledge” from which guidelines for screening would be developed once the data have been analyzed and published. A fuller analysis of the data, with more detailed results, will be prepared for publication in a peer-reviewed journal within the next few months. A paper describing the design and protocol of the NLST, “The National Lung Screening Trial: Overview and Study Design” was published yesterday by the journal Radiology.