A Closer Look
This is the fifth article in a series of stories about new technology for cancer diagnosis or treatment. View a list of articles in this series.
Low-Dose CT Shows Clear Mortality Benefit for Lung Cancer Screening in Heavy Smokers
At a press conference on November 4, NCI released initial results from the National Lung Screening Trial (NLST), showing that current or former heavy smokers between the ages of 55 and 74 who underwent screening with low-dose helical computed tomography (helical CT) experienced 20 percent fewer deaths from lung cancer than a group of peers who received screening with standard chest x-rays.
“This is really the first clear demonstration that a screening procedure can be effective in reducing mortality from lung cancer,” said Dr. Douglas Lowy, deputy director of NCI, at the press conference.
“This finding has important implications for public health, with the potential to save many lives among those at greatest risk for lung cancer,” commented NCI Director Dr. Harold Varmus. However, he clarified, “I don’t want you to come away from this announcement believing that it’s now safe to continue to smoke or to start smoking. Screening does not prevent lung cancer and it does not protect the large majority of subjects from death from lung cancer. Not smoking and quitting smoking remain important public health goals and remain the best defenses against lung cancer.”
Strength in Trial Design
NLST represents a collaboration of the Lung Screening Study group in NCI’s Division of Cancer Prevention and the American College of Radiology Imaging Network (ACRIN), which is sponsored by NCI’s Division of Cancer Treatment and Diagnosis (DCTD). The trial was conducted at 33 trial sites across the nation.
Recruitment and retention were achieved in partnership with the American Cancer Society, which raised awareness of the trial at the local community level through the activities of the Society’s regional offices. The first NLST participants were enrolled in August of 2002, and the target goal of 50,000 participants was achieved by January 2004. Final enrollment included more than 53,000 people.
The large number of participants in this trial, as well as its randomized design, helped to ensure that NLST would provide a definitive answer as to whether helical CT screening helps prevent deaths from lung cancer. Another element that strengthened the findings is that the trial’s main endpoint was the number of deaths from lung cancer, not just the number of lung cancers detected by screening.
NLST was stopped at the request of the trial’s independent Data and Safety Monitoring Board, which determined on October 20 that all data needed to answer the trial’s primary question had been collected. Intriguingly, the initial results showed a 7 percent decline in death from any cause (including lung cancer) in the low-dose helical CT group, though NLST researchers do not yet understand all the factors contributing to this reduction. “Within the next few months, [the full] results will be promptly published in a peer-reviewed journal with full and immediate access to the public,” said Dr. Richard Fagerstrom, one of the lead statisticians for NLST.
Looking Inside the Body, Not Through the Body
Previous trials testing the efficacy of chest x-rays for lung cancer screening have produced uniformly disappointing results. Although x-rays have the advantage of using an extremely low dose of radiation to image the body’s tissues, the technology is limited in the size and location of the abnormalities it can detect.
“A chest x-ray can find a nodule down to about 1 cm [in diameter] reliably, depending on where it’s located,” explained Dr. David Bluemke, director of Radiology and Imaging Sciences at the NIH Clinical Center. “In some parts of the lungs around the middle of the blood vessels, it needs to be larger than that. On a chest CT scan, nodules can be seen clearly at 1 to 2 mm in size.
“In addition, on a chest x-ray, you are trying to look through a wealth of other anatomical information, including the bones and the blood vessels, to find a nodule,” he continued. “In a chest CT there is very little that’s hiding that nodule—you’re looking inside the patient instead of through the patient.”
When CT entered the clinic in the 1970s, the scanners slowly gathered images in parallel slices (see Figure A), leaving small information gaps that had to be reconstructed by a computer program. In the 1990s, helical CT (also called spiral CT) technology emerged, gathering continuous pictures of the body in a rapid helical motion (see Figure B), so there are no gaps in the pictures collected.
“When it was first clear that CT scans were so much more precise than x-rays, people started looking at potentially developing them for screening purposes, but the limitation had always been the capabilities of the machine,” commented Dr. Giuseppe Giaccone, chief of the Medical Oncology Branch and head of the Thoracic Oncology Section in NCI’s Center for Cancer Research. “But the development in scanners over the last decade or so has been tremendous. In the ‘90s, doing a scan would take minutes. Now you hold your breath, and it’s done,” he added.
“It’s the speed of helical CT and also the overlapping nature of the slices that make it possible to find small nodules in the lung,” said Dr. Christine Berg, NCI project officer for NLST. “So the helical scanning technology was critical for screening applications, and also the realization that you could probably see things just as well if you turned the dose down. The concern about radiation dose has been around for a long time, and the dose used for screening [in NLST] is substantially less than the dose of a diagnostic CT,” she explained.
Cautions and Caveats
“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 followed judiciously, we have the potential to save thousands of lives,” said Dr. Denise Aberle, the NLST national principal investigator for ACRIN. “However, given the high association between lung cancer and cigarette smoking, the trial investigators re-emphasize that the single best way to prevent lung cancer deaths is to never start smoking, and if already smoking, to quit permanently.”
One major caveat to the findings is that, for now, the researchers can only comfortably extrapolate the results to the population that participated in the trial—current or former smokers (defined as having quit within 15 years of trial entry) between the ages of 55 and 74 who smoked the equivalent of at least a pack a day for 30 years.
“The NLST findings should not be interpreted to mean the general public should now get regular CT scans,” cautioned Dr. Lowy. “This trial answered specific questions about a well-defined high-risk population. Further analysis and modeling of NLST data will be needed before specific recommendations can be made about the possible broader use of this screening method.”
At this time, NCI is not releasing recommendations for the use of lung screening CT for any population. Once the final data have been fully analyzed and published, explained Dr. Varmus, recommendations will be made by any of several bodies commonly called upon to make medical service recommendations, including the United States Preventive Services Task Force and the American Cancer Society.
The potential harms of lung cancer screening, which exist alongside the potential benefits, will also need to be factored into any future recommendations. Approximately 25 percent of all scans in the trial showed false-positive results, meaning that on follow-up the observed abnormalities turned out not to be cancer. All of the affected patients underwent some kind of additional diagnostic procedure, ranging from follow-up diagnostic CT scans, which use higher doses of radiation, to lung biopsy and, in some cases, thoracotomy (surgical opening of the chest), all of which carry risks, explained Dr. Giaccone.
“This will be an important consideration in drawing up recommendations for how this technology should be used even in this high-risk group,” said Dr. Varmus at the press briefing.
According to Dr. Giaccone, the risk of false-positive results and unnecessary follow-up procedures may become more of an issue as lung screening CT is adopted in the wider medical community. “As this becomes more widespread in community hospitals and small practices, there will be a learning curve,” he explained.
However, guidelines for both dose and evaluation of abnormalities found on screening are already publicly accessible, explained Dr. Berg. ACRIN has posted parameters for low-dose scanning that were used during this study. And the Fleischner Society, an international, multidisciplinary medical society for thoracic radiology, has published guidelines for the evaluation of lung nodules found on CT scans.
“So the metrics for acquiring the images and the metrics for interpreting abnormalities are already accessible to the community,” said Dr. Berg. “They just need to be followed.”