The National Lung Screening Trial (NLST), a randomized, national trial involving 53,000 current and former heavy smokers, compared the effects of 2 screening procedures for lung cancer
The National Lung Screening Trial (NLST), a randomized, national trial involving 53,000 current and former heavy smokers, compared the effects of 2 screening procedures for lung cancer—low-dose helical computed tomography (CT) and standard chest x-ray— on lung cancer mortality. In November, the study authors reported 20% fewer lung cancer deaths among trial participants screened with CT scans.
In its wake, patient advocate groups are calling for swift implementation of national screening guidelines, while researchers are pursuing follow-on studies that will both refine testing protocols and expand the scope of the study.
The results were particularly striking because there are no early-screening protocols in place for lung cancer, and, in their absence, few of these tests are now performed. The disease kills nearly 80% of the approximately 200,000 people treated for it each year—more than any other cancer—in large part, researchers say, because the majority of lung cancers are detected at later stages. Participants in the trial were asymptomatic.
“Effective screening changes the nature of the disease,” noted Bruce E. Johnson, MD, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute and a professor at Harvard Medical School, Boston, Massachusetts. “We take care of many lung cancer patients too often after the horse is out of the barn. Most people we see end up dying.”
“If we can change outcomes for 40,000 people a year, that would be almost the numbers of deaths from pancreatic and head and neck cancer combined,” said Mary E. Reid, PhD, an oncology professor and director of collaborative research for the Department of Medicine at Roswell Park Cancer Institute, Buffalo, New York.
NCCN Guideline Changes Are Under Consideration
Indeed, the results are so compelling that cancer experts, while noting that the study awaits peer review, are acting on them nonetheless.
“The control group in this study got chest x-rays, while the control in the real world gets nothing, so this may underestimate the true benefit,” said Douglas E. Wood, MD, a professor and chief of general thoracic surgery at the University of Washington School of Medicine in Seattle. Wood, who is chairman of the lung cancer screening committee for the National Comprehensive Cancer Network (NCCN), says the screening panel will likely release its guidelines by late spring.
“We have decided that we don’t need to wait for publication of the NLST results to publish our guidelines. A lot of people depend on the NCCN for guidance and our goal is to get the best data to physicians and patients as soon as possible,” he said. “It is no problem for us to refine our information as it becomes available. And we expect there will be new information coming that we will work in—better and more information.”
Wood declined comment on the guidelines, which will address both whom to screen and how best to screen, but noted that the NLST “gave us better data to talk about” and “a stronger validation of screening than any study that exists to date.”
He called publication and peer review important steps, while adding, “We’re enthusiastic and look to see details in forthcoming publications that validate the study results. And so, presuming that this follows as expected, this is an enormous, radical, major sea change in lung cancer detection and management—the largest in our lifetime.”
While cautioning that the NLST results apply only to the group studied, current or former heavy smokers who are 55 to 74 years old, Christine Berg, MD, chief of the NCI’s Early Detection Research Group and project officer for the study, said recently that individuals within that population “should have a conversation with their physicians about their options.”
Research studies that build on the NLST findings—some long underway and others still in the proposal stage—will refine its results by better defining the population of high-risk patients who would benefit most from screening and, following that, more invasive testing if nodules are discovered.
NCI points to studies indicating that 20% to 60% of screening CT scans of current and former smokers will show abnormalities, such as scars from smoking, areas of inflammation, and other noncancerous conditions. Most abnormalities are not lung cancer, the agency notes, and biopsies can cause partial lung collapse, among other complications. More major chest surgery to remove larger amounts of tissue poses even greater risks for patients with heart or lung conditions.
“The number of false positives is not trivial and so the clinical screening guidelines will have to be refined in the future,” said Reid.
Looking to Biomarkers for Clues
The hunt for valid biomarkers to identify patients most likely to develop cancer is central to much of this research.
Avi Spira, MD, MSc, who leads a bioinformatics group at Boston University School of Medicine in Massachusetts, is among the researchers studying them. He is the principal investigator for a proposed early screening study, to be funded by the US Department of Defense, to identify molecular biomarkers that would indicate whether a patient with nodules of indeterminate malignancy is genetically susceptible to developing cancer. The researchers will examine cells collected from brushings from the lungs and scrapings from the nasal passages and mouth to see if they can detect genetic changes that would indicate whether those patients are likely to progress to cancer.
“There are several biomarkers that show promise, including gene expression studies from the cells in the airways, genetic changes in the lung tissues, whole-blood gene expression, proteomics, inflammatory markers, angiogenic markers, and epigenetic markers,” said Reid, who is the epidemiologist for the proposed study. “These are all currently under investigation to detect earlier lung cancers.”
Researchers say that the NLST itself will yield important new information upon further analysis that will also help refine screening protocols, including whether particular subgroups of participants, such as men, women, and some ethnic groups, benefited from the tests more than others. The study will continue to track participants.
“The findings from this study will become more mature,” Johnson said. “We’ll see what happens with the passage of time and whether the benefits expand or not. We’ll plug in real numbers about where distinctions are drawn, such as the age of participants and the number of packs smoked, for guidance on what to do for patients who do not fit within the design of the study.”
Additionally, more than 10,000 participants agreed to provide specimens of blood, urine, and sputum at each of their annual screens to establish a biorepository that will support research on molecular biomarkers of early lung cancer. All NLST participants who underwent lung cancer resection were invited to provide small samples of the resected tumors to supplement the biorepository.
Existing imaging technology is also a powerful tool for monitoring nodules that can be “delivered in an economic fashion,” said James L. Mulshine, MD, vice president for research and associate provost for research at Rush University Medical Center, Chicago, Illinois.
While stressing the need for “rigorous clinical trials,” Mulshine pointed to research studies “that suggest we can leverage the rapid improvements in CT imaging to further assist with the management process of lung cancer screening. We can segregate nodules that are clinically aggressive from those with no growth.”
Advocates Press for Screenings
Based upon their review of the NST findings and continuing improvements in imaging capability, patient advocacy groups are calling on government regulators to “swiftly translate this scientific validation into a public health benefit in a safe, uniform and cost effective way,” as Laurie Fenton Ambrose, president and chief executive officer of
the Lung Cancer Alliance, put it.
“Screening for lung cancer is not automatically covered like mammography, PSAs [prostate-specific antigen tests], and colonoscopies,” Ambrose said. “But now with the National Cancer Institute’s validation of the lung cancer screening mortality benefit, government screening recommendations for lung cancer should be revised to reflect this new development. This would then trigger changes in public and private coverage.”
Shortly after the NLST findings were released, Ambrose, with the heads of other patient advocacy groups, wrote to the director of the Agency for Healthcare Research and Quality (AHRQ) to urge the agency to review its screening recommendations for lung cancer.
The AHRQ, which is part of the US Department of Health and Human Services, provides administrative, technical, and research support to the US Preventive Services Task Force (USPSTF), an independent panel of experts that conducts scientific evidence reviews of clinical preventive healthcare services and develops recommendations for primary care clinicians and health systems. The USPSTF’s current recommendation is an “I,” meaning the task force believes there is insufficient evidence to recommend for or against screening asymptomatic persons for lung cancer with either low-dose CT, chest x-ray, sputum cytology, or a combination of these tests.
“While it is our understanding that USPSTF’s standard practice is to review all topics on a 5-year schedule, we urge that a review commence immediately, given the irrefutable evidence provided by the analysis of the NLST data,” Ambrose and the others wrote.
The task force, however, does not plan to consider updating its recommendation until 2012, Ambrose said she has since learned.
“I am disappointed that a now proven benefit that could save tens of thousands of lives has not been more positively and aggressively embraced. I do not see a sense of urgency among public health leaders and medical professionals to translate this benefit into public health infrastructure,” she commented.
Advocates for lung cancer patients contend that the demonization of tobacco use—and patients by association—has caused research into one of the most complex cancers to lag well behind that of diseases with greater political support.
“Lung cancer is the most stigmatized and ignored of all cancers and for decades has lacked a comprehensive public health strategy. That is because lung cancer is viewed singularly as tobacco driven, when it is in fact more complex than that,” Ambrose said, adding that the majority of people diagnosed with the disease are former smokers who heeded public health messages to quit.
Pace of Research Draws Scrutiny
Researchers do not disagree with her assessment, noting that basic science around the disease has been comparatively slow to emerge.
“It’s as if it’s not random, as if they did it to themselves,” Reid said of the perceptions of lung cancer patients. “Only 1 to 2 out of 10 smokers and former smokers will get lung cancer. My chance of breast cancer is 1 out of 7. I have risk factors, some behavioral, that increase my risk of breast cancer.” She added, “With breast cancer screening, there are questions about whether it changes mortality, and about whether we should do it once every 1 or 2 years. But there is an overwhelming advocacy there. Who is going to look a woman in the eye and say no to screening? The insurance companies aren’t either. With the PSA test, too, results are unclear. It’s not that there is no controversy, but there is a huge advocacy.”
Wood noted that in the absence of protocols, amid the “high bar that has been set for evidence-based medicine,” few early tests are now performed. “To date, physicians are not really promoting lung cancer screening. It’s predominantly patients who are assertive, proactive, or nervous, who seek it for themselves,” he said, adding that it is often detected “during a chest x-ray or CT scan for something else.”
Earlier screening studies, involving chest x-rays and sputum analyses, proved inconclusive. The International Early Lung Cancer Action Program (I-ELCAP), which used CT screening to detect early lung cancer, reported results in 2006 that suggested that CT screening might be beneficial. It was a nonrandomized trial, however, that did not use mortality as the endpoint.
Researchers say that effective screening modalities became available in the 1990s with the advances provided by CT scans.
“The technology from CT scans was much better in terms of accuracy and efficiency. We had information by 1999 that one could pick up nodules as small as 2 mm that when resected were usually the earliest stage lung cancer—stage IA,” Johnson recalled. “The findings from the study were used for the NLST design, and the trial started in 2002.” (Henschke CI, et al. Lancet. 1999; 354:99-105).
Berg noted that while the test was available, “it was conducting a trial of this size and cost to determine true validity that took time. Lung cancer is actually many diseases, some of which are highly aggressive, much more so than breast cancer, so technology had to advance and be studied appropriately to actually find an intervention that was effective in detecting the cancers early enough in their natural history to have an impact.”
Screening Protocols Deemed Vital
Low-dose helical CT, also known as spiral CT, uses x-rays to scan the entire chest in about 7 to 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. A computer creates images from the x-ray information coming from the scanner and then assembles these images into a series of 2-dimensional slices of the lung at very small intervals so that increased details within the organs in the chest can be identified.
Researchers say its accuracy of detection over many prospective trials has proved to be >90%. And while there is some concern about the exposure from repeated CT scans, those risks are weighed against the short life expectancy of patients who develop lung cancer.
“I don’t see any other screening modality employed in a broad population of subjects at risk in the next decade,” Johnson said.
Mulshine also noted that it is quick, not painful, and “deployed everywhere—and the cost of the technology for an individual study is not expensive.” Each scan costs from $300 to $1000, according to the NCI.
But while the technology is widely available, screening procedures will have to be implemented carefully, Mulshine added. “Going forward, there are cost issues, quality issues, and issues around support services. How effective and safe will this be? What are the triggers for more testing and what are the quality controls?”
Ambrose is working with members of Congress to establish a demonstration program.
“We need to make sure there is proper guidance around screening protocols, as screening is not a procedure, it is a process. In other words, it is more than a picture. It is a process for managing what is found,” she said. “This is why we are calling for a federal lung cancer demonstration screening program as part as of the Lung Cancer Mortality Reduction Act, just as was done for mammography and colonoscopy to ensure that the screening protocol is tested before best practices are standardized and uniformly adapted within the broader public health infrastructure.”
Johnson said it is also important to make sure that screening is deployed effectively and efficiently.
“The group at risk of lung cancer tends not to be the group that takes the best care of itself. People who smoke a lot may not have an internist, for example. We need to make sure these patients have access to the screening and there is appropriate follow-up for them,” he said.
“Cancer deaths are falling wherever we have effective screening, which is true in breast, prostate, and colon cancer. The discussion around cost is a solvable problem, and having an effective screening is a first step,” he added. “It’s the responsibility of the medical community to see that screening can be done in a way that’s reasonable for both subjects at risk and for the third-party payers.”