June 29, 2011 — Results from the landmark National Lung Screening Trial (NLST), which indicate that screening with low-dose helical computed tomography (CT) reduces mortality from lung cancer, have been published online in the New England Journal of Medicine.
The 53,000-person trial found a 20% reduction in deaths from lung cancer among current and former heavy smokers screened with low-dose helical CT, compared with those screened with chest radiograph (P = .004); the study has a median follow-up of 6.5 years. These principal findings were first reported publicly in October 2010, and were covered at the time by Medscape Medical News.
The newly published paper includes previously unavailable details on the diagnostic procedures performed after positive screenings and their related complications rates, as well as details on the lung cancers that were diagnosed.
The study has been accompanied by expressions of enthusiasm and gratitude from the American oncology community.
"It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, chief medical officer at the American Cancer Society (ACS), told Medscape Medical News.
"This study fills a huge gap in lung cancer control," said Bruce Johnson, MD, in a press statement from the American Society of Clinical Oncology, where he is a board member. "This is a very exciting and important result," added Dr. Johnson, who is from the Dana-Farber Cancer Institute in Boston, Massachusetts.
The positive study results beg the question of whether or not it is time for lung cancer screening programs in the United States.
The study authors, led by Christine Berg, MD, from the National Cancer Institute, think the evidence is not complete enough yet. "The current NLST data alone are . . . insufficient to fully inform such important decisions [on lung cancer screening recommendations]."
The authors have estimated the immensity of the potential impact of such policies.
Although there are only 7 million adults in the United States who meet the entry criteria for the NLST, there are an estimated 94 million adults who are current or former smokers, and thus potential screens, they suggest.
Whatever the target population, "a national screening program of annual low-dose CT would be very expensive," writes Harold Sox, MD, from Dartmouth Medical School in West Lebanon, New Hampshire, in an editorial that accompanies the NLST study. "I agree with the authors that policy makers should wait for more information before endorsing lung cancer screening programs," he writes, citing cost as his principal objection.
However, one clinician has seen enough data to endorse screening.
"There should be a national screening policy, with CT offered to and even recommended for all patients who meet the same criteria as the eligibility for the NLST," said Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, and author of the Blowing Smokelung cancer blog.
If such a policy is not forthcoming, the lung cancer community, including medical professionals, "should ask the government and insurance company leadership why they so clearly devalue the lives of people with lung cancer, compared with those afflicted with other cancers," Dr. West told Medscape Medical News.
Dr. West said that if results of this magnitude were seen in other cancers, especially breast cancer, there would be no questioning the cost of the screening. "Screening in other cancers that is widely accepted is based on far, far less impressive improvement in actual survival," he said.
"Our society routinely places a very different threshold for acceptance of lung cancer interventions than breast cancer interventions, which are often routinely and unquestioningly accepted as worthwhile interventions based on remarkably minimal absolute differences in outcomes," he pointed out.
"There is nothing less valuable about a life saved from lung cancer than a life saved from breast cancer or another cancer," said Dr. West.
Dr. Brawley suggested that professional opinion will influence forthcoming lung cancer screening policy. The ACS began drafting a lung cancer screening guideline when the NLST results were first announced. The ACS guideline will now be informed by the paper's new data, as well as by the medical communities' reaction to it, said Dr. Brawley. The ACS will be "monitoring the 'Letters to the Editor' reaction to the paper," he said.
Concerns About Harms
In NLST, participants were between 55 and 74 years of age and had a history of heavy smoking. They were screened once a year for 3 years, and were followed for 3.5 additional years with no screening.
There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, which is a relative reduction in mortality from lung cancer with low-dose CT screening of 20% (95% confidence interval [CI], 6.8 to 26.7).
The number needed to screen with low-dose CT to prevent 1 death from lung cancer was 320, Constantine Gatsonis, PhD, one of the study coauthors, told Medscape Medical News. He is from the Warren Alpert Medical School of Brown University in Providence, Rhode Island.
The rate of positive screening tests was more than 3 times higher with low-dose CT than with radiography (24.2% vs 6.9%) over all 3 rounds.
Most of the positive tests were false — 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false-positive results.
"The rate of false positives is very high, although the thoracic/pulmonology communities have certainly seen high rates of false positives with screening in the past," noted Dr. West.
The authors address the issue of false positives. "The vast majority of false-positive results were probably due to the presence of benign intrapulmonary lymph nodes or noncalcified granulomas," they write.
In a related concern, they note that the rates of complications after a diagnostic evaluation procedure for a positive screening test were "low." The rate of 1 complication or more was 1.4% in the low-dose CT group and 1.6% in the radiography group. The diagnostic methods and algorithms varied at the 33 sites and were not uniform per the protocol, the authors point out.
Dr. Sox observes that invasive diagnostic procedures were "few, suggesting that diagnostic CT and comparison with prior images usually sufficed to rule out lung cancer in participants with suspicious screening findings."
Dr. West said that lung screening is akin to prostate-specific antigen monitoring for prostate cancer. "Undergoing CT screening for lung cancer will require a careful discussion of the road that this may well lead people down, including the anxiety, additional imaging, and potentially invasive procedures that this pathway might well entail," he said.
The study authors point to another finding from the NLST as proof of the relative safety of lung cancer screening. The rate of death from any cause was reduced in the low-dose CT group, compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P = .02). "The decrease in the rate of death from any cause with the use of low-dose CT screening suggests that such screening is not, on the whole, deleterious," they conclude.
Another concern with CT screening is overdiagnosis, says Dr. Sox.
"Overdiagnosis probably occurred in the NLST," he writes. After 6 years of observation, there were 1060 lung cancers in the low-dose CT group and 941 in the radiography group. This may be evidence of overdiagnosis because, in a large clinical trial of screening tests, "the proportion of patients in whom cancer ultimately develops should be the same in the 2 study groups," he said. If the difference found to date between the 2 screening methods persists with more follow-up, this "suggests that one test is detecting cancers that would never grow large enough to be detected by the other test," Dr. Sox notes.
Finally, the study authors cite one last safety concern with CT screening — cancer caused by the CT scans themselves. "The association of low-dose CT with the development of radiation-induced cancers could not be measured directly," they write, adding that it is a "long-term phenomenon." Dr. Brawley said that previous research has indicated that for every 2000 spiral CT scans, there is at least 1 cancer caused (Radiology. 2004;232:735-738).
Cancers Detected
Low-dose CT screening fulfills an often-touted claim about cancer screening — that it detects more cancers earlier than would have been likely detected clinically. Indeed, 40% of the cancers in the low-dose CT group were stage 1A, whereas 21.7% were stage IV.
"Cancers discovered after a positive low-dose CT screening test were more likely to be early stage and less likely to be late stage than were those discovered after chest radiography," Dr. Sox explains.
Will the benefits of screening seen in the NLST be seen in community settings? Dr. Sox believes the applicability of the results is "mixed."
Diagnostic work-up and treatment did take place in the community, he acknowledged. "However, the images were interpreted by radiologists at the screening center who had extra training in the interpretation of low-dose CT scans and presumably a heavy low-dose CT workload," he writes.
Furthermore, both Dr. Sox and the study authors point out that the study population was not typical. Trial participants were younger and had a higher level of education than a random sample of men and women with a history of heavy smoking. This might have contributed to the high rate of adherence to the screening protocol in the study (more than 90%), says Dr. Sox.
The influential US Preventative Services Task Force (USPSTF) will make a determination about recommendations for lung cancer screening "by next year," said Dr. Brawley. In the meantime, while the USPSTF and organizations such as the ASC, which helped fund the study, and the American College of Radiology make their recommendations, physicians and patients should have a conversation about the harms and benefits of screening, he said.
Dr. Brawley, while emphasizing concerns about low-dose CT screening, said that "it's wonderful that we can say to high-risk people: 'We have something to offer you folks."
The study was conducted by the American College of Radiology Imaging Network and the National Cancer Institute's Lung Screening Study Group.
N Engl J Med. Published online June 29, 2011. Abstract, Editorial
The 53,000-person trial found a 20% reduction in deaths from lung cancer among current and former heavy smokers screened with low-dose helical CT, compared with those screened with chest radiograph (P = .004); the study has a median follow-up of 6.5 years. These principal findings were first reported publicly in October 2010, and were covered at the time by Medscape Medical News.
The newly published paper includes previously unavailable details on the diagnostic procedures performed after positive screenings and their related complications rates, as well as details on the lung cancers that were diagnosed.
The study has been accompanied by expressions of enthusiasm and gratitude from the American oncology community.
"It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, chief medical officer at the American Cancer Society (ACS), told Medscape Medical News.
"This study fills a huge gap in lung cancer control," said Bruce Johnson, MD, in a press statement from the American Society of Clinical Oncology, where he is a board member. "This is a very exciting and important result," added Dr. Johnson, who is from the Dana-Farber Cancer Institute in Boston, Massachusetts.
The positive study results beg the question of whether or not it is time for lung cancer screening programs in the United States.
The study authors, led by Christine Berg, MD, from the National Cancer Institute, think the evidence is not complete enough yet. "The current NLST data alone are . . . insufficient to fully inform such important decisions [on lung cancer screening recommendations]."
The authors have estimated the immensity of the potential impact of such policies.
Although there are only 7 million adults in the United States who meet the entry criteria for the NLST, there are an estimated 94 million adults who are current or former smokers, and thus potential screens, they suggest.
Whatever the target population, "a national screening program of annual low-dose CT would be very expensive," writes Harold Sox, MD, from Dartmouth Medical School in West Lebanon, New Hampshire, in an editorial that accompanies the NLST study. "I agree with the authors that policy makers should wait for more information before endorsing lung cancer screening programs," he writes, citing cost as his principal objection.
However, one clinician has seen enough data to endorse screening.
"There should be a national screening policy, with CT offered to and even recommended for all patients who meet the same criteria as the eligibility for the NLST," said Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, and author of the Blowing Smokelung cancer blog.
If such a policy is not forthcoming, the lung cancer community, including medical professionals, "should ask the government and insurance company leadership why they so clearly devalue the lives of people with lung cancer, compared with those afflicted with other cancers," Dr. West told Medscape Medical News.
Dr. West said that if results of this magnitude were seen in other cancers, especially breast cancer, there would be no questioning the cost of the screening. "Screening in other cancers that is widely accepted is based on far, far less impressive improvement in actual survival," he said.
"Our society routinely places a very different threshold for acceptance of lung cancer interventions than breast cancer interventions, which are often routinely and unquestioningly accepted as worthwhile interventions based on remarkably minimal absolute differences in outcomes," he pointed out.
"There is nothing less valuable about a life saved from lung cancer than a life saved from breast cancer or another cancer," said Dr. West.
Dr. Brawley suggested that professional opinion will influence forthcoming lung cancer screening policy. The ACS began drafting a lung cancer screening guideline when the NLST results were first announced. The ACS guideline will now be informed by the paper's new data, as well as by the medical communities' reaction to it, said Dr. Brawley. The ACS will be "monitoring the 'Letters to the Editor' reaction to the paper," he said.
Concerns About Harms
In NLST, participants were between 55 and 74 years of age and had a history of heavy smoking. They were screened once a year for 3 years, and were followed for 3.5 additional years with no screening.
There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, which is a relative reduction in mortality from lung cancer with low-dose CT screening of 20% (95% confidence interval [CI], 6.8 to 26.7).
The number needed to screen with low-dose CT to prevent 1 death from lung cancer was 320, Constantine Gatsonis, PhD, one of the study coauthors, told Medscape Medical News. He is from the Warren Alpert Medical School of Brown University in Providence, Rhode Island.
The rate of positive screening tests was more than 3 times higher with low-dose CT than with radiography (24.2% vs 6.9%) over all 3 rounds.
Most of the positive tests were false — 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false-positive results.
"The rate of false positives is very high, although the thoracic/pulmonology communities have certainly seen high rates of false positives with screening in the past," noted Dr. West.
The authors address the issue of false positives. "The vast majority of false-positive results were probably due to the presence of benign intrapulmonary lymph nodes or noncalcified granulomas," they write.
In a related concern, they note that the rates of complications after a diagnostic evaluation procedure for a positive screening test were "low." The rate of 1 complication or more was 1.4% in the low-dose CT group and 1.6% in the radiography group. The diagnostic methods and algorithms varied at the 33 sites and were not uniform per the protocol, the authors point out.
Dr. Sox observes that invasive diagnostic procedures were "few, suggesting that diagnostic CT and comparison with prior images usually sufficed to rule out lung cancer in participants with suspicious screening findings."
Dr. West said that lung screening is akin to prostate-specific antigen monitoring for prostate cancer. "Undergoing CT screening for lung cancer will require a careful discussion of the road that this may well lead people down, including the anxiety, additional imaging, and potentially invasive procedures that this pathway might well entail," he said.
The study authors point to another finding from the NLST as proof of the relative safety of lung cancer screening. The rate of death from any cause was reduced in the low-dose CT group, compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P = .02). "The decrease in the rate of death from any cause with the use of low-dose CT screening suggests that such screening is not, on the whole, deleterious," they conclude.
Another concern with CT screening is overdiagnosis, says Dr. Sox.
"Overdiagnosis probably occurred in the NLST," he writes. After 6 years of observation, there were 1060 lung cancers in the low-dose CT group and 941 in the radiography group. This may be evidence of overdiagnosis because, in a large clinical trial of screening tests, "the proportion of patients in whom cancer ultimately develops should be the same in the 2 study groups," he said. If the difference found to date between the 2 screening methods persists with more follow-up, this "suggests that one test is detecting cancers that would never grow large enough to be detected by the other test," Dr. Sox notes.
Finally, the study authors cite one last safety concern with CT screening — cancer caused by the CT scans themselves. "The association of low-dose CT with the development of radiation-induced cancers could not be measured directly," they write, adding that it is a "long-term phenomenon." Dr. Brawley said that previous research has indicated that for every 2000 spiral CT scans, there is at least 1 cancer caused (Radiology. 2004;232:735-738).
Cancers Detected
Low-dose CT screening fulfills an often-touted claim about cancer screening — that it detects more cancers earlier than would have been likely detected clinically. Indeed, 40% of the cancers in the low-dose CT group were stage 1A, whereas 21.7% were stage IV.
"Cancers discovered after a positive low-dose CT screening test were more likely to be early stage and less likely to be late stage than were those discovered after chest radiography," Dr. Sox explains.
Will the benefits of screening seen in the NLST be seen in community settings? Dr. Sox believes the applicability of the results is "mixed."
Diagnostic work-up and treatment did take place in the community, he acknowledged. "However, the images were interpreted by radiologists at the screening center who had extra training in the interpretation of low-dose CT scans and presumably a heavy low-dose CT workload," he writes.
Furthermore, both Dr. Sox and the study authors point out that the study population was not typical. Trial participants were younger and had a higher level of education than a random sample of men and women with a history of heavy smoking. This might have contributed to the high rate of adherence to the screening protocol in the study (more than 90%), says Dr. Sox.
The influential US Preventative Services Task Force (USPSTF) will make a determination about recommendations for lung cancer screening "by next year," said Dr. Brawley. In the meantime, while the USPSTF and organizations such as the ASC, which helped fund the study, and the American College of Radiology make their recommendations, physicians and patients should have a conversation about the harms and benefits of screening, he said.
Dr. Brawley, while emphasizing concerns about low-dose CT screening, said that "it's wonderful that we can say to high-risk people: 'We have something to offer you folks."
The study was conducted by the American College of Radiology Imaging Network and the National Cancer Institute's Lung Screening Study Group.
N Engl J Med. Published online June 29, 2011. Abstract, Editorial
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