CHICAGO-- "To screen or not to screen?" That was the question posed by lung cancer experts at CHEST '99, the annual meeting of the American College of Chest Physicians. Dennis E. Niewoehner, MD, argued that large, randomized, controlled trials have shown no benefit from radiographic screening for lung cancer--and no advantage to adding sputum cytology to the already valueless chest film. Gary M. Strauss, MD, opposed that proposition, contending that the mortality analyses in those same studies were flawed and that more accurate analysis reveals improved cure rates with screening.

EXAMINING THE PAST

The first efforts to screen for lung cancer were made in the 1950s, after the link between lung cancer and tobacco smoking was established. But during the 1960s and 1970s, "a number of screening trials yielded rather uniformly disappointing results," said Dr. Niewoehner, chief of the pulmonary section at the Minneapolis VA Medical Center and a professor of medicine at the University of Minnesota. "As a result, the enthusiasm for doing screening for lung cancer waned." He conceded, however, that there is currently some debate about how the results of those screening trials should be interpreted.

The primary problem, Dr. Niewoehner explained, is the confusion between survival and mortality rates. For the survival rate, the number of patients with cancer who survive is divided by the total number of patients with a diagnosis of cancer. But the mortality rate is calculated as the total number of deaths divided by the total number of patients in the study.

This difference can have a profound impact when study results are analyzed. As an example, Dr. Niewoehner described a hypothetical group of 10,000 patients who underwent mass screening in two simultaneous studies and then were followed for five years. In the first study, the screening method could detect only advanced cancers, and thus only 100 cases of cancer were diagnosed. The second study, which used a more refined screening method capable of finding early-stage carcinomas, detected 200 cases of cancer; however, the additional 100 cases were clinically benign. At the end of the five years, 50 out of 10,000 patients in either study had died of cancer. In the first study, the survival rate was 50%, whereas in the second study, it was 75%. Yet, the mortality rate in both studies was 0.5%, indicating that no additional lives were saved despite the apparent improvement in survival rates.

Thus, explained Dr. Niewoehner, survival rates are heavily influenced by the number of cancers detected. Clearly, in some situations (eg, cervical cancer), detection and treatment of early lesions can have a marked impact on outcome. However, in other settings (eg, prostatic cancer), screening may uncover lesions that are highly unlikely ever to become clinically significant (this is sometimes referred to as overdiagnosis). Detection of such lesions might make it appear that survival is improving; but in reality, there has been no change in outcome. For this reason, most researchers believe that the best outcome measure is the mortality rate. When this yardstick is used, Dr. Niewoehner said, studies have failed to find a benefit from lung cancer screening.

LOOKING AT THE STUDIES

A number of major clinical trials have attempted to determine the value of lung cancer screening, but only a handful meet current standards of evidence-based medicine. Of these, the largest is the Mayo Lung Project, which enrolled more than 4,000 patients in each of two groups.[1] Screened patients received a chest film and sputum cytology every four months for six years. The control group was simply told to get a chest film every year.

Dr. Niewoehner acknowledged that many more cancers were detected in the screened group than in the controls. Most of these cancers were found on chest films, not during sputum cytology, he noted. Furthermore, most of the additional cancers detected were early-stage lesions, which meant that there were many more resectable cancers in the screened group. Although survival was better in the screened patients, there was no difference in mortality between the two groups.

"There was absolutely no mortality advantage associated with screening," Dr. Niewoehner concluded; this remained true even when follow-up was extended by five years. "In fact, there were even a few more patients who died of cancer in the screened group than in the controls," he said. "This is not very encouraging, but it is consistent with [the results of] other prospective, controlled trials, which also failed to detect any benefit from lung cancer screening. We can't say with certainty that there is not some advantage to screening," Dr. Niewoehner noted, "but it is very unlikely that screening by chest radiology will yield a mortality advantage of greater than about 5% or 10%."

RE-EXAMINING THE DATA

"The data show what the data show," acknowledged Gary Strauss, MD, an assistant professor of medicine at Harvard Medical School in Boston. "The question is: How do we interpret them? I believe that the conventional interpretation is wrong. Cure rates, not mortality, should be the most important end point."

Dr. Strauss drew on several lines of evidence to explain his position. "The Memorial Sloan-Kettering[2] and Johns Hopkins[3] studies were randomized trials that compared yearly chest films to chest films and sputum cytology," he observed. "Both studies showed no benefit from the addition of sputum cytology to chest film alone. Yet five-year survival in both studies was two- to three-fold higher than [that shown in] SEER data based on contemporary statistics." [The Surveillance, Epidemiology, and End Results (SEER) program is a 27-year-old effort by the National Cancer Institute to collect information on cancer incidence and patient survival in the United States.]

The Mayo Lung Project[1] and a similar study from Czechoslovakia[4] failed to find a difference in mortality, Dr. Strauss admitted. But these studies detected "significant advantages [for screening] in stage, resectability, and survival, which suggests an improvement in cure rate," he added. "Dr. Niewoehner said that we would not see more than a 5% to 10% mortality advantage [with screening]." However, while no mortality advantage was seen in the Mayo study, "we did see a survival advantage at five years: 33% in the screened group versus 15% in the unscreened group." In the Czech study, Dr. Strauss noted, a similar survival benefit was found even though "both groups of patients underwent chest radiography at the end of the third, fourth, fifth, and sixth years. Thus, the improvement in survival cannot be explained by overdiagnosis."

Dr. Strauss also suggested that the methodology used in large screening trials is questionable. Techniques for randomization developed for smaller treatment trials may not be appropriate for mass screening. And "overdiagnosis was never an a priori hypothesis in any of these studies," he explained. "The only way to determine [if overdiagnosis could explain mortality results] would be to do a prospective study."

DIFFERENT OUTCOME MEASURES NEEDED

It is for these reasons, Dr. Strauss said, that he believes that the wrong outcome measures are being selected. "A reduction in disease-specific mortality in a randomized trial is not the proper measure of screening efficacy," he contended. "An improvement in the cure rate is the appropriate end point.… I believe that significant stage, resectability, and long-term survival advantages associated with chest x-ray screening are not attributable to overdiagnosis. In fact, screening has led to an improvement in cure rates. It is my position that the 33% five-year survival that we saw in the Mayo study reflects an improvement in cure rate."

"Clearly, what patients are interested in is whether we can cure them, but 'cure' is relevant only to the affected subpopulation," Dr. Strauss added. "My conclusions are that the randomized trials demonstrate that chest x-ray screening produces a two- to three-fold improvement in cure rates, from about 10% to 15% to about 30%. Based on those numbers, I believe that a public policy recommendation in support of chest x-ray screening can be justified. This would save about 30,000 lives in the US and about 300,000 lives worldwide each year."

--Janis Kelly

References
1. Fontana RS, Sanderson DR, Woolner LB, et al. Screening for lung cancer. A critique of the Mayo Lung Project. Cancer. 1991;67(4 suppl):1155-1164.
2. Flehinger BJ, Melamed MR, Zaman MB, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study. Am Rev Respir Dis. 1984;130:555-560.
3. Frost JK, Ball WC Jr, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis. 1984;130:549-554.
4. Kubik A, Parkin DM, Khlat M, et al. Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial on a population of high-risk males in Czechoslovakia. Int J Cancer. 1990;45:26-33.