NEWS

Lung Project Update Raises Issue Of Overdiagnosing Patients

Laura Newman

Several screening tests are becoming popular based on only short-term survival data and with no evidence that they reduce the rate of late-stage cancers and cancer-specific mortality. An extended follow-up study of the Mayo Lung Project in this issue of the Journal and a recent outcomes analysis of 20 major cancers show no overall mortality reduction despite increases in survival from the date of diagnosis. The authors of both papers say that there is a very real concern about harm that must be addressed, a possibility that often gets short shrift.

The 20-year Mayo Lung Project extended follow-up study (p. 1308) suggests that a phenomenon known as overdiagnosis —finding disease that may be clinically irrelevant—was a major factor in explaining the survival/mortality differential between a group of patients aggressively screened for lung cancer and a group of patients who received usual care. The project was launched in 1971 and ended in 1983. At that time, with an average follow up of just 3 years after the last screening, the original study compared lung cancer mortality in male smokers randomized to an intensive screening schedule of quarterly chest x-rays and sputum cytology tests or to "usual care"—an initial reminder to get annual screening, without further efforts to have the control group screened.

Lung cancer mortality turned out to be similar in both arms—3.2  lung cancer deaths per 1000 person-years in the intervention arm versus 3.0 deaths per 1000 person-years in the usual care arm.

To this day, the original Mayo Lung Project has been debated, with numerous critics challenging the study’s design. One major criticism of the study was that it was not large enough to find anything short of a 50% mortality benefit—a difference far greater than anybody would expect today—and much greater than that being examined in the much larger Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, an ongoing NCI-sponsored study. Another key criticism was that the follow-up time was too short to detect a mortality reduction.

Aiming to address these limitations, the latest analysis looked at the study data an average of 20 years from entry into the study. Pamela Marcus, Ph.D., an epidemiologist in the National Cancer Institute’s Division of Cancer Prevention, and her colleagues found that people in the intervention arm with resected early-stage lung cancer lived longer than those in the usual care arm (median survival: 16 years versus 5 years), and they again found similar mortality rates between the groups (4.4 lung cancer deaths per 1000 person-years in the intervention group and 3.9 deaths per 1000 person-years in the usual-care group).



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Dr. Pamela Marcus

 
Overdiagnosis Bias

With such extended follow-up, Marcus and her colleagues were able to look for overdiagnosis, she said. They examined whether the "lesions picked up in the screened group had little to no clinical relevance and would never kill the [patient]." It is a conclusion that she admits is "totally heretical" to many advocates of lung cancer screening.

Marcus added that people do not consider the downsides to early detection when the test’s merits are unknown. Patients may be faced with a cascade of questionable tests and invasive procedures, morbidity and anxiety that goes along with the procedures and a cancer diagnosis, and the possibility that they may have indolent lesions that will never threaten their lives. These risks are ones that patients should be educated about before they get screened, she said.

The study may give pause to proponents of the use of spiral computed tomography in lung cancer screening. "This study is tremendously important in thinking through what data are necessary to properly assess the usefulness of helical computed tomography for screening and whether such a test—if it is released too soon—could cause harm," Marcus said. "Given its excellent resolution, spiral CT will identify lesions at a rate much higher than chest x-ray, but some of them might have absolutely no clinical relevance."

But it may prove difficult to use the paper to educate people that "early detection is not necessarily the be-all and end-all," said Marcus.

"The findings are counter to our understanding of screening," said William C. Black, M.D., professor and chair of radiology at Dartmouth Medical School in Hanover, N.H., and author of a companion editorial (p. 1280). No matter, Black argues that the study’s methodology is strong.



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Dr. William C. Black

 
Black raises very serious concerns about overdiagnosis with an aggressive, unproven screening strategy. In his editorial, he makes his case. "Overdiagnosis plays havoc with our understanding of cancer statistics," he wrote. "Because overdiagnosis effectively changes a healthy person into a diseased one, it causes overestimations of the sensitivity, specificity, and positive predictive value of screening tests and the incidence of disease . . . overdiagnosis does not reduce the disease-specific mortality because treating subjects with pseudodisease does not help those who have real disease."

Limitations of Survival Analysis

The utility of survival data in assessing whether a new screening test meets muster is a major question. In a June 14 analysis in the Journal of the American Medical Association of population-based statistics for 20 major cancers taken from NCI’s Surveillance, Epidemiology, and End Results Program, H. Gilbert Welch, M.D., and his colleagues show that 5-year-survival figures bear no relationship to changes in the cancer death rate.



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Dr. H. Gilbert Welch

 
"The problem with [survival data] is that if you look at 5-year survival, you might conclude that there has been progress against cancer—when in fact that figure is affected by our diagnostic practices," said Welch, who is a professor of medicine at Dartmouth Medical School and senior researcher with the department of Veterans Affairs in White River Junction, Vt.

Co-author Steven Woloshin, M.D., research associate at the VA Medical Center in White River Junction and an assistant professor at Dartmouth Medical School, said that armed with only 5-year data, "you can’t really declare victory—you are not ready to judge progress against cancer. When you introduce a new screening technique that is broadly disseminated, you introduce all sorts of detection biases."



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Dr. Steven Woloshin

 
For example, Woloshin said that with the broad use of prostate-specific antigen screening, 5-year survival has improved, but prostate cancer mortality has changed little, a point stressed in the paper by Welch et al. "We are certainly not saying that there hasn’t been progress in combating cancer, but to judge progress, it is imperative that you look at mortality."

Yet Welch admits that looking at mortality is easier said than done. "Survival is a common currency. It’s easy to understand," he explained, noting that people can relate to a 0% to 100% survival. "It’s when you express mortality as 271 per 100,000," that is when people get lost, Welch said. And he recognizes that it will prove tough for epidemiologists to counter the screening literature in which some put emphasis on survival.

But Robert Hiatt, M.D., Ph.D., deputy director of NCI’s Division of Cancer Control and Population Sciences, said that survival data should not be entirely discarded, emphasizing its appropriate role in epidemiology and biostatistics. Athough Hiatt acknowledges that the argument against using survival in assessing screening tests seems quite relevant to "the current feverish interest in pushing spiral CT for lung cancer," he pointed out that "survival is still a valuable measure to have when comparing therapies in a randomized controlled trial." That point is also discussed in the Welch paper.

Leveling With Patients

Still, some epidemiologists say that doctors are abandoning their Hippocratic oath to "first do no harm" when promoting screening techniques with no proven mortality benefit and in not informing patients about the uncertain risks and potential harms of innovative screening techniques. Virginia Ernster, M.D., professor and co-chair of epidemiology and biostatistics at the University of California at San Francisco, pointed out that when mortality data are absent, there are definite hazards. "You can pick up more trivial cancers in perfectly healthy individuals. Unless there is evidence of a reduction in the rate of late-stage disease and mortality, a patient has to be warned of these potential harms."


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