Study favoring routine screens in older women draws fire

A recent study that linked improved survival in elderly breast cancer patients with regular screening mammography is "fatally flawed" and "naïve," according to some cancer screening experts. The authors, however, maintain that their results offer insights into a patient population that is generally underserved.

While the critics also stress that cancer screening in women age 80 and up is an important topic, they are concerned that the study by Dr. Gildy Babiera and colleagues from the M.D. Anderson Cancer Center in Houston may promote overdiagnosis and unnecessary treatment.

"The science of the paper and the methods are fatally flawed," said Dr. Rebecca Smith-Bindman, an associate professor in residence at the radiology department of the University of California, San Francisco. "This (research) doesn't . . . contribute at all in terms of showing a decrease in death or an increase in survival."

Babiera's group reviewed records of 12,358 women aged 80 and up from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. All had been diagnosed with, and treated for, breast cancer between 1996 and 2002. The researchers' goal was to determine the effect of regular mammographic screening on disease stage at presentation and survival (J Clin Oncol online, April 21, 2008).

The results of the study found that 27% of the women aged 80 to 84 years underwent regular mammography. The mean tumor size for these women was 2.90 cm versus 5.22 cm in the nonusers of mammography. Regular screening participants also had fewer positive lymph nodes at surgery and were more likely to undergo breast conserving surgery and radiotherapy. Nonusers of mammography had higher comorbidity scores, according to the authors.

Based on their multivariate analysis, Babiera's group found that "each mammogram obtained results in a 37% decrease in risk of late-stage cancer."

"Breast cancer-specific five-year survival among nonusers was 82%, that among irregular users was 88%, and that among regular users was 94%,"they said.

The group concluded that regular screening in elderly women was associated with earlier stage disease. They also acknowledged, however, that improved survival was difficult to demonstrate. Critics may consider that an understatement.

"This study is just flat-out wrong," said Donald Berry, Ph.D., chair of the department of biostatistics at M.D. Anderson. "It is naïve, and . . . it provides no evidence whatsoever that there is a benefit for screening women in their 80s. It doesn't provide positive evidence; it doesn't provide negative evidence. It's a worthless study."

But not everyone is as dismissive of the results.

"This is a good study for clinicians to recognize that there is certainly a role for continued mammography screening in this age group," said Dr. Karen Lane, clinical director of the Breast Health Center at the University of California, Irvine.

The critics charge that Babiera's group failed to account for the two major limits of randomized screening trials: lead-time bias and length-time bias (see table).

"There is no way to assess the real benefits (of screening) without addressing lead-time bias and length-time bias," Smith-Bindman said.

When a screening-oriented study doesn't address these biases, results are bound to be rosier, with screening turning in an artificially positive performance, Berry said. To complicate matters, lead-time bias is difficult to pin down, especially in older women. He pointed out that previous mammographic screening studies have focused on younger women, and even then lead-time bias has proved slippery.

"The problem is that we don't know what the lead-time bias is, except that it's huge," he said. "That's the reason we did randomized clinical trials-because we couldn't address the question by looking at clinical practice.

Moreover, whatever the lead-time bias is for younger women, it's different for older women. We have almost no information about that, but I expect that the lead time is greater in older women than it is in younger women."

Babiera did not respond to Diagnostic Imaging's request for an interview, but in an M.D. Anderson news release, she and coauthor Dr. Brian Badgwell recognized that "finding breast cancer early in this age group may not result in survival benefit, and it may even increase unnecessary angst in elderly women with other ailments."

They reiterated in the written statement, however, that finding these cancers early enough through routine screening may guide elderly women in good health to less invasive and toxic treatment options.

But prior observational studies that have taken lead-time bias into account did not show a significant decrease in mortality because of screening, said Dr. Mara Schonberg, an instructor in internal medicine at Harvard University and Beth Israel Deaconess Medical Center.

"This study only addressed the potential benefits of screening and did not consider any of the risks," Schonberg said. "Also, by excluding women with a history of other cancers and whose tumors were unstaged or not histologically confirmed, this study examined a healthier population of women aged 80 and older than the general population."

For Lane, the exclusion of lead-time and length-time bias was not a problem. Given that randomized controlled studies will never be conducted in this patient population, database studies are the best bet for advancing knowledge on breast health in older women, she said.

"I find that these studies can bring to light areas that are difficult to study with randomized controlled trials," she said. "I don't think in this case that (lack of lead-time/length-time bias discussion) is a critical argument. I think these database (studies) supply us with the best information for a very large number of women, and we just have to deal with whatever shortcomings database work might present to us. This type of work does help us start thinking about the appropriate treatment in this population."

In its paper, Babiera's group acknowledged that a selection bias was possible because healthier women were more apt to comply with regular screening guidelines. This self-selection is not a minor point, said Robert Kaplan, Ph.D., chair of the department of health services at the University of California, Los Angeles' School of Public Health.

"It is not possible to determine whether mammography extends life from this type of study. The study is observational and there is clearly self-selection into screening by more affluent and healthier women," Kaplan said.

A similar bias led the healthcare community to believe that hormone replacement therapy was beneficial to postmenopausal women until randomized screening trials proved otherwise, he said.

The current guidelines vary for mammographic screening in elderly women. The American Cancer Society recommends yearly mammograms for women aged 40 and over. The U.S. Preventative Services Task Force advises that in women older than 70, the benefits of early detection must be weighed against other comorbidities. The American Geriatric Society advocates screening every one to two years for women with life expectancies of at least five years until age 85.

The current study should not be taken as a sign that screening guidelines need to be radically altered to accommodate older women.

"In the case of mammography, we still have no clinical trial data on screening of older women, because the trials typically exclude women beyond the age of 70. The only way we will ever figure this out is by conducting a trial," Kaplan said. "For now, I am not convinced that there is any evidence supporting screening mammography for older women."

Berry said that while the scientific community may understand the pros and cons of a study like this, he feared that the average woman might take away the wrong message.

"The problem is that the woman in the street is not necessarily going to know to ignore the article," he said. "It has a negative aspect that goes well beyond the 80-year-old woman who is considering mammography. It's the kind of thing that gives medical research a bad name."

Ms. Pal is deputy editor of Diagnostic Imaging.