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Cancer deaths not deterred by prostate tests

According to new research from two large-scale trials published online today in the New England Journal of Medicine, the answer is very likely no.

Data compiled by U.S. and European researchers found that screening men early for prostate cancer prevented no more deaths than leaving them alone. But even the scientists familiar with the long-awaited research say they know that won’t settle it.

“We now have a clear idea of what the tradeoffs are between benefits and risks but not so clear that anyone can tell you ‘This is a no-brainer, you’ve got to get screened,’ or ‘You should never get screened,” said Dr. Michael J. Barry of Harvard Medical School, who wrote an editorial accompanying the new data titled, in part: “The Controversy that Refuses to Die.”

“You have to wrestle with the tradeoffs.”

At issue is data from the partially completed U.S. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, or PLCO, and the European Randomized Study of Screening for Prostate Cancer, or ERSPC, both of which are sure to fuel more debate about the value of routine tests given to men, usually starting at age 50.

“The stakes are very high,” said study author Dr. Barry Kramer, associate director of the office of disease prevention at the National Institutes of Health. “Not just in dollar costs but in human costs.”

Approximately 186,000 men in the United States are diagnosed with prostate cancer every year. Most of those diagnoses start with a screening test: either a digital rectal exam, during which a doctor feels the prostate to check for irregularity or enlargement, with a blood test to check the level of prostate-specific antigen, or PSA, in the blood, or both.



Prostate cancer: What you need to know

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But these tests, especially the PSA, are indirect markers. The PSA doesn’t check for cancer, it checks for a protein that may signal cancer is present. The higher the PSA, the greater the risk. But because PSA doesn’t prove cancer, invasive tests, like biopsies, are required to diagnose disease. Even then, doctors can’t always be sure what kind of prostate cancer a man has — whether it will be very slow-growing and never cause a problem, or whether it will be life-threateningly aggressive.

Earlier studies have indicated that up to half of men are “overdiagnosed,” causing them to have invasive procedures and treatments they don’t need and would be better off without. Those treatments have a high rate of life-changing complications, like impotence and urinary incontinence.

On the other hand, since the beginning of the PSA era, in about 1985, the rate of prostate cancer death has dropped about 4 percent every year, pushing the 10-year survival rate to 91 percent. Some doctors believe much of that improvement should be credited to early detection through screening.

“There is no question that diagnosis today occurs at a different stage and grade than happened a decade and a half ago,” said Dr. Christopher Logothetis, chair of genitourinary medical oncology at the M.D. Anderson Cancer Center at the University of Texas in Houston. “It is an unusual event to see patients present with far advanced disease and I think much of that can be attributed to deploying PSA clinically.”

But these new study results call that thinking into question and leave men with a difficult decision.

Screening failed to save more lives

In the PLCO study, 38,343 men received a choice every year of PSA screening or a digital rectal exam. A large majority were screened. After seven years, 2,820 cancers had been found. In a nearly equal number of men who did not receive that annual choice (though some were screened as part of regular care), 2,322 cancers were found. There were 50 deaths in the screening group, and 44 deaths in the control group.

In other words, more intensive screening did not save any more men from dying of prostate cancer.       

The ERSPC results, compiled from centers in countries around Europe, were slightly more in favor of screening. When a group of 82,816 men in a screening group were compared to 99,184 men in a control group, the risk of dying from prostate cancer was reduced by about 20 percent in the screening group.

Or, as the authors of the study put it, “1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.”

“In both trials, the benefits of regular PSA screening are smaller than lots of people expected,” noted Barry in the NEJM editorial.

All sides of the screening debate agree that medicine as a whole has to punt the issue to practitioners and their patients.

“Everyone would agree that men should not be screened routinely without an informed decision process,” Kramer said. “This is not the type of test that lends itself to automatically checking the lab slip [that orders tests] without a man knowing what we know about the benefits and harms.”

But while “personal choice” sounds empowering, it doesn’t help men use the information logically.

“Some men might say ‘Gosh, you have to find and treat 50 men to prevent one death,’” Barry said. “‘Those are good odds of being overtreated; I don’t want it.’ Others might say ‘I might be that one in 50, so it’s worth it.’” 

No hint of benefit’

As for younger men aged 50 to 54, Kramer said “there was no hint of benefit,” to PSA screening. 

But several issues with both studies add murk to the message. In both, some members of the control groups were screened at least once since, for some practitioners, screening is a routine part of regular care. This screening added “contamination” to the data.

As Logothetis pointed out, the near-ubiquity of PSA testing “has confounded the ability to detect population differences.”

Second, since the European study was performed as a consortium of centers spread across the continent, some centers joined late, and some used different protocols, standards, and treatments for diagnosed cases, making it difficult to reconcile the death data from one center to another.

Third, therapy for prostate cancer has improved. If control group men diagnosed with cancer don’t die, there would be fewer deaths to record, helping the control group death rate match the death rate in the screened group.

Fourth, the confidence intervals — the certainty that the results truly reflect reality — are wide in both studies.

Finally, the U.S. study is being publicized earlier than originally planned. The design called for men to be followed for 13 years. So far, all the men have been followed for seven years and 65 percent for 10 years.

Results not definite

“So this is not definitive, but this is what we have at this moment,” said David Chia, an epidemiologist at the University of California, Los Angeles, and one of the PLCO authors.

Chia said the Americans decided to publish now because the Europeans were releasing their data, taking the Americans “by surprise.”

“So the decision was made to publish the U.S. results so people do not go right away and say ‘Yes, there is a benefit.’”

Kramer denied that and said the decision to publish was made by the study’s safety monitoring board because the information was so compelling.

“At seven years,” he said, “the risk is in the wrong direction” away from screening.

Far too many men, Chia said, go through “a lot for nothing.”

But even Kramer doesn’t expect either of these studies will settle the issue, partly because testing is so entrenched in clinical practice. “As a matter of fact, I’ve said for years that even if both trials show many more deaths in the screening arm, it will not be resolved completely.”

The uncertainty leaves men facing prostate cancer screening in a quandary. If randomized trials of screening cannot provide reliable evidence, many doctors will continue to order the test routinely as the safest course.

Many men may object to being screened, or, worse, treated for a cancer they may never get. But many other men will have to ask themselves how much they would regret not being tested if they turn out to be the one out of 50.