PSA testing pioneers, from left, Bill Catalona and
Fritz Schroeder. Schroeder, who led the European
Randomized Study on Screening for Prostate Cancer,
credits Catalona for galvanizing his interest in this
project."In 1990, when Dr. Catalona was our visiting
professor at Erasmus University in Rotterdam, I saw
the data that he would soon publish in the
New England Journal of Medicine, which showed that
PSA testing led to the earlier diagnosis of curable
disease. This inspired me to initiate pilot studies,"
which culminated in this landmark study.
Two recent studies on PSA testing — both long-awaited, both published in the March 2009 issue of the New England Journal of Medicine — seem to contradict each other.One of them said that screening with PSA reduced deaths from prostate cancer by up to 27 percent. The other said that PSA testing didn't work.
When studies collide, how do you find the truth?"Like many things, the devil is in the details," explains Patrick C. Walsh, M.D., Distinguished Service Professor of Urology. But in this case, he adds,"understanding these details could save your life."
The European study, a landmark project carried out in seven countries, looked at 162,000 men. One group of these men was randomly assigned to PSA screening every four years; men in the other group were not screened. These men were followed for a long time, some as long as 14 years.Of the men who were screened, there was a 27-percent decrease in prostate cancer deaths."This is similar to the 30-percent reduction in deaths from breast cancer in women who undergo mammography, and the 33-percent drop in deaths from prostate cancer that occurred in the United States between 1994 and 2003 following the introduction of PSA screening," says Walsh."The results from the European study unequivocally demonstrate that PSA testing can save lives."
What happened in the second trial? The American study was only half as large as the European one, and it had many major flaws, says Walsh: It compared screening with PSA every year for six years with no screening afterward, versus no screening at all, and at seven years, it showed no improvement in deaths from prostate cancer. The biggest problem here, explains Walsh, is that in terms of statistics,"death from prostate cancer at seven years is meaningless. Screening and aggressive treatment, first of all, are meant for men with at least a 10-year life expectancy. Any man who dies within seven years of being diagnosed with prostate cancer has advanced, non-curable disease at the time of diagnosis, and would not benefit from PSA screening."In the European trial, there was no improvement in survival at seven years, either. It was just too soon.
“ If the authors had set out to
design a study to discredit PSA
testing, it would have been
difficult to do a better job."
The U.S. trial failed to achieve some important milestones that have been shown in successful screening trials. For example, screening for breast cancer has led to an increase in the number of cases diagnosed, and a decrease in the number who are found too late to be curable. The European prostate cancer trial showed a 71-percent increase in the number of new cases, and a 41-percent decrease in the number of men diagnosed with incurable disease."It just makes sense that the longer these men are followed, the greater decrease we can expect to see in prostate cancer deaths," says Walsh. In contrast, the U.S. study found only a 17-percent increase in the number of new cases, and no decrease in the number of men diagnosed with advanced disease. Because of the study's design, even if men are followed longer,"unfortunately the results will not change," says Walsh.
What's wrong with this study?
First, Walsh says, is that"it did not test screening versus no screening. It just compared more screening versus a little less screening."
Second, fewer than one-third of the men in the U.S. trial who developed a PSA greater than 4 actually underwent a biopsy. Walsh finds this aspect of the study most difficult to understand."If most of the men with elevated PSA levels never underwent a biopsy, how can anyone expect this trial to show that screening saves lives?
And finally, the American study used an outdated cutoff point for PSA — greater than 4.0, as opposed to greater than 3.0 in the European study — as the trigger-point for a biopsy.
"If the authors had set out to design a study to discredit PSA testing, it would have been difficult to do a better job," he says. It could be that the U.S. investigators were trying to simulate what would happen if every man in the United States had a PSA performed, but few followed up with a biopsy or treatment."If that were the question, I think we could have already guessed at the answer without spending $110 million." For prostate cancer screening, Walsh adds,"10 years is the earliest time at which we would expect to see any benefit. For a 50-year old man who is going to be alive for another 35 years, those odds are entirely different, and screening is very worthwhile." The key to successful screening is knowing who is most likely to benefit from it,"to avoid over-diagnosis in men who are too old or too ill to live longer than 10 years, and to avoid over-treatment in men over age 65 who have low-volume disease. Most of all, it is imperative for us as physicians to continue to improve the quality of treatment. If one day we could reduce the side effects to a minimum, the debate would end. The"take-home message" here is simple, Walsh believes."If you are the kind of person who doesn't wear a seat belt or go regularly to the dentist or your family doctor for a check-up, and you're not worried about dying from prostate cancer, do not undergo PSA testing. On the other hand, if you are a healthy man aged 55 to 69 who does not want to die from prostate cancer, the European trial provides conclusive evidence that PSA testing can save your life."
The Bottom Line: Testing Does Save Lives
The European study: 162,000 men, one group randomly assigned to PSA screening every four years; men in the other group not screened. The men were followed for as long as 14 years.
Results: A 27-percent decrease in prostate cancer deaths.
The U.S. study: Half as large as the European study. At seven years, a time point too early to be of value, showed no improvement in deaths from prostate cancer. Because 50 percent of the men in the control group actually underwent PSA testing, this study did not test"screening versus no screening," but"more screening versus a little less." Also, fewer than one-third of the screened men with an elevated PSA actually underwent a biopsy.