Have you ever wanted something for such a long time that when it finally arrived you found yourself terribly disappointed?
Maybe that’s the best way I can summarize my feelings about two studies reported today in the New England Journal of Medicine on the topic of prostate cancer screening and whether or not it really makes a difference.
For years we have been saying that there wasn’t sufficient evidence to prove that screening for prostate cancer saved lives. That was almost always followed by a statement that we were waiting for the results of two trials in the United States and Europe. “They will show us the answer” we said. In the meantime, millions of men continued to get tested and undergo treatment, even though no one could really say if we were saving lives, or just sending millions more men to unnecessary treatment with all sorts of side effects.
Well, my friends, the waiting is over. The day has arrived. And I don’t know that we now have any better idea whether or not prostate cancer screening actually works.
Prostate cancer in the United States in 2008 was estimated to occur in 186,320 men (we haven’t made our 2009 estimates yet, due to a delay in getting 2006 mortality data from the Centers for Disease Control (CDC), in part because of budget cutbacks. But that is a story for another day.) The American Cancer Society estimated that 28,660 men would die from prostate cancer in the United States in 2008. Prostate cancer is the most common cancer in men, accounting for 25% of cancers diagnosed in men in 2008. It is the second leading cause of cancer death in men—behind lung cancer—accounting for 10% of cancer deaths. A man in this country has a 1 in 6 chance of being diagnosed with prostate cancer during his lifetime, with most of those diagnoses occurring at ages 70 and older. Importantly, and not mentioned as often, is the fact that only one in 34 men will die of the disease.
The two research papers in the New England Journal of Medicine describe early results from two different trials—one in the United States and one in Europe—which were designed to find out whether or not tests to find prostate cancer early reduced deaths in men from the disease.
In the United States trial, 76,693 men between the ages of 55 and 74 years were randomly assigned to be screened or receive “usual care” from 1993 to 2001. The men in the screened group had annual PSA testing for 6 years and digital rectal examinations every year for 4 years.
The good news is that the men in this trial who were in the screened group did a reasonably good job of following the directions of the trial: 85% of them had their PSA blood test and 86% did the rectal exam as requested.
The not so good news is that by the sixth year of the trial, 52% of the men in the control group—who were left to their own devices as to whether or not they should get the PSA blood test—had the test. 46% of these men had a rectal exam.
What that leaves us with is a clinical trial where the men who were asked to get screened did get screened. And of the men who were not told to get screened, about half of them got screened anyway.
The end result was that after 7 years of follow-up (the follow-up ranged from 7.2 to 14.8 years, with half of the men followed for 11.5 years or more), there were more cancers diagnosed in the screened group (no surprise there: go looking for prostate cancer in a man and you have a pretty good chance of finding it) compared to the “control group,” but the deaths were a bit higher in the screened group compared to the supposed no-screening group (although these numbers were not significantly different).
The conclusion? “After 7-10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.”
The authors acknowledged some limitations in their study, including the fact that treatment for prostate cancer may have improved so much as to negate any benefit that screening may have had. They also point out that it may yet be too early to draw a definite answer from the study, and that further follow-up of the men participating in this study may be warranted:
“Risks incurred by screening, diagnosis and resulting treatment of prostate cancer are both substantial and well documented in the literature. To the extent that overdiagnosis occurs with prostate cancer screening, many of these risks occur in men in whom prostate cancer would not have been detected in their lifetime had it not been for screening. The effect of screening on quality of life is a subject of an ongoing substudy and should be completed within the next several years. Follow-up in the PLCO trial (the name of this study) is planned to continue until all subjects reach at least 13 years. A final report will be presented once the planned duration of follow-up is completed.”
What about the European trial? That one is even a bit more confusing to understand.
182,000 men between the ages of 50 and 74 in seven European countries were randomly assigned to get a PSA test “at an average of once every 4 years” or to a control group that did not get screened. Of this group, 162,387 were actually part of the current report, and these men were between the ages of 55 and 69 years.
Half the men were followed for more than 9 years, and half less than 9 years. 82% of the men who were offered screening got at least one PSA test. Of those who had at least one PSA test, 8.2% were diagnosed with prostate cancer, and of those who did not have the test, 4.8% had a diagnosis of prostate cancer made during the period of the study.
The end result was that the risk of death in the men who were screened was 20% less than those who were not screened. In more plain terms, according to the authors, “1410 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.”
When one considers all of the problems (urine incontinence, impotence, pain and bleeding among others) associated with treatment for prostate cancer, that is a lot of men left with a lot of symptoms to save one life.
In this study, the authors concluded, “PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis.”
When you dig deeper into the study, you begin to see some inconsistencies that may have influenced the results.
Recruitment and randomization procedures were not the same in every country that participated. Portugal stopped participating, and France joined late. All countries included men ages 55-69, but Sweden also included men who were 50-54. The Netherlands, Italy, Belgium and Spain included men up to the age of 74, and in Switzerland men were screened up to the age of 75. In all countries except Finland, men were randomly assigned on a “50-50” chance basis to screening or no screening. Finland decided to screen 2 men for every one in the control group.
Some other interesting tidbits: In the United States trial, men had to have a PSA level of 4 or more before being referred for further diagnostic studies. In the European trial, the PSA level that triggered diagnostic studies was 3. The result is that fewer men would be diagnosed in the US, while more men would be diagnosed in Europe. But, the rate of overdiagnosis in the European trial was likely greater, and the possibility exists that there was underdiagnosis in the US.
Here is another interesting piece of information: In the European trial, 75.9% of the men who underwent prostate biopsy because of a PSA of 3 or greater did NOT have prostate cancer.
The conclusion of this study?
“Although the results of our trial indicate a reduction in prostate-cancer mortality associated with PSA screening, the introduction of population based screening must take in to account population coverage, overdiagnosis, overtreatment, quality of life, cost and cost-effectiveness. The ratio of benefits to risks that is achievable with more frequently screening or a lower PSA threshold than we used remains unknown. Further analyses are needed to determine the optimal screening interval in consideration of the PA value at the first screening and of previously negative results on biopsy.”
Sounds like a draw to me.
There was an editorial that accompanied these two articles, which reported that—in the mode of “do as I do”—95% of male urologists and 78% of primary care physicians who are age 50 or over have had their own PSA tested. The author also noted that there has been a significant decline in deaths from prostate cancer since the early 1990’s.
The editorialist goes on to say:
“Neither set of findings seems definitive; that is, there was neither a clear declaration of futility in the PLCO trial (United States) nor an unambiguous net benefit in the ERSPC (European) trial. Both studies are ongoing, with future updates promised…(The) decisions to publish now can be criticized as premature, leaving clinicians and patients to deal with the ambiguity…
“The implications of the trade-offs reflected in these data, like beauty, will be in the eye of the beholder. Some well-informed clinical and patients will still see these trade-offs as favorable; others will see them as unfavorable. As a result, a shared decision-making approach to PSA screening, as recommended by most guidelines, seems more appropriate than ever.”
Shared decision making about getting a PSA test and digital rectal examination for the early detection of prostate cancer is exactly what the American Cancer Society recommends. You need to talk about prostate cancer screening with your doctor or other health care professional. You need to know the risks, benefits and harms that can occur as a result of screening for prostate cancer before you embark on getting these tests as part of your routine medical care.
What is the impact of these reports?
Unfortunately, now armed with the knowledge I have been waiting for, I am completely underwhelmed.
Our recommendation regarding prostate cancer screening is no different now than what the Society has been saying for years. Men need to talk with their health care professionals about the test.
The only difference now is that the long awaited studies have been reported. And our message hasn’t changed.
Maybe more men will give some thought as to whether or not they really want or need a PSA test and rectal examination. I don’t think that is a bad thing.
I suspect the “gung-ho go forward at any cost” attitude of those in the medical and advocacy communities who have promoted prostate cancer screening with a vengeance—absent evidence that it really saved lives—is going to calm down just a bit.
At first blush, my reaction was that these studies don’t really give us the answer we were waiting for. But on further reflection, maybe they did—sort of like not making a decision is in fact a decision. Perhaps not getting a clear answer to the question as to the value of prostate cancer screening is in fact a clear answer.
At the end of the day, each of us will have to be our own judge on the merits of the case and what we want to do for ourselves when it comes to the early detection of prostate cancer.
