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Prostate cancer screening guidelines called into question

Thursday, May 5, 2016

Jim Hu, M.D.Jim Hu, M.D. Researchers from Weill Cornell Medicine/NewYork-Presbyterian have questioned the results of a large-scale clinical trial assessing the value of PSA screening that served as the basis for the U.S. Preventative Services Task Force’s 2012 recommendations against routine prostate cancer screening.

In a letter to the editor published in the New England Journal of Medicine, Jim Hu, M.D., and Jonathan Shoag, M.D., say limitations in the study’s methodology underscore the need for healthcare policy leaders to reevaluate the nation’s approach to PSA screening.

“We expect this article to have a profound impact on the debate over the value of PSA screening,” said Dr. Hu, director of the LeFrak Center for Robotic Surgery at NewYork-Presbyterian/Weill Cornell Medical Center and the Ronald Lynch Professor of Urologic Oncology at Weill Cornell Medicine. “While there are risks of over-diagnosis and over-treatment associated with PSA testing, it can play an important role in preventing prostate cancer deaths as part of a personalized approach to cancer screening. We’re going to have to reconsider this issue.” 

PSA testing measures antigens in the blood that are linked to the presence of prostate cancer, as well as benign conditions such as prostatitis. Since the introduction of PSA screening in the early 1990s, the United States has seen roughly a 50 percent reduction in the prostate cancer mortality rate. However, while PSA screening clearly resulted in more prostate cancer diagnoses, it was not clear what role it played in this mortality reduction, and there was concern that prostate cancer was being over-diagnosed and over-treated, with consequent morbidity and costs.  

Several major U.S. organizations have now recommended against PSA screening based on the results of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial. As a part of this some $400 million study sponsored by the National Cancer Institute, a group of men who were assigned to receive prostate cancer screening including PSA testing were compared with a control group who received usual care by their physicians.

The researchers concluded that there was effectively no difference in the mortality rate between the two groups, and this has been interpreted to mean that PSA screening is ineffective. However, after carefully examining the study’s methodology, the NewYork-Presbyterian and Weill Cornell Medicine researchers found that many men in the control group who received PSA testing were not included as tested in the study reports, and the study results have therefore been misinterpreted. The researchers found that around 90 percent of men in the control arm of the study had received PSA testing during the trial, meaning that comparing the control and intervention arms of the trial is not useful to evaluate the effectiveness of PSA screening.

The PLCO trial is one of two major studies that have attempted to address the impact of widespread PSA testing on a large population. The other, the European Randomized Study of Screening for Prostate Cancer, found that PSA screening is associated with a substantial reduction in prostate cancer mortality over time, contrary to the findings of the PLCO study.  

Dr. Shoag, a NewYork-Presbyterian and Weill Cornell Medicine urology resident and lead author on the article, will discuss PSA screening at the annual American Urological Association meeting in San Diego, California on May 9. “We demonstrate that the PLCO study did not compare a group of men who received PSA screening to a group of men who were not screened, but compared men who were screened to other men who were screened, and we should therefore reconsider any decisions based on the study,” said Dr. Shoag.  

More about why the doctors think the earlier guidelines were flawed and how their study may impact patient care across the country:

What is PSA testing for prostate cancer? When did doctors start using it? 

Prostate Specific Antigen (PSA) is a blood test that is used to detect prostate cancers and to follow cancer’s response to treatment. PSA was widely implemented as a screening tool for prostate cancer in the early 1990s, and became a routine test during an annual physical for men age 40 years and older. Doctors started using it because values above a “normal” threshold were associated with a greater risk of prostate cancer. Following the adoption of PSA screening in the early 1990s, there has been a large increase in the number of men diagnosed with cancer, a decrease of approximately 50 percent in the rate of prostate cancer death and an 80 percent decrease in the likelihood of metastases at diagnosis.

What was the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial? What did it say about PSA screening for prostate cancer and how did this inform public health decisions?

The PLCO trial was a large randomized trial designed and funded by the National Cancer Institute (NCI) to determine the effect of PSA screening on death from prostate cancer. It was initiated to look at the effect of prostate cancer screening, and was modified to include lung, colorectal and ovarian cancer as well. It incorporated more than 76,000 men and 78,000 women, and was estimated to cost in excess of $400 million.

The PLCO trial found that men randomly assigned to prostate cancer screening had the same number of prostate cancer deaths as men in the control group of the trial, and the investigators argued that PSA screening does not decrease prostate cancer mortality. It is pretty much the only evidence suggesting PSA testing doesn’t save lives.

It was a major piece of evidence used by the U.S. Preventative Services Task Force (USPSTF) to form its 2012 recommendation against PSA screening. The argument was that we now had high-quality evidence showing no benefit to PSA testing in the United States. However, there was other evidence demonstrating a benefit to PSA testing, including U.S. epidemiologic trends showing a 50 percent decline in prostate cancer mortality since 1992 and another large randomized trial performed in Europe that showed that PSA screening was effective.

As a result of the task force’s recommendations, we have seen dramatic declines in prostate cancer screening in the United States since 2012.

But what’s the downside of PSA testing? Why would it potentially lead to negative outcomes? 

Prostate cancer is unique in that many men will get slow-growing prostate cancers that will never cause them problems. While the PSA test itself is a simple blood test, it did lead to the detection of many of these slow-growing cancers. When these cancers were detected, historically they were treated aggressively with surgery and radiation. The main side effects of these interventions were erectile dysfunction and urinary incontinence.

Have there been any other major studies of PSA testing? What were the results?

The European Randomized Study of Screening for Prostate Cancer (ERSPC) is the second major randomized trial, and its initial results were actually published in the same issue of the NEJM as those of the PLCO Trial in 2009. This trial randomized more than 160,000 men in Europe, and in contrast to PLCO, found that PSA screening decreased prostate cancer mortality by 21 percent. This trial however was also imperfect, and some analyses of subgroups from the trial have found decreases in mortality of around 50 percent with screening.

What made you go back and examine the results and methodology of the original PLCO study?

In any trial, the goal is to compare two different things, say apples to oranges, to see which is better. One major concern with the PLCO trial was that many men in the United States were getting PSA testing done by their primary care physicians by the time the trial had started. So the concern was that if men in the control group were also getting tested and compared to men in the intervention group who were randomized to prostate cancer screening, then comparing prostate cancer mortality between arms wouldn’t be useful, like comparing apples to apples.

We noticed that there was significant variation regarding the rate of testing in the control group,  also called contamination, that was quoted in the literature; from those who said 50 percent cumulatively had PSA testing (as the USPSTF did) to those who said it was 50 percent annually or higher. Because this number is so important, and other than the mortality difference is probably the most important consideration when evaluating the trial, we were curious as to why the numbers were so discrepant. Needless to say we were very surprised by what we found. 

So what does this mean about the results of the PLCO study? Should we still consider them when making recommendations to patients?

The short answer is no, the trial results are uninterpretable. Essentially everyone in the control group had PSA screening during the trial. That the trial results showed no difference in prostate cancer death between the two arms is therefore pretty meaningless, because practically everyone was screened. They compared apples to apples, and found no difference, and therefore cannot assess the true benefit of PSA screening on death from prostate cancer.  

What would you like patients and physicians to take away from your paper in NEJM? What kind of impact will this have on public health?

PSA screening was wrongfully convicted because of the PLCO trial. Based on the available data, PSA screening clearly prevents men from dying of prostate cancer. While the magnitude of that effect may be up for discussion, the presence of an effect should not be. Currently, 26,000 men die a year of prostate cancer in the United States, and without PSA testing some estimates put that number much higher. As physicians, we would not want our patients among the potentially large number of what we know are preventable deaths from a painful, debilitating cancer.

Avoiding those deaths certainly comes at the cost of the potential for over-diagnosis of slow-growing cancers that will not affect life expectancy. Because of additional research on better classification on prostate cancers, and the natural history of low-risk prostate cancers, we have begun avoiding definitive therapy for these indolent tumors and choosing active surveillance, but more work still needs to be done. Smarter screening strategies that incorporate PSA testing will also likely decrease the harms of over-treatment.

The first step is for policymakers to rapidly change their recommendations on PSA testing, or it will be abandoned altogether. We are already seeing evidence that doctors are being trained that prostate cancer screening is not “evidence-based,” which is untrue. This should be followed by the development of approaches to screening, diagnosis and treatment that limit the harms of over-detection while preserving the survival benefits. We still have a lot to learn, but that PSA screening saves lives is not one of those things.