Landmark prostate cancer screening trial criticized

The results of a landmark study that serves as the foundation for U.S. prostate cancer screening recommendations are flawed and threaten optimal prostate care for American men, according to a letter published May 5 in the New England Journal of Medicine (2016; 374:1795-6).

The letter, by Jonathan Shoag, MD, and Sameer Mittal MD, of New York Presbyterian Hospital, New York, and Jim C. Hu, MD, MPH, of Weill Cornell Medical College, New York, calls into question the validity of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Drs. Shoag, Mittal, and Hu were also among the authors of a study presented at the AUA annual meeting in San Diego that evaluated the PLCO Trial.

One expert told Urology Times that it’s crucial for urologists to disseminate the message that there is “very credible evidence” as to PSA screening’s benefits.

PLCO, a large randomized trial designed and funded by the National Cancer Institute to determine the effect of PSA screening on death from prostate cancer, was initially designed to study prostate cancer screening’s effect, and was later modified to include lung, colorectal, and ovarian cancers. The PLCO trial found that men randomly assigned to prostate cancer screening had the same mortality rate as men in the trial’s control group, leading many to the conclusion that PSA screening does not decrease prostate cancer death (N Engl J Med 2009; 360:1310-9).

The U.S. Preventive Services Task Force (USPSTF) relied heavily on the trial’s finding to form its 2012 recommendation against PSA screening.

“As a result of the task force's recommendations, we have seen dramatic declines in prostate cancer screening in the United States since 2012,” according to Dr. Hu.

The result and ripple effect fueled by PLCO is based on a major flaw, and it’s worse than even most urologists suspected, according to the letter’s authors.

“There were many reasons to question the prostate cancer screening results of the PLCO trial. The major critique has generally been the degree of screening in the control arm, both before and during the study, also known as contamination. While many urologists may have been skeptical of the trial results previously, the presence of a major randomized trial suggesting no benefit to PSA screening was always something that had to be addressed,” Dr. Shoag told Urology Times.

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As nearly 90% of men in the control group were getting their PSA checked, comparing mortality to men in the intervention group who were randomized to prostate cancer screening isn’t useful, Drs. Shoag, Mittal, and Hu argued.

Next: What prompted the investigation

What prompted their investigation was the observation by Drs. Shoag, Mittal, and Hu significant variation regarding PLCO trial contamination quoted in the literature-from those who said 50% cumulatively had PSA testing to those who said it was 50% annually or higher.

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Even Drs. Shoag, Mittal, and Hu said they were surprised by what they found when they analyzed the numbers.

They found that in the PLCO trial, more than 80% of the participants in the control group without baseline screening contamination (which was defined as two or more PSA tests within 3 years before trial entry) reported having undergone at least one PSA test during the trial, with more than 50% undergoing testing within the past year and 70% within the past 2 years, according to the study’s abstract. So, by including the 10% of control participants with baseline PSA screening contamination, the proportion of controls who reported having undergone at least one PSA test before or during the trial was near 90%.

There’s more. When both trial groups were surveyed with the Health Status Questionnaire, men in the control group reported having had more cumulative PSA testing than men in the intervention group.

The European Randomized Study of Screening for Prostate Cancer, the second major randomized trial of screening, the initial results of which appeared in the same New England Journal issue as those of the PLCO Trial in 2009, randomized more than 160,000 men in Europe (N Engl J Med 2009; 360:1320-8). It found that PSA screening was a lifesaver, decreasing prostate cancer mortality by 21%. However, this trial was also imperfect, the letter authors argued in an article from Weill Cornell Medicine. Some analyses of subgroups from the trial have found decreases in mortality of around 50% with screening.

This is a particularly hot topic, now, according to Dr. Hu, because the Centers for Medicare & Medicaid Services only months ago temporarily suspended the development of a proposed “Non-Recommended Prostate-Specific Antigen (PSA)–Based Screening” measure that would discourage PSA screening in all men. And the USPSTF, an organization that Dr. Hu said has a lot of influence over primary care physicians, is currently updating its recommendation on PSA screening.

“Also, it has recently become clear that PSA screening has fallen out of favor with primary care physicians because of the 2012 USPSTF grade D recommendation, as well as the AAFP and Cochrane Reviews finding no benefits to screening. All of these analyses relied on an incorrect interpretation of contamination in the PLCO trial, and as result PSA screening was 'wrongfully convicted,’ ” Dr. Hu said.

There will likely be a continued trend toward decreased PSA screening by primary care physicians if urologists and experts in the field do not get the message out that PSA screening prevents prostate cancer metastasis and deaths, according to Dr. Hu.

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“An important step is the USPSTF revising their recommendation, but efforts to educate primary care physicians and the public about what should now be considered largely unequivocal data supporting a mortality benefit to screening are key,” Dr. Hu said. “Limiting the over-diagnosis and over-treatment associated with population-based PSA screening is equally important though. As such, physicians need to use screening in indicated populations at recommended intervals and to be judicious about when to biopsy and who to treat.”

Next: Dr. Thrasher comments on letter

Urology Times Editorial Consultant J. Brantley Thrasher, MD, of University of Kansas Medical Center, Kansas City, KS, said he could not agree more with the letter authors that PLCO’s PSA findings should not be the basis of PSA recommendations in the U.S.

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“I think a couple of bad things happened because of all this. A lot of the people… in primary care and internal medicine have stopped using PSA altogether. And I think we’re already-at least in my practice-starting to see a lot more advanced cancers coming into the office in young men than I have in the past. I think this may be a reflection of people just taking the U.S. Preventive Services Task Force information to heart and they’ve stopped using PSA as a screening tool,” Dr. Thrasher said.

PSA isn’t the problem, and the screening shouldn’t be clinically demonized, Dr. Thrasher said.

“If people take this PLCO trial as the only evidence that we have, ultimately the policymakers will use that to stop using PSA altogether, and that’s going to be terrible for our patients,” he said. “That takes me back to when I was a resident, before PSA screening came into effect, and about 30% of the people that walked into our doors already had advanced disease. We couldn’t do that much for them. I really don’t want to go back to those times.”

Dr. Thrasher said he also agrees that the commentary’s finding is a call to action for urologists.

“[We] need to be out there spreading the word to patients, to referring docs, to primary care physicians that there is very credible evidence out there that PSA saves lives. And that this one trial that has been so often quoted by policymakers is a flawed trial,” Dr. Thrasher said. “PSA is the best marker that we have available right now, if used appropriately.”

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Utility of PCa markers in African-Americans differs

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