The two trials included in the analysis were the ERSPC (European Randomized Study of Screening for Prostate Cancer) and the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Both trials randomly assigned men to either a screening arm, in which men underwent routine PSA testing, or a control arm. In the ESRPC control arm, men were not supposed to have PSA testing. In the PLCO control arm, men were not supposed to be routinely given the "opportunity" to have a PSA test. (See "Contamination in the PLCO trial" on page 2.) Both studies were long-term and followed the men for at least 11 years to determine if they'd been diagnosed with prostate cancer.
Previously, these two studies reported conflicting results regarding whether PSA screening prevents deaths from prostate cancer. The ERSPC trial showed a 21% decrease in prostate cancer mortality with PSA testing, whereas the PLCO study found no reduction in prostate cancer mortality.
However, the new analysis clarified the evidence concerning the PSA screening benefit in these two studies. Specifically, the researchers compared the "mean lead times," which measure on average how much earlier men in the screening arms of the studies were diagnosed compared to an unscreened population of men (based on the national cancer registry data from 1986, before the PSA screening era). They found a strong correlation between the mean lead time and prostate cancer mortality reduction. After accounting for mean lead times, the prostate cancer mortality reduction did not differ between ERSPC and PLCO. The authors concluded that the way screening was implemented produced a 25-31% reduction in prostate mortality in ERSPC and 27-32% reduction in PLCO, when compared to men who had no screening.
In addition to this new data, evidence from the Göteborg, PROTECT and PIVOT trials also favors screening.
"Contamination" in PLCO Trial
In recent years, the PLCO trial has been criticized for its high "contamination" rate in the control arm. This means that the majority of men in the control arm actually underwent PSA testing. About 50% of men in the control group had PSA testing before enrolling in the study. In addition, an independent re-analysis of PLCO data by Shoag et al. in 2016 found that nearly 90% of men in the control arm had PSA tests before or during the trial. These high rates of PSA testing in the control group skewed the data against screening.
The new analysis from the Cancer Intervention and Surveillance Modeling Network of the National Cancer Institute managed the PLCO contamination rate by comparing groups of men in both studies to an unscreened population to "capture the intensity of screening in each group."
The Impact of PSA Testing
In the U.S. during the PSA era, there has been an 80% decrease in the percentage of men with metastases at diagnosis and a more than 53% decrease in prostate cancer mortality. Statistical modeling studies estimate that stopping screening would result in twice as many metastatic cases, returning to pre-PSA era levels by 2025, and a 13-20% increase in preventable prostate cancer deaths. Not screening men older than 70 years would fail to prevent 36-39% of avoidable prostate cancer deaths.
Effect of PLCO on USPSTF
When writing its earlier recommendations against PSA testing, the U.S. Preventive Services Task Force (USPSTF) heavily weighed the negative PLCO trial, relying on the incorrectly reported 50% rate of PSA testing in the control arm in its initial report. In 2008, the USPSTF recommended against screening men older than 75 years. In 2009, following the first published results from ERSPC and PLCO, the USPSTF immediately began a new evidence review, one year ahead of schedule and, in 2012, issued a grade "D" recommendation against screening for all men, concluding "harms outweigh benefits." The USPSTF panel included no urologists, radiation oncologists or medical oncologists.
Following the grade "D" recommendation, PSA screening and prostate cancer interventions declined, rates of diagnoses of local/regional disease has decreased, but distant disease at diagnosis began to increase. Despite fewer prostate cancer cases overall, there is a higher absolute number of metastatic cases at diagnosis.
Shoag et al. pointed out that before their re-analysis, guideline panels did not realize the high extent of contamination in PLCO and speculated that millions of men have not been offered PSA screening because of a lack of knowledge of this shortcoming.
The USPSTF has now backed away from its PSA screening ban and issued a new draft grade "C" recommendation for screening men ages 55 to 69. "This is a good start," said Dr. William J. Catalona, "but more revision is needed. Baseline screening for risk should be performed in men ages 40 to 54, healthy men 70 years or older also should be screened, and more intensive screening is indicated for high-risk men - men with African heritage, family history, or carriers of genetic risk factors."
In an editorial accompanying the analysis, Andrew J. Vickers, PhD, said "The controversy about PSA-based screening should no longer be whether it can do good but whether we can change our behavior so that it does more good than harm."
Ann Intern Med. 2017 Oct 3;167(7):449-455. doi:
10.7326/M16-2586. Epub 2017 Sep 5.
Ann Intern Med. 2017 Oct 3;167(7):509-510. doi: 10.7326/M17-2012. Epub 2017 Sep 5