A randomized prostate-specific antigen (PSA) screening trial of more than 400,000 men followed for a median of 10 years is calling into question population-based PSA screening.

The benefits and harms of one-time PSA screening in detecting prostate cancer and in improving prostate cancer-related mortality have been the subject of considerable debate, and the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) trial sought to bring clarity about the downstream effects of one-time screening.

The trial’s findings, published in the Journal of the American Medical Association (JAMA), show that a single PSA test still detects too many low-risk prostate cancers, Emma Turner, PhD, Cancer Research UK scientist at University of Bristol and a senior co-author of the study, told CLN Stat. “Although the study did detect some dangerous cancers that could benefit from treatment, the approach of one-off PSA testing and transrectal ultrasonography-guided biopsy missed a number of lethal cancers,” she said.

Other large investigations such as the U.S. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial have failed to resolve the controversies surrounding the potential harms and benefits of PSA screening. As Clinical Laboratory News reported in 2013, researchers and clinicians alike were disappointed by the inconclusive results these trials yielded on the value of screening and the PSA test’s effects on mortality rates.

The CAP trial sought to find out what impact a single PSA screening could have in comparison with usual care without screening. In all, the researchers recruited 415,357 men between the ages of 50 and 69 from 573 primary care practices across the United Kingdom, making it the largest randomized PSA study conducted over a decade’s time.

Investigators divided up trial participants into an intervention group of 189,386 men, which provided information and offered the opportunity to take a PSA test, and a control group of 219,439 men. Forty percent in the intervention group went to a PSA testing clinic, and 36% underwent testing. Among the 64,000-plus individuals with valid PSA test results, 11% had a PSA level between 3 ng/mL and 19.9 ng/mL. A majority of these participants ended up getting a prostate biopsy.

Following up with the participants over 10 years, the investigators discovered higher rates of prostate cancer in the intervention group compared with the control group: 8,054 and 7,853 cases, respectively. In comparison, mortality due to prostate cancer didn’t differ significantly among the two groups. “The group who had been screened had the same percentage of men dying from prostate cancer as those who had not been screened (0.29%),” Turner observed.

“The results highlight the multitude of issues the PSA test raises—causing unnecessary anxiety and treatment by diagnosing prostate cancer in men who would never have been affected by it and failing to detect dangerous prostate cancers,” said the study’s lead author Richard Martin, PhD, a Cancer Research UK scientist at the University of Bristol, in a statement. For these reasons, the study authors concluded that single PSA testing is not a viable option for screening whole populations.

That said, it points to finding better methods for diagnosing aggressive prostate cancers at the early stages. Turner said researchers are evaluating new technologies that could pave the way for safe and effective screening policies. “Genetic tools may help to guide decisions of who to screen towards men at the highest risk of aggressive prostate cancer requiring treatment,” she said.

One new test that could aid in the detection and targeting of clinically significant prostate cancer at biopsy is multiparametric magnetic resonance imaging (MP-MRI), which uses a powerful magnetic field, radio frequency pulses, and a computer to provide a detailed image of the prostate, Turner said. “Performing an MRI scan before prostate biopsy could reduce the number of men with low-risk disease who undergo unnecessary biopsy and treatment while improving the diagnosis of aggressive disease that requires treatment,” she said.

Other options are under investigation such as evaluating a strong family history of prostate cancer, issuing additional blood tests to predict future risk of prostate cancer, or to screen for the presence of early disease, Turner added.  

Whether PSA screening could undergo certain modifications to improve its worth to both individuals and society at large, is still unclear, Michael J. Barry, MD, wrote in a related editorial. “How ‘active’ active surveillance needs to be and which men are candidates requires further research. More selective treatment, including avoiding overtreatment of men with low-risk cancer cases but also avoiding undertreatment of men with high-risk cancer cases, combined with offering screening to men aged 55 to 69 years (the core group in the ERSPC trial), even has the potential to make PSA screening cost-effective,” Barry suggested.