Major Trial: No Mortality Benefit With 'One-Off' PSA Test

Nick Mulcahy

March 06, 2018

The largest-ever prostate cancer screening trial, in which asymptomatic men received a "one-off" blood test for prostate-specific antigen (PSA), has found no mortality benefit.

After 10 years, there was no significant difference in deaths from prostate cancer among men who were screened with this single PSA test and men who were not screened.

The findings come from a British study, the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP), published today in JAMA.

In an accompanying editorial, Michael Barry, MD, professor of medicine, Harvard Medical School, Boston, Massachusetts, had a plain-spoken summary:  "The results of the CAP trial…do not provide compelling support for PSA screening."

"One-time screening isn't effective," he told Medscape Medical News.

The CAP researchers invited more than 400,000 men with a mean age of about 59 years to participate when they made primary care visits throughout United Kingdom between 2001 and 2009. In the end, a total of 67,313 (36%) underwent a one-time PSA test.

After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) in the PSA group died of prostate cancer vs 647 (0.31 per 1000 person-years) in the control group (P = .50).

Lead author, Richard Martin, professor of clinical epidemiology, University of Bristol, United Kingdom, described the single PSA test design as "low-intensity" screening in an email to Medscape Medical News.

That stands in contrast to the repeated or "serial" PSA testing in the two other major PSA trials, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial.

In CAP, at 10 years, there was a higher percentage of prostate cancers in the screened group (8054 [4.3%]) than in the control group (7853 [3.6%]). The difference was mostly related to the increased detection of tumors with a Gleason score of 6 or less. In the screened group, 1.7% (n = 3263) of the men had these low-risk tumors compared with 1.1% (n = 2440) of the control group.

Importantly, both groups had the same percentage of prostate cancer–related deaths (0.29%).

"The problem remains that the PSA test identifies too many low-risk prostate cancers that do not require diagnosis or treatment, while missing some potentially harmful cancers," summarized Dr Martin.

The study participants will be followed for at least another 5 years to see whether a longer-term mortality benefit emerges with more time.

Best Estimates From European Study

In the editorial, Barry comments that for prostate cancer screening with serial PSA tests, the results from the ERSPC trial provide the best "direct estimate" of the benefits (and harms) of that approach. They show a relative rate reduction of prostate cancer–related death of 20% after 9 years and 21% at 13 years.

However, in absolute numbers, prostate cancer mortality benefit in the ERSPC trial "comes at the cost of a considerably higher risk of being diagnosed with prostate cancer," Dr Barry writes. He repeats the ERSPC estimations, noting that  "27 additional men were diagnosed with prostate cancer at 13 years for every man who avoided a prostate cancer death through screening."

In comments to Medscape Medical News, Barry said he would include the new CAP results in discussions with his patients in Boston because of its unique one-time design. "I would definitely mention the results of this trial, along with the PLCO and ERSPC trials, in a PSA discussion. I'd make it clear to men that selection of PSA screening [in the United States] commits to doing a series of tests, every 2 to 4 years."

The Issue of 10-Year Data

Approached for comment, William Catalona, MD, professor of urology at the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and outspoken supporter of PSA screening, opined that the "one-off" study design of CAP is "unrealistic."

"Cancer screening strategies do not rely on a single test performed once to be effective," Catalona said in an email to Medscape Medical News. He explained that "a persistently rising PSA is a better predictor of clinically significant prostate cancer."

Dr Catalona also examined another design element in the trial. As described by the authors, men in the screening group were also, when needed, randomly assigned to the Prostate Testing for Cancer and Treatment (ProtecT) trial. (Results from the ProtecT trial were published last year in the New England Journal of Medicine and reported at the time by Medscape Medical News.) That is, men in the CAP trial diagnosed with prostate cancer were offered randomization to radical prostatectomy, external-beam radiotherapy, or active monitoring in the ProtecT trial.

He criticized the fact that the CAP authors "assert that randomization of their screening arm patients to the ProtecT trial did not affect the prostate cancer mortality results based on the assumption that active treatment was not superior to observation in ProtecT, which has not yet been validated."

Dr Catalona argues that in the ProtecT trial, half the patients randomly assigned to monitoring were treated with surgery or radiation, and the monitoring group had twice the rate of clinical progression and distant metastases, which was statistically significant, and a proportionately higher prostate cancer death rate compared with patients randomly assigned to active treatment.

The CAP authors also likely underestimate the contamination (screening in the control group) that took place, he continued. The investigators estimate that the percentage was only 10% to 15% over 10 years. 

"This is low in comparison with other studies in which screening of controls before, during, or after the trial was far higher both in Europe and in the US and was sometimes initially underreported," contended Dr Catalona.

Also, he emphasized that a median follow-up of 10 years is "insufficient" to evaluate prostate cancer–specific mortality. 

"Clinical trials conducted over a limited time period do not reveal true information about absolute benefits of screening over a man's lifetime. The early trial data underestimate benefits and exaggerate harms," he argued. 

Dr Catalona also asserted that the authors "glossed over the dramatic separation of the PC mortality curves [favoring the intervention] after 12 years of follow-up." 

However, the CAP investigators, in their paper's discussion section, addressed that eye-catching graph.

"Although the cumulative incidence of prostate cancer mortality in the intervention and control groups appeared to diverge after 12 years of follow-up, only 71/1196 of the prostate cancer deaths occurred after 12 years and an exploratory analysis found no significant change in the rate ratio over time," they write.

In his editorial, Barry also addressed the 10-year follow-up, but he noted that in the ERSPC trial, while there was an increase in the absolute benefit of periodic screening over time, it was "a modest one."

The lead author of the CAP study left the door open to the possibility of improved performance of the one-time PSA test over more years. "Longer follow-up is needed to see if a difference develops after 15 or 20 years," he told Medscape Medical News.

The CAP trial was funded by grants from Cancer Research UK and the UK Department of Health, and the National Institute of Health Research provided partial funding. The study authors have disclosed no relevant financial relationships. Barry is a member of the US Preventive Services Task Force (USPSTF).  Catalona has disclosed no relevant financial relationships.

JAMA. 2018;319:883-895, 868-869. Abstract, Editorial

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