Can 'Smarter' Use Resurrect PSA Testing?

Nick Mulcahy

June 17, 2016

Prostate-specific antigen (PSA) testing in the United States is now in rapid decline, but urologists are attempting to learn whether "smarter" deployment of the prostate cancer screening tool could enhance its usefulness by improving the accuracy of detecting aggressive disease.

In a new study, the results of PSA testing of American men at midlife, when they were in their 40s and 50s, "strongly predicted" future lethal cases of prostate cancer, conclude lead author Mark Preston, MD, a urologist at the Harvard Medical School and Brigham and Women's Hospital, in Boston, and colleagues.

The approach, which involves establishing a patient's baseline PSA level, allows for "risk stratification" of screening.

The new study was published online June 13 in the Journal of Clinical Oncology.

The declining use of PSA testing is "problematic" and is a matter of "throwing the baby out with the bathwater," Dr Preston told Medscape Medical News. "PSA is by no means perfect but definitely has value."

His comments are borne out by new data showing that the rate of distant-stage prostate cancers in the United States has recently increased, according to a population-based study (Cancer Epidemiol Biomarkers Prev. 2016;25:259-263).

"We need smarter screening practices based on actual risk, such as baseline PSA level, family history, or race, in order to identify cancers that will cause symptoms or death in time to provide curative treatment," Dr Preston said.

In the new study, which used 30-year data from a large observational trial, the higher the initial PSA value, the greater the risk for a later lethal prostate cancer and, therefore, the greater the need for monitoring.

On the other hand, the lower the initial value was, the lesser the risk was of an aggressive cancer, which in some cases means that follow-up testing could eventually be omitted.

"Men with a PSA below 1 at age 60 (the median for that age) have an incredibly low risk of developing lethal prostate cancer and likely don't need further screening," said Dr Preston.

The new results generally confirm findings from two studies of an unscreened Swedish population (Cancer. 2011;117:1210-1219; and BMJ. 2013;346:f2023). The Swedish studies showed that a single PSA test before the age of 50 or 60, depending on the study, predicted long-term risk for a prostate cancer diagnosis and metastases during a median follow-up period of 27 years.

But the United States has had wide opportunistic testing, so Dr Preston and colleagues decided to see whether results of a one-time PSA test at a relatively young age were predictive of prostate cancer -- specifically, lethal disease -- among American men.

The team conducted a case-control study among men aged 40 to 59 years who gave blood at enrollment into the Physician's Health Study. That study began in 1982 and now has long-term follow-up data for 22,000 participants.

Baseline PSA levels were available for 234 patients with prostate cancer and 711 age-matched control persons. Seventy-one participants who developed lethal prostate cancer were rematched to 213 control persons.

Among control persons, the median PSA level was 0.68, 0.88, and 0.96 ng/mL for those aged 40-49, 50-54, and 55-59 years, respectively.

A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA levels higher than the median at ages 40-49, 50-54, and 55-59 years, respectively.

Some of the more specific findings were dramatic.

For example, 1 of 7 men with PSA levels > 3.0 ng/mL at age 55-59 years and 1 of 12 men with PSA levels >2.1 ng/mL at age 50-54 years died as a result of prostate cancer within 30 years, report the study authors.

Furthermore, the authors report that when a baseline PSA level was "markedly elevated" (>90th percentile), the cumulative incidence of lethal prostate cancer 30 years later was "substantial," with rates of 4.5%, 8.4%, and 14.1% for men aged 45-49, 50-54, and 55-59 years, respectively.

The findings were strong enough for the authors to recommend the adoption of such screening.

"Risk-stratified screening on the basis of midlife PSA should be considered in men age 45 to 59 years," they write.

The study authors also attempted to use some of their data to determine the needed screening intervals after a baseline PSA assessment.

Even when baseline PSA levels were lower than the median, the researchers found that there was a risk of developing lethal prostate cancer in the next 30 years (< 2%). "Although risk was small, it remained present, and so screening should be continued, albeit with longer intervals," they write.

The authors made a a recommendation about repeat PSA tests for youngish men whose baseline scores are lower than the median.

"It seems that baseline PSA level below the median at age 45 years followed by repeat measurements at 5-year intervals would capture most lethal cases, given that the 15-year cumulative incidence for lethal prostate cancer at age 40 to 44 years is zero and in the 45 to 49 year age group only 0.07%," they report.

At age 60, some men could probably drop out of screening, as noted above.

The new study and the previous Swedish studies are not likely to be widely replicated, say the authors, because there are few study populations worldwide for which the combination of baseline blood samples, records of lethal prostate cancer outcomes, and long-term follow-up is available.

The new American study and Scandinavian studies "provide consistent and compelling data that baseline PSA levels are robust predictors of future life-threatening prostate cancer," Stacy Loeb, MD, from the New York University in New York City, writes in an accompanying editorial.

Baseline PSA levels at midlife should be used to tailor a screening protocol, she argues, explaining that the measure is now proven to be a stronger predictor of future prostate cancer risk than race or family history.

Downsides and an Endorsement of Baseline Screening

As good as the data from the Physicians Health Study are, there are still "obvious pitfalls" to any use of the PSA test in younger men, reminds Alexander Kutikov, MD, a urologic oncologist at the Fox Chase Cancer Center, in Philadelphia, Pennsylvania, who was not involved in the study.

"The key challenge is exposing younger men to the risks of biopsy, screening-related anxiety, and potential treatment early in life," he told Medscape Medical News.

On the other hand, there are benefits of this screening approach, including the obvious one — earlier detection of lethal prostate cancers.

At least one guideline currently recommends early baseline screening, said Dr Kutikov, referring to the 2013 Melbourne Consensus Statement on Prostate Cancer Testing.

It advises that "baseline PSA testing for men in their 40s is useful for predicting the future risk of prostate cancer" and says the strategy should be discussed with men.

The Melbourne statement was bolder than Dr Preston and colleagues in their recommendations about the need for ongoing PSA testing if a PSA test result was lower than the median (0.5 - 0.7 ng/ml) at age 40-49 years.

"Those men with a PSA below the median could be spared regular PSA testing as their future risk of developing prostate cancer is comparatively low, whereas those with a PSA above the median are at considerably higher risk and need closer surveillance," the Melbourne authors, who include urology luminaries such as Patrick C. Walsh, MD, of the James Buchanan Brady Urological Institute at Johns Hopkins University, Baltimore, and Declan Murphy, University of Melbourne and the Peter MacCallum Cancer Centre, Australia.

Funding for this study was provided by the Department of Defense Prostate Cancer Research Program, the Dana-Farber Cancer Institute Mazzone Awards Program, the Prostate Cancer Foundation Young Investigator Award, the American Urological Association Urology Care Foundation, the National Cancer Institute, the Swedish Cancer Society, Fundaçion Federico, and the Sidney Kimmel Center for Prostate and Urologic Cancers. The authors and Dr Kutikov have disclosed no relevant financial relationships. Dr Loeb reports financial ties to Sanofi and Bayer.

J Clin Oncol. Published online June 13, 2016. Abstract, Editorial

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

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