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Coinciding with declines in prostate-specific antigen (PSA) screening over the last decade, the incidence of intermediate- and high-risk prostate cancer has continued to increase across the U.S. in men 50 and older, a nationwide, population-based analysis has shown.

From 2008 to 2012, ahead of the United States Preventive Services Task Force (USPSTF) recommendations against PSA testing for prostate cancer, incidence of distant-stage disease was increasing by 2.4% per year for men 50 to 74 years. But this more than doubled to 5.6% per year from 2012 to 2015, reported Ahmedin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, and colleagues.

Their analysis in the also found that in men 75 and older, incidence of distant-stage prostate cancer increased by 5.2% per year from 2010 and 2016.

In contrast, incidence of local-stage disease decreased by 6.4% per year in men 50 to 74, from 2007 to 2016. And in men 75 and older, declined by 10.7% per year from 2007 to 2013, and then stabilized.

From 2009 to 2016, the researchers estimated that 11,387 more men were diagnosed with distant disease than would have been diagnosed had the incidence rates remained at their 2008 nadir. But 633,111 additional local cancers would have been diagnosed from 2008 to 2016, had rates for local disease remained at their 2007 peak.

"These data illustrate the trade-off between higher screening rates and more early-stage disease diagnoses (possibly overdiagnosis and overtreatment) and lower screening rates and more late-stage (possibly fatal) disease," the investigators wrote. "The persistently increasing regional- and distant-stage prostate cancer incidence during the past 5 years has public health implications given the substantial morbidity and premature mortality associated with it."

Starting about 5 years ago, investigators including Daniel Barocas, MD, MPH, of Vanderbilt University in Nashville, began documenting a and hinted at a rise in the incidence of non-localized disease in the wake of the 2012 USPSTF recommendations against PSA-based screening.

"The study by Jemal et al actually quantifies the trade-offs associated with this policy," Barocas told 乌鸦传媒視頻. By 2016, localized cases -- representing a combination of "overdiagnosed" low-risk cases and higher-risk localized cases that are destined to progress -- had declined by over 115,000 per year.

At the same time, "non-localized (lethal) cases had increased by over 3,500," Barocas wrote in an email. Although the USPSTF updated the recommendations for PSA screening in 2018, suggesting that decision-making for PSA-based screening should be "individualized" for men ages 55 to 69, "decoupling" the diagnosis of localized disease and treatment , he added.

Furthermore, "urologists, all reputable guideline bodies, and increasingly the public, have embraced the concept of observing low-risk prostate cancer. And continued efforts to improve the specificity of screening and to increase the use of observation for low-risk disease will preserve the survival benefit and reduce metastatic disease associated with screening while minimizing the harms associated with overdiagnosis," Barocas continued.

For the new study, all prostate cancer cases diagnosed from 2005 to 2016 were obtained from the U.S. Cancer Statistics 2001 to 2016 Public Use Research Database, which covers 100% of the U.S. population. Men were stratified by disease stage, age, and race/ethnicity.

Incidence of local-stage disease in men 50 and over increased from 456.4 to 506.1 per 100,000 from 2005 to 2007, and then plummeted to 279.2 per 100,000 by 2016, Jemal and co-authors reported.

In contrast, incidence of regional-stage disease generally increased across the same study interval, from 5.7 to to 9.0 per 100,000 men from 2005 to 2016. For distant-stage disease, incidence rates declined from 23.1 to 22.4 per 100,000 from 2005 to 2008, but then increased to 29.7 per 100,000 men by 2016.

"For all races/ethnicities combined, the incidence patterns for age 50-74 and ≥75 years are generally similar to those of age ≥50 years, with the incidence rates after the late 2000s declining for local-stage disease but increasing for regional- and distant-stage disease" -- the one exception being for men 75 years of age and older, among whom the incidence of local-stage disease stabilized from 2013 to 2016, Jemal and co-authors noted.

Jemal and co-authors also noted a "substantial decline" in the racial disparity in the incidence of distant disease in black and white men age 50 to 74. But this coincided with a steeper increase in the incidence of distant disease in non-Hispanic white men over the study period, and the incidence of distant disease in non-Hispanic black men still remains two to three times higher than in non-Hispanic white men among those under 75, and is 65% higher in men 75 and older, the researchers noted.

"The harms associated with high PSA screening rates can be mitigated while preserving the benefit of screening through PSA-stratified strategies including longer screening interval based on baseline PSA, higher PSA threshold for biopsy referral in older men, and restricting routine testing to men age ≤70 years," the team wrote. "And future studies are needed to elucidate the reasons for the rising incidence trends for regional- and distant-stage disease and for the disproportionately high burden of the disease in black men."

Asked for his perspective, Thomas Ahlering, MD, of the University of California (UC) Irvine, noted that he and his colleagues have documented a similar pattern of prostate cancer incidence rates as an unintended consequence of decreased PSA-based prostate cancer screening. In a , the team found that the proportion of low-grade prostate cancers decreased significantly from a pre-recommendation average of 30.2% in 2012 to an average of 17.1% in 2016.

In contrast, the incidence of high-grade cancers with Gleason scores of 8 and over increased from a pre-recommendation low of 8.34% to a post-recommendation high of 13.5%. There was also a 24% increase in absolute numbers of Gleason 8 and above cancers in the post-recommendation interval.

"The major difference between this study and our own is that their study is clinical and ours was pathological, meaning it used a surgical database," Ahlering told 乌鸦传媒視頻. "We were picking up much more regional disease with metastatic potential."

This regional disease -- which can be thought of as intermediate risk, he said -- is much more burdensome for patients and especially for the healthcare system, because it usually necessitates some form of secondary intervention. And that secondary intervention likely costs about the same as the first intervention cost -- i.e., around $40,000 per year.

Linda Huynh, MSc, also of UC Irvine, noted that has shown that if PSA screening were continued, but only for men younger than 70, more than half of avoidable cancer deaths could be prevented, while at the same time the strategy would dramatically reduce overdiagnoses compared with continued PSA screening for all ages.

"Etzioni has said, and we applaud it: 'Discontinued screening for all men eliminated 100% of overdiagnoses but failed to prevent 100% of avoidable cancer deaths,'" Huynh said. "So it really is a matter of systematically screening first, and then you can worry about overtreatment and complications from treatment after the cancer is diagnosed."

Ahlering also noted that screening recommendations may be "tinkered" with as much as anyone might like, but what is really needed are centers of excellence where prostate cancer is expertly treated: "The initial intervention for a man with prostate cancer needs to last 22 years or more," he said. "So how a patient gets treated is as important or more important than anything else -- that is what we are pushing for at least -- you just can't pull the plug and stop doing PSA screening."

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