More High-Risk Prostate Cancer Now in the US Than Before

Pam Harrison

March 27, 2018

COPENHAGEN, Denmark — More men are now presenting with higher-grade, more invasive prostate cancer in the wake of 2012 recommendations from the US Preventive Services Task Force (USPSTF) not to routinely screen asymptomatic patients to detect early disease, more epidemiologic evidence indicates.

As predicted by urologists in 2012 after the recommendations were released, there has been a consistent, stepwise increase in cancers of higher Gleason score, as well as a stepwise increase in the median level of prostatic-specific antigen (PSA), in the 4 years after the USPSTF recommendations were released compared to the 4 years before the recommendations were issued.

At the same time, both surgical volume and the proportion of low-grade cancers have been dropping, as reported by Thomas Ahlering, MD, University of California, Irvine, and colleagues during a poster session of the European Association of Urology (EAU) 2018 Congress.

"Treating high-risk disease has its limitations, because you are not going to cure the majority of patients no matter what you do, so the better answer is to diagnose prostate cancer earlier," Ahlering told Medscape Medical News.

"If our data are correct, the most important thing to do is to start screening more intensely again," he reaffirmed.

Two Related Studies

In one of two related studies, Ahlering and colleagues carried out a retrospective analysis of nine high-volume referral centers throughout the United States to compare patients who presented with prostate cancer of Gleason grade 8 or higher and who had seminal vesicle and lymph node involvement before the 2012 USPSTF recommendations were issued with such patients after the recommendations were issued.

A total of 19,602 men were analyzed; 4-year average diagnoses were compared between October 2008 and September 2012, and between October 2012 and September 2016, before and after the recommendations had been released.

The researchers observed a 22.6% reduction in surgical volume in the postrecommendation period compared to the prerecommendation period.

They also noted an increase in the median PSA level from 5.1 ng/mL prior to the recommendations to a median of 5.8 ng/mL after they had been released (P < .001).

The mean age at the time of diagnosis also increased, from 60.8 years before the recommendations to 62 years after the recommendations (P < .001).

"Expectedly, the proportion of low-grade Gleason 3+3 cancers decreased from 30.2% to 17.1% (P < .001)," the investigators write.

In contrast, the incidence of high-grade Gleason 8+ prostate cancers increased from 8.4% prior to the recommendations to 13.5% after the recommendations (P < .001).

"In this Gleason 8+ group, we saw a 24% increase in absolute numbers [of prostate cancer diagnoses]. One-year biochemical recurrence (BCR) rose from 6.2% to 17.5% (P < .0001)," they report.

Ahlering and colleagues also performed a propensity score–matched analysis to rule out the possibility that the increase in high-risk disease was not due to referral patterns.

"For any given age and PSA, propensity matching demonstrates that there is now more aggressive disease in the post-recommendation era," the researchers report.

"So these centers dispersed throughout the US have witnessed a tripling of BCR and a quadrupling of nodal metastasis," the team concludes.

"The potential of an epidemiological shift towards high-risk disease raises concern for increased PCSM [prostate cancer–specific mortality], secondary interventions, and associated side effects," they warn.

Population-Based Cohort

In a separate but related study, Linda Huynh, BS, clinical research assistant, University of California, Irvine, assessed the effect of the 2012 USPSTF recommendation in a population-based cohort.

Huynh also assessed national diagnostic patterns during three eras: 2004 to 2007 (era 1), 2008 to 2011 (era 2), and 2012 to 2015 (era 3).

In total, the researchers analyzed data from 1,380,219 men who had undergone radical prostatectomy in one of the three eras assessed.

"Pathological endpoints of p-stage, lymph node metastasis, and surgical margins were compared between screening eras," the researchers note.

The investigators observed a 15.8% drop in surgical volume from both era one and era 2.

Importantly, the age at which men had undergone a radical prostatectomy dropped in the period 2008 to 2012 after an earlier USPSTF recommendation not to screen men aged 75 years and older (P > .001).

"In contrast, preoperative PSA experienced an upward trend from 69 to 67 and 73 ng/mL (P < .001)," the researchers observe.

The risk in absolute numbers of high-risk prostate tumors of Gleason score 8 to 10 also increased in a stepwise fashion — "meaning that as we get further and further away from the 2012 recommendations, each year we are seeing more high-grade disease, so it does not look as if we are plateauing," Huynh explained to Medscape Medical News.

The investigators also reported a steady increase in diagnoses of prostate cancer with lymph node involvement across the three eras, from 1% in era one, to 2% in era 2, to 3% in era 3 (P < .001).

Similarly, the incidence of high-stage disease (pT3/T4) increased from 6% in era one, to 10% in era 2, to 19% in era 3 (P < .001).

After adjusting for age and PSA levels in a propensity score–matched analysis, the researchers also observed significant increases in positive surgical margin rates, tumor volume, and lymph node involvement.

Since era one, the USPSTF has made two recommendations against the use of PSA screening, first with respect to men aged 75 years and older, and in 2012, against PSA screening in men of all ages.

The USPSTF recently changed its recommendation on PSA screening. In 2017, an updated recommendation emphasized that the decision to undergo PSA screening must be individualized for men aged 55 to 69 years. For men aged 70 years and older, the USPSTF still does not recommend PSA-based screening.

Despite this backtracking, it appears the fallout from the 2012 null recommendation remains unchecked.

High-grade Shift

Asked by Medscape Medical News to comment on the high-grade shift in prostate cancer now being seen in the United States, Hein van Poppel, MD, PhD, professor of urology, University of Leuven, Belgium, pointed to data from the Scandinavian countries, where more intense PSA screening is performed.

"They have the best data, and they have the best outcomes showing that if you are screened for prostate cancer, the likelihood you will die from it is dramatically reduced," van Poppel said.

"Everybody knows that screening decreases prostate cancer mortality," van Poppel reaffirmed. "There is no way around it."

He commented that the original finding that PSA screening does not reduce mortality, from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) study that was carried out in the United States, has now been overturned; when confounding factors are taken into account, the study does show an effect.

"The big problem with the PLCO study, and a major criticism of it, was that there was, in fact, widespread screening in substantial numbers of patients in the arm randomized to no screening," van Poppel explained.

"So while this arm was not formally screened for PSA, men went to their doctor and had their PSA determined, so they were widely screened for PSA, and this meant that there was no difference in cancer mortality outcomes between the two arms, because of contamination," he added.

As previously reported, a new analysis of data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the PLCO trial now indicates that both studies support a prostate-cancer mortality benefit with PSA screening.

The new analysis showed a 25% to 31% lower risk for prostate cancer mortality in the ERSPC and a 27% to 32% lower risk in the PLCO among men who were screened compared to men who were not screened.

Dr Ahlering and Dr Huynh have disclosed no relevant financial relationships.

European Association of Urology (EAU) 2018 Congress. Abstracts 268 and 269, presented March 17, 2018.

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