Prostate Cancer More Aggressive in Post-USPSTF Era

Pam Harrison

August 01, 2018

High-volume referral centers throughout the United States are seeing a consistent decrease in low-grade prostate cancer and an absolute increase in intermediate- and high-risk disease compared with earlier years, before the 2012 US Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA)–based screening.

This finding, presented earlier this year at the European Urology Association annual meeting, has now been published in the World Journal of Urology.

It has ominous implications for the prognosis of these men being diagnosed with higher-grade prostate cancer and more extensive involvement than in the past, say the authors, led by Thomas Ahlering, MD, University of California, Irvine Health, Orange County.

The researchers compared clinical and pathological characteristics of prostate cancer diagnosed before and after 2012.

They found that the absolute number of patients with PSA levels in excess of 10 ng/mL had increased by 24%, from 8.5% of the total number of cases diagnosed between 2008 to 2012 to 13.2% of the total number of cases diagnosed between 2012 and 2016.

At the same time, the absolute number of patients with PSA levels in excess of 20 ng/mL increased by 44%, from 2.4% of all diagnosed prostate cancers before the recommendations to 4.2% of the total after their release (P < .0001).

"Further, there was an increase in the absolute number and percent of total for higher grade clinical (cGS) [Gleason score] and pathological (pGS) cancers (P < 0.0001)," the investigators add.

Indeed, the proportion of low-grade GS 3 + 3 cancers dropped from 30.2% in the pre-recommendation era to 17.1% in the post-recommendation era.

Conversely, high-grade GS 8+ cancers increased from 6.2% before the 2012 recommendation to 17.5% after its release. At the same time, there was a 24% increase in absolute numbers of GS 8+ prostate cancers between the two comparative study eras, the authors note.

In the postscreening era (ie, after 2012), Ahlering and colleagues also document a higher relative proportion as well as greater absolute numbers of prostate cancer with seminal vesicle invasion, lymph node involvement, and positive surgical margins compared with the prescreening era (P < .001).

More than twice as many men (at 7.5%) presented with lymph node involvement after the USPSTF recommendation than they did before it (P < .001), the investigators add.

There was also a corresponding increase in the absolute number and proportion of cases in which men presented with lymph node metastasis after the USPSFT issued its recommendation compared with before (P < .001).

One year after surgery, rates of biochemical recurrence almost tripled to 17.5% in the 4 years following the USPSTF recommendation compared with the pre-recommendation era.

"Our findings suggest an urgent need to collaboratively design better screening parameters that minimize overtreatment and maximize curative treatment outcomes," Ahlering and colleagues conclude.

Expected Consequences of Reduced Screening

"These findings are consistent with expected consequences of reduced screening: cancers diagnosed at a later point in their natural history [and these cancers] are associated with more advanced characteristics and poorer clinical outcomes despite treatment," Roman Gulati, MD, Fred Hutchinson Cancer Research Center, Seattle, Washington, told Medscape Medical News in an email.

He also noted that findings are consistent with increased uptake of active surveillance, which removes low-risk cancers from the study population.

"The observed shift likely reflects a combination of these two explanations," Gulati suggested.  

Gulati also pointed to a study of his own, which found that the risks for disease progression among untreated prostate cancer contributes to a near doubling in prostate cancer–specific mortality (PCSM).

That study by Gulati and colleagues (Cancer Epidemiol Biomarkers Prev.  2011;20:740-750) was based on the three natural history working models developed by the Cancer Intervention and Surveillance Modeling Network (CISNET) prostate cancer working group. These models projected that between 23% and 34% of men aged 50 to 59 years with GS 2 to 7 cancers and 62% to 80% of men with GS 8 to 10 cancers were likely to die of their disease in the absence of primary treatment.

Investigators then worked out the extent to which radical prostatectomy could reduce these percentages and found that surgery could reduce 18% to 27% of the deaths in the GS 2 to 7 prostate cancer group and 51% to 66% of the deaths in the GS 8 to 10 prostate cancer group.

"These modeling results suggest that, even under meaningful treatment benefit, less favorable tumor characteristics may be associated with substantially worse outcomes," Gulati observed.

Substantial Overdiagnosis

As Ahlering and his colleagues acknowledge, the USPSTF recommended against the use of PSA screening for all men on the basis of results from two randomized trials suggesting that PSA-based screening would inevitably lead to a "substantial overdiagnosis and overtreatment" of patients who would otherwise have never even developed symptoms from their disease.

However, the authors point out that "while eliminating screening would alleviate potential overtreatment, it could also increase [the] number of high-risk patients, potentially increasing PCSM by 13–20%, along with associated increased costs due to secondary interventions such as radiation, chemotherapy and hormonal therapy."

A compromise may be somewhere in the middle.

In Gulati's view, the most promising solution for reducing overdiagnosis and overtreatment — while preserving benefits of early detection and treatment — is risk-stratified screening, risk-stratified diagnostic workup, and risk-stratified treatment.

For example, screening might be considered only for men at increased risk for prostate cancer, including African Americans or those with a relevant family history, Gulati suggested. 

Screening might also be considered by men who are at average risk for prostate cancer but have at least a 15-year life expectancy, he added.

"Biopsy, in turn, might only be recommended for men with a high PSA level (eg, PSA > 10 ng/mL) or for men with an intermediate PSA level (eg, 4-10 ng/mL) and high value of a validated reflex marker," Gulati continued.

Next, immediate curative treatment might be recommended only for men with intermediate- or high-risk disease, he noted.

No Survival Difference

Asked by Medscape Medical News to comment on the study, Marc Garnick, MD, professor of medicine, Harvard Medical School, Boston, Massachusetts, pointed out that randomized studies that specifically look at PSA-based screening programs have shown no difference in survival with mature follow-up and little to no differences in prostate cancer–specific survival.

"What this study does underscore is the need for continued improvements in better fine-tuning those selected for screening and for identifying men who may potentially benefit from interventions," he said in an email.

This needs to be followed by a randomized study that specifically addresses various active treatment arms according to prostate cancer risk, Garnick indicated.

Garnick also observed that data from several large randomized trials on the effect of PSA-screening on mortality risk have been disappointing thus far and indicate that there is a demand for more precision in including men potentially likely to benefit from treatment.

This assumption then needs to be tested in an appropriately rigorous study, he added.

Garnick is editor-in-chief of the Harvard Annual Report on Prostate Diseases and Patients Perspectives on Prostate Diseases.

World J Urol. Published online July 12, 2018. Abstract

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