PSA risk levels could help men avoid frequent PSAs and reduce emotional distress, German researchers suggest
Five-year interval is safe for prostate cancer screening, research shows
By Howard Wolinsky
Men with low blood levels of PSA (prostate-specific antigen) can safely avoid the screening tests for five years and potentially up to a decade, German researchers told the European Association of Urology Congress in Paris late last week.
Protocols vary on the use of PSA. Many of us have one or more PSAs per year to surveil our prostate cancer. They can be occasions for “PSAnxiety,” “Scanxiety” from MRIs, and prostate biopsies during ramp-ups to the test, waiting for the results, and reacting to the findings.
Medical groups that write guidelines in the U.S. and around the world vary widely in PSA cutoffs for Active Surveillance and even in whether PSAs are recommended at all.
German researchers found benefits for a risk scale for PSAs that I hope researchers and guideline writers in the U.S. will heed. If this is successful, it could spare many men from PSAs and potentially reduce emotional distress that upsets more than half of us as we head in for testing, await results, and react to the findings.
Give me a breakdown
Here’s how the German researchers stratified their subjects:
—Men with PSAs under 1.5 nanograms per milliliter (ng/mL) are deemed low risk and followed up with a second test after five years.
—Men with a PSA level between 1.5-3 ng/mL are deemed intermediate risk and followed up in two years.
—Men with a PSA level over 3 ng/mL are seen as high risk and given an MRI scan and biopsy.
Results show many can avoid biopsies and MRIs
Of over 20,000 men recruited to the PROBASE trial and deemed low risk, 12,500 have now had their second PSA test at age 50.
Researchers found that only 1.2% of the men (146 in total) had high levels of PSA (over 3 ng/mL) and were referred for an MRI and biopsy. Only 16 of these men were subsequently found to have cancer – just 0.13% of the total cohort.
What a dramatic funneling effect of eliminating men from unnecessary tests and stress.
What the researchers say
Lead researcher, Peter Albers, MD, a urologist at Heinrich-Heine University Düsseldorf, said: “By raising the bar for low risk from 1 ng/mL to 1.5, we enabled 20% more men within our cohort to have a longer gap between tests and very few contracted cancer in that time.
“With nearly 14 million men aged between 45-50 in Europe, the numbers affected by such a change would be significant. Our study is still underway, and we may find that an even longer screening interval, of seven, eight, or even ten years, is possible without additional risk.”
Similarly, E. David Crawford, MD, a urologist and biomarker expert at the University of California San Diego, has suggested 1.5 ng/mL as the cutoff for active surveillance in the U.S.
He told me in an interview for MedPageToday that this approach can spare many men from biopsies, which carry risks of sepsis and other infections, and also can alleviate years of worry from "anxious surveillance."
"I picked that cutoff because when you start going above that you do have a risk of prostate cancer that is significant. And if you let it get above a cutoff of 4, you'll find more cancers but you'll also miss some bad ones that might have been found earlier," Crawford said.
His research showed that with this approach, 70% of men could bypass biopsies and avoid years of anxiety. He suggests a follow-up in 5 to 10 years, following a model like that for colonoscopies.
"This is where you get into trouble and that's where we started integrating what already had been done in a lot of other cancers -- molecular markers -- to find the people who had a problem. Everybody got very proud of themselves for finding all these cancers and putting patients on active surveillance rather than doing surgery or radiation," said Crawford, who runs the website PCmarkers.com.
The many opinions ion PSAs
Many European doctors have been skeptical about PSAs because they consider the tests unreliable.
The new findings suggest that the screening interval for those at low risk could be much longer while taking on minimal additional risk.
The researchers said current guidelines and policies from European governments and health bodies remain contradictory and unclear, leading to high levels of opportunistic testing and inequality of access to early diagnosis. The study reviewed early detection policies across the European Union and carried out focus groups with urologists to identify how guidelines were interpreted in clinical practice.
In Europe, only Lithuania routinely screens men for prostate cancer based on their PSA levels, as the test has historically been seen as insufficiently reliable.
Meanwhile, guidelines for PSA have been hotly debated in North America since PSA screening was introduced in the mid-1990s.
An epidemic of prostate cancer
Initially, there was an epidemic of prostate cancer. PSA ferreted out advanced cancers early, which saved lives.
But the cases were inflated by diagnosing men with low-risk prostate cancer, who we know now probably shouldn’t have been diagnosed at all.
The pendulum began to swing when Drs. Laurence Klotz, of the University of Toronto, Peter Carroll, of UCSF, and Ballentine Carter, of Johns Hopkins, came up with the idea of close monitoring—Active Surveillance— to help men avoid or delay treatment. The idea took about 30 years to catch on, and still, only 60% of low-risk patients opt for AS.
Taking the task force to task?
Meanwhile, in 2012, the U.S. Preventive Services Task Force, a semi-governmental agency that writes screening guidelines, rejected PSA testing because of the harm it caused low-risk men, including unnecessary treatment causing such side effects as incontinence and impotence.
Primary care doctors, who order most (90%) of the PSAs, cooled on PSA testing. And many urologists and patient advocates attacked the task force as PSA screening declined.
In 2018, responding to the political pressure, the task force somewhat liberalized its guidelines, urging men to discuss with their doctors the pros and cons of PSA screening.
However, the task force gives a C grade for screening undiagnosed men 55-69. The task force now says patients 55-69 should discuss the decision to screen periodically with their clinicians.
A C grade is hardly a ringing recommendation at all. Here’s what that means: C - No Recommendation: The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation.
The task force recommends against screening (D grade) men 70 and above.
Was the reduced use of PSA at fault in the epidemic?
Critics pointed fingers at the USPSTF guidelines as being the cause of an upswing in cases of and deaths from prostate cancer. In January 2023, the American Cancer Society revealed what it called "alarming" news about prostate cancer: After two decades of decline, the number of men diagnosed with the disease in the United States rose by 15% from 2014 to 2019. About 300,000 men will be diagnosed with prostate cancer this year, according to the ACS.
Deaths from prostate cancer have stabilized at about 35,000 in the U.S.
Still, Prostate cancer is the most common cancer skin cancer diagnosed in American men. It is the second leading cause of cancer death after lung cancer.
And at the European Association of Urology of Congress Congress in Paris last week. the Lancet Commission on Prostate Cancer predicted that a tsunami of PCa cases are coming in the next 20 years, including in poor-, medium-, and high-income countries.
An "inevitable" global surge in prostate cancer is coming, with a worldwide doubling of cases to 2.9 million and an 85% increase in deaths to nearly 700,000 by the year 2040, the Lancet Commission on Prostate Cancer warned this week.
Nick James, MD, lead author of the Lancet report and professor of prostate and bladder cancer research at The Institute of Cancer Research, in London, said that the surge, in part, is a medical success story. "Prostate cancer paradoxically is a problem baked into the biology. Men get prostate cancer as they age," James said.
According to the report, screening, combined with MRIs, can help:
"The case for prostate cancer screening for all men aged 50–70 years (and all men of African origin aged 45–70 years) in high-income countries is strengthening with improved use of technologies such as MRI and growing evidence for the safety of active surveillance."
Let’s do PSA right
Andrew Vickers, PhD, a biostatistician at Memorial Sloan Kettering Cancer Center in New York City, said that the Lancet Commission came to similar conclusions as he and an international group of researchers did in a 2023 policy paper in The BMJ. A major gap, Vickers said, is misuse of PSA screening. (See more on the amazing Dr. Vickers below.)
"We found that the ubiquitous policy compromise of letting patients decide for themselves about PSA has led to the worst possible outcomes of overuse in men unlikely to benefit, high rates of overdiagnosis and overtreatment, and economic and racial inequity," Vickers said. "Our view is that PSA screening should be done well — by implementing straightforward harm-reduction strategies like restricting screening in older men and use of secondary tests before biopsy — or not at all."
What’s an elevated PSA?
There is a lack of agreement on what an elevated PSA is and also on whether PSA screening should be done.
Organizations recommendations on PSA vary all over the map.
The task force says American Academy of Family Physicians and the Canadian Task Force on Preventive Health Care recommend against PSA-based screening for prostate cancer.
The American Urological Association notes how the definition of an elevated PSA has changed over time.
AUA points to 4 ng/mL being the threshhold for surveillance that is the most commonly cited.
The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial of prostate cancer screening that showed a significant reduction in prostate cancer deaths among patients who entered the trial between ages 55 to 69 years and were referred to biopsy based on a threshold of 3 ng/mL
AUA also observes that most studies identifying age-varying thresholds specify threshold values of 2.5 ng/mL for people in their 40s, 3.5 ng/mL for people in their 50s, 4.5 ng/mL for people in their 60s, and 6.5 ng/mL for people in their 70s.
The European Association of Urology recommends that men should be offered a risk-adapted strategy (based on initial PSA level), with follow-up intervals of 2 years for those initially at risk, where they include men with PSA over 1 ng/mL. The National Comprehensive Cancer Network’s guidelines have a 1.0 ng/mL cutoff of PSA for surveillance.
Institutions can have their own guidelines. Check out Memorial Sloan Kettering Cancer Center’s guidelines.
Are you exhausted yet?
Disagreements like this leave patients and doctors adrift.
American men have low uptake of PSA testing. One recent study noted that PSA testing frequencies were 32.3% ( among non-Hispanic whites and 30.3% among non-Hispanic Blacks compared with even lower numbers in other minorities such as 21.8% among Hispanics, and 17.7% among Asian and Pacific Islander men.
Meanwhile, as advanced cancers increasingly are being diagnosed.
Euro confusing uro overview
Dr Katharina Beyer, of the Department of Urology at the Erasmus MC Cancer Institute in Rotterdam, Netherlands, said: “Some country’s guidelines are actively against screening, others are non-committal, and a few, such as Lithuania, have some form of screening. But in many countries, if you ask for a test, you can get one, sometimes free and sometimes not. This means that well-educated men, who know about PSA tests are more likely to be screened and get an early diagnosis, while others with less knowledge are at a disadvantage.”
Rule, Britannia?
This is also the situation in the UK, according to Dr. Phillip Cornford, of Liverpool University Hospitals NHS Trust, who chairs the EAU Prostate Cancer Guidelines Committee.
Cornford said: “The NICE guidelines here in the UK are incongruous. They say there’s no evidence that PSA screening is worthwhile, but at the same time say any man can ask for a PSA test if they want it. The result is that well-educated, driven men ask and others, including many Afro-Caribbean men who are actually at higher risk, don’t ask and so prostate cancers get missed.
“There is clearly a need for more organized prostate cancer screening and last November, the UK government and the charity, Prostate UK, announced a £42m research program to look at this. The details of that should soon be made public. Each country will need to design a screening program that fits their health system and the resources they have available. But there is still plenty we can learn from other countries and the work underway in the EU. New findings, such as those from the PROBASE trial, can help us design an appropriate screening program both in the UK and elsewhere.”
The myths of PSA testing
(Note: Andrew Vickers, PhD, a biostatistician at Memorial Sloan Kettering Cancer Center at NYC, is one of the giants in prostate care even though he treats NO patients. He has been involved in many major studies. He recently spoke at the 2024 annual meeting of the American Association for Cancer Research on “Seven Myths About PSA and Prostate Cancer Screening.” I am sharing part of his talk below. To read all about the myths of PSA, go to the MSKCC website.
Prostate-specific antigen (PSA) blood tests are the main screening tool for prostate cancer, measuring levels of this protein in the blood. In the past, some experts have suggested that PSA testing caused more harm than good, saying it can lead to unnecessary biopsies and therapies for cancers that actually don’t need to be treated, Vickers explained.
Today, the PSA test should be used as part of the tool kit for finding cancer and identifying which cancers should be treated, said Vickers, who receives royalties from the sale of the 4Kscore test.
Here are a few of the Myths of PSA screening.
Myth: PSA test results will show you whether your levels of PSA are elevated or normal.
Many people are not clear about what a PSA test really shows.
“I often hear from friends that the result of their PSA test was negative,” Vickers said. “But the PSA test result is not like a COVID-19 test. It doesn’t suddenly turn positive when you develop prostate cancer.”
The test tells you how much PSA protein is in your blood, measured in nanograms per milliliter (ng/ml). Results between 0 and 3 ng/ml were once considered “normal,” but recent research has shown a gradient of risk, even at these low levels of PSA.
For patients with results of 3 ng/ml or higher, Vickers said the test should always be repeated to confirm the results. Elevated PSA levels can be caused by conditions other than cancer, including an enlarged prostate or a prostate infection. It’s important to rule out those potential causes.
If your doctor can’t find a benign (not cancerous) cause for your elevated PSA level, the next step should be additional tests like an MRI scan or a 4Kscore test — rather than going straight to an invasive prostate biopsy. An MRI can detect the presence of a tumor. The 4Kscore test, a blood test developed at MSK, looks at additional markers in the blood and can help determine whether a biopsy is needed.
Doctors used to believe that changes in PSA (known as “PSA velocity”) were an indicator that cancer might be present, even in patients with no history of the disease. But researchers from MSK published several studies showing that looking at changes in PSA was not of value. Since then, PSA velocity has been removed from practice guidelines.
(Andrew Vickers, PhD.)
Myth: PSA is not an accurate test for prostate cancer.
What makes this a myth is that it isn’t very important.
“Almost all men will get prostate cancer if they live long enough,” Vickers explains. “So we aren’t at all interested in prostate cancer as an endpoint. What we want to know is whether PSA can predict who gets the sort of prostate cancer that can cause symptoms and threaten a patient’s life. It turns out that PSA is very good at doing that.”
Because the PSA test is very sensitive, if your PSA is low, you can be reassured that you’re at low risk of having aggressive prostate cancer.
That said, because the test is not specific, a higher PSA level doesn’t necessarily mean you will get aggressive prostate cancer. That’s because there can be many other reasons it is elevated.
Myth: The benefits of PSA testing are controversial.
“We know there are benefits, and that’s not controversial,” Vickers said. “We have evidence that prostate cancer screening reduces the risk of dying from prostate cancer.”
One of the most well-known randomized studies demonstrating that PSA reduces cancer mortality was conducted in Sweden in collaboration with MSK researchers. Vickers explains that the real controversy “isn’t whether there are any benefits at all, but whether the benefits outweigh the harms.”
Myth: PSA screening inevitably leads to a large amount of overtreatment and overdiagnosis.
“Over the past few decades, many hundreds of thousands of American men have been diagnosed and treated for prostate cancer that never would have become apparent if not for PSA testing,” Vickers said. “But the amount of overdiagnosis and overtreatment depends on how the test is used. If screening guidelines based on more up-to-date knowledge are followed and treatment is limited to aggressive cancers, the number of men being unnecessarily diagnosed with and treated for prostate cancer can be dramatically reduced.”
For patients with prostate cancer that does not appear aggressive or likely to spread, MSK’s Active Surveillance Program offers the option for regular monitoring. This program can help patients avoid the side effects associated with treatment.
Myth: The best national policy for PSA screening is to only test men who ask their doctor.
Most countries have adopted a policy that PSA testing should be done after “shared” decision-making. “But for the most part, anyone who asks their doctor for a PSA test is going to get one,” Vickers said. “The result we see across the globe is overuse of the test in men who are not going to benefit from it.”
Another major problem with these policies is that they exacerbate inequality, with PSA testing more common in wealthier rather than in underserved communities, he added.
The Pathology Report: Atypical Intraductal Proliferation
Question: What is “atypical intraductal proliferation (AIP)”?
Dr. Zhou answers: "Atypical intraductal proliferation" (AIP) is a relatively new concept in prostate pathology. It describes abnormal findings in the prostate gland which bears some similarities to the two diagnoses we discussed previously, ie, high-grade prostatic intraepithelial neoplasia (HGPIN) and intraductal carcinoma (IDC), but is worse than HGPIN and yet not enough for IDC. Simply put, AIP is a lesion between HGPIN and IDC.
How to diagnose AIP?
AIP is diagnosed through histopathological examination of prostate biopsy and resection specimens. Pathologists look for specific features such as architectural changes in ductal structures, nuclear atypia, and cellular proliferation to distinguish AIP from benign, HGPIN, IDC, and invasive cancer.
What does “atypical intraductal proliferation” mean for patient outcomes and management?
When reported in prostate needle biopsy, AIP is potentially a marker of unsampled cancer, ie, cancer that is present within the prostate gland but missed by the biopsy. Several studies found cancer and/or IDC was found in repeat biopsies in 50% of patients who had AIP in the initial biopsies. Therefore, National Comprehensive Cancer Center Network (NCCN) guidelines recommend repeat biopsy using MRI targeting and systematic biopsy to look for invasive cancer when AIP is seen on biopsy in the absence of invasive cancer.
It is, however, unclear at this time how an AIP diagnosis may impact the management decision in a patient who otherwise is eligible for active surveillance.
Reference:
Shah RB, et al. Atypical intraductal proliferation detected in prostate needle biopsy is a marker of unsampled intraductal carcinoma and other adverse pathological features: a prospective clinicopathological study of 62 cases with emphasis on pathological outcomes. Histopathology 2019;75:346-353.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Prostate Cancer Early Detection Version 2.2023 — September 26, 2023.
Dr. Zhou is the Chair and Pathologist-in-Chief of the Tufts Medical Center, and Professor and Chair of the Department of Anatomic and Clinical Pathology, Tufts University School of Medicine in Boston. He has published over 200 peer-reviewed articles and numerous book chapters and edited five textbooks of urological and prostate pathology. He is currently a member of the United States and Canadian Academy of Pathology Board of Directors, and the immediate past President of the Genitourinary Pathology Society (GUPS), an international organization for urological pathologists.
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