To Test or Not to Test for PSA Levels, The Question Remains in Prostate Cancer

CURE, CURE® Genitourinary Cancer 2022 Special Issue,

As PSA testing recommendations change and the debate surrounding testing continues, people with a high-risk of prostate cancer and their families need to stay informed.

John Salata says he is grateful his prostate-specific antigen (PSA) was tested when it was, even if it was by accident.

When Salata was 48, his primary care doctor mistakenly checked the box for a PSA test when ordering his panel of bloodwork. When Salata’s score came back high, she referred him to a urologist who gave him an antibiotic.

A few months later, his PSA tested even higher. He had a biopsy and received a diagnosis of cancer. He had a radical prostatectomy (surgery to remove the prostate gland and seminal vesicles after a prostate cancer diagnosis) in January 2011.

“When the pathology came back, it was 60% cancerous and it had spread beyond the surgical margins,” Salata recalls. “If we hadn’t found it, then it probably would have spread outside the prostate within a few years. It would have spread throughout the body. Even at that point in time there are usually no symptoms, so there would’ve been no need for me to see a doctor. Because the guidelines didn’t recommend testing until (age) 55 or 60, it would have gone unnoticed for some time. Then once you’re at stage 4, the care is generally palliative.”

Changes in recommendations for PSA testing as a screen for prostate cancer are a frequent occurrence. Why is it so difficult to decide whether or when it should be done? And what do the changes mean for men over the age of 50 as they enter the risk zone for this cancer type?

What is PSA?

PSA is a protein made by prostate cells and released into the bloodstream. It is produced by both cancerous and noncancerous cells, but cancer cells tend to secrete PSA more directly into the blood, so PSA levels are often higher in patients with prostate cancer, according to Dr. Michael S. Leapman, associate professor of urology at Yale School of Medicine and clinical program leader of the Prostate and Urologic Cancers Program at Yale Cancer Center in New Haven, Connecticut.

“The PSA test does not diagnose prostate cancer,” Leapman says. “If you have a higher than average PSA, you’re identified to be in a higher risk category that typically triggers further investigation.”

PSA is specific to the prostate but not to prostate cancer, notes Dr. Mihir M. Desai, professor of clinical urology and director of robotic urologic surgery at Keck Medicine of USC in Los Angeles. High PSA levels also can be caused by infections, inflammation and other prostate procedures.

Why PSA Screening Recommendations Keep Changing

As with many cancer types, some prostate cancers may be so slow growing that they will not affect a patient significantly in their lifetime, so their detection and treatment may end up being worse than the cancer having been left alone. To ensure that prostate cancer screening is focused on those who would benefit, there are multiple organizations that issue medical guidelines in the United States, including the American Urological Association, National Comprehensive Cancer Network and American Cancer Society. Each formulates its guidelines based on data from clinical trials that are available at that time.

A patient may find that their PSA test is ordered by a primary care doctor who consults one source, and then by a urologist who consults another.

The U.S. Preventive Screening Task Force (USPSTF), an organization made up of public health and primary care experts, changed its PSA recommendations in 2018. According to their website, that year, the recommendation for men 55 to 69 years old to undergo periodic PSA-based screening for prostate cancer should be an individual one, and that clinicians should not screen men who do not express the preference.

Additionally, the recommendations were against PSA-based screening in men 70 years and older.

“In 2012, the USPSTF issued a statement saying that no one should be screened for prostate cancer with the PSA test. At the time, the judgment from the USPSTF was that the net harms of screening outweighed the potential benefit,” Leapman says.

This recommendation was based on the Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) trial. In the trial, investigators randomly assigned men into two groups: those who were given a PSA test and those who were not. The trial results, released in 2009, showed that the difference in number of deaths between the two groups was statistically insignificant.

Also in 2009, results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial were published. The trial was similar to the PLCO trial in that participants were randomly assigned into groups to receive PSA screening or not. However, results of the ERSPC showed a 29% relative reduction in mortality for the PSA-tested group.

Why the difference?

“One question we asked was how was the U.S. study conducted?” Leapman adds. “The main concern was that there was significant contamination — about 90% of the people in the ‘do not screen’ group had actually received PSA testing at some point. It really minimized the potential benefit that could have been seen because men were getting diagnosed in both groups. That contamination was not as prevalent in the European study.”

What’s the Harm of PSA Testing?

“The test itself is just a blood test,” Leapman says. “It’s usually combined with other routine bloodwork. So it’s not the test itself that is dangerous; it’s really what happens downstream.”

Often, the next step after receiving a high PSA test score is a biopsy. Dr. Kenneth Lin, professor of clinical family medicine at MedStar Georgetown University Hospital in Washington, D.C., says there can be real harm in this.

“Many men can be told they don’t need a definitive intervention,” Lin explains. “But nonetheless, when someone is walking around thinking there is some probability they have cancer, it often pushes them into treatments they don’t need because they’re never absolutely certain they don’t have it. So a lot of men do have removal of the prostate or radiation therapy when they don’t need to.”

Henry Wigglesworth, 64, is one such patient. When he was 55, he started having his PSA level tested regularly, and it climbed slowly and steadily in the following years until it reached 5. A score between 4 and 10 is in the range of “suspicious,” and approximately 25% of these patients with a score in that range have prostate cancer. Wigglesworth received a diagnosis of a nonaggressive form of prostate cancer in 2017.

“I still remember getting the call,” Wigglesworth says. “My urologist said the results of my biopsy showed I had cancer. Nobody wants to hear that. Then he said the good news was that I had the least harmful type of cancer that exists. It was still very upsetting. I’m healthy in all other respects. I never thought I would have cancer.”

That doctor recommended active surveillance that included frequent monitoring, but then told Wigglesworth that most men usually ended up opting for some form of treatment after five years or so. This prompted Wigglesworth to enroll in a study through the National Institutes of Health (NIH), where they monitored his cancer with regular PSA tests, MRIs and biopsies. They didn’t find any signs of progression.

When Wigglesworth later went to a urologist about his enlarged prostate, he explained his history, and the urologist said he never would have ordered the biopsy because Wigglesworth’s inflamed prostate likely had caused the high PSA result.

Approximately a year after the first biopsy, Wigglesworth returned to NIH. His doctor found a lesion, and Wigglesworth had another biopsy. He left the NIH with a catheter that remained in for four days. When the results came back inconclusive, the doctor ordered another biopsy.

“And I said, ‘No,’” Wigglesworth recalls. “I’m sorry. I’m not going to let you poke me again with that needle.”

While Wigglesworth has opted for active surveillance for his prostate cancer, Salata’s story shows the dangers of not testing. His cancer could have been diagnosed later in life, at the recommended age for testing, when, as he said, it could have been too late.

Current PSA Testing Recommendations

After the results of the ERSPC trial in 2018, the USPSTF updated its recommendations to state doctors should discuss the benefits and risks of PSA screening with patients who are between the ages of 55 and 69.

“PSA testing shouldn’t be a knee-jerk reaction,” Desai explains. “If patients are warned upfront that ‘Look, even if we do detect prostate cancer, it may be low risk and low grade, and we don’t even need to treat it,’ then they’re much more accepting of that fact afterward, so you can minimize the risk of overtreatment.”

Leapman says the use of active surveillance (close monitoring) as a form of treatment increased in the years USPSTF did not recommend PSA screening. This means prostate cancer is less likely to be overtreated. Desai uses a number of tools to assess a patient’s prostate cancer risk, including looking at the trajectory of their PSA numbers.

“If somebody has a brisk upshoot that doesn’t go down, then that’s more concerning,” Desai says. “If it happens in somebody who has a strong family history, that is concerning. African American men have a higher risk of prostate cancer, so the trigger for a biopsy is lower.”

The general trigger, or signal, to do a biopsy is when the PSA is at 4 or higher. However, if there is a quick upshoot, if the patient is Black or if there is a family history of prostate cancer, physicians may decide to do a biopsy with a lower PSA level.

But even with discussion, there are still overlooked costs of running PSA tests.

“I’d rather spend five minutes counseling somebody about nutrition or exercise,” Lin says. “But I may not have that time because I’m committed to discussing this test, which I think has a pretty marginal benefit at best.”

A Decrease in PSA Testing

Leapman says the number of men given PSA tests decreased by approximately 15% between 2012 and 2018.

“After 2018 when the guidelines were changed,” he says, “there was a significant increase. We estimate that rates of testing have approximately gone back to levels prior to 2012.”

There were fewer PSA tests given during those years, but was there a decrease in the number of prostate cancer cases diagnosed?

“Overall the total incidence of prostate cancer has gone down because less testing means fewer biopsies, which means less detection,” Desai says. “But there is also evidence that the incidence of advanced or metastatic disease has begun to go up.”

Lin says the studies for these years can be challenging to interpret.

“What I’ve seen is that the percentage of cancers being diagnosed at a more advanced stage has gone up relative to the lower, earlier-stage cancers,” Lin says. “But you would expect that to happen because we were no longer screening as much. The proportions have changed. I haven’t seen good data showing that the absolute number of late-stage cancers has gone up relative to the population.”

What’s Next for Prostate Cancer Screening

Although MRIs have been around for a while, Leapman says the quality of the image has improved and can reliably show cancer in the prostate. This makes the biopsy more targeted and accurate.

“I think the MRI will hopefully spare some men biopsies,” Lin says. “Or if they have to undergo a biopsy, it’ll be more definitive.”

There are also other blood and urine-based biomarkers that when taken together with a PSA, Leapman says, can help doctors calculate the patient’s prostate cancer risk.

Salata and Wigglesworth say they have moved on with their lives. Salata says he was the first in his family to receive a diagnosis of prostate cancer, but his uncle and cousin also received diagnoses not much later. Salata’s son, who is 26, is planning to have his first PSA test in the next few years.

Wigglesworth notes he recently talked to someone who received a diagnosis of late-stage prostate cancer due to an early PSA test.

“And I thought, Oh my gosh, this test is amazing,” he says. “Everybody should have it. But then there’s the other side, the harm that can be done, not from the test itself, but from this odyssey that you have to go on to identify how it should be treated.”

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