Years ago, decisions about screening men for PSA looked relatively straightforward. You offered screening to patients aged 40 or older, performed a biopsy on the ones with a total PSA >4.0 ng/mL, and offered treatment to those with positive biopsies. Today, conflicting guidelines and new techniques in cancer detection and treatment have left clinicians with a more complicated puzzle. The good news, experts say, is that physicians who put these pieces together stand a better chance of protecting their patients’ health than ever before.
Years ago, decisions about screening men for prostate-specific antigen (PSA) looked relatively straightforward. You offered screening to patients aged 40 or older, performed a biopsy on the ones with a total PSA >4.0 ng/mL, and offered treatment to those with positive biopsies.
Today, conflicting guidelines and new techniques in cancer detection and treatment have left clinicians with a more complicated puzzle. The good news, experts say, is that physicians who put these pieces together stand a better chance of protecting their patients’ health than ever before.
Most people who have researched the history of the PSA test agree that widespread use in decades past came with pluses and minuses.
Dr. Carter“The data that are available suggest that there are men who benefit greatly from having their cancer diagnosed and having it treated,” said H. Ballentine Carter, MD, professor of urologic oncology and director of the division of adult urology at Johns Hopkins Medicine in Baltimore. “But there is at this point also very strong evidence that a substantial proportion of individuals get detected with a cancer that would never harm them, and they get treated. And that’s a big problem.”
Concerned about this overtreatment, as well as psychological stress and the side effects of prostate biopsy, the U.S. Preventive Services Task Force (USPSTF) in 2012 recommended against use of the PSA test in any man. The USPSTF is now reviewing that guidance. But some studies show it has already resulted in a drop in the number of men being tested.
Meanwhile, more sophisticated tests such as the Prostate Health Index (phi), the prostate cancer gene 3 (PCA3), the 4Kscore Test, and new applications of magnetic resonance imaging (MRI) have become available, potentially reducing the risks of screening. And more men with a diagnosis of prostate cancer are choosing active surveillance as an alternative to immediate treatment.
So what approach should urologists take in advising their patients and their primary care colleagues about screening for prostate cancer?
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The American Urological Association’s “Early Detection of Prostate Cancer: AUA Guideline,” last updated in 2013, still offers a useful starting point, says Dr. Carter, its lead author. The AUA has reviewed the guidelines since 2013, but so far without changing the content.
In essence, the AUA guideline recommends that clinicians discuss the pros and cons of the PSA test with men who are 55 to 69 years of age. Dr. Carter and his colleagues concluded from studies on the test that it could save the life of one man for every 1,000 tested.
But the AUA guideline also points out that men in this age bracket who are not likely to live longer than 15 years are less likely to benefit. And it says the test should be offered only where the risks can be fully discussed.
Different men may weigh the potential harms and benefits differently, Dr. Carter points out. For example, some may prize quality of life more than longevity or vice versa.
For most men under age 55 or age 70 and older, the risks are more likely to outweigh the benefits, Dr. Carter and his colleagues concluded. They say the PSA test should “not be encouraged” in these men.
However, the AUA guideline includes some exceptions. Clinicians should also discuss the relative merits of the test with men age 40 to 54 years with a positive family history of prostate cancer or of African-American race, it says.
Also, some men over 70 years of age who are in excellent health might also benefit from the screening, the guideline says. But the risk of harm increases and the chance of a benefit decreases with age, it warns.
For those men being screened, the AUA recommends 2-year PSA intervals, with longer intervals for men over age 60 with PSA levels <1.0 ng/mL.
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As for interpreting the test, the AUA guideline recommends that a urologist “consider factors that lead to an increased PSA including prostate volume, age, and inflammation rather than using an absolute level to determine the need for a prostate biopsy.”
So how did the researchers at the USPSTF and the AUA come up with such different advice? In part, the organizations interpreted the research differently.
Where the AUA sees the PSA test saving the lives of some men, the USPSTF thinks the data is indecisive. Two major randomized, controlled trials examined PSA screening: the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (U.S. PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). U.S. PLCO did not show any reduction in mortality. The ERSPC showed a reduction of 1 in 1,000. But in five out of seven countries participating, the ERSPC study also failed to show a statistically significant reduction in mortality.
The USPSTF also concluded that there was not enough evidence to show that benefits outweigh risks of PSA testing in any group of men, including African-Americans and men with a family history of prostate cancer.
Beyond different interpretations of the literature, however, Dr. Carter sees a difference in orientation. The USPSTF is looking at the test from the standpoint of public policy, while the AUA is looking at it from the standpoint of clinical care, he says. From a public health perspective, the bucks spent on PSA screening and the downstream consequences might get a bigger bang if spent on some other public health measure.
“That’s an interpretation that you might criticize, but I’m not sure from a public health standpoint that it’s wrong,” said Dr. Carter. “On the other hand, if you are a urologist caring for people with prostate cancer, and prostate screening can reduce the number of people who show up with metastatic cancer, your perspective is going to be totally different.”
Researchers may never be able to reconcile these positions, says Dr. Carter. “I’m not sure the controversy can be settled because it’s a societal issue that has to do with how many people we are willing to harm to prevent a death from prostate cancer.”
Dr. LoebStill, the USPSTF may have good reason for revising its position, says Stacy Loeb, MD, MSc, assistant professor of urology and population health at New York University, who has published a number of studies on prostate cancer screening.
Most clinicians take a more personalized approach to screening than they did when the randomized controlled trials were conducted, she says. “Now we have a much better understanding of all the risk factors involved with prostate cancer and many better ways to reduce the downstream harm. So I think if the studies were done now, they would be done very differently and the USPSTF would reach very different conclusions,” Dr. Loeb said.
Dr. Carter agrees, pointing out that fewer than 10% chose active surveillance when diagnosed with favorable disease at the time the controlled trials were being conducted. Now the rate is more than 40%, he says. That change alone could have resulted in a drop in the rate of people being unnecessarily treated, changing the balance of harms and benefits.
Other advances in the field also may have altered this equation, Dr. Loeb says. “For men who have not yet had a prostate biopsy, if their PSA is above 3.0, there are a few other reflex tests they can do.”
Two such measurements are the phi and the 4Kscore Test. The phi is a formula combining total PSA, free PSA, and [-2]proPSA that provides a probability of prostate cancer on biopsy and risk of high-grade disease. Similarly, the 4Kscore Test combines 4 kallikrein protein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2) with other clinical information in an algorithm that provides a percent risk for a high-grade cancer on biopsy.
“The Prostate Health Index and the 4Kscore Test have been shown in large prospective studies to be more specific for clinically significant prostate cancer than the regular PSA,” Dr. Loeb said. “So as I see it, if a man wants more information to decide on a biopsy, why not offer additional testing options now that we have them?”
Dr. Loeb cites the National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection guidelines, which include both of these tests as optional reflex tests to help decide on initial or repeat prostate biopsy. Such testing might in fact be more useful than total PSA as first-line screening tools, but they can’t be recommended for that purpose since they weren’t studied in that way, says Dr. Loeb. For men who already had a negative biopsy, these guidelines offer an additional testing option called PCA3, a urine test shown to be more specific than PSA in predicting who is most likely to have prostate cancer on repeat biopsy, she says.
In addition, says Dr. Loeb, new multiparametric MRI techniques can help identify suspicious lesions, which can both assist in deciding whether to perform a biopsy and in making the biopsy itself more effective.
The AUA guideline takes a more cautious position on these tests, as well as the digital rectal exam. It “recognizes that these tests can be useful as adjuncts for informing decisions about the need for a prostate biopsy-or repeat biopsy-after PSA screening, but emphasizes the lack of evidence that these tests will increase the ratio of benefit to harm,” the guideline states.
One point where Dr. Loeb and Dr. Carter differ is on the usefulness of a “baseline” PSA score. “Men should get baseline PSA in their 40s,” said Dr. Loeb. In her own research, men who had PSA levels above the median at that age had a significantly higher risk of being diagnosed with prostate cancer, and a higher risk that the cancer would be aggressive.
Dr. Carter sees such early screening as an open door to excessive screening. “There is no such thing as a baseline PSA,” he said. “Once you draw a PSA, screening begins and it will not stop, and I’m not convinced that starting screening at age 40 is going to add benefit over beginning screening at a later age.”
Further randomized controlled trials of total PSA are unlikely in the future, Dr. Carter says, both because they are expensive and because attention has shifted to the newer tests. Although these may never take the place of total PSA as an initial screening tool, they offer great promise to reduce the harms of screening, he says.
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