What’s the latest on prostate cancer and the PSA screening test?

Originally published in MedPage Today

by Chris Emery, MedPage Today Contributing Writer

Prostate specific antigen (PSA) tests may lead to unnecessary treatment of healthy men for prostate cancer, and there is little evidence supporting the common but controversial test for routine cancer screening, two new studies found.

medpage-today Measurements of blood concentrations of PSA failed to predict cancer with the accuracy generally required of a screening test, and only very low concentrations of PSA (less than 1 nanogram per milliliter) reliably ruled out the disease, according to a Swedish study published Sept. 24 in the British Medical Journal.

“Taken together, our study and the recent findings from screening trials strongly indicate that in addition to serum concentrations of prostate specific antigen, further biomarkers are needed before population-based screening for prostate cancer can be recommended,” Benny Holmstrom, of Gävle Hospital in Sweden, and colleagues concluded.

In a separate review of past studies and current PSA guidelines published in the same issue of BMJ, researchers in the U.S. found that PSA screening cannot differentiate between harmless and lethal prostate cancer. They concluded that evidence about the costs and benefits of PSA screening is insufficient to support its general use.

“The financial and psychological costs of false positive results, overdiagnosis, and overtreatment of prostate cancer need to be measured more precisely,” Jennifer R. Stark, ScD, of the Harvard School of Public Health, and colleagues wrote. “Better estimates of these costs should emerge from further evaluations of the large randomized trials.”

Prostate cancer affects 679,000 men and causes 221,000 deaths worldwide each year, according to a global estimate published in 2005.

The U.S. Food and Drug Administration approved PSA testing for early detection of prostate cancer in 1994, and the American Urological Association recommends annual screening for men ages 40 and older who have a life expectancy of at least 10 years.

Yet many agencies in the U.S. and Europe, including the European Association of Urology and the American Cancer Society, do not recommend routine prostate cancer screening. Recently, the test has come under fire from a variety of sources.

In August, a study published in the Journal of the National Cancer Institute found that only one of every 20 prostate cancer diagnoses leads to a benefit that would not have been realized without PSA screening.

The authors estimated that one million excess diagnoses have accrued since 1986, while the incidence of prostate cancer remains well above levels that existed prior to widespread PSA screening.

In the latest study, Stark and colleagues reported that “even without consensus on routine screening, more than half of U.S. men ages 50 and older report having had a PSA test within the past year. Furthermore, a third of men screened for prostate cancer were not aware that their PSA level had been tested within the previous three months.”

To further investigate the effectiveness of PSA as a cancer test, Holmstrom and colleagues in Sweden followed the progression of cancer in 540 men who took PSA tests and were subsequently diagnosed with prostate over the following several years (by 2006). The researchers also followed 1,034 healthy men who served as controls.

All of the subjects were part of a population-based intervention study begun in 1985 in Västerbotten County, Sweden.

By comparing the results of a patient’s PSA tests to the records in a national cancer registry, the researchers found that the levels of PSA in the patients’ blood were poor predictors of whether they developed life-threatening prostate cancer.

Although the likelihood ratio (a statistical measure) of a test typically needs to be at least 10 to be considered sensitive enough to predict disease, the study found that common PSA cutoff values of 3, 4, and 5 nanograms per milliliter had positive likelihood ratios of only 4.5, 5.5 and 6.4, respectively.

On the other end, the commonly accepted likelihood ratio for ruling out a disease is 0.1. Looking at the same PSA test cutoff values, the likelihood ratios for ruling out disease were 0.47, 0.61 and 0.70, respectively. All were well short of the common standard.

“Although prostate specific antigen has a relatively high validity for prediction of subsequent prostate cancer, this longitudinal study shows that no cutoff value for prostate specific antigen attains the likelihood ratios formally required for a screening test,” the researchers wrote.

“However, prostate specific antigen concentrations below 1.0 ng/ml virtually ruled out a diagnosis of prostate cancer during follow-up,” the authors added, “and higher prostate specific antigen concentrations expressed a continuum of prostate cancer risk.”

The authors said their findings could be generalized to other white European populations in which no widespread screening with prostate specific antigen tests is ongoing. They cautioned that the study was limited by a lack of a follow-up with the participants well after their blood was initially taken.

In the other paper, Stark and colleagues noted that while some men have an aggressive form of prostate cancer for which screening might be helpful, many have a slow growing cancer that will never progress to cause serious illness.

Extrapolating from earlier research, they concluded that a 61-year-old man might live 10 years longer if an otherwise lethal case of prostate cancer was caught with PSA testing. To prevent this one death, 1,410 men must be screened, providing an average survival gain of about 2.6 days per man screened.

The authors contrast this benefit with estimates that nearly half of men diagnosed with prostate cancer do not have cancer at all — and that many of those who do have cancer have indolent varieties that do not require treatment.

“Ideally, a screening tool would selectively identify lethal prostate cancers for which treatment would be effective but avoid detecting cancers that would not be lethal and might not ever cause symptoms,” they wrote. “Detecting slow growing cancers causes needless anxiety and brings unnecessary medical treatment with all its attendant risks.”

They concluded that PSA testing should be approached deliberately and with the same forethought and discussion used for screening for other cancers, such as mammography for breast cancer or endoscopy for large bowel cancer.

“Before testing, men should be informed about the test itself and the interpretation of a positive or negative result,” they wrote. “Moreover, they should be advised that the test cannot tell whether they have a life threatening cancer but that it could lead them through a thicket of tests and treatments that they might have better avoided.”

In an accompanying editorial, Dragan Ilic, PhD, and Sally Green, PhD, of Monash University in Australia, support the notion that men should be told they are being tested for PSA and of the uncertainty involved in the test.

“Clinicians should consider using likelihood ratios together with a patient’s individual risk factors for the disease to explain the potential benefits and harms of the PSA test, allowing patients to contribute to decisions,” they wrote.

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