PSA: What's the Prognosis?

These are the facts: Prostate cancer kills more than 200,000 men worldwide annually. And in the United States alone, about 230,900 new cases will be diagnosed each year-enough people to fill nearly 600 Boeing 747 planes.

Since the late 1980s, the prostate specific antigen (PSA) test has held its ground as the best screening method for prostate cancer-but not without controversy. Some critics blame the assay for too many false positive test results, which lead to unnecessary biopsies. Others want to lower the threshold for recommended biopsies to catch cancer earlier.

The arguments have been simmering for some time. Now the debate is more intense than ever, and questions abound on either side. What can be done to reduce unnecessary biopsies? Should the threshold for recommended biopsies be lowered? And can the process of prostate cancer screening possibly be improved?

Welcome to the PSA debate.

Sorting through the Criticism

PSA was identified in 1979. In 1986, Hybritech Inc. (now part of Beckman Coulter) became the first company to receive approval from the Food and Drug Administration (FDA) for the use of a total PSA blood test for the monitoring of prostate cancer. Eight years later, the company was the first to receive FDA approval for use of the total PSA test in detecting prostate cancer in conjunction with a digital rectal exam (DRE).

According to a study of 6,374 men 50 years of age and older on which the 1994 approval was based, the Hybritech(r) PSA test detected 41 percent (94/230) of cancers that DRE did not. DRE detected 21 percent (48/230) of cancers that PSA determinations did not. Therefore, many healthcare experts believe that performing both DRE and PSA testing together is improves cancer detection even further.

But the PSA assay has its fair share of critics. According to Bernard Cook, Ph.D., lead scientific advisor for Beckman Coulter, some of the criticism stems from how clinicians are using the test results. "Depending on how the clinician interprets the PSA test results and what intervention results, some prostate cancer may be missed while others may be overtreated with surgery or radiation. This, in turn, is raising new questions about how to appropriately manage men with no symptoms."

It's also prompting an even more controversial question: Should the threshold for recommended biopsies be lowered to catch cancer even earlier?

Those against lowering the threshold point out that the PSA test already leads to too many unnecessary biopsies. Biopsies are routinely performed on men with a PSA level of 10 ng/mL or higher, since these men have a greater than 50 percent chance of cancer. But the decision becomes less clear with PSA results between 4 and 10 ng/mL-the so-called "diagnostic gray zone."

During the early and mid-1990s, when four-core and six-core biopsies were performed, the detection of cancer in men with PSA levels from 4 to 10 ng/mL was about 25 percent. Within the last few years, improved placement and an increased number of biopsy cores - to 10 or 12 - has increased detection rates to as high as 40 percent. It is estimated that this single improved biopsy regimen detects the cancer in greater than 90 percent of men with prostate cancer.

However, in men with PSA results between 2.5 and 4 ng/mL, the biopsy detection rate drops to about 20 percent. Whether its the 2.5 to 4 or the 4 to 10 ng/mL range, the criticism persists that the PSA test is only picking up mainly insignificant cancers-those that are not expected to become life threatening. The remainder of the men-60 to 80 percent-will have endured the discomfort, cost and anxiety of a prostate biopsy unnecessarily.

On the Flip Side

Despite criticisms, the PSA test has a strong base of defenders. And the evidence in support of PSA screening's contribution to reduced mortality is compelling.

Prior to the introduction of PSA testing, two-thirds of prostate cancers were discovered after they were at an incurable stage of disease. Now, PSA proponents are crediting the test with helping doctors catch cancer before it spreads beyond the prostate. In fact, according to a study in Epidemiology, increased PSA testing during the past several decades has been linked to a decrease in prostate cancer mortality. These studies suggest that the PSA test is not just picking up insignificant cancer.

In other words, the test works, says William J. Catalona, M.D., director of the prostate cancer program at Northwestern University and medical director of the Urological Research Foundation. "Clinical studies have shown that most prostate cancers detected with the aid of PSA testing have the features of tumors that are likely to affect patients clinically," he says.

One of prostate cancer's most prominent thought leaders, Dr. Catalona is leading the charge to change the commonly accepted PSA testing protocol. Instead of waiting until total PSA levels exceed 4 ng/mL, he often recommends biopsies when the level reaches 2.5 ng/mL. In Dr. Catalona's view, men with PSA levels above 2.5 ng/mL are likely to progress to levels greater than 4 ng/mL, so it is better to detect and treat this cancer in its earlier, more curable stage.

"The goal is to catch cancer earlier while it is still confined to the organ," he says. In a study published in the Journal of the American Medical Association, Dr. Catalona and other researchers looked at men with PSA levels between 2.6 and 4 ng/mL. Within four years, 50 percent of this group had PSA levels above 4 ng/mL, and 22 percent of this group had cancer. In 80 percent of the cancer cases, the tumor had not spread outside the prostate.

But lowering the threshold isn't the only method available to clinicians for making decisions whether to biopsy.

"When it comes to changing the cutoff, doctors have to ask themselves what they want from the test," says Dr. Cook. "If the goal is to reduce unnecessary biopsies, then clinicians can mitigate this risk with a follow-up test like free PSA."

Putting Free PSA to Work

PSA molecules come in many forms: some are bound to other proteins, while some are "free" or floating freely in the bloodstream. In the critical range of 4 to 10 ng/mL of PSA test results, prostate cancer is more likely to be present in men who have a low percentage of free PSA relative to the total amount of PSA.

Beckman Coulter's Hybritech free PSA test aids in distinguishing prostate cancer from benign prostate conditions.

"We can use the ratio of free PSA to total PSA to help distinguish prostate cancer from benign prostatic conditions," says Dr. Cook. "Studies have shown that the free PSA assay can help 20 percent of men in the diagnostic gray zone avoid unnecessary biopsies, while still detecting 95 percent of cancers."

There is substantial clinical support for free PSA testing. For example, about 10 to 20 percent of total PSA tests at Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, also include the free PSA test.

"Percent-free PSA results can be interpreted using a single cutoff value or as a continuum of values for risk assessment," says Lori Sokoll, Ph.D., associate director of clinical chemistry at Johns Hopkins. "When we perform the free PSA test, we include a table showing the probability of cancer for different ranges of percent free PSA in our lab report."

Dr. Catalona agrees that free PSA is a step in the right direction. "PSA is the best tumor marker, but there is understandable pressure to improve its accuracy," he says. "Free PSA is one way to do this."

Ultimately, the day may come when PSA and free PSA are replaced by more accurate methods. Beckman Coulter scientists are working hard to discover new markers and develop genetic tests that may someday provide a breakthrough for prostate cancer screening. Until then, the PSA debate rages on.

"Some see great value in the PSA test, others don't, and the majority are somewhere in between," summarizes Dr. Cook. "But the fact is that PSA is the best test we have right now to aid in the prognosis and management of patients with prostate cancer."