Putting free PSA into playwhy and
Seeking answers from complexed PSA
William Check, PhD
By consensus of clinicians and laboratory professionals, prostate-specific
antigen is the best marker for screening for prostate cancer and is
now accepted as an integral part of diagnosing and managing this malignancy.
"Total PSA is the best serum screening marker for any cancer,"
states Kevin Slawin, MD, assistant professor of urology and director,
The Baylor Prostate Center, Baylor College of Medicine.
"PSA has revolutionized the diagnosis of prostate cancer," adds
Michael Brawer, MD, director, Northwest Prostate Institute, Northwest
Hospital, Seattle. "Using PSA screening, we find lots of cancers
and at an earlier stage. It has changed the demography of prostate
But as good as it is, total PSA measurement lacks specificity:
It does not adequately differentiate between prostate cancer and
benign prostatic hypertrophy in the so-called gray zonetotal
PSA values between 4 and 10 ng/mL. Values in this range are considered
abnormal, requiring biopsy, yet 75 percent of men with such values
and a negative digital rectal examination will not have cancer on
It became possible about five years ago to measure the different
forms in which PSA is found in the blood, either free (fPSA) or
bound to serum proteinase inhibitors (complexed PSA; cPSA). It was
observed that these molecular forms occur in different proportions
in benign prostatic hypertrophy and prostate cancer. Patients with
prostate cancer show a lower proportion of fPSA, while those with
BPH have a higher percentage. Assays were developed to measure fPSA,
and researchers set up prospective clinical trials. Even before
results were in, many predicted that determination of percent fPSA
(%fPSA) would add value to PSA screening.
Assays to measure cPSA directly were more difficult to devise
but have now entered clinical testing. (See "Seeking
answers from complexed PSA.")
Summing up results of the clinical studies with %fPSA, Milenko
Tanasijevic, MD, associate director of Clinical Laboratories, Brigham
and Women’s Hospital, Boston, says, "We believe that there is sufficient
evidence showing the clinical usefulness of percent free PSA in
clinical practice, especially for patients in whom total PSA is
between 4 and 10 and who have a negative DRE."
The positive results of the clinical trials raise two questions:
How can %fPSA best be used in practice, and how widely is it being
adopted? Jerome Richie, MD, Elliott Cutler professor of surgery,
Brigham and Women’s Hospital, and chairman of the Harvard Program
in Urology, says, "Those are both controversial questions. Anytime
a new test is introduced, studies are performed and physicians from
academic centers publish and present data at national meetings.
Over time, findings from these studies are gradually integrated
into practice. I think that is what is happening now with free PSA."
Several ways to use %fPSA values have been proposed, and practitioners
are using different approaches.
Whether clinical outcomes improve with earlier detection
of prostate cancer is a crucial question. One of the pioneers in
PSA testing, William Catalona, MD, believes they do. "I think there
is increasing evidence for the efficacy of radical prostatectomy
and increasing evidence that PSA testing is reducing prostate cancer
mortality rates," says Dr. Catalona, professor of urology, Washington
University School of Medicine, St. Louis.
Clinical utility of the %fPSA assay was established by a prospective
multicenter study conducted on 773 men with total PSA of 4 to 10
ng/mL and a negative DRE, with histopathological diagnosis available
for all subjects (JAMA. 1998;279:1542-1547). As %fPSA rose,
probability of cancer decreased. If a cutoff of 25 percent were
used-that is, not performing biopsies in men with fPSA greater than
25 percent80 (20 percent) of 394 unnecessary biopsies would
have been avoided.
How does one assess the clinical value of this 20 percent increase
in specificity from using %fPSA? Is it cost-effective to perform
an additional assay on 773 men to avoid 80 biopsies? "It is difficult
to do formal studies in this area," says Dr. Tanasijevic. He points
to an analysis by Littrup showing that small changes in the specificity
of a PSA assay could produce large reductions in net cost per patient
screened (Cancer. 1995;75: 1987-1993). But these savings
were derived from a model, not from actual study data or clinical
Dr. Catalona cites ballpark costs for biopsy, including ultrasound
at $1,000 to $2,000 and free PSA assay at $30 to $60. Using median
figures ($1,500 for biopsy and $45 for free PSA), 800 free PSA tests
would cost $36,000 and 80 biopsies averted would save $120,000.
"I think that is cost-effective," he states.
But these are maximum savings. "In practice," says Daniel Chan,
PhD, "there is a very tough question: Do you really want to tell
a patient they do not need a biopsy when PSA is clearly elevated?
And do you have any liability issues?" asks Dr. Chan, professor
of pathology, urology, oncology, and radiology, Johns Hopkins University,
and director of the Clinical Chemistry Division, Johns Hopkins Hospital.
These issues would not apply if free PSA were expanded to persons
with a total PSA below 4 ng/mL, which some physicians have suggested,
Dr. Chan notes. "Twenty to 30 percent of patients with total PSA
under 4 could have cancer," he says. So a possible next step might
be to lower the threshold for invoking %fPSA to a total PSA of 2.5
or 3 (Urology. 1999;54:220-224). "Patients with these PSA
values will not be expecting biopsy, so they will not complain if
they don’t get one," he says. "And they will be grateful if you
pick up prostate cancer." [However, one study found that free PSA
"is only useful in eliminating the need for prostate biopsies in
men with total PSA of at least 4.0 ng/mL" (Urology. 1998;52:450-454).]
Further analysis of data from the multicenter study found that
higher %fPSA was associated with more favorable histopathological
findingsorgan-confined tumors, Gleason score of less than
7, and 10 percent or less involvement of the prostate. Radical prostatectomy
was performed on 268 patients. Among the 96 for whom complete data
were available, 30 of 40 (75 percent) with fPSA greater than 15
percent had all three favorable findings on the pro-sta-tectomy
specimen, compared with 19 of 56 (34 percent) who had fPSA of 15
percent or less. Percent free PSA "may assist both patient and physician
in making more informed treatment decisions," investigators concluded
(J Urology. 1999;162:1346-1351).
In the multicenter trial, %fPSA was measured using the Hybritech
assay. Recently, Wayne Markus, MD, a pathologist at Physicians Laboratory,
P.C., Omaha, performed beta-testing of the Hybritech assay on an
automated Beckman Coulter Access instrument. "Subjectively, free
PSA with the manual Hybritech RIA method looks very comparable to
the nonradioactive assay done on the instrument," he says. On March
8, this combination became the first automated free PSA assay approved
as an aid in detecting prostate cancer.
Other assays for free PSA are being tested or reviewed, though
none are yet approved. Says Dr. Chan, "I have been involved with
Abbott’s free PSA assay in clinical trials, and I know that it works."
If approved, Abbott’s free PSA assay would most likely be performed
on the AxSym instrument.
Different assays give different results and have different cutoffs
for clinical response. New material sent by the CAP Surveys program
minimizes differences between methods, Dr. Chan says, but variation
Most important, the same system needs to be used to determine
total and free PSA. "This is a real problem, and I see it in my
hospital," Dr. Catalona says. "A patient, one of our distinguished
professors, goes to an internist for an evaluation, and the internist
finds total PSA is 3.8, slightly higher than before. So I get a
call from the internist: ’Does the patient need a biopsy?’ I say,
’Let’s get a free PSA on him.’ So they send it to a commercial laboratory,
which reports a total PSA of 4.5 and a free PSA of 0.4." Now there
are two slightly different total PSA values: Which one should be
used to calculate %fPSA? "That is the scenario that I find frequently,"
Dr. Catalona says. "Total PSA at our hospital laboratory and from
a reference laboratory are different. From my standpoint, the ideal
situation would be to use one assay that has been tested in clinical
trials and approved by FDA to be safe and effective for that procedure."
Physicians offer different estimates of the degree of adoption
of %fPSA. Says Dr. Slawin, "A lot of physicians use it, but many
don’t. I couldn’t practice without it. But some community urologists
say to me, ’You use it? You believe that it works?’"
In Dr. Tanasijevic’s institution, "It has been adopted as much
as we thought it would," he says. He reports that a recent increase
in volume at his hospital has warranted setting up the test in-house.
But not all estimates are so clear-cut. Says Dr. Chan, "My expectation
for free PSA usage was not as high as most other people’s." Some
physicians predicted that %fPSA would be done on 50 percent of men
having a total PSA assay. But right now that figure is between 10
and 20 percent. "I believe that the number of requests will go up
as more clinicians have experience working with free PSA and understand
how to use it," Dr. Chan says.
Is utilization lower in the community? "That may not be the case,"
Dr. Chan says. "Patients with prostate cancer read up and know things.
I was told by some community urologists that patients are asking
for it and are even willing to pay for it themselves."
In Dr. Markus’ experience, "Initially there was very little interest
[in %fPSA]. There has not been any significant interest until the
last several months. It is still not a high-volume test." One reason
may be that a "small but significant" percentage of total PSA values
are within the 4 to 10 range, where %fPSA is most valuable, he says.
"The great majority of men [more than 85 percent] have a normal
total PSA," Dr. Markus points out.
Even more interesting than how widely %fPSA is being used is how
it is being used. In principle, the value of %fPSA is to reduce
the number of false-positive biopsies in men with total PSA between
4 and 10 ng/mL. Above 10, the likelihood of prostate cancer, even
with a negative DRE, is greater than 50 percent, high enough to
mandate biopsy. With a total PSA of 4 to 10, about 25 percent of
men would have prostate cancer. Within this group, %fPSA can segregate
likelihoods of cancer from less than 10 percent to more than 50
percent. "So that is where free PSA has its greatest applicability,"
says Dr. Richie, who took part in the multicenter trial. "It’s all
probabilities, but that is what we deal with in medicine all the
When total PSA is 4 to 10, %fPSA can be used as an initial screening
test to help decide whether to perform a biopsy. "That is how I
think it will be used once it is more accepted," Dr. Richie says.
But that is not the case currently. "Right now, most urologists
are using it in persons with one negative biopsy to decide whether
they should do further biopsies," he explains. For free PSA higher
than 20 to 25 percent, clinicians are more likely to follow patients;
otherwise they recommend additional biopsies.
Dr. Richie follows this course. "I use it to decide who should
get additional biopsies," he says. "As it becomes more available
and more accepted, I may use it as an initial screening test."
Dr. Chan cites several ways %fPSA can be used in clinical practice.
First, and most obvious, using a single cutoff25 percentyields
95 percent sensitivity and a potential 20 percent reduction in unnecessary
Another approach is to estimate the likelihood of prostate cancer
based on %fPSA. "Perhaps it is better not to use a single cutoff
but to look at whether percent free PSA is high or low, then tell
the patient his risk of prostate cancer," Dr. Chan says. The Hybritech
and Abbott assays give a graded probability of prostate cancer,
with a 60 to 80 percent probability at %fPSA values of less than
10 percent and a probability of less than 10 percent when %fPSA
is greater than 25 percent.
"We actually encourage people to use a probability based on percent
free PSA," Dr. Chan says. Such decisions are challenging and best
made among laboratory professionals, clinicians, and patients. "I
have gone into discussions about that with the urologist and patient,"
Dr. Chan says. "I would think that urologists who are knowledgeable
can use those probabilities. It depends on the comfort level of
the patient and physician to make that decision."
In the above techniques, %fPSA is used diagnostically. But it
is also useful for advising patients who might need a repeat biopsy,
as Dr. Richie described. Many patients with elevated total PSA have
a biopsy that is negative. "Percent free PSA can help decide about
a repeat biopsy," Dr. Chan says. "It is being used here by our clinicians
[in] that way as well."
Biopsy is a gold standard, but it is not perfect. A standard sextant
biopsy takes six segments of the prostate gland. "So the result
depends on whether the needle hits where the cancer is," Dr. Chan
notes. To reduce the problem of false-negative biopsies, he adds,
"Some clinicians want to do nine- or 12-core biopsies, but that
is harder on patients."
Dr. Chan also mentions the prognostic value of %fPSA. "Some
urologists feel it is not necessary to detect small cancers that
are not so significant and slow-growing, especially for an older
man," he says. It can be helpful to use total PSA and %fPSA, along
with the Gleason score and other clinical findings, to decide whether
the patient has significant tumor and should undergo surgery. But,
Dr. Chan notes, "The assay is not FDA-approved in the prognostic
For monitoring, using %fPSA is still controversial. Dr. Chan notes
that, in principle, %fPSA could be helpful in patients being treated
with hormonal therapy, which affects production of PSA. With this
therapy, changes in total PSA would not necessarily reflect the
effect of the treatment on the cancer, while %fPSA might. "But in
practice, this has not proven to be useful so far," Dr. Chan says.
He offers a similar evaluation for using %fPSA to help detect recurrence
after radical prostatectomy. "Perhaps it needs more studies," he
In Dr. Catalona’s experience, "At this stage [percent free PSA]
is probably used more often in problem cases than routinely across
the board." A problem case might be a patient who has a persistently
elevated total PSA or perhaps a progressively rising total PSA and
who has had one or more negative biopsies.
Does the physician need to worry about cancer missed on previous
biopsies? "Our work and other reports have shown that the percent
free PSA is probably one of the best ways to identify men who need
repeat biopsies," Dr. Catalona says. In this context, based on referral
calls from community urologists, Dr. Catalona explains, "Physicians
basically dichotomize. If percent free PSA is above 25 percent,
they feel comfortable. And they get scared if it is below 10 percent.
That is the message I am hearing: They are using it more at its
extremes than at its mid-zones."
Percent free PSA might be used routinely in the type of patient
included in the multicenter studya man with total PSA of 4
to 10 ng/mL and a negative DRE who has not yet had a biopsy. (This
is equivalent to what Dr. Richie calls initial screening and Dr.
Chan calls diagnostic testing.)
"The way I envisioned percent free PSA to be used, and the way
we use it, is to screen a bunch of men using total PSA," says Dr.
Catalona. If total PSA comes back less than 4 (less than 2.5 might
also be used as a cutoff) or greater than 10, they would not need
%fPSA. But if total PSA is in the 4 to 10 range, Dr. Catalona’s
laboratory would automatically run free PSA. "Such reflex testing
is not done in places where many patients get screened," Dr. Catalona
notes. "That only happens in places where the percent free PSA assay
is available and it has been set up that way." In practice, many
clinicians have to order %fPSA specifically.
To illustrate how the %fPSA value can be integrated into clinical
decision-making, Dr. Catalona describes a typical case. "Let’s say
you have an elderly patient who has an enlarged prostate and a high
total PSA. And you do a free PSA that comes back 35 percent. You
can take some comfort in the fact that, based on the free PSA test
result, the chance that a biopsy will be positive is only one of
12. So 11 times out of 12 that patient will go through biopsy unnecessarily.
And even if he is the one in 12 who has cancer, it is probably going
to be a slow-growing cancer. So it would be safe to follow him for
In Dr. Markus’ laboratory, the most common scenario is to use
total PSA as a screen and %fPSA as a followup test if the physician
orders it. He does not do reflex %fPSA. "The people we are doing
PSA tests for are urologists, and they have their own criteria for
ordering percent free PSA," he says.
His informal conversation with a few urologists reveals that,
generally, a patient with elevated total PSA undergoes ultrasound
and digital rectal examination. During ultrasound examination, the
physician may biopsy any suspicious lesions. If the biopsy is negative
and total PSA is 4 to 10, free PSA may be ordered. "If percent free
PSA is low, the urologist will do closer followup and may encourage
the patient to undergo repeat biopsy," Dr. Markus says. "If it is
high, the clinician might be a little less aggressive."
But if %fPSA comes back greater than 25 percent and the clinician
decides to biopsy anyway, the increased specificity advantage of
the %fPSA assay has been nullified. What has been gained? "Final
decision on deferring biopsy has to be made between physician and
patient," Dr. Catalona says. "They have to look at overall risk."
Dr. Slawin addresses this issue slightly differently. "It used
to be that most patients who had abnormal total PSA got two sets
of biopsies," he says. "In the past, a significant number of men
who were eventually found to have cancer had a negative initial
biopsy, so those who were negative on the first biopsy often got
repeat biopsy." As a result, many men got two sets of negative biopsies.
Now, with %fPSA, he says, "If a man is biopsy-negative and his free
PSA is not in a suspicious range, we may defer the repeat biopsy."
But he would also consider the man’s age and clinical picture.
Ultimately, the goal of measuring PSA is to detect prostate
cancer early, while curative surgery can be performed. Yet whether
radical prostatectomy is truly curative has been a topic of controversy.
To support his affirmative view of this question, Dr. Catalona looks
to historical record. Immediately after total PSA testing was introduced,
he notes, the number of cases of prostate cancer rapidly increased;
these were mostly likely "catch-up" diagnoses. "Starting around
1995," he continues, "the incidence rate has fallen dramatically.
And mortality from prostate cancer, which had been increasing for
the past 30 years, began to plateau."
Since then, there has been a seven to eight percent drop in the
overall mortality rate and a 12 to 15 percent decline in the most
favorable subpopulation, young white males. "Around Mayo Clinic,"
Dr. Catalona adds, "where screening is very prevalent, there has
been about a 20 percent drop."
Authors of an epidemiological analysis concluded that PSA screening
is at least partly responsible for a decline in incidence and mortality
trends for prostate cancer in the United States. The investigators
concluded: "The decline in IBM [incidence-based mortality] for distant
stage disease and flat IBM trends for localized/regional disease
provide some evidence of improved prognosis for screen-detected
cases, although alternative interpretations are possible" (J
Natl Cancer Inst. 1999; 91:1025-1032).
"I think the mortality rates have come down a bit quicker than
I would expect based on PSA testing alone," Dr. Catalona says. "It
takes seven to eight years for prostate cancer to kill a man. So
if somebody came up with a perfect test and a perfect treatment
today, we wouldn’t begin to see those effects for seven to eight
years." Also contributing to the decline in mortality from prostate
cancer, he believes, have been an improvement in surgical techniques
and a five- to six-fold increase in the use of radical prostatectomy
beginning in the early ’90s, about the same time PSA screening was
Rigorously proving the value of radical prostatectomy remains
important because of the high incidence of serious side effects
from this surgery. At 18 months post-surgery for clinically localized
disease, impotence was reported by 65.6 percent of men who had conventional
surgery and 56 percent of those with nerve-sparing procedures. Incontinence
was reported by 8.4 percent of the subjects (JAMA. 2000;283:354-360).
Dr. Catalona concedes that this is "a live issue."
"This debate has been likened to the evangelist versus the snail,"
says Dr. Slawin. "Evangelists are people who feel that screening
should be performed, and snails expect to see clear evidence of
reduced mortality before recommending it."
He notes that the recommendations of the U.S. Public Health Service
Preventive Task Force (2nd ed., 1995) do not endorse PSA screening
but that the American Cancer Society recommends that DRE and PSA
be offered beginning at age 50 to all men with at least a 10-year
Two ongoing developments may augment the clinical value of PSA
screening. One is the possibility of adding a marker called human
kallikrein 2 (hK2) to the screening sequence. Employing neural networks
for risk assessment is the second innovation. Using these computer
algorithms to integrate all risk factors is equivalent to doing
a multiple regression analysis on each patient. "In some preliminary
work that I have done with two separate companies that are developing
neural networks for this purpose," Dr. Catalona says, "when you
throw in the free PSA, it adds substantial value."
In addition, Dr. Slawin is working on an isoform of PSA that is
specific for benign prostate disease, called BPSA (Urology.
2000;55(1):41-45). "It appears when you include BPSA with total
and free PSA, you get even better differentiation between BPH and
prostate cancer," he says. "So as we get newer markers, we will
improve on performance."
William Check is a freelance medical writer in Wilmette, Ill.