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Prostate-Specific Antigen: What’s New in 1997

Prostate-Specific Antigen: What’s New in 1997

ABSTRACT: When used alone, prostate-specific antigen (PSA) is not sufficiently sensitive or specific to consider it an ideal tool for the early detection or staging of prostate cancer. To optimize the use of PSA, the concepts of PSA velocity, PSA density, and age-related PSA values were developed. Although PSA velocity provides excellent results, its determination requires three PSA values over a 2-year period. The value of PSA density rests on the accurate determination of prostatic volume by transurethral ultrasound (TRUS), which is examiner-dependent. Age-specific reference ranges appear to be more sensitive in men under age 60 than in those over 60. The molecular forms of PSA, especially the percentage of free PSA, seem to be useful tools for the detection of prostate cancer in men with slightly elevated total PSA. New molecular techniques, such as the reverse transcriptase-polymerase chain reaction (RT-PCR), enable the detection of minimal amounts of PSA messenger RNA (mRNA). Human kallikrein 2 (hK2), a serine protease closely related to PSA that also is expressed predominantly in the prostate, may be a new marker for prostate cancer. [ONCOLOGY 11(9)1273-1282, 1997]

Introduction

Prostate-specific antigen (PSA) is the most important tumor marker available
today for the early
detection, staging, and monitoring of men with prostate cancer.[1] This
serine protease was first identified in seminal fluid in 1971.[2] Although
minimal immunoreactivity against PSA antibodies can be detected in breast
cyst fluid, salivary glands, ductal cells of the pancreas, and endometrium,
PSA is organ-specific for all clinical purposes. However, PSA is not cancer-specific;
it is produced by nonmalignant as well as malignant prostatic epithelium.[3]
Therefore, there is a substantial overlap in PSA levels between men with
benign prostatic hyperplasia (BPH) and those with prostate cancer.[4]

When used alone, PSA is not sufficiently sensitive or specific to consider
it an ideal tool for the early detection[5] or staging of prostate cancer.[6]
In order to optimize the use of PSA, the concepts of PSA velocity,[7] PSA
density,[8] and age-related PSA values[9] have been established. Most recently,
the measurement of different molecular forms of PSA,[10] especially the
ratio of unbound, or "free," PSA to total PSA, was introduced.
Also, advances in molecular techniques, such as the reverse transcriptase-polymerase
chain reaction (RT-PCR), enable the detection of minimal amounts of PSA
messenger RNA (mRNA).[11]

Prostate-specific antigen, also known as human kallikrein 3 (hK3), is
a member of the kallikrein family. The availability of a monoclonal antibody
against human kallikrein 2 (hK2), an other member of this family that is
also expressed predominantly in the prostate, may be the first step toward
the development of a new marker for prostate cancer.[12]

This review will focus on these new developments and their use in clinical
practice.

Total PSA

The PSA assays in clinical use since 1987 detect both the complexed
and noncomplexed forms of PSA. Today, PSA assays are available that selectively
detect unbound PSA (free PSA) or PSA complexed to alpha-1-antichymo-trypsin
(bound PSA).[10] The sum of all measurable complexed (bound) and uncomplexed
(free) forms of PSA is referred to as "total PSA."

In 1996 alone, nearly 42,000 men in the United States will die from
prostate cancer.[13] A method for the early detection of men with prostate
cancer is urgently required. Early studies using total PSA for the detection
of prostate cancer suggested that, due to theoverlap in serum PSA levels
between men with BPH and prostate cancer, PSA would not be useful in prostate
cancer detection.[14] Since then, however, many studies have shown that
PSA is a valuable tool for the detection of men with prostate cancer,[15]
and recent data indicate that by using PSA screening for the early detection
of prostate cancer, men with organ-confined disease can be better identified.[16]

Screening for prostate cancer remains controversial, however. Currently,
only 60% of newly detected prostate cancers are organ-confined, and thus,
potentially curable.[13] An effective screening method should have high
sensitivity and specificity for the discrimination between malignant and
benign disease.

The use of PSA levels alone for screening is compromised by the varying
amount of PSA produced by benign prostatic tissue. Thus, this screening
test has a positive predictive value of only 47%.[17] Several studies have
demonstrated that PSA is a useful addition to transrectal ultrasound (TRUS)
and digital rectal examination (DRE) and can increase the overall detection
rates for prostate cancer among screening populations.[18-20] On the other
hand, 35% of men with organ-confined prostate cancer present with PSA levels
less than 4 ng/mL, and 38% of men treated with radical prostatectomy present
with a palpable lesion.[6]

These data underline the fact that PSA alone is not a perfect marker
for prostate cancer screening. However, the combination of PSA, DRE, and
TRUS is more effective in detecting prostate cancers.[18] A recent decline
in prostate cancer death rates has been noted in the United States—the
first time that this has occurred.[13] These statistics suggest that screening
with this combination of tests improves survival in men with prostate cancer.
Nevertheless, there is marked controversy over whether or not to screen
for prostate cancer.[21]

A National Cancer Institute (NCI) randomized trial to resolve this controversy
has been initiated but will take several years to be completed. It is unreasonable
to restrain from using PSA until a definitive answer is available. The
combination of DRE and PSA determination remains the most thorough, cost-effective
method for the detection of early prostate cancer. It should be noted,
however, that screening is reasonable only if effective treatment options
exist for the early detected disease. Today, radical prostatectomy and
radiation therapy for men with localized prostate cancer are the established
forms of definitive therapy for prostate cancer.

Concepts for Improving PSA Specificity
and Sensitivity

In order to improve the specificity and sensitivity of PSA for the detection
of men with prostate cancer, three different concepts were introduced:
PSA density, PSA velocity, and age-specific PSA reference ranges.

PSA Density

Based on the observation that malignant prostatic tissue leads to a
tenfold higher rise in PSA levels compared to an equal volume of benign
tissue,[14,22] Benson and associates determined the ratio between serum
PSA and prostatic volume assessed by TRUS, a parameter which they termed
"PSA density."[23] Seaman et al were the first to compare the
value of serum PSA levels and PSA density in detecting prostate cancer,
with histologic confirmation of the results.[8] Using a PSA density of
0.15 as a threshold, they demonstrated the increased utility of PSA density
for detecting prostate cancer in patients with serum PSA levels between
4.0 and 10.0 ng/mL.

Since then, conflicting results have been published.[24-27] Brawer et
al reported that PSA density was not superior to serum PSA alone in distinguishing
men with BPH from men with prostate cancer,[24] whereas Wolff et al found
that the use of PSA density helped discriminate between men with prostate
cancer and men with BPH.[25] Ohori and coworkers described the utility
of PSA density in only a small subset of patients with an elevated serum
PSA (more than 10 ng/mL).[26] Finally, Catalona et al, presenting the results
of a multicenter trial of nearly 5,000 men, determined that the use of
PSA density with a cut-off of 0.15 could have missed nearly 50% of the
prostate cancers.[27] The differences between these studies can be explained,
at least partially, by the fact that the determination of prostatic volume
by TRUS is examiner-dependent and often subjective.

In summary, the value of PSA density seems to be restricted to patients
with intermediate PSA levels (4.0 to 10.0 ng/mL). In this subgroup, it
is helpful in identifying patients who are at a low risk of having prostate
cancer.[28]

PSA Velocity

Carter and coworkers demonstrated that the rate of change in PSA over
time, or PSA velocity, was more useful than PSA alone in distinguishing
between men with and without prostate cancer.[7] In their study of 54 men
followed for an average of 17 years in the Baltimore Longitudinal Study
of Aging, differences in PSA velocity between BPH and prostate cancer patients
were detectable up to 9 years before the diagnosis of prostate cancer was
made. Carter et al suggested a cut-off value of 0.75 ng/mL/yr. Oesterling
et al[29] and Smith and Catalona[30] confirmed a cut-off point of 0.8 ng/mL/yr
for PSA velocity.

In a study aimed at determining the optimal time interval between the
serum samples and the optimal number of samples for calculation of PSA
velocity, Carter et al found an inverse relationship between PSA velocity
and PSA sampling interval.[31] They recommended using three consecutive
measurements obtained over 2 years rather than over a short-term period
(3 to 6 months).[31]

Kadmon et al demonstrated that, over a 2-year follow-up period, 12.5%
of 265 men without prostate cancer had a PSA increase higher than 0.75
ng/mL/yr. Thus, they recommended an observation period of at least 2 years
before using PSA velocity to make clinical decisions.[32]

In summary, PSA velocity increases the predictive value for the detection
of prostate cancer, as compared with PSA level alone. However, follow-up
of at least 2 years is required before therapeutic decisions can be made.

Age-Specific PSA Levels

The normal PSA reference range of 0.0 to 4.0 ng/mL does not account
for age-dependent prostatic growth and variations in PSA secretion and
production.[33] Oesterling et al assumed that a PSA level of 5.5 ng/mL
had a different significance in a 75-year-old man than in a 51-year-old
man. Thus, in a prospective study, they evaluated men without evidence
of prostate cancer and determined age-specific reference ranges for PSA.[9]
Compared to the standard PSA reference range, age-specific PSA was a more
sensitive tumor marker in men younger than 60 years and a more specific
marker in men older then 60 years.

Partin and coworkers demonstrated that, in younger men, the use of age-specific
reference ranges detected more potentially curable prostate tumors with
favorable pathology. The tumors missed in older men by age-specific PSA
ranges also had a favorable pathology in 95%.[34] According to Partin et
al, if urologists want to maintain sensitivity for the detection of nonpalpable
cancers in men over age 60 years, they may use the standard PSA reference
range.

In contrast, based on an analysis of 6,630 men participating in a PSA
early detection study, Catalona and associates concluded that a PSA cut-off
of 4.0 ng/mL was superior to all other cut-off values for all age groups.[35]
Their study demonstrated that the number of biopsies could be decreased
in older men.

Morgan et al showed that the use of age-specific reference ranges for
PSA are different in Caucasian and black men. In their study, 41% of the
prostate cancers detected in a group of 411 black men would have been missed
if the traditional reference ranges had been used.[36] To maintain a 95%
sensitivity among black men, the age-specific reference ranges have to
be higher than in corresponding groups of white men.[36]

DeAntoni and coworkers determined race-specific reference rates for
white, Latino, black, and Asian men.[37] The higher upper limits of race-specific
reference ranges for black men, for example, are due to a greater PSA variance.
The higher reference range would raise the cut-off level of PSA
in black men, however, thus making the test less sensitive.

In summary, the use of age-specific reference ranges seems to be clinically
useful at least for patients younger than 60 years. The clinical significance
of race-specific PSA reference ranges remains to be determined.

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