The role of prostate specific antigen measurement in the detection and

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Endocrine-Related Cancer (2000) 7 37–51
The role of prostate specific antigen
measurement in the detection and
management of prostate cancer
A F Nash and I Melezinek
Medical Research Department, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
(Requests for offprints should be addressed to A F Nash)
Abstract
The introduction of prostate specific antigen (PSA) testing has revolutionised the early detection,
management and follow-up of patients with prostate cancer and it is considered to be one of the
best biochemical markers currently available in the field of oncology. Its use with annual digital
rectal examination in prostate cancer screening programmes has led to a marked change in the
distribution of stage at presentation towards earlier disease and has led to a significant increase
in the detection of potentially curable disease. In order to improve the specificity of PSA testing
and thereby reduce the number of unnecessary prostatic biopsies, a number of refinements of
PSA evaluation have been proposed. These include free to total PSA ratio, PSA density, PSA
density of the transition zone, PSA velocity and age-specific PSA reference ranges. The utility of
these approaches is considered in this review. The role of PSA monitoring in the detection of
recurrence following radical prostatectomy and radiotherapy is discussed, as well as its role in
monitoring patients treated with endocrine therapy in terms of correlating PSA response with
outcome, in detecting disease progression and in guiding the use of subsequent therapies. Large
continuing multicentre screening and outcome studies will provide important information enabling
greater refinement of the use of this important diagnostic and monitoring tool in the future detection
and management of prostate cancer.
Endocrine-Related Cancer (2000) 7 37–51
Introduction
Physiology and metabolism of PSA
Prostate cancer represents a major global public health issue
resulting in significant morbidity and mortality. The American Cancer Society predicted that in 1997 approximately
209 000 men would be diagnosed with prostate cancer and
approximately 42 000 men would die from the disease
(Wingo et al. 1997). The disease is now the second commonest cause of cancer-related death in men (Boring et al. 1994)
and its incidence continues to rise in most regions of the
world. Indeed, it is estimated that by the year 2000 the
number of cases diagnosed worldwide will be approximately
500 000 (Boyle 1994). Widespread testing of serum prostate
specific antigen (PSA) has been available for little more than
a decade and in this short space of time has almost certainly
contributed to the increased detection of prostate cancer
observed. In addition, it has rapidly found a place in the routine follow-up of patients treated with radical therapies and
endocrine therapy and has superseded the use of serum prostatic acid phosphatase as a disease marker.
PSA is a 33 kDa single chain glycoprotein first identified in
seminal plasma in 1971 by Hara et al. and subsequently isolated from prostatic tissue in 1979 by Wang et al.; it is a
serine protease (Lilja 1985, Watt et al. 1986) with extensive
structural similarity to the glandular kallikreins (Watt et al.
1986, Lundwall & Lilja 1987, Schaller et al. 1987). It is
produced by prostatic secretory epithelium and is one of the
most abundant proteins in seminal plasma where it is found
in concentrations of 0.2–5.0 mg/ml (Sensabaugh 1978). This
level is approximately a million-fold higher than in serum,
where the normal range is 0.1–4 ng/ml. In addition to the
prostate, PSA production has been detected at very low levels
in periurethral glands (Frazier et al. 1992, Takayama et al.
1994) and, using ultrasensitive assays, very low levels of
PSA have been detected in women (Yu et al. 1995, Ellis et
al. 1997). PSA contributes to the process of liquefaction of
semen through hydrolysis of semenogelin (Schellhammer &
Wright 1993).
Endocrine-Related Cancer (2000) 7 37–51
1351-0088/00/007–037  2000 Society for Endocrinology Printed in Great Britain
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Nash and Melezinek: PSA in the detection and management of prostate cancer
PSA is predominantly found in serum in 3 different
molecular forms: (a) free PSA, molecular mass 30 kDa, (b)
bound to alpha-2-macroglobulin (A2M-PSA), molecular
mass 780 kDa or (c) bound to alpha-anti-chymotrypsin
(ACT-PSA), molecular mass 90 kDa (Christensson et al.
1990, Lilja et al. 1991). Both A2M and ACT are extracellular
protease inhibitors synthesised by the liver and are present in
104–105 molar excess to PSA in serum. PSA is also bound in
trace amounts to alpha-1-antitrypsin and interalpha trypsin
inhibitor (Lilja 1993, McCormack et al. 1995) but these
forms are not thought to be of clinical relevance. Complex
formation with alpha-1-antichymotrypsin results in exposure
of a limited number of the antigenic epitopes of PSA,
whereas complex formation with alpha-2-macroglobulin
encapsulates the currently identifiable antigenic epitopes of
PSA. As such, ACT-PSA can be detected by PSA assays
whereas A2M-PSA cannot (Christensson et al. 1990). ACTPSA is the predominant immunoreactive form in serum,
whereas free PSA, which constitutes 5–30% of immunoreactive PSA, is believed to be inactive (Lilja et al. 1991,
Stenman et al. 1991). The clinical relevance of free PSA,
complexed PSA and the ratios of these to total PSA is discussed further in this review.
The metabolism of PSA is not fully understood. Free
PSA has a relatively low molecular weight and it is likely
that it is eliminated by renal clearance. Following radical
prostatectomy, the elimination of free PSA is consistent with
a two compartment model with an initial half-life of approximately 2–3 h for the first 4 h after removal of the gland,
followed by a half life of approximately 20–25 h thereafter
(Partin et al. 1993). By contrast, ACT-PSA has a half-life of
2–3 days in blood (Stamey et al. 1993, Oesterling et al.
1995), and the liver appears to be the most likely site of its
metabolism (Agha et al. 1996).
Role of PSA in the screening and
detection of prostate cancer
Incidence of prostate cancer
A considerable increase in the incidence of disease was noted
following the introduction of screening, reaching an ageadjusted maximum of approximately 4 per 100 000 in white
men in 1992 and 6 per 100 000 in African Americans in
1993. These peaks are followed by a decline in the incidence
up until the end of 1994 when data were last available. This
profile is consistent with what would be expected from a
successful screening programme, where the increase in incidence reflects detection of previously undiagnosed asymptomatic cases, followed by a fall in incidence towards what
is likely to represent the true underlying incidence of the
disease.
Age at diagnosis
Age at diagnosis of prostate cancer has fallen since the introduction of PSA screening. Prior to PSA screening the mean
age at diagnosis was 72.0 years for whites and 70.1 years for
African Americans; this fell to 69.2 and 67.3 years respectively following the introduction of screening.
Population-specific issues
Stage of disease at presentation
The American Urological Association and the American
Cancer Society recommend screening for all men over the
age of 50 with annual digital rectal examinations and assessment of PSA (Von Eschenbach et al. 1997). Elsewhere in
the world, however, population screening for prostate cancer
is not available and this difference reflects continuing debate
about the value and cost effectiveness of prostate cancer
screening. Prostate cancer is a heterogeneous disease which
at one extreme can be a highly aggressive malignant disease
likely to kill the patient and at the other extreme a benign
incidental finding that will not lead to morbidity or mortality.
Indeed, histological evidence of prostatic carcinoma can be
found in 30–40% of men aged >50 years (Scardino et al.
1992) and more men die with prostate cancer rather than
The majority of new cases diagnosed since the advent of PSA
screening have been organ-confined disease, both in whites
and in African Americans. There has also been an increase
in the number of patients with locally advanced disease,
whereas the incidence of distant metastatic disease has
declined in both races.
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because of it. The objective of prostate cancer screening is
to identify patients with prostate cancer for whom intervention will prevent premature death from the disease and as
such an effective screening programme should reduce disease-specific mortality. Information on this key issue has
been provided by the Surveillance, Epidemiology and End
Results (SEER) programme. This was set up in 1973 by the
National Cancer Institute in order to collect cancer incidence,
treatment and survival data in 11 regions across the United
States, covering approximately 14% of the US population.
Since the introduction of PSA screening in the US in the late
1980s the following trends in incidence, age at presentation,
tumour characteristics and mortality have been observed
(Farkas et al. 1998).
Tumour grade
The majority of cases diagnosed following the introduction
of PSA screening have moderately well-differentiated disease and this is true for both races. There has also been an
increase in poorly differentiated disease detected in African
Americans but not in the white population.
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Endocrine-Related Cancer (2000) 7 37–51
The increased detection of patients with organ-confined
moderately differentiated disease is encouraging since these
patients are likely to have clinically significant disease which
is potentially amenable to cure (Humphrey et al. 1996,
Farkas et al. 1998). Indeed, it has been estimated that
between 22 000 and 29 000 of such cases per annum in the
US have been detected since the advent of prostate cancer
screening (Farkas et al. 1998).
Disease-specific mortality
The overall age-adjusted mortality rate peaked in 1991 and
a 6.7% decline was observed by 1995, representing a decline
of approximately 1.8 deaths per 100 000 men per year
(Hoeksema & Law 1996). Whether cancer screening per se
has led to this reduction in cancer-specific mortality is
unknown. Interpretation of cancer survival data is hampered
by two forms of bias namely ‘lead time bias’ and ‘length
time bias’. Lead time bias refers to the situation where survival is apparently prolonged because the diagnosis was
made earlier, rather than because death was delayed. Length
time bias refers to the situation whereby PSA screening may
identify slower growing tumours and hence apparent survival
is longer due to the detection of these slower growing
tumours. Another important factor which may have had a
bearing on the reduction of prostate cancer death is the
change in clinical practice with respect to the management
of organ-confined disease that has taken place over the last
twenty years. In 1974, 9.2% of all prostate cancer patients in
the US were treated by radical prostatectomy whereas by
1993 this proportion had increased to 29.2% (Mettlin et al.
1997).
The first randomised trial to assess the benefits of prostate cancer screening was conducted in Quebec and included
over 46 000 men (Labrie et al. 1999). The group sizes were
unequal, as only 23% of men randomised to be screened did
in fact undergo screening. Of the 8137 men screened, 5 subjects died of prostate cancer compared with 137 of 38 056
men who did not undergo screening. The prostate cancer
death rates during the eight-year period were 48.7 and 15 per
100 000 man-years in the unscreened and screened groups
respectively, which constitutes a 3.25 odds ratio in favour of
screening and early treatment (P = <0.01). The methods of
analysis and resulting conclusions from this study have been
the subject of considerable debate (Alexander & Prescott
1999, Boer & Schroder 1999, Labrie & Candas 1999a,b).
There are two further current randomised trials which will
provide additional information on the value of prostate
cancer screening, the Prostate Lung Colorectal and Ovarian
(PLCO) trial of the National Cancer Institute (Gohagan et al.
1994) and the European Randomised Study of Screening for
Prostate Cancer (ERSPC, Schröder et al. 1999); results are,
however, not expected before 2005.
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In summary, the introduction of screening for prostate
cancer with annual PSA measurement and digital rectal examination has led to an increase in the detection of potentially
curable cancers. The recent fall in cancer-specific mortality is
encouraging although the extent to which different forms of
bias and changes in clinical practice have affected this observation is unknown. Continued follow-up of population statistics
and the results of the continuing randomised screening studies
will be needed to confirm that prostate cancer screening does
indeed reduce cancer-specific mortality.
PSA screening – patient-specific issues
PSA is a protein that is expressed in the normal prostate
gland and the normal range is taken as 0–4 ng/ml. Elevated
levels of PSA are found in patients with a range of prostatic
diseases including cancer, benign hypertrophy, prostatitis and
prostatic infarction (Papsidero et al. 1980). Studies have
indicated that approximately 80% of patients with proven
prostate cancer and 30% of patients with benign prostatic
hypertrophy have serum PSA concentrations above 4 ng/ml
(Stamey et al. 1987, Catalona et al. 1991, 1994a). Elevated
serum PSA levels have also been found following ejaculation
in some studies (Moyad et al. 1994, Tchetgen et al. 1996,
Herschman et al. 1997) although Netto et al. (1996) found
no such association. In addition, surgical instrumentation has
also been associated with elevated serum PSA levels (Yuan
et al. 1992). In view of these confounding factors, the serum
PSA test for detection of prostate cancer is less sensitive and
less specific than is desirable; indeed, with a PSA cut-off of
4–10 ng/ml, only one in four men will have cancer detected
on sextant biopsy. In a screening trial involving 6630 men,
the positive predictive value of the PSA test increased from
approximately 10% in men with a PSA <4 ng/ml, to greater
than 80% in men with a PSA >20 ng/ml (Catalona et al.
1994a). In this study, most patients with mildly elevated PSA
levels had organ-confined disease but over a half with PSA
values greater than 10 ng/ml had advanced disease, hence the
detection of organ-confined and therefore potentially curable
prostate cancer requires low PSA cut-off points for screening. Regrettably, the specificity of the test at such low concentrations is relatively poor, necessitating high levels of
unnecessary biopsies. In order to increase the specificity of
PSA testing whilst retaining high sensitivity, particularly in
the diagnostic grey zone of 2.5–10 ng/ml, a number of
refinements of PSA evaluation have been proposed, including
the measurement of the free/total PSA ratio, PSA density,
PSA velocity and the use of age-specific PSA reference
ranges. These are discussed further below.
Free/total PSA ratio
The ratio of ACT-PSA/total PSA was first observed to be
higher in patients with prostate cancer than benign prostatic
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hypertrophy by Stenman et al. (1991), although the accuracy
of free PSA assays in comparison with assays of the ACTPSA complex suggests that better discrimination is obtained
by using the free to total PSA ratio instead of the complexed
to total PSA ratio (Christensson et al. 1993, Pettersson et al.
1995). The reason for this finding is unknown although it
may be related, in part, to local production of ACT by prostate cancer cells, but not by benign prostatic hypertrophy
(BPH) cells, which then complexes with PSA at the point of
secretion (Bjork et al. 1994).
Several studies have investigated the utility of assessing
the free to total PSA ratio in the detection of prostate cancer.
These have generally shown that it is a useful test to discriminate between prostate cancer and benign prostatic hypertrophy, the ratio being lower in prostate cancer and higher in
benign prostatic hypertrophy (Catalona et al. 1995, Partin et
al. 1996a, Chen et al. 1996, Prestigiacomo et al. 1996). Consideration should also be given to the possibility of underlying asymptomatic chronic prostatitis in which a reduced free
to total PSA ratio has also been observed (Jung et al. 1998).
A number of cut-offs have been applied in studies of free to
total PSA ratios ranging from 14%–28% in order to maintain
a sensitivity of at least 90%, and these have resulted in specificities ranging from 19%–64%, i.e. using specific cut-off
points in these studies to determine whether or not to perform
a biopsy would prevent 19%–64% of the negative biopsies
for cancer.
Variations in outcome across studies may be accounted
for by differences in study designs and subject populations,
and an excellent review of this topic was written by
Woodrum and colleagues (1998). Some of the key factors
which influence the results and conclusions of clinical studies
of the free to total PSA ratio include the following.
Age
Mean total and free PSA have been shown to increase with
age (Luderer et al. 1995) and in one study the percentage
free PSA increased with age (Partin et al. 1996a) although
this was not confirmed by Oesterling et al. (1995).
Total PSA
The probability of being diagnosed with cancer and having
advanced cancer increases with increasing total PSA levels
(Catalona et al. 1993, 1994a). Moreover, the positive predictive value (PPV) of total PSA in the detection of cancer also
increases such that at total PSA values in excess of 10–20
ng/ml the PPV is up to 80%. As such, the free to total PSA
ratio provides little useful additional information compared
with total PSA over this range but has shown usefulness over
the range 2.5–10 ng/ml.
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Prostate volume
Prostate volume influences the selection of an appropriate
cut-off value (Catalona et al. 1995, Partin et al. 1996a, Van
Cangh et al. 1996), such that increasing prostatic volume is
associated with increased mean percentage free PSA. The
proportion of small and large glands in the study population
will, therefore, affect the selection of cut-offs and the associated sensitivity and specificity associated with these cut-offs.
Other factors of relevance include, but are not limited to,
race, biopsy history, digital rectal examination findings and
the assay method used.
Large multicentre trials that take these various factors
into account will be needed to provide more reliable assayspecific cut-off points and probability determinations to
improve the ability of the free to total PSA ratio to discriminate between prostate cancer and benign prostatic hypertrophy.
PSA density
The concept of using PSA density, calculated from total PSA
and prostate volume, to differentiate between prostate cancer
and benign prostatic hypertrophy was first raised by Benson
and colleagues in 1992. The basis for using this approach
lies in the fact that unmolested benign epithelial cells in continuity with prostatic ducts will not leak as much PSA into
the serum as a cancer cell, which is not part of a duct to act
as a conduit for secretions. In addition, the concept supposes
that the concentration of PSA per benign cell shows less variability than that seen in cancer cells. Therefore, for any given
prostate volume there should be a limit to the number of
prostate cells that can be accommodated and consequently an
upper limit to serum PSA of benign origin. Once this level
is passed, it is assumed that the gland is occupied by cancer
cells. In a study of 61 patients with prostate disease clinically
confined to the prostate gland, PSA density assessed using
either magnetic resonance imaging of BPH or the dimensions
of the surgical specimen was higher in patients with cancer
than those with BPH, 0.581 vs 0.044 respectively; 41 patients
had prostate cancer and 20 had BPH. Of 34 patients with a
PSA density of >0.1, 33 had prostate cancer. The ability of
PSA density to predict cancer was less useful between 0.05
and 0.15 where 6 patients had cancer and 5 had BPH. Moreover, 2 patients with cancer had values less than 0.05
(Benson et al. 1992).
A cut-off of 0.15 has been advocated as useful in discriminating between prostate cancer and BPH (Bazinet et al.
1994, Keetch et al. 1996), although some studies have shown
no benefit in using this approach (Brawer et al. 1993, Catalona
et al. 1994b). Indeed, in a study of nearly 5000 men, the use
of a PSA density >0.15 to detect early prostate cancer
increased specificity but at the cost of missing half of the
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Endocrine-Related Cancer (2000) 7 37–51
tumours (Catalona et al. 1994b). Accurate estimation of prostate volume was found to be difficult such that a correlation
coefficient of only 0.61 for estimated transrectal ultrasound
volume versus pathological prostate weight was observed.
The authors concluded that for men with a PSA level of
4.1–9.9 ng/ml and normal digital rectal examination and
transrectal ultrasound findings, the decision to biopsy should
be based upon serum PSA rather than PSA density.
A further refinement of the use of PSA density assessments involves the use of transition zone prostate PSA density. The concept derives from the observation that in the
benign prostate most PSA leaking into the serum comes from
the transition zone (Hammerer et al. 1995). BPH results from
hyperplasia of the transition zone and, therefore, peripheral
gland production of PSA is relatively constant as the gland
enlarges due to BPH (Lepor et al. 1994, Hammerer et al.
1995). Above a PSA transition zone cut-off value, it becomes
unlikely that BPH accounts for the increase in PSA and,
therefore, prostate cancer should be suspected. A cut-off of
0.35 ng/ml has been proposed for discriminating between
patients with cancer or BPH (Creasy et al. 1997, Zlotta et al.
1997). A number of studies have shown that transition zone
PSA density enhances the prediction of prostate cancer in
men with a serum PSA of 4–10 ng/ml (Kurita et al. 1996,
Creasy et al. 1997, Horninger et al. 1997, Zlotta et al. 1997).
Djavan et al. (1998) reported that the use of a lower transition zone PSA density cut-off of 0.25 enhanced the specificity of serum PSA for prostate cancer detection in referred
patients with a serum PSA of 4–10 ng/ml, and was more
useful than PSA density of the whole prostate, percentage
free PSA and PSA velocity, but only when the gland volume
exceeded 30 ml. Using a 95% sensitivity for prostate cancer
detection, 47% of unnecessary biopsies would have been
avoided using PSA transition zone density compared with
32% for the free to total PSA ratio.
In view of the fact that PSA transition zone density may
be unhelpful in patients with small prostates, the use of this
technique is likely to be of limited value in screening populations in which prostate gland sizes are anticipated to be
small. The technique may have more value in patients with
lower urinary tract symptoms, a serum PSA of 4–10 ng/ml
and a prostate larger than 30 ml.
As with PSA density of the whole gland, the technique is
limited by the cost and invasiveness of transrectal ultrasound
assessments and concerns over the reproducibility of measurements. Moreover, some clinicians believe that if patients
are already undergoing transrectal ultrasound measurements,
there is little additional morbidity involved in performing
biopsies at the same time.
Overall, PSA density assessments either of the whole
gland or of the transition zone have shown promise in
enhancing the ability to discriminate between cancer and
BPH. To date their use has not, however, been widely
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adopted by the urological community and further studies are
needed to define their potential place in clinical practice.
PSA velocity
The use of PSA velocity to distinguish between men with
and without prostate cancer was first proposed by Carter et
al. (1992). In a retrospective study they observed that the rate
of increase in PSA rise was higher in patients with prostate
cancer than those with BPH. A high PSA velocity, as defined
by greater than 0.75 ng/ml per year, was observed in patients
with prostate cancer for up to 9 years before the disease was
clinically apparent (Carter et al. 1992). Application of this
technique is limited, however, by the intrinsic biological variability of PSA testing and by the need to maintain the same
assay manufacturer (Smith & Catalona 1994, Kadmon et al.
1996). In one study, 12.5% of men had a single annual PSA
increase of greater than 0.75 ng/ml per year; however when
the entire observation period of 2 years was considered, only
one individual had a persistent PSA increase of greater than
0.75 ng/ml per year (Kadmon et al. 1996). In view of this, it
is prudent to measure PSA on at least 3 separate occasions
over a period of at least 18 months. Overall, PSA velocity
may be of most use in patients whose serum PSA is in the
normal range at initial screening, but it is less helpful in
determining whether patients with a PSA between 4–10 ng/
ml should be biopsied.
Age-specific reference ranges
A direct correlation between serum PSA and patient age has
been reported by a number of investigators (Collins et al.
1993, Oesterling et al. 1993). Oesterling et al. (1993) showed
that for a 60-year-old man the serum PSA level increases by
approximately 0.04 ng/ml per year, which in their study was
3.2%. Using the 95th percentile to establish the upper limit
of normal for serum PSA, they determined reference ranges
for different age groups (Table 1). Other investigators have
proposed similar age-specific reference ranges (Dalkin et al.
1993, Crawford 1994). Oesterling et al. (1993) hypothesised
that age-specific reference ranges would increase the sensitivity of PSA in the detection of cancer in younger men at a
stage when the disease is potentially amenable to cure with
surgery, whilst detecting fewer cancers in older men who
Table 1 Age-specific PSA reference ranges
Age (years)
PSA range (ng/ml)
40–49
50–59
60–69
70–79
0.0–2.5
0.0–3.5
0.0–4.5
0.0–6.5
Data from Oesterling et al. (1993).
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may have clinically insignificant tumours. However, conflicting data on the utility of age-specific ranges for the detection of cancer have been reported. In a screening study of
1726 men, Bangma et al. (1995) observed that using agespecific PSA reference ranges and digital rectal examination
as indicators for biopsy, a reduction of 37% of biopsies
would have been obtained but with a loss of detected cancers
of 12%. Catalona et al. (1994c) evaluated the use of agespecific reference ranges in a screening study of 6630 men
and observed that in men aged 50–59 a lower cut-off (3.5
ng/ml) would have resulted in a 45% increase in the number
of biopsies being carried out, with a projected 15% increase
in cancer detection. In men aged 70 years or older, the use
of a higher cut-off (6.5 ng/ml) would result in 44% fewer
biopsies being carried out but would miss 47% of the organconfined cancers. They concluded that a serum PSA of 4 ng/
ml should be used as a general guideline for biopsy in all
age groups. By contrast, in a study by Oesterling et al.
(1995), 5.5% of 1686 biopsies would have been avoided by
the use of age-specific ranges with only 0.6% of tumours not
being detected, the majority of which were unlikely to be
clinically relevant, a finding confirmed in a study by Partin
et al. (1996b). Given the conflicting data on the value of
age-specific reference ranges and the concern that their use
could lead to an increase in unnecessary biopsies in younger
men whilst in older men delaying the diagnosis of potentially
curable disease, their use in clinical practice remains controversial.
Finasteride
Finasteride is a 5-alpha reductase inhibitor for use in the
management of benign prostatic hypertrophy. It reduces the
production of dihydrotestosterone leading to prostate gland
shrinkage, and reduces serum PSA levels by approximately
50% (Gormley et al. 1992). Studies have indicated that in
men treated with finasteride, doubling the PSA and using
normal ranges for untreated men preserves the usefulness of
PSA in the detection of prostate cancer (Oesterling et al.
1997, Andriole et al. 1998).
In summary, whilst total PSA remains the gold standard
for prostate cancer detection, the use of a number of refinements of PSA evaluation, in particular the free to total PSA
ratio may provide additional useful information in particular
subgroups of patients. Further studies will be needed, however, to define more accurately their potential utility in clinical practice.
Role of PSA monitoring in the
management of prostate cancer
In addition to its use in the detection of prostate cancer,
assessment of PSA is carried out in order to assess patients’
response to primary curative therapies such as surgery or
radiotherapy and to endocrine therapy, and also for the long
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term follow-up of patients to detect the presence of disease
recurrence or progression.
PSA monitoring post-radical prostatectomy
Following radical surgery, a post-operative PSA level of 0.1
ng/ml is generally taken to indicate disease recurrence, either
local disease in the pelvis or distant metastases, and this
biochemical failure predates the onset of clinically evident
disease by months or even years (Stein et al. 1992). The
incidence of biochemical relapse following surgery is influenced by a number of factors such as tumour stage, the presence or absence of positive surgical margins, tumour grade
and pre-treatment PSA. Catalona & Smith (1994) reported
on a series of 925 consecutive men undergoing radical retropubic prostatectomy in which the 5 year probability of
non-progression as defined by PSA recurrence was 78%.
Non-progression correlated with tumour stage; the 5 year
probability of non-progression was 91% for organ-confined
disease, 74% for patients with positive surgical margins or
minimal capsular perforation, 32% if seminal vesicle invasion occurred and virtually zero if lymph node metastases
were evident. With respect to tumour grade, the 5 year probability of non-progression was 89% for well-differentiated
disease, 78% for moderately differentiated disease and 51%
for poorly differentiated disease. For men with a normal
pre-operative PSA and those with a pre-treatment PSA >10
ng/ml, the figures were 95% and 71% respectively. Other
series have demonstrated a 5 and 10 year freedom from biochemical recurrence of 83% and 70% respectively (Partin et
al. 1993) and 69% and 47% respectively (Trapasso et al.
1994). In the latter report, the authors noted that postprostatectomy PSA doubling times were significantly shorter
for patients who ultimately progressed to develop distant
metastases (median 4.3 months) than for those with either
clinically evident local disease recurrence or a PSA elevation
as the sole indicator of recurrence (median 11.7 months). In
a series of 539 men undergoing radical prostatectomy, Pruthi
et al. (1997) observed that the median PSA doubling time
for 80 men whose PSA was initially undetectable and subsequently increased, was 284 days and the median time to
biochemical recurrence was 648 days. The authors suggested
that PSA doubling time and time to recurrence are indicative
of different biological characteristics of recurrent prostate
cancer, with doubling time appearing to reflect the aggressiveness of the original prostate cancer, whereas time to recurrence reflects the extent of residual post-operative disease.
Commercial PSA assays currently available have a sensitivity of approximately 0.1 ng/ml (Chan et al. 1987,
Takayama et al. 1993). Values below this cannot be accurately distinguished from zero and are usually reported as
<0.1 ng/ml. More recently, ultrasensitive PSA assays with
much lower detection limits have been developed. Using an
ultrasensitive chemiluminescent assay, Ellis et al. (1997)
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Endocrine-Related Cancer (2000) 7 37–51
demonstrated that the residual disease detection limit following radical prostatectomy is approximately 30 pg/ml. Below
this cut-off, PSA derived from non-malignant sources can be
detected. In principle, the use of ultrasensitive PSA assays
could facilitate the earlier detection of relapse and enable
earlier therapeutic intervention. Indeed, studies have shown
that earlier detection of relapse can be achieved by monitoring PSA in the range 0.01–0.1 ng/ml (Stamey et al. 1993,
Yu et al. 1995). Moreover, Yu et al. (1997) found that
increases in postoperative serum PSA levels of 0.001–0.1 ng/
ml after radical prostatectomy are associated with clinicopathological features of poor prognosis. It is likely, however,
that at very low levels of PSA, a PSA trend or doubling
time may prove to be more important in detecting persistent
prostate cancer since a very low, detectable yet stable, level
may indicate freedom from disease, whereas a low but rising
PSA may be indicative of treatment failure.
There is now a growing body of evidence which supports
the use of adjuvant endocrine therapy in patients who have
undergone radical prostatectomy. Wirth et al. (1997) reported
on a prospective trial of 365 patients with stage C cancer
treated with radical prostatectomy and randomised to receive
adjuvant therapy with the non-steroidal antiandrogen, flutamide, or no adjuvant therapy. The estimated rate of tumour
recurrence based upon Kaplan-Meier estimates at 4 years was
10% in the adjuvant group compared with 31% in the nonadjuvant group (P = 0.0023). More recently, Messing et al.
(1999) reported the results of a randomised prospective trial
of 98 men with node positive prostate cancer following radical prostatectomy and pelvic lymphadenectomy who were
randomised to receive immediate castration with goserelin or
surgery, or observation followed by hormonal therapy at the
time of disease recurrence/progression. After a median
follow-up of 7.2 years, 13% of men in the early hormonal
therapy group had died compared with 34% in the observation group (P = <0.01), and only 18% of patients in the early
hormonal therapy group had evidence of disease recurrence
compared with 75% in the observation group (P = <0.001).
Large prospective randomised studies to define further the
benefits of endocrine therapy as an adjuvant to radical prostatectomy are under way. In particular, the bicalutamide
(Casodex) early prostate cancer programme of studies in
which monotherapy with the non-steroidal antiandrogen,
bicalutamide (150 mg), is compared with placebo, predominantly in patients receiving radical prostatectomy or radiotherapy, has recruited in excess of 8000 patients worldwide.
Endpoints include clinical progression and survival, and
results are expected early in the next decade. If significant
benefit is demonstrated in these studies, there will be a further impetus to detect earlier those patients who have not
been cured by radical surgery and to introduce adjuvant therapy at an even earlier stage. In this regard, the use of ultrasensitive PSA assays is likely to take on a more prominent
role in the routine follow-up of post-operative patients.
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PSA monitoring post-radiotherapy
Radiotherapy is an alternative radical therapy to prostatectomy for the management of clinically localised disease
and is also employed in the management of locally advanced
disease. Fifteen year outcome studies by the Patterns of Care
Study and the Radiation Therapy Oncology Group (RTOG)
indicated that patients with stage T1 prostate cancer are in
many cases cured by radiotherapy and approximately half of
those with stage T2 cancer are cured (Hanks et al. 1994). Crook
et al. (1997) showed that T stage and pre-treatment PSA are
important predictors of treatment failure. They followed-up
207 patients who underwent external beam radiotherapy with
systematic transrectal ultrasound-guided biopsies and measurement of serum PSA levels. They observed a total failure rate
including biochemical, local and distant failure for different T
stages of 12% for T1b, T1c and T2a, 39% for T2b and T2c, and
68% for T3 and T4 (P = 0.0001). With respect to pre-treatment
PSA, the failure rate increased with increasing PSA such that
for PSA <5 ng/ml only 3% failed, compared with 32% for
values between 10 and 15 ng/ml and 88% for men with a
re-treatment PSA >50 ng/ml. In this study, the post-treatment
PSA nadir proved, however, to be the most predictive factor
for treatment failure, with values less than 0.5 ng/ml generally
indicating cure.
The exact definition of recurrence following radiotherapy
has been the subject of considerable debate and has varied
substantially across studies. Some investigators have defined
recurrence as a PSA rising above the nadir value, without
specifying a specific PSA nadir value (Zagars & Pollock
1995, Stock et al. 1996). Other investigators have proposed
post-radiotherapy PSA nadirs of 0.5 ng/ml (Schellhammer et
al. 1993, Critz et al. 1995, 1997), 1.0 ng/ml (Lee et al. 1996,
Wallner et al. 1996), 1.5 ng/ml (Hanks et al. 1994) and 4.0
ng/ml (Rosenzweig et al. 1995) to define recurrence. Critz et
al. (1997) studied 660 men with clinical stage T1T2N0
prostate cancer who received combination radioactive 125I
prostate implant followed by external-beam radiation, and
followed them up for a median of 42 months. In analysing
the data, recurrence was defined as a PSA level rising above
whatever nadir was achieved. A total of 81% of all men were
calculated to achieve a PSA nadir of 0.5 ng/ml or less and
to have a 5 and 10 year disease-free survival rate of 93% and
83% respectively, as compared with a 5 year disease-free
survival rate of 26% for those achieving a nadir of 0.6–1.0
ng/ml, the difference being statistically significant. All men
with a PSA nadir greater than 1.0 ng/ml ultimately failed
treatment. Based upon these data, the authors recommended
a post-radiotherapy PSA nadir of <0.5 ng/ml to indicate
potential cure and values above this value to indicate treatment failure. In view of the data from Crook et al. (1997)
and Critz et al. (1997) together with a more recent study by
Preston et al. (1999), the value of <0.5 ng/ml would appear
to be a reasonable PSA nadir goal to be achieved following
radiotherapy.
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Nash and Melezinek: PSA in the detection and management of prostate cancer
PSA monitoring of response to and follow-up
with endocrine therapy
The concentration of serum PSA is proportional to the clinical stage of cancer in untreated patients (Stamey et al. 1987).
Following endocrine therapy, for example with medical or
surgical castration or antiandrogens, the androgen stimulus is
withdrawn resulting in apoptosis and consequently a reduction in the number of PSA-secreting cells and a fall in the
serum PSA level. In addition, there is evidence that PSA
expression may be under the influence of androgens and that
androgen deprivation can reduce serum PSA expression independent of an antitumour effect (Stamey et al. 1989, Leo et
al. 1991). The percentage reduction of PSA at 3 months
induced in patients with advanced prostate cancer by medical
or surgical castration is relatively constant across studies,
ranging between 94% and 97% (Kaisary 1994, Chodak et al.
1995, Bales & Chodak 1996, Iversen et al. 1998). In contrast,
the percentage reduction of PSA induced by antiandrogens is
dose-dependent (Kolvenbag et al. 1998).
In studies of the non-steroidal antiandrogen, bicalutamide, after 3 months treatment, dose-dependent reductions in
PSA occur with incremental benefit up to levels seen with
castration (Fig. 1). A tendency for the dose response to plateau when doses exceed 200 mg is consistent with the profile
of the plasma steady-state drug concentration curve, which
is less than linear at doses above 200 mg (Kolvenbag et al.
1998).
Studies comparing bicalutamide 50 mg monotherapy
with castration in more than 1100 patients with metastatic
prostate cancer revealed a lower PSA fall compared with
castration and a lower number of patients with PSA in the
normal range. In turn, a survival deficit of approximately 3
months was observed for the bicalutamide-treated group
compared with castration. A subsequent analysis showed that
the PSA level after 3 months therapy was related to outcome
in terms of time to progression (Blackledge & Lowery 1994).
Further comparative studies of bicalutamide at a dose of
150 mg with castration have been conducted in patients with
metastatic disease and in patients with locally advanced nonmetastatic disease. The PSA fall at 3 months in these studies
was not significantly different for bicalutamide 150 mg compared with castration. In patients with metastatic disease a
shortfall in median survival was again observed but the deficit was only 42 days (Tyrell et al. 1998), whilst in patients
with non-metastatic prostate cancer in an analysis at 31%
overall mortality, bicalutamide demonstrated equivalent
efficacy compared with castration (Iversen et al. 1998).
Casodex has also been studied at a dose of 50 mg as part
of a combined androgen blockade regimen with luteinising
hormone-releasing hormone analogues (Schellhammer et al.
1997, Altwein & Schmidt 1999). The degree of PSA reduction at 3 months was 99%, which is a little higher than has
been seen with castration alone. Altwein & Schmidt (1999)
reported on a study of 312 men with advanced prostate
cancer treated with combined Casodex 50 mg and castration,
and as observed previously by Blackledge & Lowery (1994)
found a significant correlation between the PSA level after
12 weeks treatment with time to progression (P = 0.0001). In
addition, the PSA level at 4 weeks also correlated with time
to progression (P = 0.042).
Figure 1 Median percentage reduction in prostate-specific antigen with bicalutamide
10–600 mg monotherapy and with castration.
44
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Endocrine-Related Cancer (2000) 7 37–51
Whilst some studies have shown statistically significant
benefits for combined androgen blockade over castration
monotherapy (Crawford et al. 1989, Denis et al. 1993,
Janknegt et al. 1996), other studies have been neutral
(Eisenberger et al. 1998). A meta-analysis of 22 studies comparing combined androgen blockade with castration monotherapy demonstrated a small but non-significant benefit in
favour of combined androgen blockade (3.5% in 5 year
survival) (Prostate Cancer Trialist Collaborative Group
1995). Other meta-analyses have shown a statistically significant benefit for combined androgen blockade compared
with castration monotherapy (Debruyne et al. 1996, Klotz &
Newman 1996). It is possible, therefore, that the additional
PSA response with combined androgen blockade therapy
compared with castration is a surrogate for additional efficacy, although this is controversial.
Overall, these studies of androgen deprivation with antiandrogen or castration monotherapy and with combination
therapy lend support to the hypothesis that the degree of PSA
fall in patients treated with endocrine therapy correlates with
outcome in terms of time to progression and survival.
The response rate of prostate cancer to endocrine therapy
generally exceeds 70%. However, within 12–18 months
almost all patients with advanced disease develop androgen
independence (Lu et al. 1997), generally preceded by an
increase in serum PSA (Miller et al. 1992). The exact mechanisms underlying androgen independence are still being
elucidated but may include the development of androgen
receptor mutations (Culig et al. 1997) and androgen receptor
amplification (Visakorpi et al. 1995).
Animal data in androgen-dependent tumours demonstrated that repeated intermittent cycles of androgen withdrawal prolonged time to androgen independence compared
with continuous androgen withdrawal (Akakura et al. 1993,
Gleave et al. 1994). This led to the concept of giving intermittent endocrine therapy in patients with advanced and locally advanced disease and this management strategy has been
evaluated in a number of small non-comparative trials
(Goldenberg et al. 1995, Tunn 1996). An integral part of
this approach involves PSA monitoring whereby cycles of
endocrine therapy are reinstituted when the serum PSA off
therapy reaches a pre-defined threshold. A number of large
trials comparing intermittent endocrine therapy with continuous endocrine therapy are in progress and will shed light on
the utility of this approach in the management of advanced
prostate cancer, although results are not expected for a
number of years.
Following the emergence of androgen independence, a
number of second line therapies may be initiated including
second antiandrogens, both steroidal and non-steroidal,
adrenal inhibitors, cytotoxic agents, etc. Kelly et al. (1993)
demonstrated in a study of 110 men with hormone refractory
prostate cancer treated with a variety of different regimens,
a significant improvement in median survival in patients with
www.endocrinology.org
a 50% or greater decline in PSA compared with a less than
50% decline after treatment (21 vs 8 months, P = 0.0002).
Other studies have confirmed an association between PSA
fall and outcome (Pienta et al. 1994, Sella et al. 1994). In
most trials of new agents, a 50% fall in PSA defines a PSA
response. However, the usefulness of PSA response in the
evaluation of new therapies has been the subject of considerable debate, as a PSA response does not necessarily correlate
with a measurable disease response (Scher et al. 1990). Walls
et al. (1996) studied the effect of a differentiating agent,
phenylacetate, on human prostatic carcinoma LNCaP cells
and showed that the drug induced PSA production despite
inhibition of tumour cell proliferation. Further, in a study of
the effects of suramin in castrated nude mice injected with
an androgen-independent human prostate cancer cell line,
growth of tumour was not affected whilst the ratio of PSA
to tumour volume was significantly decreased (Thalmann et
al. 1996). Overall, these data suggest that declines in PSA in
this setting may be treatment specific and that the exclusive
use of PSA response as a criterion for disease response may
not always be appropriate.
Future perspectives
A number of recent initiatives in the field of PSA research
may be of utility in the detection, staging and management
of patients with prostate cancer. Reverse transcriptasepolymerase chain reaction (RT-PCR) assays for PSAexpressing cells in the blood circulation have been under
investigation since 1992. Whilst a number of groups have
reported that a positive RT-PCR for PSA in peripheral blood
correlated with extraprostatic disease and recurrence (Katz et
al. 1994, 1996, Ghossein et al. 1995, 1997, Olsson et al.
1996), other groups have found no such correlation (Sokoloff
et al. 1996, Ignatoff et al. 1997, Melchior et al. 1997). In
addition to circulating PSA-expressing cells, studies of bone
marrow PSA-expressing cells have been conducted. Wood et
al. (1994) showed that bone marrow RT-PCR PSA positivity
significantly correlated with extraprostatic disease and that
patients with positive bone marrow RT-PCR PSA results had
significantly shorter disease-free survival than those with a
negative result. More recently, Gao et al. (1999) showed that
bone marrow RT-PCR PSA positivity was associated with
early disease recurrence but found no association with pathological stage, grade or margin positivity. In addition to circulating and bone marrow PSA-expressing cells, the roles of
circulating and bone marrow prostate specific membrane
antigen (PSMA) and human glandular kallikrein (HK2)expressing cells in the detection of occult metastases are
under investigation. HK2, like PSA, is prostate tissuespecific and androgen-dependent and its protein sequence
shares 80% homology with PSA. It has been observed that,
in some cancer patients, HK2 message can be detected in the
absence of detectable PSA message expression (Corey et al.
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1997, Kawakami et al. 1997) and it may be an important
marker for the progression of poorly differentiated prostate
cancer and development of hormone resistance (Kawakami
et al. 1997). Further studies will be needed to determine
whether the various circulating and bone marrow parameters
under evaluation provide independent prognostic information.
Summary
The worldwide incidence of prostate cancer is increasing, in
part due to screening, although increased public awareness
and dietary changes may have a part to play. With its current
rate of growth it is clear that prostate cancer will represent
an increasingly important public health problem as we move
into the new millennium. One of the principal challenges
facing clinicians charged with the management of prostate
cancer is to ensure that cancers which need to be treated are
detected, particularly when the disease is potentially curable.
In this regard, the increased detection by PSA and digital
rectal examination of organ-confined moderately differentiated cancers in the US is encouraging and it is hoped that this
will lead to a further reduction in cancer-specific mortality.
Further, and perhaps just as important, there is a need for
better prognostic information in order to predict those
patients who are likely to have good survival and for whom
radical intervention may be inappropriate. The specificity of
PSA testing in the detection of cancer is relatively low
although it is hoped that further studies on a number of
refinements of PSA evaluation may be helpful in differentiating cancer from benign disease and reducing the need for
unnecessary further diagnostic tests.
PSA testing will remain an integral component of the
assessment of response to radical therapy and endocrine therapy where it provides important prognostic information
regarding subsequent outcome, and also in the follow-up of
these patients in order to detect recurrence/progression.
Given that prostate cancer is a slow growing disease and
PSA testing has only been available for just over a decade,
our knowledge of the correlation of PSA assessment with
disease outcome is, however, still somewhat limited. The
emergence of new data will serve to refine further our understanding of the use of this most valuable marker in the detection, staging and management of patients with prostate
cancer.
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