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The Role of PSA in the Radiotherapy of Prostate Cancer

The Role of PSA in the Radiotherapy of Prostate Cancer

ABSTRACT: Pretreatment prostate-specific antigen (PSA) level is the single most important prognostic factor for patients undergoing radiotherapy for clinically localized prostate cancer. When combined with Gleason score and T-stage, pretreatment PSA enhances our ability to accurately predict pathologic stage. Patients with pretreatment PSA levels more than 10 ng/mL are at high risk for biochemical failure when treated with conventional radiation alone. A PSA nadir of more than 1 ng/mL and a post-treatment PSA more than 1.5 ng/mL are associated with a high risk of biochemical failure. Postoperative radiotherapy delivered while the tumor burden is low (eg, PSA less than 1 ng/mL) predicts a favorable outcome. Many of these conclusions about the usefulness of pretreatment PSA are based on the assumption that PSA can be used as a surrogate end point for disease-free and overall survival from prostate cancer. However, this assumption still remains to be validated by phase III trials. [ONCOLOGY 10(8):1143-1153, 1996]

Introduction

The diagnosis, staging, treatment, and follow-up of patients with
prostate cancer have been dramatically altered by the availability
of the serum marker known as prostate-specific antigen (PSA).
Because of the sheer numbers of patients with this cancer (317,000
"new" cases were expected for 1996), no other single
break- through in oncology has had an impact on so many people
in such a short period of time. The explosion of published information
related to this marker has been exponential, and there is no evidence
yet that a plateau has been reached.

Obviously, a single brief review article cannot cover all of the
interesting observations being made about this new tool. It is
likely that as this manuscript is being prepared, new findings
concerning the use of PSA are being discovered. With this disclaimer
in mind, this review will attempt to highlight some of the practical
uses of PSA for managing patients undergoing definitive local
therapy.

What is PSA?

Prostate-specific antigen is a proteolytic enzyme that belongs
to the serine protease family and is generally believed to have
an approximate mass of 33 kd. Among its major functions, PSA causes
liquefaction of semen and release of motile spermatozoa [1].

Several forms of PSA are found in the serum. Generally, 5% to
40% of the PSA is considered to be "free," and this
portion may be inactive. From 60% to 95% of PSA may be complexed
with alpha-1-antichymotrypsin (ACT). Prostate-specific antigen
reacting with ACT is reportedly inactivated due to splitting of
the reactive center [1]. Several studies have shown that the ratio
of free to total PSA is significantly lower in patients with prostate
cancer than in those with benign prostatic hypertrophy [2,3].
Based on this difference, several investigators have reported
improvements in the specificity and sensitivity of PSA screening.

In order to avoid some of the confusion concerning the use and
prognostic significance of a given PSA level, it is important
to be aware of the differences between the two major types of
assays (polyclonal vs monoclonal assays) used in the published
literature. Several centers have reported comparisons of PSAs
in patients undergoing both monoclonal and polyclonal assays [4,5].
Despite the fact that the normal range was 0 to 4.0 ng/mL for
the monoclonal assay and 0 to 2.5 ng/mL for the polyclonal assay,
the ratio observed was the opposite of what would have been expected
based on these recommended "normal" ranges. This suggests
that the manufacturers chose different sensitivities and specificities
when their "normal" ranges were defined. A given PSA
level determined by the monoclonal assay was approximately 1.5
to 1.85 times that when determined by the polyclonal assay. Furthermore,
for most monoclonal assays, the "best" upper limit of
normal is probably 3.3 ng/mL rather than 4.0 ng/ml [6]. Alternatively,
some authorities have recommended an age-adjusted scale [7].

Staging With PSA

Prostate-specific antigen has been shown to be of value in the
staging work-up and evaluation of patients with prostate cancer.
Use of this serum marker can save millions of dollars by obviating
the need for expensive, time-consuming studies. For example, bone
scans are probably not justified if the PSA is 10 ng/mL and may
not be warranted if the PSA is less than 50 ng/mL and serum alkaline
phosphatase is normal [8,9]. In the assessment of lymph node status,
neither abdominal/pelvic CT nor MRI appear to be warranted if
the PSA is less than 20 ng/mL [10].

Problems With Use of PSA Alone

Numerous studies have demonstrated that there is a correlation
between the level of PSA and the volume of both the normal prostate
and prostatic carcinoma. Per gram of tissue, PSA levels are much
higher for cancerous than for normal tissue. This may well be
due to greater leakage of PSA into the circulation or disruption
of normal prostate parenchyma associated with cancer, because
higher levels and mRNA are expressed in benign than in malignant
tissue [1]. As the tumor grade increases (Gleason score more than
7), there is a tendency toward a reduction in the amount of PSA
produced per gram of tissue [11,12].

Anaplastic tumors may fail to produce an elevation of serum PSA
or to stain positively for it. These phenomena complicate the
use of PSA for accurately predicting tumor volume, because although
higher-grade tumors tend to be larger, the volume tends to be
underestimated for a given level of PSA. Because of this complex
interaction between PSA and tumor grade, and the confounding effects
of the presence of benign prostatic hypertrophy, PSA alone cannot
be relied on to predict tumor volume.

PSA Density

Attempts to use the so-called PSA density to compensate for this
problem have met with mixed results. Although many investigators
agree that the use of PSA density may improve specificity and/or
sensitivity for the purposes of screening, the impact on outcome
following treatment is less clear [13-15]. In a recent report,
M. D. Anderson investigators concluded that PSA density was "particularly
useful" in subdividing patients with PSAs between 4 and 20
ng/mL. In contrast, investigators at Columbia concluded that use
of PSA density did not add anything to their ability to predict
biochemical failure. The authors admitted, however, that the small
number of patients in their series may have limited the power
of their analysis.

Free PSA and PSA Doubling Time

The application of free PSA to this problem may further improve
our ability to predict tumor volume, but this possibility has
only begun to be investigated. Also, some investigators have reported
that the rate of rise of PSA, or PSA doubling time, is an independent
prognostic factor for outcome following radiotherapy [16]. The
optimal time interval for calculating this end point has not been
well defined, however.

PSA, Tumor Grade, and Clinical Stage

Several studies have shown that combining PSA with tumor grade
and clinical stage improves the prediction of pathologic stage.
Partin et al published nomograms for defining the risk of extracapsular
extension (ECE), seminal vesicle involvement (SV+), and lymph
node involvement (N+) [11]. Based on these data, three simple
equations have been described that help simplify the estimations
of the risk of N+, SV+ and ECE [17-20]. These equations were verified
initially for their predictive values using radical prostatectomy
data from the University of California, San Francisco (UCSF),
and have been since verified at other institutions as well [21,22].
The three equations are shown below:

Risk of N+ = 2/3 PSA + {(GS - 6) × 10}

Risk of SV+ = PSA + {(GS - 6) × 10}

Risk of ECE = 3/2 PSA + {(GS - 3) × 10}

In these equations, PSA is the highest value (not attributed to
other causes, such as infection) prior to treatment using a monoclonal
assay, which has a normal range of 0 to 4.0 ng/mL. When used in
this equation, PSAs measured using a polyclonal assay (eg, Yang),
with a normal range of ~ 0.0 to 2.5 ng/mL, may need to be divided
by a conversion factor of approximately 1.5. For use in this equation,
the nine possible Gleason score (GS) values are empirically grouped
into five major scoring categories (ˆequal to or less than
4 = 4, 5 = 5, 6 = 6, 7 = 7, and equal to or more than 8 = 8),
and the calculated risk values are constrained between 0% and
100%.

Table 1 compares the calculated risk of lymph node involvement
using the above equation with the observed incidence based on
data provided by Partin et al [11,17]. With the exception of the
patients with high-grade tumors, there is excellent agreement
between the calculated risk and observed incidence. In practice,
patients at UCSF are arbitrarily considered to be at "high
risk" for lymph node involvement if their calculated risk
is 15%. Based on surgical data, patients at UCSF with a calculated
risk of lymph node involvement of less than 15% have an observed
incidence of ~ 6%, while patients with a calculated risk of 15%
or more have an observed incidence of ~ 40%.

A shortcoming of the original "lymph node equation"
is that it ignores clinical stage. Stage appears to independently
affect the risk of lymph node involvement. To address this concern,
the equation for predicting the risk of N+ was modified (data
presented at the American College of Radiology, "Future Trends
in Radiation Oncology," New Orleans, Louisianna, 1994) to
include clinical stage information. The modified equation is shown
below:

Risk of N+ = 2/3 PSA + {(GS - 6) + (TG - 1.5)} × 10

For this model, the T-groupings (TG) are as follows: TG 1 (stages
T1c and T2a) is assigned a value of 1; TG 2 (T1b and T2b) is given
a value of 2; and TG 3 (T2c and T3) is assigned a value of 3.

Using this equation, patients with clinical T2c-T3 lesions have
a 15% higher risk of positive lymph nodes than was calculated
with the previous equation and patients with clinical T1c or T2a
lesions have a 5% lower risk. Figures 1A, 1B, and 1C are examples
of how this model that includes T-stage more closely approximates
the expected incidence of lymph node involvement, based on surgical
data provided by Partin et al [11,23].

Unfortunately, to date there have been insufficient surgical data
(too few T2c and T3 patients undergoing node dissections) to validate
this equation. The recently opened Radiation Therapy Oncology
Group (RTOG) 94-13 clinical trial may provide an opportunity to
indirectly test the modified equation. Patients entered into the
trial are being stratified by the T-groupings used in this equation
(in addition to pretreatment PSA and Gleason score) and are being
randomized to whole-pelvic irradiation or no whole pelvic radiotherapy.
(The trial protocol is outlined in Table 2). If the patients with
a higher calculated risk of lymph node involvement who do not
receive whole-pelvic irradiation have a higher PSA failure rate
than those receiving this therapy but an equal local control rate,
this might support the value of the model (as well as the benefit
of whole-pelvic irradiation).

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