Rising PSA After Local Therapy Failure: Immediate vs Deferred Treatment

Rising PSA After Local Therapy Failure: Immediate vs Deferred Treatment

ABSTRACT: Patients whose only sign of recurrence after local therapy for prostate cancer is a rising prostate-specific antigen level (PSA-only recurrence) have become more common. We have developed two models to predict PSA-only recurrence after radical prostatectomy, one using traditional factors (race, sigmoidal transformation of PSA, postoperative Gleason sum, and organ confinement) and a second using traditional clinical and pathologic variables combined with molecular biomarker levels. Treatment options for patients with PSA-only recurrence include observation, radiation therapy for patients who have undergone surgery, salvage surgery or cryotherapy for patients who have received radiotherapy, and traditional or nontraditional hormonal therapy. Radiation for PSA-only recurrence is likely to benefit men who have no adverse pathology, a low PSA level at recurrence, and PSA recurrence after the first year. Salvage radical prostatectomy and cryotherapy pose a relatively high risk of incontinence and other morbidity and should be reserved for carefully selected patients with a high likelihood of organ-confined disease. Hormonal therapy is probably the single most beneficial treatment for PSA-only recurrence. Nontraditional low-dose oral hormonal therapy and intermittent hormonal therapy are gaining in popularity, although their long-term efficacy is unknown. More clinical trials are needed to fine-tune prognostic models and to determine the best treatments, alone or in combination, for PSA-only recurrence. [ONCOLOGY 13(7):985-993, 1999]


The “prostate-specific antigen
(PSA)–era” (1988 to present) has dramatically altered the
epidemiology of prostate cancer in the United States and in many
other industrialized countries.[1] Although the prevalence of
prostate cancer has fallen somewhat since its peak in the early
1990s, the American Cancer Society still estimates that approximately
179,000 new cases will be diagnosed in 1999.[2]

An unprecedented stage migration has accompanied this large shift in
incidence. The Surveillance, Epidemiology and End Results (SEER)
Program of the National Cancer Institute noted a 52% decline in the
rate of distant metastatic (stage D) prostate cancer between 1990 and
1994.[3] At the same time, the rate of diagnosis of localized disease
skyrocketed. Our Department of Defense Center for Prostate Disease
Research database at Walter Reed Army Medical Center (WRAMC) found
that the incidence of localized prostate cancer (stages A and B)
increased from approximately 50% of cases in 1988 to more than 75% of
cases by 1996.[1]

Along with this change in stage distribution has come a change in
treatment patterns. The SEER program found that rates of radical
prostatectomy rose from 17.4 cases per 100,000 in 1988 to 54.6 cases
per 100,000 in 1992.[3] By 1992, 36.6% of patients with locoregional
disease underwent radical prostatectomy, and 32.3% received radiation therapy.

Furthermore, there has been a shift in the age-adjusted rates of
these treatments. Most notably, there was a three- to fourfold rise
in the rate of radical prostatectomy in men 45 to 59 years old, and a
two- to threefold rise in men 60 to 69 years of age.[3] Rates of
radiation therapy also increased one- to twofold in 45- to
79-year-old men.

In the late 1990s, clinicians are now seeing the effects of the boom
in the diagnosis and localized treatment of prostate cancer of the
early 1990s. A large number of generally younger men who were treated
for clinically localized prostate cancer have experienced a
recurrence of their disease. Figure 1
illustrates the problem clinicians are facing.

With more than 50,000 men per year developing a PSA-only recurrence
(indicated only by an elevated PSA level, as will be discussed in the
next section), it is obvious that this is a key issue for urologists,
radiation oncologists, medical oncologists, and, perhaps most
importantly, the patient and his family.

Assessment of PSA-Only Recurrence After Prostatectomy

The PSA level at which to define treatment failure after radical
prostatectomy varies in the literature. Some series have used any
detectable level; others, a single value > 0.4 or 0.5 ng/mL; and
still others, two consecutive values ³
0.2 ng/mL. At our hospital, employing the Abbott IMx assay, we use
the criterion of two values ³ 0.2
ng/mL, or any single value ³ 0.5 ng/mL.

In clinical practice, it generally is quite obvious when radical
prostatectomy patients develop a PSA-only recurrence because their
PSA becomes detectable and continues to rise. The use of an
ultrasensitive PSA assay may result in the identification of
relapsing patients 1 to 2 years earlier than can be achieved with a
conventional assay.

The timing of the rise in PSA level after surgery also is important.
Patients whose PSA never falls to an undetectable level in the
postoperative period generally are considered to have systemic
disease. However, some of these men who do not attain an undetectable
PSA after surgery do respond to salvage radiation to the prostatic
bed. This suggests that systemic disease is not universal in this
setting. Likewise, a PSA level that rises rapidly during the
postoperative period may be indicative of metastatic disease.
Patients whose PSA level remains undetectable for long periods (1 to
4 years) and then gradually rises are considered to have local
disease recurrence.

 After Radiation Therapy

Until recently, the definition of PSA-only recurrence after radiation
therapy was widely debated. In 1997, the American Society for
Therapeutic Radiology and Oncology (ASTRO) convened a consensus panel
to determine guidelines for PSA-only recurrence (biochemical failure)
after radiation therapy.[4] The panel agreed on the following four guidelines:

  1. Biochemical failure is not a justification per se to initiate
    additional treatment. It is not equivalent to clinical failure.
    Biochemical failure is, however, an appropriate early end point for
    clinical trials.

  2. Three consecutive increases in PSA level provide a reasonable
    definition of biochemical failure after radiation therapy. For
    clinical trials, the date of failure should be the midpoint between
    the postirradiation nadir PSA level and the first of three
    consecutive rises. (The use of three, rather than two, consecutive
    values reduces the likelihood of falsely characterizing a
    “bouncing” PSA level as a biochemical failure. This
    phenomenon results when sequential determinations of PSA level show
    one or two rises, followed by a fall and a subsequent failure to rise again.)

  3.  As yet, no definition of PSA-only recurrence has been shown to
    be a surrogate for clinical progression or survival.

  4. Nadir PSA level is a strong prognostic factor, but no absolute level
    is a valid cut-off point for identifying successful and unsuccessful
    treatments. Nadir PSA level is similar in prognostic value to
    pretreatment prognostic variables.

Prediction of PSA-Only Recurrence

Because early adjuvant therapy may be beneficial to patients with
localized disease in whom treatment is destined to fail, many studies
have evaluated a variety of prognostic variables in an attempt to
identify individuals who are at high risk of disease recurrence after
surgery. The following variables have shown a significant correlation
with PSA-only recurrence[5-15]: pretreatment PSA level; prostatic
acid phosphatase level; prostatectomy specimen Gleason sum;
pathologic stage; tumor volume; endorectal coil magnetic resonance
imaging results; DNA ploidy; race; and, more recently, molecular
biomarkers, such as p53, bcl-2, and Ki-67. Recently, some
investigators have combined prognostic variables into models or
equations that can be used to predict the likelihood of recurrence.

Johns Hopkins Model

Partin et al[10] at The Johns Hopkins Hospital were the first group
to develop a simple biostatistical model equation that categorized
post–radical prostatectomy patients into three risk groups (low,
intermediate, and high risk) based on their likelihood of serologic
failure. Many preoperative and pathologic variables were analyzed.
However, after multivariate regression analysis, only three variables
were included in the final model to select adequately for risk
stratification after surgery. Sigmoidal transformation of PSA level
(defined in equation in middle column), prostatectomy Gleason sum,
and specimen confinement (margin status) were incorporated into an
equation that calculated the relative risk of recurrence (Rw)
as: Rw = (0.061 × PSAST) + (0.54 ×
postoperative Gleason sum) + (1.87 × specimen confinement)

Specimen confined = organ confined or extracapsular
extension with negative margins.ecimen confined = organ confined or
extracapsular extension with negative margins.

Patients were then stratified into three risk groups depending on
their calculated value of Rw. This model employed traditional
variables that are assessed at most institutions, making this form of
risk assessment a practical clinical tool that can be used in
decisions concerning adjuvant therapy. The model allows those
patients at high risk for recurrence to be identified shortly after
surgery, while their tumor burden is theoretically at a minimum.

Department of Defense Center for Prostate Disease Research Models

Our research group at the Department of Defense Center for Prostate
Disease Research at WRAMC and the Uniformed Services University also
has been working to develop prognostic models that will predict
PSA-only recurrence after radical prostatectomy. Although the Johns
Hopkins model[10] has provided a great start, it was developed for
patients with clinical stage B2 (T2b or T2c) and may not be
applicable to the majority of patients who are being treated in the
late 1990s.

Using data from 378 patients of all clinical stages at WRAMC and data
from 91 patients in a separate hospital validation cohort, we
performed similar modeling using traditional prognostic factors.[15]
The prognostic variables that significantly correlated with disease
recurrence were incorporated into a model equation that calculates
the relative risk of recurrence (Rr) as: Rr =
exp [(0.51 × race) + (0.12 × PSAst) + (0.25 ×postop
Gleason sum) + (0.89 × organ confinement)]

Race was defined as “1” if the patient was African-American
or “0” if he was Caucasian or another race. Sigmoidal
transformation of PSA (PSAst) was calculated using the equation:

PSAst = 10 / (1+e6.8704-(0.9815 PSA level))

The postoperative Gleason sum was defined as a continuous integer
value (range, 2 to 10). Organ confinement was defined as “0”
if the tumor was organ-confined (no extraprostatic extension) or
“1” if the tumor was non–organ-confined
(extraprostatic extension and/or positive margins).

Table 1 shows the 3- and 5-year
Kaplan-Meier disease-free survival rates for the three risk groups
for both the WRAMC model cohort of 378 patients (top panel) and the
validation cohort of 91 independent patients (bottom panel). We have
placed this traditional model equation into our urologic clinic local
area computer network. Each clinician can enter patients’ race,
PSA level, Gleason sum, and pathologic stage into the Microsoft Excel
program postoperatively, and the program will automatically calculate
the Rr and show the recurrence information that appears in Table
. We can print this information and use it as an aid for
counseling patients with regard to adjuvant therapies. This model is
now available for use on our World Wide Web home page (

In addition to this recurrence model using traditional prognostic
factors, we developed a model to predict recurrence after radical
prostatectomy using traditional clinical and pathologic variables
combined with the results of molecular biomarker assays (p53 and
bcl-2 immunohistochemistry of radical prostatectomy specimens).[16]

Our models are initial attempts to combine prognostic factors and
take advantage of advances in hospital-based desktop computers so as
to improve patient care. However, large, multicenter, prospective
studies are needed to fine-tune existing prognostic models and to
develop similar models for patients who receive external-beam
radiotherapy or brachytherapy.


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