Dr. Moul discusses one of the most contemporary yet contrversial
topics in prostate cancernamely, a rising prostate-specific
antigen (PSA) level after the failure of local therapy. The way in
which patients with advanced prostate cancer present has changed
dramatically during the last decade, which, in turn, has altered the
type of treatment that they receive. Currently, approximately 25% of
newly diagnosed patients receive no treatment; 12% are treated with
hormonal therapy; 29%, with radiation therapy; 28%, with radical
prostatectomy; and 7%, with other therapies.
A substantial number of patients treated with local modalities, ie,
radical prostatectomy or radiation therapy, do not respond to such
therapies, as manifested by a rising PSA. In 1997, Dr. Brent
Blumenstein and I published a letter to the editor of Urology.
We proposed that this new substage of advanced disease be called
D1.5. In our experience, most patients are presenting with this
advanced stage (D1.5) of prostate cancer.
Dr. Moul discusses the challenges involved in diagnosing and treating
this disease stage. Clinicians face four issues related to this
rising PSA phenomenon: its definition, evaluation, treatment, and outcome.
Definition of a Rising PSA
After radical prostatectomy, the definition of a rising PSA is rather
straightforward. Depending on the assay used, the PSA should be
somewhere between 0 and < 0.2 ng/mL. Supersensitive assays allow
detection at lower levels and may give the clinician a lead time of
up to 1 year over a rising PSA measured by standard methods.
In general, a PSA that has increased above the baseline value signals
either local or distant failure, or a combination of the two.
Occasionally, a patient who has benign tissue left behind will
exhibit a subtle rise in his PSA.
As Dr. Moul notes, the definition of failure after radiation therapy
is more complex. It is very clear that a rise above a nadir usually
signifies treatment failure. Many series are now finding that the
nadir PSA with radiation therapy should, in fact, be £
In 1994, Willet, Zietman, and Shiples published data from a small
series of men who were in one of three groups: those treated with
radiation therapy to the pelvis for nonprostatic cancer conditions, a
control group, and those with prostate cancer. Patients in the
prostate cancer group who achieved continuous no evidence of
disease status over 8 to 16 years all had a PSA nadir of <
In summary, a rising PSA is defined as above a level of 0 to 0.2
ng/mL after radical prostatectomy and above a nadir after radiation
therapy. (It is assumed that the same definition applies to
brachytherapy.) Both the definition of a nadir PSA and a specific
nadir value after radiation therapy remain controversial.
The clinicians next challenge is to determine what sort of
evaluation should be performed in patients with a rising PSA. In
patients who have undergone a radical prostatectomy, some
investigators suggest the performance of a biopsy around the
anastomotic area to rule out recurrence. In my opinion, this remains controversial.
Further evaluation can include a bone scan, Prostacint scan, and
other methods of radiologic evaluation. In addition, it is important
to examine the patients preradical prostatectomy PSA,
Gleason score, and the final pathology. Obviously, if the patient has
a pretreatment PSA of 45 ng/mL, a Gleason score of 8, and multiple
positive surgical margins with seminal vesicle invasion, he most
likely is at risk for distant recurrence and also is at substantial
risk for local recurrence. Unfortunately, many patients fall into a
gray zone where one cannot differentiate local from distant recurrence.
Following radiation therapy, a number of issues must be addressed.
Again, these revolve around whether the patient has a local and/or
distant recurrence. The timing of prostate biopsy following radiation
is controversial, as are the value and feasibility of grading a
post-radiation therapy recurrence. Again, pretreatment PSA levels and
Gleason scores are helpful in determining whether a recurrence
represents a local or a distant failure. Unfortunately, no diagnostic
study reliably localizes tumor to the pelvis, and a positive study
does not exclude metastatic disease in many cases.
Treatment of a Rising PSA
The treatment of a rising PSA is controversial. Some researchers have
commented that PSA stands not only for prostate-specific
antigen but also for patient-stimulated anxiety and
patient stress amplifier. Both patients and their
physicians are bothered by a rising PSA, and it does, in fact,
negatively affect quality of life. If one considers both
psychological and physical symptoms, one might argue that a rising
PSA is just as symptomatic as a new lesion on a bone scan.
When I approach a patient with a rising PSA, I ask myself a number of
questions: Was the patient curable before treatment? Is cure still
possible? What is the patients life expectancy? What effect
will treatment have on the patients quality of life? Obviously,
there are different treatment options for a patient with a rising PSA
following radical prostatectomy vs radiation therapy.
One of the major questions following failure of radical prostatectomy
is the value of radiation, given as either adjuvant or definitive
therapy. There are no studies to support the value of adjuvant
radiation, even in high-risk patients, after radical prostatectomy.
The literature is replete with small, nonrandomized studies showing
that adjuvant radiation reduces local recurrence but fails to improve survival.
The Southwest Oncology Group (SWOG) has just completed a large
clinical trial to address this issue; the results are expected in 3
to 5 years.
The next situation in which radiation therapy can be used is for
patients with a rising PSA following failed radical prostatectomy.
Dr. Moul reviews an excellent approach promulgated by Gar et al from
Wayne State University. This is the strategy that I routinely
employ in such patients. A key message contained in their work is
that patients seem to do better if radiation therapy is instituted
before the PSA rises above 2 ng/mL.
Dr. Moul nicely outlines the role of salvage prostatectomy in
patients with localized prostate cancer who were treated
unsuccessfully with definitive radiation therapy. Recently, the FDA
approved cryotherapy as a treatment modality for localized prostate
cancer; that should result in a resurgence of interest in this
modality. Hopefully, with improved delivery systems, the
complications of this treatment will decline.
Almost any form of hormonal therapy will lower the PSA to
undetectable levels following its initial rise. The salient question
is whether such treatment will increase survival. Unfortunately, as
alluded to by Dr. Moul, there is no evidence to support this contention.
There are a number of choices for hormonal therapy, including
combined androgen blockade; monotherapy with luteinizing
hormonereleasing hormone (LHRH) agonist; orchiectomy or
estrogens; antiandrogens; and experimental therapy with low doses of
an antiandrogen, differentiation agents, apoptosis-inducing
medications, or dietary changes. If one chooses hormonal therapy,
questions arise regarding whether it should be continued over the
long term, prescribed for a defined period, or used intermittently.
Outcome of Treatment
As has been mentioned, no currently available studies have
satisfactorily evaluated the outcome of any treatment for rising PSA
after failed local therapy. Therefore, until the results of such
trials are available, clinicians must rely on retrospective reviews,
single-institution studies, and, perhaps, the use of advanced
technology, such as neural networks (a form of artificial intelligence).
One novel approach that Dr. Moul and I have used to treat patients
with a rising PSA following failed local therapy has been the
combination of low-dose flutamide (Eulexin; 125 mg twice daily) and
finasteride (Proscar; 5 mg twice daily). Our rationale for employing
this combination in this setting was better drug tolerance and the
perceived synergy between the two drugs.
We entered a total of 73 patients with a rising PSA after failed
local therapy into this trial. Length of follow-up has ranged from 1
to 88 months (mean, 28.9 months). Levels of PSA, liver function
tests, and symptoms were evaluated. Table
1 relates the PSA level at the initiation of drug therapy in
each patient, and Table 2 shows
the correlation of initial PSA with nadir time.
Of the 73 patients, 45 achieved a nadir PSA of < 0.2 ng/mL for an
average of 2.5 years. Side effects were minimal and consisted mainly
of breast tenderness (71%), breast enlargement (60%), and nipple
tenderness (33%). All of the patients who were potent prior to the
therapy remained potent during the therapy, and only two patients had
severe side effects resulting in their removal from the study.
Thus, this novel combination appears to be active in patients with a
rising PSA following the failure of local therapy. However, further
studies are indicated.
Dr. Moul mentions the Medical Research Council (MRC) study, which
seems to support the value of early hormonal therapy in patients with
asymptomatic T3 or metastatic disease. Whether this is also true of
patients with a rising PSA after failed local therapy remains
unknown. However, we recognize that as prostate cancer continues to
grow, its genetic hetero-geneity increases, which lessens its
responsiveness to hormonal and other therapies. Whether early therapy
results in an improvement in survival remains unknown.
If a patient has a rising PSA after radical prostatectomy, my initial
approach is to treat him early with radiation therapy to the
prostatic bed. If that fails to result in an undetectable PSA, I
institute early hormonal therapy or try to place the patient on a
If a patient does not respond to radiation therapy as the primary
treatment for his cancer, I carefully review his initial presentation
to determine whether he is a candidate for radical prostatectomy and,
in fact, has a radioresistant or recurrent tumor. Biopsy and intense
evaluation for metastatic disease, including bone and Prostacint
scans, are indicated if the patient is being considered for a salvage prostatectomy.
Cryotherapy may be an option in such patients. The value of early
hormonal therapy is questionable, although I personally believe it is
valuable. However, clinical trials are direly needed to ascertain
whether such therapy has an impact on survival.
In conclusion, Dr. Moul is to be congratulated for providing such a
concise, provocative review of a difficult topic.
1. Blumenstein B, Crawford ED: Rising PSA after failed local therapy,
the most common presentation of advanced prostate cancer. Urology
2. Willet CG, Zietman AL, Shiples WU: The effect of pelvic radiation
on serum levels of prostate specific antigen. J Urol 151:1579, 1994.
3. Gar MK, Tekyi-Mensam S, Bolton S, et al: Impact of
postprostatectomy prostate-specific antigen made on outcomes
following salvage radiotherapy. Urology 51(6):998-1002, 1998.