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 £ 0.5 ng/mL.
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 < 0.5 ng/mL.
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(Drug information on 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(Drug information on 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 clinical trial.
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.