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Rising PSA following Definitive Local Therapy for Prostate Cancer: A Framework for Decision Making
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Submitted By: Robert Dreicer, M.D. F.A.C.P.
One of the most important effects of the wide-spread application of PSA into clinical practice in the late 1980’s has been the significant increase in the proportion of new prostate cancers being detected at an early stage. As a result, a large number of men with presumed clinically localized disease are undergoing curative intent therapy with radical prostatectomy or radiotherapy (external beam and/or brachytherapy). Approximately one third of prostate cancer patients with clinically localized disease treated with radical prostatectomy develop evidence of biochemical failure (detectable PSA) during long-term follow-up. Although this is a much more complex issue in patients undergoing radiotherapy because of patient selection and other critical factors, one third to one-half of patients will demonstrate PSA progression with long-term follow-up. Thus the down-stream impact of our current prostate cancer screening and therapeutic strategies has created a new subset of prostate cancer patients, those with evidence of disease recurrence, biochemically (PSA) defined, potentially representing thousands of patients/year in the United States alone.
Detectable PSA following therapy: Local vs. Systemic Failure
One of the goals of making an early diagnosis of prostate cancer is to detect the disease at a time point prior to the development of metastases when local therapies such as surgery or radiotherapy may be curative. In patients undergoing radical prostatectomy, post surgical detection of PSA is consistent with recurrent or persistent disease. This issue is obviously more complicated in patients undergoing radiotherapy as the prostate remains in place. It is important to remember that PSA is not only elevated in prostate cancer, but in benign prostatic hyperplasia and inflammatory conditions of the prostate.
For post prostatectomy patients, the determination of local vs. systemic failure is a critical distinction. Although the use of radiotherapy as a “salvage” treatment for men with detectable PSA values following prostatectomy remains controversial, it is intuitive that a patient with systemic spread of disease is likely to have limited benefit from another local therapy. For patients with relatively low PSA values in this setting the traditional tests used to evaluate for the presence of recurrent disease are unfortunately of limited help. CT scans of the abdomen and pelvis and bone scans, are not sensitive enough to detect early disease recurrence. The utility of radioimmunoscintigraphy (ProstaScint) to help distinguish between local and systemic failures remains controversial and is unfortunately rarely helpful in reaching a definitive conclusion. Most clinicians rely on the time to detectable PSA (within the first year or later) and the PSA doubling time in addition to the above diagnostic studies to determine the likelihood of local vs. systemic failure.
One of the vexing aspects of attempting to develop interventions for managing biochemical failure is the lack of a clear understanding of the natural history (what happens to patients) of PSA relapse following radical prostatectomy. Part of the explanation for this relative lack of knowledge is due to the relatively short follow-up of such patients. A more significant issue however, is the confounding effects of salvage radiotherapy and/or hormonal therapy which is administered to a substantial number of patients. The limited use of radiation and hormonal therapy in the series reported by Pound et al. makes this the most import report detailing the natural history of biochemical failure following radical prostatectomy. Of 304 patients who had a detectable PSA relapse after surgery, 103 (34%) developed metastatic disease. The median actuarial time from PSA elevation to metastatic disease was 8 years with the median time to death following development of metastatic disease being approximately 5 years later.
The natural history of patients with PSA progression following radiotherapy is also poorly defined, however, there is emerging evidence suggesting that patients whose PSA values nadir at levels of 0.5-1.0 have a much lower chance of ultimately developing disease progression.
Hormonal Therapy for Managing Biochemical Failure
Among the most controversial subjects in prostate cancer circles today revolves around the role and timing of hormonal therapy for patients with detectable PSA values following local therapy. This subject is complex and a full discussion of this issue is beyond the scope of this brief overview. However, there are some fundamental points that should be understood as a starting point for patients faced with this decision.
As of today, there are no completed, prospective, randomized trials (the kinds of trials that have for example established the role of adjuvant therapy in breast cancer as a standard of care ) comparing early vs. delayed hormonal therapy in patients with PSA only failure, therefore no definitive guidance is available to patients and clinicians. Much of the ongoing debate centers around the appropriateness of extrapolating the findings of other clinical trials performed in different prostate cancer subsets (for example, patients with metastatic disease, node positive disease and locally advanced disease) and applying them to patients with PSA failure. It is also important to remember that patients with advanced prostate cancer treated with hormonal therapy are not cured, as essentially all patients will ultimately experience disease progression to an androgen-independent state. Patients who are treated with hormonal therapy at time of PSA relapse will potentially be exposed to this therapy with all of the potential side effects associated with its use for prolonged periods of time, typically far greater than the typical period of 2-3 years when used to treat patients with advanced disease. One of the potential consequences of this prolonged exposure is the development of osteoporosis and its complications (increased risk of fracture).
Not all patients with biochemical failure are the same or have the same risk of progressing on to having metastatic disease. The 75 year old patient treated with external beam radiotherapy 9 years ago, who has had a slowly rising PSA for 5 years with a PSA of 3.2 and a PSA doubling time of 20 months, is not the same as the 65 year old patient who is 11 months out from a radical prostatectomy with a PSA of 5 with a PSA doubling time of 4 months. Although our ability to determine absolute risk of disease progression remains rudimentary, the application of a therapy which has the potential to significantly impact on quality of life needs to be carefully considered. The treatment should not be worse than the disease.
Closing on a more promising note, there are an increasing number of ongoing clinical trials for patients with PSA failure using various novel targeted drug therapies and other immune-based strategies currently being conducted at numerous centers around the country. Given the current uncertainty regarding the appropriate management for some patients with biochemical failure, for the motivated patient, entry into a clinical trial represents a viable alternative to observation or early hormonal therapy.
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Works Cited: |
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SELECTED REFERENCES
1. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of
progression after PSA elevation following radical prostatectomy. JAMA
281:1591-1597, 1999
2. Walsh PC, Deweese TL, Eisenberger M: A structured debate: Immediate versus deferred androgen suppression in prostate cancer-evidence for deferred treatment. J Urol 166:508-516, 2001
3. Herr HW, O'Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 163:1743-1746, 2000
4. Hanlon AL, Diratzouian H, Hanks GE: Posttreatment prostate-specific
antigen nadir highly predictive of distant failure and death from prostate
cancer. Int J Radiat Oncol Biol Phys 53:297-303, 2002
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