STAGING

Is There A Correct Way to Treat Prostate Cancer?

By Stephen B. Strum M.D., 1998

"Is There a Better Way to Treat Prostate Cancer?" I believe there is. Most physicians will respond to this question based on the bias that is inherent in their own specialty. Urologists will be biased towards surgery, and radiation therapists towards external beam or seed implantation and cryosurgeons towards cryosurgery. However, I firmly believe that there is a correct way to treat prostate cancer that is based on an understanding of key concepts in the evaluation and treatment of this disease.

The concept that I find most often improperly dealt with is the concept of organ-confined disease versus non organ-confined disease. Over and over again, we see patients with no significant probability of prostate-confined prostate cancer being treated with local therapy. These patients have been led to believe that such therapy is likely to cure them. An example is a patient who I saw in consultation this week. He presented with a PSA of 22 and a Gleason’s Score of 8. He had been advised by another physician to have three month’s of hormone blockade using Flutamide and Lupron and then to have external beam radiation therapy, followed by seed implantation. This was done at a center of international repute. There is no doubt that local control was achieved, but within three months of seed implantation his PSA was over 100. His case clearly points out a story that is routinely seen in our practice- a presentation that is not consistent with local disease, but which is dealt with as if the main priority were local treatment. Therefore, in my understanding of this disease, I would say that the correct first approach to prostate cancer is to determine the extent of the disease.

Staging Studies Based on Risk Assessment

What does proper staging mean? Staging is determining the extent of disease. In the prostate cancer patient, proper staging means to assess the patient’s risk of having organ-confined disease vs capsular penetration vs seminal vesicle involvement vs lymph node involvement vs bone involvement. We use the experiences of over 12,000 patients to aid us in determining the risk of non-organ confined disease. These experiences are presented using predictive algorithms which have been published in the peer reviewed urologic literature. They involve human experiences that correlate pre-surgical findings with the findings at radical prostatectomy. These algorithms yield a risk assessment expressed as a probability- they do not define an exact number for an individual patient. They are, however, useful in guiding the patient to the proper staging studies and possibly to exclude disease which is NOT local. A table with some of the predictive algorithms is shown below:
 

Patients (Pts) Enrolled in Various Studies Involving Predictive Algorithms  

Senior Author: Institution	# of Pts	Reference
Partin(New):Hopkins,Baylor,  Michigan	4,133*	JAMA 277: 1445-1451, 1997
Bluestein: Mayo	1,632*	J Urol 151: 1315-1320, 1994
Lerner: Mayo	904*	J Urol 156: 137-143, 1996
Narayan: U of Florida	813*	Urology 46: 205-212, 1995
Eastham: Baylor	766*	J Urol 157: 298, 1997
Partin (II):Hopkins	542	Urology 43: 649-659, 1994
Pisansky:Mayo	500	Cancer 79: 337-344, 1997
D’Amico: Harvard	480*	Cancer J Sci Am 2: 343-350, 1996
Dugan: Mayo	337*	JAMA 275: 288-294, 1996
Huncharek:Mass General	300	Cancer Invest 13: 31-35, 1995
Bostwick:Mayo,Baylor,WashU, Laval,	186*	Urology 48: 47-57, 1996
Oesterling: Mayo Clinic	852	JAMA 269: 57-60, 1993
Powell: Wayne St, Michigan	369*	Urology 49: 726-731, 1997
Kleer:Mayo Clinic	945*	Urology 41: 207-216, 1993
Total	12,759

* Refer to studies involving 10, 565 radical prostatectomy patients

For example, if a patient presents with a PSA of 22 and a Gleason’s Score of 8 and a clinical stage of T1c, one can then determine his risk by using algorithms containing the new Partin data published in JAMA, 1997. In addition, if we know the patient has had evidence of disease in both lobes of the prostate, we can also use the data published by Narayan to determine the probability of risk for the same extent of disease. The Partin Predictions would tell us that the above patient has a 10% chance of organ-confined disease with significant risks at the capsular level (34%), the seminal vesicle (31%) and also at the lymph node level (24%). Therefore, our approach would be to advise the patient of this and to guide him in terms of staging studies.

Because his PSA exceeds 10, we would advise the patient to have a bone scan first. We know that if the PSA is 10 or less, the chance of a positive bone scan is only 0.5%, or one in 200 patients. In such instances, we often tell patients that a bone scan is not necessary, especially if their Gleason’s Score is less than seven. In the case of the Narayan predictive algorithm, if the patient had disease found on biopsy to involve both the right and left sides of the prostate, this would yield a 13% prediction for organ-confined disease, a 66% likelihood for capsular extension, a 55% likelihood for seminal vesicle involvement and a 65% likelihood for lymph node involvement. Therefore, in the hypothetical case of the above-mentioned patient, after first excluding disease in his bones based on bone scanning, we would then proceed to advise the patient to have a ProstaScint scan to exclude nodal involvement.

We realize that the ProstaScint scan has its limitations, but it is far better than a CT scan which is more often than not, a worthless study in a newly diagnosed patient with prostate cancer. The ProstaScint scan has approximately a 70% sensitivity in diagnosing prostate cancer. If there is a question about false positive results, the patient may elect to have a lymphangiogram to evaluate the ProstaScint findings. The lymphangiogram has lost popularity because it is a much more tedious and labor-intensive study, but it is certainly a highly accurate method to confirm abnormal lymph node findings that may be detected with the ProstaScint. If both the bone scan and ProstaScint scan are within normal limits, we would then proceed to evaluate the patient’s seminal vesicle and capsular status by an endorectal MRI. The endorectal MRI is far superior to a routine pelvic MRI. We refer our patients to a center of excellence at the University of California at San Francisco (UCSF) where they employ MRI technology in combination with spectroscopy. John Kurhanewicz Ph D. and his outstanding staff have been refining this technique for years. A second site for endorectal MRI and spectroscopy is now at the University of Florida in Gainesville. The combination of MRI imaging and spectroscopic imaging is associated with a 95% accuracy rate when there is agreement between both modalities of imaging. Using the above approach, we can advise the patient on whether he has a high probability of organ-confined disease. With the above approach, we can tell the patient in good faith, that we have excluded as best as we could the possibility of lymph node disease, seminal vesicle involvement and capsular extension.

Biomarkers in Assessing the Tumor Cell Population

In addition to the risk assessment approach outlined above, we obtain blood studies on the patient for baseline biomarkers. These biomarkers may provide clues to the presence of a heterogeneous population of prostate cancer cells that often are associated with a Gleason score of seven or higher. For example, our baseline biomarker assessment of new patients would include a PSA, PAP, NSE, CGA and CEA. If these are all normal, with the exception of the PSA, we feel comfortable skipping further evaluation of these tests unless the patient has a change for the worse in his clinical course. If that occurs, we reassess these markers. However, we find that the utility of these markers is sufficient to warrant their being obtained on a routine basis in the newly diagnosed patient and especially in those patients with a high Gleason Score. There is data which suggests that the PAP is actually very valuable in predicting recurrence after radical prostatectomy. If a PAP is done, using an immunoenzymatic approach, and if it is at or above the level of three, there is a significantly increased risk of biochemical failure within the first 4 years following radical prostatectomy (Moul JW, Connelly RR, Perahia B, McLeod DG: The contemporary value of pretreatment prostatic acid phosphatase to predict pathological stage and recurrence in radical prostatectomy cases. J Urol 159: 935-940, 1998). Therefore, in our assessment, in terms of a correct way to evaluate and treat prostate cancer, we have established a sound, logical approach to evaluating the patient at baseline insofar as extent of disease, as well as to try to characterize the tumor cell population in terms of what markers the tumor cells express. If the tumor cells are expressing proteins or enzymes that are reflective of a de-differentiated tumor cell population (CEA and NSE), we are more concerned about this patient not having organ-confined disease and likely having micro-metastatic disease.

In the future new technology will be able to more properly assess the likelihood of micro-metastatic disease using RT-PCR PSA and PSMA technology. Landmark studies done by Edelstein, et.al. in Boston evaluating lymph node RT-PCR PSA, and Ferrari at Mt. Sinai in New York and Wood from the University of Michigan examining bone marrow RT PCR PSA, have shown the utility of RT-PCR technology in pointing out high-risk patients that likely have micro-metastatic disease based on finding DNA in places where this DNA does not belong, i.e., lymph nodes or bone marrow. Please realize that this technology is not commercially available at this time. However, I feel it is essential that we share with the patient what we are learning about this disease in 1998 since these tools will soon be available.

Obtaining a Baseline Hormonal Evaluation

With this foundation of knowing the extent of disease and having a basis for understanding the tumor cell population, I inform the patients that it is also important that we understand the status of their hormonal axis. We routinely obtain a serum testosterone and sex-hormone binding globulin, a DHT level, a DHEA-S and androstenedione level and a prolactin level. What do these things mean? The testosterone and its more active metabolite dihydrotestosterone (DHT) are important to evaluate if we are going to treat the patient with hormone blockade therapy (androgen deprivation therapy). We routinely see patients who other physicians have placed on androgen deprivation therapy without any assessment as to whether the androgen deprivation therapy is actually working. To confirm androgen deprivation, it is essential that we know what the baseline testosterone and DHT levels are as well as the adrenal androgen levels which are expressed as DHEA-S and androstenedione. These baseline hormone levels are also important if the patient’s therapy with hormone blockade is not achieving the desired outcome, i.e. a falling PSA. In such circumstances we often wonder whether or not the patient has had an androgen receptor mutation induced by the antiandrogen (Eulexin, Casodex, or Nilandron).

By knowing what the baseline adrenal androgens are and whether they are rising or falling in response to the antiandrogen, we can assess this issue with a high degree of accuracy. For example, in the face of antiandrogen and LH-RH receptor antagonist therapy (Lupron or Zoladex), if we were to see a patient’s PSA rising after first falling, we would want to exclude an androgen receptor mutation. We could do this by determining if the adrenal androgen levels were suppressed, since their suppression would suggest that the prostate cells are sensing the anti-androgen as an androgen. In such cases, we have a paradoxical situation where the antiandrogen is actually acting to stimulate the growth of the prostate cancer (acting as an agonist) rather than to inhibit it (acting as an antagonist). However, this paradoxical effect of the antiandrogen results in the pituitary gland sensing that there is adrenal androgen and therefore shutting down its stimulation of DHEA-S and also androstenedione. Therefore, low levels of adrenal androgens are a clue that the anti-androgen is acting as an agonist. We can then proceed with antiandrogen withdrawal (AAW), either alone or combine AAW while starting other therapy (Nizoral or Cytadren), to establish a therapeutic response. This somewhat complicated example, however, highlights the value of having baseline hormonal levels insofar as adrenal androgens.

The baseline DHT level is also very helpful in terms of assessing the effect of medications such as Proscar. We see dramatic drops in DHT with the routine use of Proscar as part of hormone blockade therapy. Of interest to those patients who equate saw palmetto (serenoa repens) with Proscar (Finasteride), is that we don’t see any drops in DHT with men on saw palmetto.

Prolactin is a known stimulator of androgen receptors and is also associated with an adverse clinical course in men with prostate cancer. Because we now have new drugs that have an anti-prolactin effect, we find it important that we assess the prolactin level as a baseline and also at times when the clinical course is changing for the worse. It is also conceivable that we should monitor and perhaps treat elevated prolactin levels of men on anti-cancer therapies that stimulate prolactin, e.g. estrogens, and Emcyt.

How does this all fit into a treatment strategy?

Given the above setting of understanding the extent of disease, the tumor cell populations that may or may not be present, and the patient’s fundamental baseline hormonal status, we can now proceed to advise the patient in an intelligent fashion. If the patient appears to have systemic disease, we then focus our attention on systemic therapy such as hormone blockade and chemotherapy. If the patient has evidence of disease confined to the prostate, we then focus our attention on local therapy with or without the use of androgen deprivation therapy to reduce the tumor burden and to enhance the effectiveness of local therapy. If we see evidence of local extension to the seminal vesicles or to the capsule, we advise the patient of our concern and we consider the use of hormone blockade therapy to reduce tumor volume followed by either external beam RT alone or in combination with a seed implant boost.

Yes, we know that there is no long-term data on this approach, but this strategy does have, as part of its value, the fact that we are addressing the treatment of prostate cancer with therapy (ies) that are tailored to the individual’s extent of disease. We have used this approach in patients treated with combination hormonal blockade and seed implants, as well as hormone blockade and cryosurgery. Preliminary results now being reported show confirmation with improved response rates and apparently decreased relapse rates. The EORTC studies on combination hormone blockade and radiation therapy in men with a high Gleason score (8, 9 and 10) and a high clinical stage (T3 - T4) indicate the superior results used in combination compared to radiation therapy alone.

Concluding Remarks

There is no way to easily tell you in a short paper how to treat an individual patient who has prostate cancer. The above is a capsulation of the approach that we use in our practice. Over the last 15 years of following patients with prostate cancer, I have found that this logical and methodical evaluation of the patient and treatment lends itself well to a greater quality and quantity of life.

 

Prostate Cancer Research Institute (PCRI)
 

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