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Prostate Cancer

PSA Leak Is Relatively Low in Undifferentiated PC

Another aspect of the PSA that may be misleading is in the setting of patients with a low PSA level that is associated with a high Gleason score, for example, (4,3) or higher. The problem here is that high Gleason score lesions, having a significant component of Gleason grade 4 or 5 PC, do not secrete as much PSA into the blood as lower grade lesions. This is called the PSA leak. Table 11 shows the PSA leak as a function of average (weighted) Gleason grade.

Here is where the Gleason score is very important in elaborating on the significance we give the PSA during the initial and subsequent evaluations of the patient. I have seen patients present with Gleason scores of 9 and 10 with low levels of PSA and yet they had large tumor volumes reflecting PC that was outside the prostate gland and not amenable to cure with local therapy.

A Microsoft Excel software program for tumor volume (which can be found on the PCRI website at www.pcri.org) shows the above relationships clearly. The program requires the b (baseline) PSA, gland volume, and Gleason score. The PSA leak is calculated from the weighted Gleason grade. The outputs of this program give you benign PSA, PC-related PSA, and calculated tumor volume. Additional integrated programs give you probability of organ-confined disease, probability of cure with RP, and likelihood of freedom from biochemical relapse at 20 months after RT.

Table 11. PSA Leak Versus Weighted Gleason Grade

The weighted Gleason grade is applicable when there are multiple core biopsies showing various Gleason scores. In such a setting, an average weighted Gleason score is determined. Half of that number would be the weighted Gleason grade. If all biopsy cores indicate (3,3), it makes no difference; the average weighted Gleason grade would, of course, be 3. In this table, an undifferentiated PC with a Gleason score of 10 would have an average Gleason grade of 5 (bolded) and a PSA leak of only 0.93, or approximately 1 (both bolded). In contrast, the most common Gleason score (3,3) having a weighted Gleason grade of 3 would have a PSA leak that is 4.26, or approximately 4 times higher. That means that for each cubic centimeter of PC, the Gleason score 10 lesion is leaking one-fourth the amount of PSA into the serum.

Gleason Grade (weighted)

PSA Leak (rounded off)

PSA Leak (exact)

5

1

0.93

4.5

1.5

1.36

4

2

1.99

3.5

3

2.92

3

4

4.26

2.5

6

6.23

2

10

9.12

1.5

15

13.33

1

20

19.49

After Aihara et al.(1994)127

Gleason Score Versus Gleason Grade

The Gleason score is composed of two grades: the primary grade and the secondary grade. The primary grade is the preponderant glandular pattern of PC as seen under the microscope. By definition, it composes a minimum of 51% of the picture and possibly as much as 95% of the picture. In contrast, the secondary grade must represent at least 5% and as much as 49% of the glandular architectural pattern.

The most common Gleason score seen in biopsies obtained during contemporary times is (3,3). Gleason scores of (4,4), (4,5), (5,4), and (5,5) make up about 17% of all PC cases.153 The Gleason score of 7 is a special situation that has significant implications depending on whether the 7 is a (3,4) or a (4,3). This distinction is based solely on the amount of Gleason grade 4 PC that is present. As previously stated, a (3,4) could have as little as 5% Gleason grade 4 disease or as much as 49%. In contrast, a Gleason score of (4,3) must, by definition, have at least 51% Gleason grade 4 disease and possibly as much as 95% (since there must be at least 5% of Gleason grade 3 PC in a (4,3) lesion). A major difference in prognosis has been found for patients with a Gleason score of (3,4) versus (4,3) located within the RP specimen.154-156 The Partin Tables for 2001 have different readings of risk assessment for Gleason score (3,4) versus (4,3) on the diagnostic biopsy specimen.157 This distinction is easily seen when using the PC Tools II software program developed by Dr. Glenn Tisman (available on the PCRI website at www.pcri.org).

In the hands of expert pathologists, focused only on PC pathology, the Gleason score identification is one of the most important biological determinants of prognosis. I have suggested that the Gleason score be embellished with what I call the Gleason differential: a quantification of the amount (in percent) of Gleason grade 4 or 5 in the pathology specimen. Therefore, a patient with a Gleason score of 7 that is (4,3) might have 95% Gleason grade 4 and only 5% Gleason grade 3 to give the following Gleason differential: GS(4,3)[95/5]. In contrast, he might only have 51% Gleason grade 4 or a Gleason differential of GS (4,3)[51/49]. Evaluations of the diagnostic biopsy material that quantitate the amount of Gleason grade 4 or 5 disease may allow for a further enhancement in the prognosis of PC.

These variables are part of the equation to determine extent and amount of PC as well as the ability to deliver specific kinds of therapy with greater or lesser probability of disease progression after completion of such therapy. Pending this kind of input, the astute physician, empowered patient, and partner can determine what other tests should be considered or discarded. Additionally, with this foundational information at hand, the healthcare team can use history to develop a risk assessment for the patient that relates to outcome: What is the probability that your treatment will be successful? Again, the latter presumes that the therapist delivering the treatment is as talented as the physicians involved in the studies that were the basis for the risk assessment.

Cross One Bridge at a Time

A common path that patients and partners as well as physicians take after a diagnosis of PC is to immediately make the choice of a treatment option the main focus. Too often, a patient goes from a diagnosis to a bone scan, often a CT scan, and then to the discussion of treatment options. The medical detective work of assessing the patient's risk for organ-confined disease versus nonorgan-confined disease is just not done routinely.

The risk assessments involved with PC take the form of multiple inputs into a statistical evaluation in which the output has more statistical significance than any single input. In such a scenario, the whole is greater than the sum of its parts. These assessments are termed algorithms, nomograms, neural nets, etc.154,158-160 They look at data in terms of searching for meaningful variables and then combine these variables to provide a closer sense of the truth about a particular patient based on how other patients with the same variables fared in a large series of patients. This is the essence of what we call the Partin Tables.

Partin et al. looked at the findings of radical prostatectomy (RP) and noted whether or not the pathologic findings showed the PC to reflect OCD, and whether there was evidence of capsular penetration (CP), seminal vesicle (SV) or lymph node (LN) involvement.104,157,161 Statistical analysis was done to determine which presurgical findings would equate with a high probability of these RP findings upon pathological review of the surgical specimens. This is the essence of many of the tools we use to assess risk for the hypothetical patient. Everyone is unique in his or her biology, but a general statement of risk can still be presented to the patient.

Unfortunately, despite the availability of this tool and many others similar to it, perhaps only 5-10% of physicians go through the discipline of doing the Partin Table and/or other algorithmic calculations. Sitting down and inputting medical variables of known significance and doing the homework involved in the risk assessment of the PC patient is a very crucial step in a logical, rational approach to this disease. Not only the patient but also the physician should be crossing one bridge at a time. When this is done, the PPP team reaches a superior understanding of the disease process and attains a greater sense of what is likely to be the reality for a particular patient.

Appendix F in the Primer goes into great depth about these diagnostic and staging variables. The reader is referred to Appendix F for further information. In addition, the May 2001 issue of the PCRI Insights newsletter contains a comprehensive review of risk assessment algorithms by Glenn Tisman, M.D. This issue can be obtained online at www.pcri.org or by calling the PCRI at (310) 743-2110. The software section on the PCRI website also has risk assessment computer programs that can be downloaded without charge.

What does all this lead to? It leads to a more accurate assessment of the patient's true status. Knowing where the PC may have spread gives direction to the PPP team to perform certain tests to exclude disease at those site(s). For example, if the algorithms show a high risk for lymph node disease, the staging process should include the monoclonal antibody scan called ProstaScint. However, if the risk is negligible for lymph node involvement, this study could be excluded. The same approach is used to evaluate disease at the different stations of involvement. Is there disease in the capsule of the prostate, the seminal vesicles, the lymph nodes, or the bones? If one finds a high probability of disease confined to the prostate, then local therapies such as RP, RT (3D conformal radiation, IMRT, seed implantation, HDR, or a combination of these radiation approaches), or cryosurgery can be used with a greater probability of success. However, there are caveats that relate to the successful use of these therapies as well.

What Does This Mean for Patients?

Algorithms involve human experiences of men who have gone before you. Take advantage of the information that others have provided you. Obtaining data from the algorithms is critical homework that must involve you and your medical coaches. Assessing your risk for PC spread to particular sites and evaluating those sites with special testing is an essential part of the successful management of the man with PC. Remember, if man does not learn from history, he is forced to repeat it.

6. Knowing Pros and Cons of Weaponry: Understanding Pros and Cons of Treatment Options

In winning a military battle, an understanding of the appropriate strategy for the situation at hand is critical for success. Military tactics, including the weapons used, must be matched intelligently to the circumstances that are present. The same is true for the management of PC and other illnesses. The most important aspect of this match is the realization that a local treatment will have its greatest chance of being curative if the biological expressions of disease suggest that it is likely that only local disease is present. Therefore, obtaining as many insights as possible into what constitutes a high probability of OCD is warranted.

The preceding sections have laid the groundwork, the reconnaissance so to speak, for the gathering of that information. The medical strategist takes these variables into account and builds a case for or against local therapy. The major algorithms such as the Partin 2001 Tables157 and the nomograms from Kattan et al.,162-164 D'Amico et al.,76,158 Narayan et al.,73 Bluestein et al.,165 Gilliland et al.,166 Lerner et al.,167 Pisansky et al.,168 and others72,109,154,159,160,169-180 should be used. These only take minutes to do and there is little to lose in seeing if a consensus is present for organ-confined disease.

If an assumption is made that a patient has a high probability of organ-confined disease and that there are no medical issues or financial issues that preclude any particular choice of local procedure to cure PC, the $64,000 question is this: "What procedure has the best track record?" Certainly, given the many publications on this subject over the last few years, one would have to state that overall there is no striking difference in success rates between any of the local therapies for PC--RP, RT of any type, or cryosurgery.181-183 The longest follow-up period after definitive local therapy relates to RP. However, it appears unlikely that the 10- and 11-year data following RT are going to suddenly deteriorate or that the 15-year data after RP are going to change. The follow-up data after cryosurgery are at most 10 years old with most of the modern-day approaches to this technique beginning in 1992 with the work of Onik and Cohen et al.184,185 The cryosurgery literature is more difficult to evaluate because in the last 10 years there have been major technological advances. These include the following:

  • The use of temperature monitoring using thermo-couples143,186,187
  • The use of double and triple freezing techniques143,186
  • The use of Argon gas188-190 instead of liquid nitrogen to induce the freezing necessary for creation of the iceball
  • The recent use of templates to guide the placement of the cryosurgery probes, similar to those used in brachytherapy191

The fine points of RP, RT, and cryosurgery are extensively dealt with in the Primer (now available through Amazon.com, Barnes & Noble, and Life Extension at (800) 544-4440).

The issue then is which of these local therapies, if any, does the patient choose. Assuming that the patient at risk is not a candidate for watchful waiting, any of these therapies might be a perfectly reasonable strategy to eradicate organ-confined or regionally confined PC. My recommendations to patients on this matter are based on the following differential factors:

  • Age
  • Overall medical status after a detailed examination
  • Patient priorities
  • Patient access to expertsin the selected modality of therapy
  • Financial and insurance issues
  • Lower urinary tract symptoms (LUTS) at the time of diagnosis
  • Prostate gland volume
  • History of scar formation (keloids) after any prior surgery
  • Baseline PAP
  • Baseline plasma TGF-b1, IL-6, and IL-6 soluble receptor levels
  • PSA response to ADT (androgen deprivation therapy) after 3 months of therapy

In essence, a combined modality analysis of sorts is being employed. This involves variables that have not been interactively evaluated as part of an effort to define the best local therapy for an individual patient. Hopefully, a true nomogram or artificial neural net (ANN) looking at such additional variables can validate their significance for such an analysis.

Some of these issues have been discussed in prior sections. A short review of each of these topics is justifiable for this section.

Age

Traditionally, patients beyond age 70 are excluded as being candidates for RP. I believe that this decision should be individualized based on the patient's health, youthfulness for his age, and the other listed factors rather than using age as an arbitrary reason for excluding a patient. I have evaluated some men in their 50s who are much older in appearance and in biological status than their stated age. I have seen others in their late 70s who appear to be in their early 60s and who are healthier on examination than men in their 60s.

Overall Medical Status After Detailed Examination

This has been alluded to in the section on medical record-keeping and the use of summary and/or surveillance forms. Patients being considered for any invasive procedure should have a thorough physical examination. Factors that place them at much higher risk for morbidity after RP, RT, or cryosurgery should be candidly discussed with the patient and his partner.192 Cardiovascular disease, Type II diabetes, kidney disease, hypertension, and neurodegenerative diseases should be red flags that an invasive procedure may be associated with greater adverse effects.192,193 The evaluation of the patient's cardiac status with triglyceride/HDL ratios194,195 as well as the conventional LDL and total cholesterol levels, the use of hypersensitive C-reactive protein,196-198 and homocysteine levels are reasonable to do in this setting (discussions of these topics can be found in several other protocols in this volume).

The use of fasting insulin levels and the ratio of AA to EPA may be an excellent screening tool to evaluate the overall health of a patient considering any of these procedures.199-202 In addition to a very thorough internal medicine history and physical examination, the studies that I have found particularly revealing include a stress echocardiogram with calculation of the ejection fraction and electron beam tomography with coronary artery calcium scoring.196

A significant factor in patients having problems with RP, RT, or cryosurgery is small vessel disease due to diabetes or hypertension. Diabetic patients represent a great challenge because of the prolonged delay in return of urinary function after any local therapy. Tissue healing is not optimal in such a setting.

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