The Dimension of Time--The Importance of Trends
The so-called prediagnostic history often provides laboratory information that when properly analyzed indicates a high probability that PC was already present but unfortunately not suspected or perhaps not pursued sufficiently to establish an earlier diagnosis. We know, for example, that PSAV determinations of greater than 0.75 ng/mL a year should raise a red flag as to the presence of PC. For accuracy in analysis, such calculations should be made using one PSA assay, for example, Tosoh, DPC, Hybritech, Bayer, etc., which is being run in the same laboratory facility.Correlation of Patient Age, Total PSA, and Free PSA Percentage with the Probability of Having PC
Stability of PSA Over 10 Years of Testing in Dr. Stephen Strum
Percentage of Free PSA
||6.0 - 6.9%
||7.0 - 14.9%
||15.0 - 25%
||Probability of Prostate Cancer(%)|
|71 and older
|71 and older
These PSA values were obtained over a 10-year span. They show minimal changes which are consistent with the known literature on minute increases in PSA in the healthy prostate. The PSA slope in such situations is essentially flat. Earlier PSA levels dating back to 1987 were in the 0.7-0.8 range, but unfortunately these records were lost by Dr. Strum's former primary physician. (Always keep a backup of your medical records!)
PSAV and PSADT determinations are most valid when the PSA testing interval selected for the analysis is approximately 6 months or more. However, what is important to stress in this context is the PSA trend or slope over time. Serial PSA values showing a progressive increase in PSA should always raise concern that a biological process is occurring. It is the rapidity of such an increase that will suggest if this is a malignant or a benign process.139
The PSA increases over time associated with a healthy prostate are tiny. They amount to average increases of less than 0.1 ng/mL a year (range 0.055-0.128) of PSA in the blood.140-142 Therefore, the use of PSAV thresholds of greater than 0.75 ng/mL a year is quite generous in raising concern about the presence of PC.
The PSA trend or slope (also referred to as PSA kinetics or dynamics) is a far more important biological expression than any one PSA absolute value. Such kinetic values express active changes in the status of the PC patient over the dimension of time. Realizing that aberrations in laboratory testing do occur should mandate that, when a major change is found in a laboratory test result, repeat testing for validation purposes should be required until a definite trend is clearly seen. Too often, patients with PC are ready to make major changes in their evaluation or management based on one or two PSA changes. This also applies to other biomarkers such as PAP (prostatic acid phosphatase), CGA (chromogranin A), CEA (carcinoembryonic antigen), and NSE (neuron-specific enolase), which the physician may be using to monitor the PC patient.
TRENDS ARE IMPORTANT IN BOTH THE EVALUATION AND MANAGEMENT OF ANY ILLNESS--INCLUDING PROSTATE CANCER.What Does This Mean for Patients?
In prior paragraphs, it was emphasized that first-time PSA levels of less than 2.0 are uncommonly associated with PC and that, in such patients, PSA testing can be done every 2-3 years. Patients with first-time values of PSA that are less than 4.0 ng/mL but at least 2.0 ng/mL should not be regarded as having a PSA within the normal range. The guidelines for a normal first-time PSA are up to 1.9 ng/mL.
It was also pointed out that the PSA and its derivatives, such as PSA velocity, PSA doubling time, PSAD (total gland and for transition zone), and free PSA percentage, are instrumental in our understanding of biological reality. It is akin to the story of the three blind men feeling different parts of one elephant and describing three entirely different animals. What is needed in the elephant story, in the management of PC and other health issues, in a military campaign, and in the management of any world challenge, is an integrative way of thinking, which fosters unified concepts and embodies principles of synergy and harmony.
We also presented new findings on the free PSA percentage; it can be done on PSA levels as low as 2.0. This finding, coupled with the information on first-time PSA readings being significant when the PSA is found to be 2.0 or higher, should lead to an earlier diagnosis of PC and greater probability of cure.
Software on free PSA percentage versus the diagnosis of PC, correction for PSA results if ejaculation has occurred within 48 hours of PSA testing, and calculators for PSAV and PSADT can be found on the PCRI (Prostate Cancer Research Institute) website at www.pcri.org
. This software, PC Tools I and PC Tools II, was developed by Glenn Tisman, M.D., a medical oncologist in Whittier, California, who specializes only in PC.Assessment of the Enemy: Risk Assessment of the PC Patient
- Baseline PSA and Baseline PAP Are Keystones
- PSA Leak
- Gleason Score Versus Gleason Grade
- Cross One Bridge at a Time
- What Does This Mean for Patients
Once a diagnosis of PC is established by means of tissue biopsy and microscopic findings showing PC, the foundation of the medical record should have further information added to it to allow for an even greater understanding of the patient's true status. In this context, status refers to the actual extent of disease, or stage of disease. Is the PC really confined to the prostate gland or does it penetrate the capsule of the prostate or perhaps invade local surrounding tissues such as the seminal vesicles and nearby lymph nodes? Are there any clues that the PC has spread or metastasized to more distant lymph nodes or bone?
We know that the orientation of most specialists will be toward recommending a local therapy to eradicate PC within the gland. This is the essence of the reasoning behind the surgical removal of the prostate--RP. We realize that the other approaches toward treating PC with curative intent may be slightly more regional, but most are still designed to primarily treat the prostate gland. For example, external beam radiation therapy (EBRT) will include not only the prostate gland itself, but also a margin around the gland to kill any tumor cells that may be in this area trying to escape and spread to more distant sites. The same is true for the iceballs created by cryosurgery.143 The critical concept here is that local measures treat local disease. The determination of the true extent or stage of the disease is one of the critical variables in the strategy of successful treatment of PC. For example, if the disease is present outside the prostate gland in tissues such as the seminal vesicle or nearby regional lymph nodes (the obturator or internal iliac lymph nodes), an RP will have a significantly diminished chance in curing the patient with PC. The same is true for RT or cryosurgery. For such therapies to have a great chance of cure, the cancer must be within the scope of the scalpel, within the boundaries of the radiation ports of therapy, and within the periphery of the iceball(s) created by cryosurgery.
An additional limiting factor for radiation therapy and cryosurgery is the amount of PC. The tumor volume has a bearing on the ability of RT or cryosurgery to destroy the entire tumor mass.78,144,145 This second variable in the equation may relate to the penetrating ability of the radiation particle used (photon < proton < neutron)146-148 or to the understanding that the core of a large tumor has a diminished oxygen supply (a hypoxic center) that confers resistance (called radioresistance) to the treatment.149,150 This actually may not be as critical a factor in cryosurgery as it is in RT.
A third variable, one underdiscussed with the patient for obvious reasons, is the variability in skill of the physician, regardless of the specialty. Although it is stated that "all men are created equal," this is true in relation to their rights, but not their skills. Some physicians are just plain outright talented artists, while others are average in skill and still others are below average.
Unfortunately, all physicians quote the outstanding literature on a particular treatment but very few present to the patient their own scorecard of performance statistics. In baseball we have concepts such as Earned Run Average (ERA) to grade pitchers and batting average, runs batted in (RBIs), and errors for other players. In medicine, a scorecard has not evolved. We have no legitimate grading system for physicians. All physicians are reimbursed equally by insurance companies. However, when it comes to talent, or talent combined with caring, it is clear that all physicians are not created equal. This is the tough reality that a patient with a potentially catastrophic diagnosis has to face--and to deal with successfully--if an optimal outcome is to be achieved.
There are additional variables relating to diagnosis and staging. The number of these biological observations is increasing as we learn more and more about the cancer process. Some of these variables (that I find to be of major importance in guiding patients) include the following:
Baseline PSA and Baseline PAP Are Keystones in Our Understanding of PC
- Baseline PSA and PAP
- Gleason score read by a recognized expert in PC
- Clinical stage based on DRE
- Gland volume--the volume of the prostate gland in cubic centimeters or grams
- Core percentage involvement--the percentage of biopsy cores involved with PC
- DNA status
- AUA symptom index score and uroflowmetry
- TGF-b1 and IL-6sR
Let me make a few salient points. The PSA is a blessing. There are no other common malignancies that forecast their development through such a simple and inexpensive blood test as the PSA. But there are limitations to the PSA, as there are with everything in life.
One major limitation of the PSA is that it is a laboratory test, which makes it subject to error and to conditions that elevate the PSA and possibly result in false alarms. However, one can state safely that a healthy prostate is one not subject to progressive or persistent elevations of PSA. In such situations, if PC is not the underlying cause, then prostatitis or BPH is the cause. These conditions significantly affect the quality of life of many men. Many scientists involved with PC research also believe that prostatitis may be a precursor to PC.151,152
In regard to the laboratory errors that may occur with PSA; these may occur with all tests. The rule of thumb is that if a test shows a reading at any time that is of concern, the test should be repeated and then repeated again after a short period of time to confirm whatever trend now seems apparent. It is this persistent trend that is so important in declaring the presence of biological conditions that should concern us.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. The table 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 home page 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.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)|
Source: After Aihara et al.(1994)127Gleason 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 about17% 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 new 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.
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.Continued
. . .