Prostate Cancer-7

Effect of Pressure on the Prostate Gland and PSA Elevation

In testing the PSA over periods of time, we hope that the same laboratory is being used and that confounding circumstances are not present. The latter would include physical activity that puts pressure on the prostate and falsely elevates the PSA, e.g., bicycle riding, motorcycle and horseback riding, and any instrumentation of the rectum, e.g., an endorectal ultrasound probe or endorectal MRI study.129 The issue of the effect of strenuous exercise unrelated to pressure on the prostate gland and elevation of PSA readings remains controversial. Most studies do not show any elevation of PSA based on exercise alone,130 and some studies report no effect of bike riding on elevating the PSA.131

Knowing that the PSA obtained is a valid result and that it was not influenced by an activity that puts vigorous pressure on the prostate or by instrumentation of the rectum that affects the nearby prostate has serious implications relating to the presence of PC.


Ejaculation Can Increase the PSA
Moreover, we know that ejaculation within 48 hours preceding the PSA blood draw can elevate the PSA. The closer the time of ejaculation prior to obtaining the PSA specimen, the more falsely elevated the PSA will be.132

Table 7 shows a hypothetical patient with first-time PSA values of 2.0-2.5 where the effects on ejaculation may have accounted for elevations in PSA leading to further investigations (including prostate biopsies) that might have been unnecessary.


Importance of the First-Time PSA Value
The importance of obtaining a valid PSA determination is pertinent to whether a physician suggests further studies that may involve invasive procedures such as transrectal ultrasound with biopsies of the prostate. The absolute value of the first-time PSA also has implications insofar as the presence or absence of PC. A first-time PSA value of less than 2.0 ng/mL is uncommonly associated with PC.133,134

In a study by Crawford et al. of 11,022 subjects with an initial PSA of less than 2 ng/mL, fewer than 2.6% (287) converted to a PSA of 4 ng/mL during the 3-year follow-up period. In contrast, in 1,912 subjects with initial PSAs of 2.0 to 2.99 and in 1,147 subjects with initial PSAs of 3.0 to 3.99, the conversion rate to a PSA of 4.0 or higher was 23.6% and 66.0%, respectively (see Table 8).

First-Time PSA Levels Relate to Risk of Progressive PSA Rise and PC Diagnosis
If the first PSA level is less than 1.0 or 2.0, one has only a 1.2% or 4.5% chance of the PSA rising to 4.0 within the following 3 years, respectively. At first-time PSA levels of up to 2.99 or 3.99, the risk increases to 23.6% and 66%, respectively.

First-Time PSA Ranges in Nanograms per Milliliter (ng/mL)

a)Patient Number:6378
Mean Age:62.8
First-Time PSA Ranges
0-0.99 (ng/mL)
PSA = 4.0 by year 3* Number (%)-77(1.2%)

b)Patient Number:4644
Mean Age:63.4
First-Time PSA Ranges
1-1.99(ng/mL)
PSA = 4.0 by year 3* Number (%)-210(4.5%)

c)Patient Number:1912
Mean Age:64.5
First-Time PSA Ranges
2-2.99 9ng/mL)
PSA =4.0 by year 3* Number(%)- 451(23.6%)

d) Patient Number:1147
Mean Age:64.6
First-Time PSA ranges
3-3.99
PSA=4.0 by year 3* Number(%)-757(60.0%)

Free PSA Percentage
One additional biological consideration in the prediagnostic phase of PC is the understanding that the total PSA is composed of subunits that have special significance in raising or lowering our index of suspicion about the presence of PC. Consider an analogy of PSA being like a pepperoni pizza with the normal production of PSA from benign prostate cells represented by the basic pizza dough and cheese; this is the free PSA or benign-related PSA. The PSA associated with PC is reflected by the pepperoni; this is the complexed PSA or cancer-related PSA. The relationship of benign-related PSA to cancer-related PSA is commercially measured in a test called the free PSA percentage, which essentially reflects the ratio of benign-related PSA (free PSA) to total PSA (free plus complexed PSA).

Therefore, the greater the amount of complexed PSA there is, the lower the free PSA percentage and the more concerned we are that PC is present. The larger the amount of free PSA, the more likely the process is a benign-related one. The statistical cut-off point where we feel less concerned that PC is present is at a free PSA percentage of 25% or higher.135

The free PSA percentage is a valid test when the PSA is as low as 2.51 ng/mL.136 The free PSA percentage can even be used at total PSA levels as low as 2.0 ng/mL when special statistical tools (artificial neural nets) are employed to analyze clinical and laboratory patterns associated with a high probability of PC.137 The combination of free PSA percentage with other tools such as PSAD-TZ is a highly accurate method to diagnose PC and is independent of the potentially confounding factors of age and prostate gland volume (to be discussed later).109

Table 9 should be helpful to those concerned about a diagnosis of PC and whether their risk of having PC should justify undergoing a TRUSP with guided biopsies of the prostate gland.138

The following data are based on a study population of 428 men. This table shows only results in the PSA ranges 2.5-4.0 and 4.1-10.0. Readers may refer to the original publication138 or to the software program at www.pcri.org (PC Tools I) if their particular data fall outside of that presented in this table. Note that for a specific total PSA range and free PSA percentage, the risk of PC increases with increasing age groups.


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 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

A)Patient Age :50-59
Total PSA:2.5-4.0
Percentage of Free PSA-6.0-6.9%
Probability of Prostate Cancer(%)-84
Percentage of Free PSA-7.0-14.9%
Probability of Prostate Cancer(%)-23
Percentage of Free PSA-15.0-25%
Probability of Prostate Cancer (%)-10
Percentage of Free PSA->25%
Probability of Prostate Cancer (%)-2

B)Patient Age:60-70
Total PSA:2.5-4.0
Percentage of Free PSA-6.0-6.9%
Probability of Prostate Cancer (%)-94
Percentage of Free PSA-7.0-14.9%
Probability of Prostate Cancer (%)-47
Percentage of Free PSA-15.0-25%
Probability of Prostate Cancer (%)-25
Percentage of Free PSA->25%
Probability of Prostate Cancer (%)-6

C)Patient Age :71 and older
Total PSA -2.5-4.0
Percentage of Free PSA-6.0-6.9%
Probability of Prostate Cancer (%)-96
Percentage of Free PSA-7.0-14.9%
Probability of Prostate Cancer (%)57
Percentage of Free PSA-15.0-25%
Probability of Prostate Cancer (%)33
Percentage of Free PSA->25%
Probability of Prostate Cancer (%)-9

D)Patient Age :50-59
Total PSA -4.1-10.0
Percentage of Free PSA-6.0-6.9%
Probability of Prostate Cancer (%)-87
Percentage of Free PSA-7.0-14.9%
Probability of Prostate Cancer (%)-28
Percentage of Free PSA-15.0-25%
Probability of Prostate Cancer (%)-12
Percentage of Free PSA->25%
Probability of Prostate Cancer (%)-3

E)Patient Age :60-70

Total PSA -4.1-10.0
Percentage of Free PSA-6.0-6.9%
Probability of Prostate Cancer(%)-95
Percentage of Free PSA-7.0-14.9%
Probability of Prostate Cancer (%)52
Percentage of Free PSA-15.0-25%
Probability of Prostate Cancer (%)-29
Percentage of Free PSA->25%
Probability of Prostate Cancer (%)-7

F)Patient Age :71 and older
Total PSA -4.1-10.0
Percentage of Free PSA-6.0-6.9%
Probability of Prostate Cancer (%)-97
Percentage of Free PSA-7.0-14.9%
Probability of Prostate Cancer (%)-62
Percentage of Free PSA-15.0-25%
Probability of Prostate Cancer (%)-38
Percentage of Free PSA->25%
Probability of Prostate Cancer (%)-11

Stability of PSA Over 10 Years of Testing in Dr. Stephen Strum

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!)

Date:11/2/92 3/5/94 5/1/94 4/2/95
PSA 0.75 0.83 0.83 1.0


Date:5/17/96 4/13/97 1/26/98 2/19/98 5/14/99
PSA 0.82 0.7 0.75 0.83 0.6

Date:8/4/99 9/6/00 8/31/01 9/4/02
PSA 0.73 0.571 0.66 0.75

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. Table 10 shows my PSA values over the course of 10 years.

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.

Additional reading on the subjects of free PSA, PSADT, and PSAV can be found in the Primer published by Life Extension Media and available either by telephoning (866) 820-7457 or on the Life Extension website at www.lefprostate.org . 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.


5. RISK ASSESSMENT OF THE PC PATIENT
1)Baseline PSA and PAP
2)PSA Leak
3)Gleason Score Versus Gleason Grade
4)Cross One Bridge
5)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?

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. 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. These aspects of RT are discussed and illustrated in detail in the Primer. The reader is recommended to review pages 90-127 of the Primer to better understand these concepts.

A third variable, one under-discussed with the patient for obvious reasons, is the variability in skill of the physician, regardless of the specialty. 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.

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 include the following:

1)Baseline PSA and PAP
2)Gleason score read by a recognized expert in PC
3)Clinical stage based on DRE
4)Gland volume--the volume of the prostate gland in cubic centimeters or grams
5)Core percentage involvement--the percentage of biopsy cores involved with PC
6)DNA status
7)PSAD
8)AUA symptom index score and uroflowmetry
9)TGF-b1 and IL-6sR

Baseline PSA and Baseline PAP Are Keystones in Our Understanding of PC
The Primer goes into great depth on the importance of the baseline PSA and PAP. 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.

Everything in life is a two-edged sword.
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.