Early Recognition of Enemy Activity: Early Diagnosis of PC
What Does This Mean for Patients?
- PSAD of Transition Zone
- PSA Velocity
- Doubling Time
- Effect of Pressure on the Prostate Gland
- Ejaculation Can Increase the PSA
- Importance of the First-Time PSA
- Free PSA Percentage
- The Dimension of Time
In the prior three sections, I have presented:
- The use of measures that have been shown to prevent PC
- Medical references for using preventive measures in PC
- The need for interactive assistance in obtaining basic medical comprehension and the associated reference tools that can provide this
- How an organized medical log ties all relevant information together in an integrative fashion
Given this groundwork, what can be said about an early diagnosis of PC?
It seems uncanny that in the year 2003 we are still debating the virtues of an early diagnosis of PC by means of PSA-associated tools and the DRE.
The problem is not with the early diagnosis of this disease but with what we do with the realization of such a diagnosis in the following contexts:
1. The patient's overall biological setting
2. The skills and lack of skills of the medical professionals available to the patient
3. The constraints, if any, of the patient's personal finances or medical insurance
4. The patient's wishes in response to such a diagnosis
For example, if we were to discuss an 85-year-old man with far-advanced Alzheimer's disease, it makes no sense to pursue a diagnosis of PC unless we have reasons to believe that such a diagnosis would substantially benefit the patient. In a different situation, if a patient is diagnosed with PC and his biological findings, for example, PSA velocity and doubling times, indicate a very small tumor volume and stability of the biological process, then both nutritional and lifestyle changes can be suggested to slow the biological process. This often allows the patient to outlive the PC. We can use a strategy of watchful waiting (WW) if such a strategy involves more than burying our heads in the sand. WW does not mean ignoring biological parameters. Perhaps the term WW should have been replaced long ago with the term Objectified Ongoing Observation (OOO). Currently, more and more medical articles are pointing out the value of using a rational approach to OOO by listening to the biology of PC.91-97
We should not tell patients that making a diagnosis of PC is dangerous because of the morbidity and mortality of various invasive therapies when such therapies in the hands of the upper echelon of medical practitioners are not at all significantly associated with such adverse findings in the overwhelming majority of patients.98,99
One paradox of our modern times is the involvement of insurance carriers in the medical decision-making processes such as screening for PC, the staging of PC, and what treatment choices are available to the patient. It is not so surprising that the insurance companies wish to control this, but it is incredibly painful to observe that the physicians working for such companies would allow their professional training and judgment to be overridden by the economic needs of the insurance carrier. I believe that this reflects a conflict of interest on the part of those physicians. In my opinion, this conduct violates the Hippocratic Oath and is certainly a violation of human rights that is being tacitly accepted and therefore condoned in a supposedly sophisticated society.
Ironically, if the advisers to those insurance companies would read medical literature more carefully, they would be utilizing ways to prevent significant disease, diagnose disease early when present, and avoid the very expensive costs associated with a late diagnosis of PC and other diseases. I would attribute this to short-term vision and being "pennywise and poundfoolish." In my experience, the frightening aspect of this control over disease management by some insurance companies is that they are deferring active treatment until the patient is so far advanced that death often precedes any chance to do the patient good. I believe that the economics of the insurance carrier has invoked the pathological concept that "death is cost-effective." I have seen this too often to regard it as an aberration in dealing with organizations so motivated. Consumer advocacy and safeguarding are badly needed. The expression caveat emptor or "let the buyer beware" is operative here.
The patient's wishes--that is, the informed and educated patient and partner's wishes--must be taken into account. One unusual but true story that relates to this is that of a patient who was recently diagnosed with PC. His sex life was not at all important to him in comparison to the necessity of his feeling assured that the entire prostate gland and surrounding tissues were removed at the time of RP. Although he expressed this to his physician, and specifically his decision not to have a nerve-sparing procedure, the patient was disappointed and depressed when he realized that he had been subjected to a bilateral nerve-sparing procedure. This was not what the patient wanted. This is the only time that I have personally witnessed a man who was unhappy about having erections after a radical prostatectomy (RP). The patient's wishes had been discounted and ignored by the physician.
With all of these situations discussed, what relatively simple and inexpensive tools can be used to discern that PC might be present? How can we pick up enemy activity at an early stage?PSA Density Higher Than 0.15 ng/cc Should Raise Concern about PC
If a determination of the volume of the prostate has been made by ultrasound or some other radiological technique, we can calculate the PSA density (PSAD) or the amount of PSA (expressed in nanograms) for each cubic centimeter of the prostate volume. The PSAD is simply the serum PSA value divided by an accurate gland volume determination.PSAD = Serum PSA ÷ Gland Volume (per TRUSP or Endorectal MRI)
Some physicians are incredibly astute in having the ability to estimate the gland volume within 10% of more objective gland volume determinations that are obtained using radiological studies such as transrectal ultrasound of the prostate (TRUSP), or endorectal magnetic resonance imaging (endorectal MRI). PSAD results of 0.15 ng/cc or greater are more consistent with a diagnosis of PC than if the PSAD is less than this.100-102 There is very little in medicine that is an absolute guarantee, a definite yes or no. Therefore, it is strongly suggested that a combination of modalities be used to enhance the accuracy of any kind of assessment. This combined modality analysis was the basis for the breakthrough approaches of Oesterling103 and Partin104 and the many subsequent analyses that we use in a comprehensive risk assessment for the individual patient.PSAD of Transition Zone More Accurate Than PSAD for Diagnosis of PC
A recent improvement to the value of the PSAD is doing a PSAD of the transition zone (TZ) of the prostate; this is called PSAD-TZ. The zonal anatomy of the prostate was proposed originally by McNeal.105 He divided the prostate into three glandular zones: transition, central, and peripheral zones. The PSAD-TZ has been shown to be more accurate than a simple PSAD of the entire prostate gland.PSAD-TZ = Serum PSA ÷ Gland Volume (per TRUSP or Endorectal MRI of TZ)
In a prospective study of 559 patients, 217 men with PC and 342 with histologically confirmed BPH were evaluated with PSA, PSAD, PSAD-TZ, and percent free PSA. Multivariate analysis and ROC curves showed that PSA-TZ and percent free PSA (f/t PSA) were the most powerful and highly significant predictors of PC. Areas under the receiver operating characteristics (ROC) curve for PSA-TZ and percent free PSA were 0.827 and 0.778, respectively (p = .01). The combination of f/t PSA with PSA-TZ [Area Under Curve (AUC) = 88.1%] significantly increased the AUC as compared to each of the other parameters alone as well as their combination (p = .02). The next best combinations were PSA-TZ + PSAD, PSA-TZ + PSA, and f/t PSA + PSA.
Note: Accuracy is measured by the area under the ROC curve. An area of 1 represents a perfect test: an area of .5 represents a worthless test. A rough guide for classifying the accuracy of a diagnostic test is the traditional academic point system:
.90-1 = excellent; .80-.90 = good; .70-.80 = fair; .60-.70 = poor; .50-.60 = fail.
With regard to an individual test, PSA-TZ followed by f/t PSA and PSAD were the most powerful single predictors of PC in patients having a serum PSA between 4-10 ng/mL. The f/t PSA plus PSA-TZ was the most effective combination.107 The same findings held true for PSA values of 2.5-4 ng/mL.108PSA Velocity Reflects the Biological Activity of the PC Process
The PSA velocity (PSAV) is a statement of how fast the PSA is accelerating. It is the rate of change of PSA calculated per year of time. Therefore, if the PSA on 1/1/98 was 0.5 ng/mL and on 7/1/98 it was 1.0 ng/mL and then rose to 2.0 ng/mL on 1/1/99, the PSAV would be 1.5 ng/mL per year. The PSADT would be 6 months because the PSA is consistently doubling every 6 months. The faster the PSAV, the shorter the PSADT. Such PSA kinetics are additional inputs of information for the observant physician and/or the empowered patient and partner. Results of such tests should raise or lower suspicion about the presence of a pathologic process, that is, PC.109-111 It is important to emphasize that combining multiple sensory, or data inputs, enhances our understanding of the biology of disease. If it looks like a zebra, walks like a zebra, and has stripes, it probably is a zebra. The ability to manipulate multiple sensory inputs into an action plan for improved diagnosis and survival is a hallmark of higher-level thinking. Too often, in medicine or in life, we try to hang all of our hats on one hook. The PSAV has also been shown to be an important determinant in survival in patients with Androgen Independent PC (AIPC) or so-called hormone refractory PC.112
The more data points in these determinations and the longer the time period over which a trend is maintained, the greater the validity of such calculations.113,114 The important concept underlying the above is the persistent generation of PSA by the tumor cell population reflecting itself in the bloodstream and determined by repeated testing.PSA Doubling Time Reflects Tumor Growth
The PSAV tells us how rapidly the PSA is increasing per year. The PSADT tells us the length in months it takes for the PSA to double in amount. All of the mathematical derivatives of serial PSA testing are expressing the biological process.115 The average PSADT of PC is approximately 48 months, or 4 years. Men with an absolutely healthy prostate gland do not have any appreciable PSADT; their PSA levels remain essentially flat over decades of observation. Men with BPH have very slow PSA doubling times--usually over 12 years.
Men presenting with historical data showing PSADT of less than 12 years must be presumed to have PC until proven otherwise.116 The PSADT in men with histologically established PC is a valuable tool in:
- The management of PC (watchful waiting versus active treatment).97,117,118
- The prediction of extent or stage of disease.119
- The correlation of PSADT with normal versus abnormal DNA (ploidy).120
- The probability of local recurrence and metastatic disease after local treatment.121-124
The same concept of the PSA doubling time paralleling the biological growth rate of the tumor may be applied to other biological markers of PC malignancy. Biomarkers such as PAP (prostatic acid phosphatase), CEA (carcino-embryonic antigen), CGA (chromogranin A), and NSE (neuron-specific enolase) may be expressed in PC variants that usually are associated with high Gleason scores, for example, 8-10.125,126 In such patients, the expression of PSA in the blood or serum may not be great. This has been referred to as the PSA leak.127 The PSA leak in high Gleason score PC is relatively low. For example, a Gleason score of 10 has a PSA leak of approximately 1.0 mg/cc versus 4.0 mg/cc for a Gleason score of 6.
Therefore, in patients with a Gleason score of 8-10, the PSA becomes less of a reliable marker of disease activity. Some tumors may show evidence of dedifferentiation and express relatively little PSA despite other findings of PC activity such as a progressive bone scan, bone pain, and elevations in alkaline phosphatase and lactic dehydrogenase (LDH) as well as other tests. This is uncommonly seen in newly diagnosed PC unless the disease has been diagnosed late and the chance of mutation affecting the PC population has occurred. Such patients with a late diagnosis often present with PSA levels greater than 20 and not uncommonly greater than 50. The probability of disease outside the prostate is greater in such patients, again reflecting the more aggressive nature of the PC cell population.
Therefore, we learn about a tumor based on the biological activity it manifests. In a likewise fashion, in our military metaphor, we learn or should learn about the enemy based also on the degree and nature of their activity.
The same principle involving biomarker kinetics has value in the monitoring of patients with various common malignancies. Important concepts in the use of biologic markers are to obtain blood at baseline after the diagnosis is established to see what markers the tumor is producing and to monitor the patient's course after treatment to ensure that any elevated marker(s) have returned to normal levels and that they remain there.128 This is the same principle used in the evaluation of PC and monitoring the response to all types of therapy. Is there troop activity, and if so, is it persistent and to what degree? This is a simple tool that should be regarded as an excellent means of assessing biological activity. It is the laboratory version of a seismograph.Biomarkers That May Reflect Tumor Activity in Major Cancers and Blood Diseases
Biomarkers are products of the tumor cell that play a functional role in the growth, spread, or sustenance of the tumor cell population. As tumor activity increases, tumor volume also increases, which often is mirrored in the level of the biomarker.
Ejaculation Increases the Serum Prostate-Specific Antigen Concentration
||CGA, CEA, NSE, TGF-b1, IL-6sR, CA 125|
||CA-15-2, CA 27-29, CEA, TPA
||BCA225, CA 549, MCA|
|Lung (non-small-cell lung cancer)
|Lung (small cell lung cancer)
||CEA, CA 19-9, CA 72-4
||CEA, CA 19-9
||IgC, IgM, light chains
A patient undergoing PSA testing might be inadvertently channeled into a full PC work-up--with biopsies--if attention was not paid to his history of sexual activity with ejaculation prior to the drawing of the blood sample for PSA. If his apparent PSA was 2.0, this effect is substantial in all time periods up to 48 hours. If the apparent PSA was 2.5, the corrected PSA would only have significance for the ejaculation 1 hour prior to laboratory testing. The bottom line is: do not do PSA testing within the 48-hour period following ejaculation.
|Apparent PSA (ng/mL)
||Hour(s) Prior to PSA Testing When Ejaculation Occurred
||Corrected PSA (ng/mL)|
Source: Data from Tchetgen et al.(1996)132Effect 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
The above table 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.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)|
|PSA > 4.0 by year 3* Number(5)
* Cumulative by year.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
The next table 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.Continued
. . .