by Stephen B. Strum, MD, FACP
Medical Oncologist and PCRI Co-founder
Edited from PCRI Insights August, 2008 v 11.3
In Part I and Part II of this series, I presented an in-depth discussion of key issues relating to the chemoprevention of PC, and I discussed in depth the results of the PCPT (Prostate Cancer Prevention Trial) published in 2003, as well as preliminary results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) Trial from 2004. I related my surprise and disappointment that the highly significant findings of these trials had not been translated into the every-day care of men at risk for PC. Coincidentally, beginning shortly after publication of Part II, a number of peer-reviewed articles and news briefs have been published attesting to the value of finasteride (Proscar) in the prevention of PC. These articles provided evidence-based medicine to dispel prior findings that using finasteride in the chemoprevention of PC leads to the development of high-grade PC.1-5
Will these articles finally spark the use of finasteride in academic and community circles? This remains to be seen. What is clear to me, however, is that if we are to advance in our understanding of the prevention, diagnosis, staging and treatment of PC, we should not tolerate a lag time averaging ten years or more between presentation of key advances and their implementation. Over the 45 years I have been involved in cancer research and treatment, this lapse has been the rule, and rarely the exception. The only force with the potential to change the lugubrious pace in medical advances is that coming from the PC patient community, as we should have learned from the AIDS movement in the USA. Can we utilize those advances relating to the diagnosis and staging of PC — two of the foundation stones relating to the concept of “Status Begets Strategy”?
This is the topic of discussion in this Part III, and in future installments in this series.
Diagnosis of PC
In my opinion, and without any question of doubt, the discovery and use of PSA has been the most important occurrence that has changed our understanding of this disease. In the realm of diagnostic importance, PSA still rules supreme, but there are some relatively “new” kids on the block, such as PCA3 and EPCA, which I will discuss later. The serum PSA and its derivatives such as Free-to-Total PSA ratio , PSAV (PSA velocity), PSA slope, PSA doubling time (PSADT), and PSA density (PSAD), provide significant insights into a man’s status where a diagnosis of PC is the main concern. However, in this area and closely related ones, there are controversial issues that merit discussion of whether or not a man has PC. These are:
1. The “normal range” of PSA between 0.0 – 4.0 ng/ml
2. Recommendations not to check PSA
3. The use of free-to-total PSA percentage
4. The use of nomograms and neural nets in PC diagnosis
5. The use of PSAV, PSADT, and PSAD
My contention is that there is no normal range of PSA. Seeing a patient present with a delayed diagnosis of PC because the internist, GP, FP or other clinician waited until the PSA was greater than 4.0 is a sad event. This is even more the case with aggressive high-grade PC where PSA production by the tumor cell population is decreased.6 The take-home-lesson for PSA is whether the PSA slope is flat, rising, or decreasing in regard both to the issue of the diagnosis of PC, and to virtually all settings relating to PC status.
It is true that a man with repeated PSA values of ≤ 1.0 will have a healthy prostate gland 99% of the time. However, a solitary value in that range does not tell us about what biological events are in progress within the gland; we can only glean that information by knowing the PSA values over time in order to establish status. This need to incorporate the context of time is not only true of PSA in determining whether PC is present, but also for just about all biological – social – human-related events ranging from CO2 emissions in the atmosphere to how well or badly your stock is doing. Here is where the value of the chart, flow sheet or graph becomes paramount. This graphical approach is the most obvious means to alert the patient-partner-physician team to the presence of a problem: seeing an unmistakable serial increase in the slope of the PSA, or any other marker shown to be of importance in PC. Figure 1 depicts this obvious cause for alarm.
Given today’s computer technology, there is no reason that we cannot routinely portray biological values graphically, or at least as a slope value. What we have done is to sacrifice the patient’s chances of an early diagnosis and cure of their illness in exchange for either being too lazy or forgetting to utilize this important tool in our arsenal. All laboratory reports should be presented with slope findings. The most painful reminder of the cost of not doing this occurred when I reviewed the records of one of my former employees who asked for help after her mother was diagnosed with cancer of the stomach. A review of her medical records preceding this diagnosis by years showed (1) a serial fall in the mean cell volume (MCV) of her red blood cells (which reflected the development of iron deficiency) and (2) a serial fall in hematocrit from high-normal to normal, to low-normal, and then to abnormal. These findings, if made obvious to the practitioner, would have beckoned for a diagnostic workup that hopefully would have led to an upper endoscopy that would have indicated gastric cancer – before the disease had spread to the lymph nodes and liver!
In the context of a man with a one-in-six lifetime risk of PC, the take-home-lesson is to obtain a baseline PSA when the man reaches age 40, or age 35 if he has a family history of PC or breast cancer, and to recheck the PSA at reasonable intervals (yearly initially) until a PSA slope or trend is established. If the slope is found to be flat, then continue to sample the PSA at appropriate intervals throughout all of that man’s history. Table 1 below shows my PSA values that have been taken over the course of almost 20 years.
Table 1: PSA Values of Stephen Strum from 1989 to 2008.
The values show a general consistency despite the fact that they involve the development of new testing approaches (assays) for PSA such as Yang, Tosoh, and DPC. The potential trend of the last three values (0.60, 0.80, 0.93) mandate the need for a repeat test in the very near future.
These values were not all obtained using the same PSA assay due to the ongoing improvement in assays over the last 20 years. I strongly recommend that (1) you use the same assay, (2) obtain the PSA either in the morning or in the afternoon, (3) restrain from any activity involving ejaculation for 48 hours prior to testing, and (4) not be involved in any examination of the prostate or any athletic activity exerting pressure on the prostate area, e.g. bicycle riding. Although my last three PSA values (obtained between 2006 and 2008) are normal, I do need a repeat value(s) in light of the possible upward slope that may be starting. I concur with the saying that you teach what you need to learn.
I have been shocked to see articles advising men NOT to have PSA testing, stating that this will lead to a treatment such as RP (radical prostatectomy), RT (radiation therapy), Cryosurgery, or HIFU (High Intensity Focused Ultrasound) that could harm the patient and impair his quality of life (QOL). This may be a reality that relates to any kind of human interaction insofar as the quality of a service to be delivered. But it is ridiculous to confuse cause and effect insofar as the value of an early diagnosis of PC.
An early diagnosis of PC, at any age, is a meaningful milestone in the potential welfare of the patient because prostate health is too intimately associated with bone integrity, vascular integrity, lipid abnormalities, the status of carbohydrates, fatty acids and vitamin D, neurologic and male sexuality, and urinary flow issues. In other words, a diagnosis of PC serves as a signal that although not every man with a PC diagnosis needs to be treated, all certainly should be evaluated for co-existing illnesses – illnesses that if unrecognized and untreated may lead to a further decline in health and possibly to death. The fact that more men die with PC than from PC is a testimony to the validity of this statement. Read through the first six Physician’s Notes in The Primer on Prostate Cancer by Strum and Pogliano and especially focus on Note 6: ”Good comprehensive PC management often leads to the marked overall health of the patient.” If 95% of men newly diagnosed with PC have osteopenia or osteoporosis,7 and if such loss in bone density has been shown in hundreds of peer-reviewed articles to be associated with cardiovascular disease, renal disease and neurologic disease,8-15 then we can perform a huge service to the man with PC by at least focusing our attention on such issues – even if it is determined that no invasive therapy is indicated for the treatment of the PC–the illness that brought the patient to the physician.
Moreover, our decision on whether or not to treat an individual patient with PC should be based on the context of that patient. It should take into account factors such as age, mental status, co-existing illnesses, healthcare costs and access to skilled physicians who may be the principals involved in an invasive procedure. For this reason, I have repeatedly stated that the major ingredients in the successful management of a man with PC are:
1. Selection of the Patient.
2. Choice of a Therapy Appropriate for that Patient.
3. Selection of an Artist.
4. Supportive Care of the Patient Throughout the Entire Life of the Patient.
The PSA derivative called Free-PSA is actually a percentage of the ratio of Free-PSA to Total-PSA. The Total-PSA is made up of the Free-PSA in addition to bound or complexed PSA. It is complexed because it is attached to a protein called alpha chymotrypsin (ACT). Therefore, the Free-PSA Percentage = Free-PSA divided by (Free-PSA + Complexed-PSA) with the result multiplied by 100. Values over 25% are most consistent with a benign process, while those less than 15% are worrisome for a diagnosis of PC. Those values in between are in a gray zone.
All the biologic inputs that present circumstantial evidence that PC is likely or is not likely should be used as part of the medical detective work involved in the diagnosis of PC. I have found the Free-PSA percentage to be of great value in the diagnostic dilemma of “does this man have prostate cancer?” One potential exception to this is if the patient has significant prostatitis; in this case, the free PSA percentage may be quite low, even less than 10%.16-20 However, the PSA slope is entirely different in the context of prostatitis versus PC. Figure 2 shows the typical up and down pattern of prostatitis. There is no trend line that shows serial progression in PSA that is characteristic of PC.
It is disturbing that although there are plentiful papers defining the value of the Free-PSA percentage to help in ruling in or ruling out a diagnosis of PC, I find that this test is often not ordered in many patients, especially in those with low but serial increasing PSA levels.21-23 Catalona et al showed the value of the Free-PSA percentage in the PSA range of 2.6 to 4.0 and a normal DRE, but for no obvious reason, this test is usually forgotten in this context. In this important study, all cancers detected were clinically localized, and 81% that were surgically staged by RP were pathologically organ confined.24 In another study by Catalona et al involving men with total PSA levels of 4.0-10.0 and a normal DRE with a gland volume less than 40 cm3, the use of a Free-to-Total percentage threshold of 14% or less would have eliminated 79% of unnecessary biopsies.25
Even less utilized is the use of the Free-PSA percentage over time. In longitudinal evaluations of Total- and Free-PSA (using frozen serum) among men who were diagnosed with PC in the pre-PSA era, Pearson et al demonstrated that Total-PSA increases while the Free-PSA percentage decreases over the decade prior to the diagnosis of PC. If a Free-PSA percentage cut-off of < 10% is used as a marker for PC, the longest lead time of 9.7 years was obtained. Unfortunately, at this cut-off there were too many false positive predictions of PC among the control cases, especially for Total-PSA values of < 2.0 ng/ml. This resulted in a low specificity of 59%. But, with a Free-PSA percentage cut-off of < 12%, when Total-PSA levels were 4.0 or higher, the specificity for predicting a correct diagnosis of PC was 94%.26 The average curves for Free-to-Total PSA in control and PC patients over a 14-year span are shown in Figure 3.
Rarely do I see physicians monitoring this PSA derivative in undiagnosed patients who are suspected of having PC. Thus, at least part of the PC diagnostic mindset, in my opinion, should be one of seeing a PSA trend showing a rising slope reflecting serial increases in Total-PSA, and then confirming that concern by seeing a Free-PSA percentage that is less than 25%, and most often in the 15% or less range. And, if a diagnosis is not established after biopsy, the physician should repeat the Free-PSA percentage (to see if this value is dropping further); if so, it would alert the physician to maintain a red alert status – and to utilize other tests that should lead to a timely diagnosis of PC.
On the Prostate Cancer Research Institute website, there is a free software program (PSA II analysis within Partin/Narayan Table analysis) at
http://prostate-cancer.org/tools/software/pctools.html. This enables the user to input the total PSA, Free-PSA percentage, and age of the patient and determine the probability of PC. This nomogram is based on the study by Chen et al who found a low probability (< 15%) of PC when the Free-PSA percentage was > 25%, in contrast to more than 90% likelihood of PC for men with a Free-PSA percentage of < 7% at total PSA levels between 2.5 and 20.0 ng/ml for all ages.27
The nomogram that most patients and physicians are familiar with is the one by Partin et al that uses PSA, clinical stage and Gleason score to predict the findings at RP. There are many nomograms and some neural net programs that deal with the full scope of the genealogy of PC – from prevention to diagnosis, to assessment of stage and prediction of findings at RP, to determinations of local versus systemic recurrence after RP, to results of treatment modalities such as RP and RT, and to predicting results in the setting of advanced disease. These applications use a combination of clinical and pathologic findings for a particular patient to derive more statistically significant outcomes compared to what can be obtained from any single variable (biologic input).
The philosophy involved in the above mindset is “don’t hang all your hats on one hook”. D’Amico attempted to popularize the importance of nomograms with the phrase “combined variable analysis”. The topic of nomograms was discussed in great depth in the May 2001 and November 2005 issues of Insights. Artificial Neural Nets (ANNs) utilize a pattern recognition approach simulating the human brain. Sometimes the variables involved in ANNs may appear to make little sense, but the ANN is programmed to look for patterns associated with a particular outcome. Examples of three different ANN programs forecasting the likelihood of (1) cancer spreading outside the prostate, (2) lymph node involvement and (3) PSA recurrence after RP are available on the Internet at http://www.prostatecalculator.org. Check it out.
Approximately 10 years ago, Babaian et al published a highly provocative article describing the use of an ANN called the ProstAsure Index to diagnose PC.28 The patients studied were men with a total serum PSA of 4.0 ng/ml or less and a normal DRE. The input variables were patient age, total PSA, total creatinine phosphokinase (CPK) isoenzymes, and PAP (prostatic acid phosphatase). The sensitivity (true positive/(true positive + false negative)) of the ProstAsure Index was 93%. The specificity (true negatives/(true negatives + false positives)) was 81%. In this study, when the Free-PSA percentage was compared to the ProstAsure Index, it showed a sensitivity and specificity of 80% and 74%, respectively, using a Free-PSA percentage cut-off of 15% or less. A graphic portrayal of the performance of ProstAsure versus Free-PSA percentage using receiver operating curves (ROC) is shown in Figure 4. Unfortunately, this most important advance to assist in the diagnosis of PC was never realized due to lack of approval of this test by the FDA.
Babaian’s work was continued with additional training sets of data from three medical institutions, along with additional biologic inputs of Free-PSA percentage to create a new ANN called PCD-I (Prostate Cancer Detection Index). A comparison of the specificity of PCD-I with % fPSA, PSAD (PSA density), and PSAD-TZ (PSA density of transition zone) when sensitivity was held constant at 92% revealed that the specificity of the PCD-I was significantly better (p <0.0001). This is shown in Table 2.
Babaian et al noted that if the threshold to recommend a biopsy is lowered to a PSA value of 2.5 ng/mL, approximately 100,000 additional prostate biopsies would be performed annually. If PCD-I was used instead of the %fPSA, 46.8 million dollars (excluding any test charge differences) would be saved annually (39,000 biopsies/year X $1200/biopsy). Sadly, PCD-I has never been approved for clinical use in the detection of PC.29
T h e PSA assay became commercially available for use in 1987. Within a few years of its use in the clinical management of patients, it was clear that PSA was one of the key ingredients in understanding the biologic process we call PC. Evidence for this is seen by the incorporation of PSA into virtually all nomograms and neural nets involving this disease.
What are forgotten too often by physicians and patients alike, are the basic behavioral characteristics of prostate cancer that are part and parcel of the concept of profiling. As a malignant cell population expands, it does this essentially in a geometric fashion – one cell dividing into two, two into four and so on. Cancer cells do die along the way but the basic growth pattern is geometric and is called Gompertzian growth, named after the self-educated British mathematician and actuary Benjamin Gompertz (1779-1865). Gompertz observed that a law of geometric progression was an inherent part of different tables of mortality for humans. His equation described an exponential rise in death rates between sexual maturity and old age – an essential law of mortality that was first among the reliable empirical tools for describing the dying out process of living organisms – including cancer cells.30
A second feature of the cancer cell population is that it is no different than the normal cell population in its push to elaborate a myriad of molecules that act to further the survival of each cell. Prostate-specific antigen is such a cell product with vital functions to both the normal prostate epithelial cell (it liquefies the ejaculate) and to the malignant prostate cell (it is a protease enzyme that helps break down the basement membrane to allow cancer spread). The test we call PSA involves determining PSA levels in the serum; its level(s) reflects the number of PSA producing cells (benign and malignant) and also, in the context of a malignancy, the nature of the PC population. These are the basics for explaining the utility of the tests labeled as “PSA derivatives”, which include PSA velocity (PSAV), PSA doubling time (PSADT), and PSA density (PSAD), to name three of the most important ones.
PSA Velocity (PSAV)
In the Primer on Prostate Cancer, we stated that a PSADT shorter than 12 years and a PSAV greater than 0.75 ng/ml/year relate to a greater probability of a malignant condition. After years of involving many patient calculations (pun intended), I would now maintain the PSADT threshold but would reduce the PSAV threshold for concern about PC to 0.3 ng/ml/year, perhaps less. I emphasize – strongly – to use many hooks upon which to hang your hat for diagnosing PC. The pitfall that is painfully obvious involves putting full emphasis on one particular manifestation of PC, be it the Total-PSA versus Free-PSA percentage, etc. Using a single biologic input is terribly disappointing when it comes to the act or art of profiling. Using PSA kinetics is only a part of the MD (medical detective) work that is the essence of the discipline of PC medicine, but for me, it remains highly valuable.
In 1992, Carter et al pointed out that the average PSAV in men without subsequent evidence of PC was 0.02 ng/ml/yr, while for those with BPH it was 0.1 ng/ml/yr, and for those with PC, it was 0.3 ng/ml/yr.31
In a landmark study published in 2007, Berger et al32 evaluated longitudinal PSA changes during a 10-year observation period in a screening study involving a cohort of 4,272 men without evidence of PC and a cohort of 528 men who eventually developed PC. In those men without evidence of PC, the mean PSAV was 0.03 with the actual PSA mean levels increasing from 1.16 to 1.49 ng/ml during the 10 years. Of the 528 men with PC, the mean PSAV was 0.39 ng/ml/yr. In that group, the PSAV 8-10 years before diagnosis was 0.225 ng/ml/yr in comparison to 0.98 ng/ml/yr in the two years before diagnosis (Figure 5).
Berger et al’s study also showed that in men eventually diagnosed with PC, the PSAV starts to increase in the six-year period prior to diagnosis and that the PSAV was greater (median 0.53) in patients with pathologic stage T3-T4 cancer than for those with pathologic organ-confined PC (median 0.32.)32 The similarities in PSAV findings between the 2007 Berger et al study and those of the 1992 Carter et al study are striking.
D’Amico et al used the PSAV results obtained one year prior to RP (radical prostatectomy) to identify men at mortality risk. They showed that a PSAV greater than 2.0 ng/ml/yr resulted in a shorter time to death from PC (p< 0.001) (See Figure 6) and death from any cause (p = 0.01). Additional factors that also correlated with a shorter time to death included a Gleason score of 8-10, total PSA level at diagnosis, and a clinical stage of T2. In this crucial study, up to 28% of men died of PC in the seven years that followed an RP that was preceded by a PSAV of greater than 2.0 ng/ml/yr.33
The value of PSAV, in my opinion, is sufficiently established by these two seminal studies. This important biologic parameter should be routinely evaluated in the profiling of patients with a major consideration being the implementation of some form of systemic therapy in those men found to be at greater risk for death due to PC.
In 2006, Berger et al published the results of their study relating pre-diagnostic PSAV to tumor volume and to subsequent PSA recurrence post-RP. Although these findings do not relate to the topic of “Diagnosis”, further discussion is warranted in the context of discussing the value of PSAV at this time. At five years after RP, the median PSAV in men with relapse was 1.98 ng/ml/yr compared to 1.05 ng/ml/yr in men who had no evidence of disease five years after RP. The median tumor volume in those men with recurrence of any kind post-RP was 2.55 cm3 +/- 4.17 compared to 0.94 cm3 +/- 1.23 in men without PC recurrence. The median PSAV in those with tumor volumes greater than 1.0 cm3 was 2.03 ng/ml/yr versus 1.1 ng/ml/yr when tumor volumes of 0.51 to 1.0 cm3 were found. The PSAV for primary tumors 0.5 cm3 or less was 0.59 ng/ml/yr. These findings are summarized in Table 3.34 It is clear that an understanding of PSA velocity is helpful to determine not only a man’s risk for PC but also to assess the degree of aggressiveness that would relate to the need for intensive interaction in contrast to an approach involving non-invasive measures.
PSA Doubling Time (PSADT)
In the many thousands of calculations I have done for PSAV and PSADT, I have found consistent value by utilizing these PSA derivatives. PC cells secrete PSA and the number of PC cells obviously relates to the tumor volume as well as to the proliferation (growth) rate of the cancer cell population. It then stands to reason that any index of PSA, either rate of increase (PSAV, PSA slope, lnPSA slope (see below)) or of rapidity of doubling of the PSA amount (PSADT) can provide valuable insights about the status of the patient during the entire course of PC, from diagnosis to death. Yet rarely do I see such calculations in the medical records of PC patients, despite 25 years of work in this field. I believe that the major reason for this is the lack of an easy-to-use electronic tool that can be readily accessed by mathematically challenged physicians involved in PC care.
As this article was being submitted for publication, I was fortunate to have a collegial interchange with Luigi Benecchi. His group recently presented their findings at the AUA (American Urological Association) meeting this year in Orlando on the value of the lnPSA slope (the natural logarithm of the PSA slope). As shown in Table 4, using ROC analyses, they found that the lnPSA slope showed better results then PSA, PSAV, PSA slope and PSADT in discerning men with PC than in control patients.(Benecchi 2008 abs, Benecchi 2008 optimal measure paper58,59).
Dr. Benecchi and his colleagues from Parma, Italy have made available a very user friendly software program as an Excel spreadsheet to perform these calculations. This is available at: http://www.urologiaparma.com/lnPSAslope.htm
The pitfalls in these calculations relate to the need to use the same laboratory methodology (assay type)35,36 (1) to obtain the PSA samples either in the a.m. or in the p.m.) due to some reports of diurnal variations in PSA,37) (2) to obtain sufficient numbers of sampling points at reasonable intervals (at least three PSA levels and ideally at six-month intervals), and (3) to ensure that no ejaculation occurs for 48 hours prior to PSA testing.38,39 Bicycle riding and other situations (such as those mentioned in Section 1) that may raise PSA remain controversial issues.40-49 I avoid the above issues by advising patients to defer from any potentially confounding situation and to remind physicians to obtain PSA levels prior to any manipulation of the prostate gland.
Of course, PSA-related calculations have little meaning in the setting of levels that are up and down due to prostatitis or that are lowered by 5-alpha reductase inhibitors like finasteride (Proscar) or dutasteride (Avodart). After the PSA has reached its nadir due to the use of such drugs, the PSA values then take on renewed meaning and calculations can be performed.
Most students of PC would agree that a short PSADT of < six months is correlated with highly aggressive PC and a high risk of mortality due to PC. In an Egawa et al study of established patients with PC, a PSADT of < three years was associated with pathologic T3 disease at RP.50 The impact of a short PSADT on PSA progression is shown in Table 5 in a hypothetical patient starting with a PSA of only 1.0.
In the context of using PSADT as a high risk factor for the diagnosis of PC, I do not recall seeing a single patient where multiple PSA values obtained with the same laboratory and showing a DT of < 12 years who was not eventually diagnosed with PC. Clearly, we do not have to hang all of our hats on any PSA kinetic value and we can use multiple inputs such as Free-PSA percentage, PCA-3, DRE, family history of PC, PSA slope, and PSAV to determine if systematic and targeted biopsies should be performed.
A diagnosis of PC is important to establish even if so-called definitive (potentially curative) treatment, e.g. RP, RT, Cryo, or HIFU is NOT performed. Because PC is linked with so many other medical problems that affect morbidity and mortality, an early diagnosis and appropriate evaluation of PC can result in significant improvement in the quality and quantity of a man’s life. Thus, an early diagnosis of PC becomes an impetus to look closely at a man’s status regarding bone integrity, renal disease, cardiovascular disease, endocrine status, erectile and urine flow status, and neurodegenerative disease, to name the most important linked issues.
Most of the published studies on PSADT evaluate its value in the setting of response to local treatments such as RP or RT, or in the response to salvage therapies or treatment with ADT. In 1998, McLaren et al evaluated PSADT in the setting of observation involving 113 untreated men with PC. PSADT was found on multivariate analysis to strongly correlate with clinical progression (P < 0.0001), stage progression (P = 0.01), and time to treatment (P = 0.0001). As shown in Figure 7, approximately 50% of patients with a PSADT of < 18 months progressed within six months.51
More recently, Klotz et al have also used the PSADT as one of the measures to assess men in an active surveillance setting. They selected a PSADT threshold of greater than three years as one of the parameters to direct patients into the surveillance arm, while advising those with a PSADT of less than or equal to three years to seek radical intervention. The mean PSADT in their series of 231 patients was 7.0 years.52 Patients on the active surveillance arm had close monitoring of serum PSA and periodic repeat prostate biopsies at years 1, 4, 7 and 10 years. In another series of patients treated in this way, 65% have remained free of treatment at eight years, and the PC-specific survival was 99.3% at eight years.
It would stand to reason that if PSADT is being used in this manner in a context of already diagnosed PC, the same approach, or at least part of it, could be used in men where a timely diagnosis of PC is of concern. I have used this approach as part of a risk assessment “package” and find that the threshold of PSADT < 12 years works nicely along with other medical detective adjuncts (PSA velocity, PSA slope, PSAD, DRE, PCA-3, Free-PSA percentage, family history of PC or breast cancer) to help identify men needing focused studies to rule in or rule out PC. Optimizing this evaluation involves understanding the need for multiple variables biologic inputs) to do superior profiling. If it looks like a duck, walks like a duck, quacks like a duck, has webbed feet and feathers, then you can be pretty sure it’s a duck.
PSA Density (PSAD)
PSAD is calculated by dividing the total PSA by the prostate gland volume. The gland volume for this determination is almost always determined by TRUSP (transrectal ultrasound of the prostate), but there are a few published articles on PSAD using the results of magnetic resonance imaging (MRI).53 My experience with PSAD is that it provides another bit of information that is helpful in ascertaining whether PC may be present, as well as in giving prognostic information if one confirms a diagnosis of PC by tissue biopsies.
On the PCRI website (www.pcri.org) at the URL (http://prostate-cancer.org/tools/software/tumorvol.html) is an Excel software program that calculates tumor volume based on total PSA, PSA leak and gland volume. An integral part of this software is the calculation that the prostate gland volume x 0.067 equals the amount of benign-related PSA, (i.e. that produced by normal prostatic tissue). This benign-related PSA, subtracted from the total PSA, should equate with excess PSA – that produced by the PC, assuming that inflammation is absent. The term PSA leak takes into account the finding that as the Gleason score becomes higher, there is less PSA leaked into the blood.6 The excess PSA divided by PSA leak is thus used as a calculation of tumor volume.54
I have found this quite useful and often highly consistent with the pathology findings in men who undergo RP. I believe that the concept of PSAD should take into account the contribution of the gland volume insofar as the production of benign PSA and the excess PSA that reflects the PC volume. In Table 6, we show the same PSA of 6.0 in 4 different men presenting with different gland volumes: 20 cc, 40cc, 50 cc and 80 cc. The malignant PSA divided by a PSA leak of 4.26 (presuming the Gleason score is 6) is shown as calculated tumor volume.
The PC in the small gland is of greater concern than that in the large 80cc gland for a given PSA. But these same principles should also have relevance in relationship to the likelihood of the presence of biologically significant PC in any man concerned about a possible diagnosis of PC. My advice is to review as many of the biologic variables that are available and to weigh their value in the context of the full picture. Is the PSAD 0.15 or higher, and if so, what about the Free-PSA percentage, PSADT, PSAV and ideally PSA slope? Use as many of these parameters along with family history, DRE findings, and even calculate a tumor volume based on what you might expect if PC were present, assuming the most commonly found Gleason score of 6.
For the most part, a review of the literature indicates that PSAD has value in the diagnosis of PC. Kawai et al showed that at cut-off values of 0.15 for PSAD and 25% for Free-PSA percentage, the combined use of both of these biologic inputs resulted in a sensitivity of 100% and specificity of 46.5%. That means that there would be approximately 50% false-positive impressions that PC would be present when in fact the biopsies would not show any evidence of PC.55 A combination of PSAD of > 0.15 and a PSA slope of > 0.75 was related to more than a 3.5 times probability of detecting PC in contrast to values less than 0.15 and 0.75, respectively.56 At a PSAD of 0.18 or more, a sensitivity of 70% and a specificity of 67% for the diagnosis of PC was reported by Gohji et al.57
The tools presented represent reasonable assumptions that seem to work in the reality of the man with PC. As the PC population grows almost exponentially, so does the PSA level. This results in elevations of PSA velocity and increases in PSA slope with subsequent shortening of the PSA doubling time. As the PSA increases in the setting of underlying PC, the PSAD increases. If this goes unchecked, then the status of a normal DRE degrades into one revealing a palpable abnormality reflecting an increasing tumor volume. In time, this decreases the chances of finding organ-confined PC. What is astounding is that given the use of TRUSP since about 1985, and PSA since 1987, the above-described tools are not used as often as they should be and the development and implementation of ANNs incorporating these variables are seldom seen.
I am hopeful that leaders in the field of ANN in PC will continue to contribute new programs that show usefulness in the diagnosis and evaluation of PC. It is planned that future installments of this series on What We Should Have Learned About PC will cover the topics of:
Imaging Issues in the Diagnosis (Dx) of PC
• Variability in TRUSP (transrectal ultrasound of the prostate) equipment and in the nature of ultrasound (gray scale vs color Doppler vs contrast enhanced Doppler)
• Variability in skill of ultrasonagrapher (choice of an artist issue)
• Need for a standard reporting format for ultrasound report
• Lack of use of endorectal MRI with spectroscopy along with lack of FDA approval of 3Tesla magnets (utility in targeting areas that need to be biopsied)
Pathology Issues in the Dx of PC
• Systematic 5-region biopsy should be mandatory
• Pathologists and Urologists fail to identify biopsy cores as to anatomic site, or even left versus right
• Need for accreditation of experts in pathology of PC
• Need for a standard reporting format for diagnostic biopsy
• Use of PCA-3 and EPCA (early prostate cancer antigen)
1. Thompson IM, Tangen CM, Parnes HL, et al: Does the level of prostate cancer risk affect cancer prevention with finasteride? Urology 71:854-7, 2008.
2. Thomas LN, Douglas RC, Lazier CB, et al: Levels of 5alpha-reductase type 1 and type 2 are increased in localized high grade compared to low grade prostate cancer. J Urol 179:147-51, 2008.
3. Redman MW, Tangen C, Goodman P, et al: Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res Online, 2008.
4. Pinsky P, Parnes H, Ford L: Estimating rates of true high-grade disease in the Prostate Cancer Prevention Trial. Cancer Prev Res Online, 2008.
5. Lucia MS, Darke AK, Goodman P, et al: Pathologic characteristics of cancers detected in the Prostate Cancer Prevention Trial: implications for prostate cancer detection and chemoprevention. Cancer Prev Res Online, 2008.
6. Aihara M, Lebovitz RM, Wheeler TM, et al: Prostate specific antigen and Gleason grade: an immunohistochemical study of prostate cancer. J Urol 151:1558-64, 1994.
7. Smith MR, McGovern FJ, Fallon MA, et al: Low bone mineral density in hormone-naive men with prostate carcinoma. Cancer 91:2238-45, 2001.
8. Burnett JR, Vasikaran SD: Cardiovascular disease and osteoporosis: is there a link between lipids and bone? Ann Clin Biochem 39:203-10, 2002.
9. Carr JJ, Register TC, Hsu FC, et al: Calcified atherosclerotic plaque and bone mineral density in type 2 diabetes: The diabetes heart study. Bone 42:43-52, 2008.
10. Demer LL: Boning Up (or Down) on Statins. Arterioscler Thromb Vasc Biol 21:1565-1566, 2001.
11. Parhami F, Basseri B, Hwang J, et al: High-density lipoprotein regulates calcification of vascular cells. Circ Res 91:570-6, 2002.
12. Parhami F, Garfinkel A, Demer LL: Role of Lipids in Osteoporosis. Arterioscler Thromb Vasc Biol 20:2346-2348, 2000.
13. Parhami F, Morrow AD, Balucan J, et al: Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 17:680-7, 1997.
14. Watkins BA, Li Y, Lippman HE, et al: Omega-3 Polyunsaturated Fatty Acids and Skeletal Health. Experimental Biology and Medicine 226:485-497, 2001.
15. Watson KE, Abrolat ML, Malone LL, et al: Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 96:1755-60, 1997.
16. Game X, Vincendeau S, Palascak R, et al: Total and free serum prostate specific antigen levels during the first month of acute prostatitis. Eur Urol 43:702-5, 2003.
17. Jung K, Meyer A, Lein M, et al: Ratio of free-to-total prostate specific antigen in serum cannot distinguish patients with prostate cancer from those with chronic inflammation of the prostate. J Urol. 159:1595-8, 1998.
18. Nadler RB, Collins MM, Propert KJ, et al: Prostate-specific antigen test in diagnostic evaluation of chronic prostatitis/chronic pelvic pain syndrome. Urology 67:337-42, 2006.
19. Scattoni V, Raber M, Montorsi F, et al: Percent of free serum prostate-specific antigen and histological findings in patients undergoing open prostatectomy for benign prostatic hyperplasia. Eur Urol 36:621-30, 1999.
20. Villers A, Chautard D: [Free PSA: its routine use is premature in the screening of prostatic cancer]. Prog Urol. 10:618-21, 2000.
21. Finne P, Auvinen A, Aro J, et al: Estimation of prostate cancer risk on the basis of total and free prostate-specific antigen, prostate volume and digital rectal examination. Eur Urol 41:619-26; discussion 626-7, 2002.
22. Lujan M, Paez A, Miravalles E, et al: Prostate cancer detection is also relevant in low prostate specific antigen ranges. Eur Urol 45:155-9, 2004.
23. Recker F, Kwiatkowski MK, Huber A, et al: Prospective detection of clinically relevant prostate cancer in the prostate specific antigen range 1 to 3 ng./ml. combined with free-to-total ratio 20% or less: the Aarau experience. J Urol 166:851-5, 2001.
24. Catalona WJ, Smith DS, Ornstein DK: Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 277:1452-5, 1997.
25. Catalona WJ, Smith DS, Wolfert RL, et al: Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 274:1214-20, 1995.
26. Pearson JD, Luderer AA, Metter EJ, et al: Longitudinal analysis of serial measurements of free and total PSA among men with and without prostatic cancer. Urology 48:4-9, 1996.
27. Chen YT, Luderer AA, Thiel RP, et al: Using proportions of free to total prostate-specific antigen, age, and total prostate-specific antigen to predict the probability of prostate cancer. Urology 47:518-24, 1996.
28. Babaian RJ, Fritsche HA, Zhang Z, et al: Evaluation of ProstAsure index in the detection of prostate cancer: a preliminary report. Urology 51:132-6, 1998.
29. Babaian RJ, Fritsche H, Ayala A, et al: Performance of a neural network in detecting prostate cancer in the prostate-specific antigen reflex range of 2.5 to 4.0 ng/mL. Urology 56:1000-6, 2000.
30. Olshansky SJ, Carnes BA: Ever since Gompertz. Demography 34:1-15, 1997.
31. Carter HB, Pearson JD, Metter EJ, et al: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 267:2215-20, 1992.
32. Berger AP, Deibl M, Strasak A, et al: Large-scale study of clinical impact of PSA velocity: long-term PSA kinetics as method of differentiating men with from those without prostate cancer. Urology 69:134-8, 2007.
33. D’Amico AV, Chen MH, Roehl KA, et al: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 351:125-35, 2004.
34. Berger AP, Deibl M, Strasak A, et al: Relapse after radical prostatectomy correlates with preoperative PSA velocity and tumor volume: results from a screening population. Urology 68:1067-71, 2006.
35. Komatsu K, Wehner N, Prestigiacomo AF, et al: Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology 47:343-6, 1996.
36. Zhang L, Loblaw A, Klotz L: Modeling prostate specific antigen kinetics in patients on active surveillance. J Urol 176:1392-7; discussion 1397-8, 2006.
37. Mermall H, Sothern RB, Kanabrocki EL, et al: Temporal (circadian) and functional relationship between prostate-specific antigen and testosterone in healthy men. Urology 46:45-53, 1995.
38. Herschman JD, Smith DS, Catalona WJ: Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology 50:239-43, 1997.
39. Tchetgen MB, Song JT, Strawderman M, et al: Ejaculation increases the serum prostate-specific antigen concentration. Urology 47:511-6, 1996.
40. Batislam E, Arik AI, Karakoc A, et al: Effect of transurethral indwelling catheter on serum prostate-specific antigen level in benign prostatic hyperplasia. Urology 49:50-4, 1997.
41. Erdogan K, Gurdal M, Tekin A, et al: The effect of urethral catheterisation on serum prostate- specific antigen levels in male patients with acute urinary retention. Yonsei Med J 44:676-8, 2003.
42. Hua LX, Wu HF, Sui YG, et al: [The effect of acute urinary retention on serum prostate specific antigen concentration]. Zhonghua Nan Ke Xue 8:134-5, 2002.
43. Kratz A, Lewandrowski KB, Siegel AJ, et al: Effect of marathon running on total and free serum prostate-specific antigen concentrations. Arch Pathol Lab Med 127:345-8, 2003.
44. Lechevallier E, Eghazarian C, Ortega JC, et al: Effect of digital rectal examination on serum complexed and free prostate-specific antigen and percentage of free prostate-specific antigen. Urology 54:857-61, 1999.
45. Luboldt HJ, Peck KD, Oberpenning F, et al: Bicycle riding has no important impact on total and free prostate-specific antigen serum levels in older men. Urology 61:1177-80, 2003.
46. Oremek GM, Seiffert UB: Physical activity releases prostate-specific antigen (PSA) from the prostate gland into blood and increases serum PSA concentrations. Clin Chem 42:691-5, 1996.
47. Ornstein DK, Rao GS, Smith DS, et al: Effect of digital rectal examination and needle biopsy on serum total and percentage of free prostate specific antigen levels. J Urol 157:195-8, 1997.
48. Rodriguez-Rubio FI, Robles JE, Gonzalez A, et al: Effect of digital rectal examination and flexible cystoscopy on free and total prostate-specific antigen, and the percentage of free prostate-specific antigen. Differences between two PSA assays. Eur Urol 33:255-60, 1998.
49. Ulman C, Buyukyazi G, Taneli F, et al: Recreational and master athletic activity does not affect free and total prostate-specific antigen levels but lowers the free-to-total prostate-specific antigen ratio. J Int Med Res 32:583-9, 2004.
50. Egawa S, Arai Y, Tobisu K, et al: Use of pretreatment prostate-specific antigen doubling time to predict outcome after radical prostatectomy. Prostate Cancer Prostatic Dis 3:269-274, 2000.
51. McLaren DB, McKenzie M, Duncan G, et al: Watchful waiting or watchful progression?: Prostate specific antigen doubling times and clinical behavior in patients with early untreated prostate carcinoma. Cancer 82:342-8, 1998.
52. Klotz L: Active surveillance with selective delayed intervention: a biologically nuanced approach to favorable-risk prostate cancer. Clin Prostate Cancer 2:106-10, 2003.
53. Graser A, Heuck AF, Sommer B, et al: MRI-based PSA density and PSA density of the transitional zone compared with PSA alone: correlation with prostate cancer Gleason score. J Comput Assist Tomogr 30:891-5, 2006.
54. D’Amico AV, Chang H, Holupka E, et al: Calculated prostate cancer volume: the optimal predictor of actual cancer volume and pathologic stage. Urology 49:385-91, 1997.
55. Kawai M, Okajima K, Kobayashi K, et al: [Combined use of PSA density and free to total PSA ratio for cancer detection from patients with PSA elevations]. Hinyokika Kiyo 52:113-7, 2006.
56. Keetch DW, McMurtry JM, Smith DS, et al: Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J Urol 156:428-31, 1996.
57. Gohji K, Nomi M, Egawa S, et al: Detection of prostate carcinoma using prostate specific antigen, its density, and the density of the transition zone in Japanese men with intermediate serum prostate specific antigen concentrations. Cancer 79:1969-76, 1997.
58. Benecchi L, Pieri AM, Pastizzaro CD, et al: LnPSA slope. J Urol 179:644-645, Abst 1877, 2008.
59. Benecchi L, Pieri AM, Destro Pastizzaro C, et al: Optimal measure of PSA kinetics to identify prostate cancer. Urology 71:390-4, 2008.