A Strategy Of Success
in the Treatment of Prostate Cancer

PCRI Insights July, 2002 vol. 5, no. 1
By Stephen B. Strum, MD, FACP

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The PSA and PSA Dynamics

The absolute values of PSA, the changes in PSA over time, factors associated with PSA increases, and the volume of the prostate gland itself are some of the issues that enhance our understanding of what is happening with men at risk for PC or with men already diagnosed with PC.

Absolute Values of PSA – First-Time Testing
The so-called “normal” range of PSA from 0-4.0 ng/ml is no longer considered valid. First time PSA values of greater than 2.0 are associated with a diagnosis of PC in approximately 20-25% of men so studied.8 Initial first-time PSA values of less than 2.0 ng/ml relate to a state of prostate health. Such PSA values change minimally over a sequential 3 year follow- up. However, first-time PSA values of 2.0-2.99 are associated with progressive increases of PSA to = 4.0 in 6.9% of men after year 1, 15.1% of men after year 2, and 23.6% of such men after year 3 of serial PSA testing. The proportion of increase is worse when the first-time PSA values are in the 3.0-3.99 ng/ml range. Increases in PSA values to = 4.0 ng/ml in this setting are 35.7%, 57.1% and 66.0%, respectively with serial testing at years 1, 2 and 3.9

PSA doubling time (PSADT)
The history of the patient’s PSA values over years of observation, before the formal diagnosis of PC, provides important clues as to the rapidity of PC growth. This is true for most prostate cancers because the PSA level correlates well with the cancer volume. If the PSA has been done using the same assay technique (ideally in the same lab), the time it takes for the PSA to double provides valuable information about the nature of the PC. PSA doubling times of less than six months indicate a rapid cell proliferation and in such situations metastatic PC must be ruled out. Most commonly, PSA doubling times in newly diagnosed men with PC range from two to four years.

Factors Other Than PC That Elevate the PSA
In the evaluation of PSA dynamics, the medical detective must take into account factors that can elevate the PSA but are apparently unrelated to the existence of prostate cancer. For example, sexual activity with ejaculation in the 48 hours preceding a lab draw for PSA, bicycle riding or horse-back riding, instrumentation of the prostate gland with TRUSP or biopsies within the preceding six weeks, or the insertion of a urethral catheter are all explanations for increasing levels of PSA. However, these situations do not explain a persistent progressive rise in PSA over months to years. A history of prostatitis with expressed prostatic secretions showing white blood cells or bacteria, a drop in PSA in response to 4-8 week courses of antibiotics, and a DRE detecting a soft or tender prostate are clues that prostatitis may be a cause for PSA elevations and fluctuations – but prostatitis does not usually cause serially progressive rises in PSA.

PSA Trend
Therefore, the PSA trend, just like a stock market trend, is an important concept. This is true at the time of diagnosis of PC and all throughout the course of the disease. The patient and his physicians should be observing trends reflecting values over time.10 Too often we see patients flit from one treatment to the next without seeing a definite trend in the PSA or applying other tests to judge success or failure of treatment. In a different context, a man diagnosed with PC with a stable, slowly creeping elevation of PSA over years may be a good candidate for watchful waiting. All of this relates to listening to the biology and working with your physician to observe what is happening in your case.

Prostate Gland Volume
Other factors need to be brought into this analysis as well. A large prostate gland associated with benign conditions such as benign prostatic hyperplasia (BPH) contains more prostate cells.11 This results in a greater amount of benign PSA being secreted into the blood. The basic formula we use to evaluate this is:

The gland volume multiplied by 0.066
equals the amount of benign PSA.

Subtracting this result from the total PSA leaves unexplained PSA that might well reflect the PC component. For example, a hypothetical patient, Charlie Darwin, is diagnosed with PC with a PSA of 9.0. His DRE was not suspicious for PC, but his prostate gland volume, measured at the time of his biopsies using the transrectal ultrasound, was 90 cubic centimeters (cc). Using the formula above, 5.94 ng (90 x 0.066) of PSA could be attributed to BPH. Subtracting this from his PSA of 9.0 results in 3.06 ng of unexplained PSA that relates to PC until proven otherwise (Fig. 7).

Figure 7: Tumor Volume Calculation Using Gleason score, baseline PSA, Gland Volume and the Concept of PSA Leak – the Case of Charlie Darwin  In the hypothetical scenario of Charlie Darwin, a high gland volume in association with afavorable Gleason score and a baseline PSA of < 10 has resulted in a calculated tumor volume of only 0.72 cc. This low calculated tumor volume is associated with an 80% probability of organ confined PC as well as an 80% chance of cure by radical prostatectomy (RP).

If Charlie had a Gleason score (read by an expert in PC pathology) that indicated a value of (3,3) or 6, we could estimate his cancer volume using the concept of PSA leak.12 The higher the Gleason score, the less the PC cells leak PSA into the blood stream (Table 1).

Gleason Grade -weighted- PSA Leak   Rounded Exact   5 1 0.93   4.5 1.5 1.36   4 2 1.99   3.5 3 2.92   3 4 4.26   2.5 6 6.23   2 10 9.12   1.5 15 13.33   1 20 19.49   Table 1: PSA Leak vs. Weighted Gleason Grade The PSA leak relates to the amount of PSA (ng) that enters the blood stream for each cubic centimeter (cc) of PC tissue that has a specific average Gleason grade. In a patient with all biopsy cores showing a Gleason score of (3,3), his weighted Gleason grade would of course be 3. If a patient had four cores from the right lobe of the prostate with a Gleason score of 8, and two cores from the left lobe with a Gleason score of 6, his weighted Gleason grade would be: 4x8 + 2x6 divided by total number of cores (6) = average Gleason score of 7.33 with a weighted Gleason grade of 3.67 and a PSA leak of 2.57 ng/cc.

A GS of 6 is associated with a PSA leak of 4.26 ng for every cubic centimeter of PC tissue. Therefore, Charlie would have a calculated tumor volume of 3.06 ng ÷ by 4.26 ng/cc or 0.72 cc of tumor. Such a small amount of PC is associated with an excellent chance of the disease being confined to the prostate. In this situation, a methodical process of evaluation has led to treatment options that could involve RP, RT, Cryosurgery, Watchful Waiting or Androgen Deprivation Therapy. However, this is just the first chapter in our evaluation of such a hypothetical patient.

The above hypothetical story is a good one. However, PC patients may have Gleason scores of 9 or 10 with low levels of PSA and yet large tumor volumes. Charlie’s hypothetical son, Billy Darwin, when diagnosed with PC at age 54 years had the same baseline PSA of 9.0, the same clinical stage of T1c, but his gland volume was 20 cc and his Gleason score read by an expert was (5,4). The calculation for benign-related PSA for Billy Darwin indicates a value of 1.32 ng (20 cc x 0.066). His PC-related PSA would be 9.0 minus 1.32 or 7.68. With an average Gleason score of 9, his weighted Gleason grade would be 4.5 giving him a PSA leak of 1.36. His calculated tumor volume would be 7.68 divided by 1.36 or 5.6 cc (Fig. 8).

Figure 8: Calculated Tumor Volume Indicative of Low Probability of OCD (organ confined disease) – the Case of Billy Darwin.  In this scenario, a lower gland volume and a higher Gleason score relates to a large calculated tumor volume. Such a patient profile would indicate a high risk of non-organ confined prostate cancer and mandate that additional studies be done to exclude the presence of disease outside the confines of the prostate. Such studies could include PAP, a bone scan, endorectal MRI with spectroscopy, and a ProstaScint-CT fusion study.

This gives Billy a 34% chance of organ-confined PC based on the work of D’Amico et al13,14 and a 50% chance of cure with an RP based on published statistics from Stanford15 relating tumor volume to successful outcomes with RP. Of course, these are only guidelines that help the Darwins assess their status more scientifically.

The Excel software program that was used to create the worksheets seen in Figures 7 and 8 can be found on the PCRI Web site at: www.prostate-cancer.org/tools/software/tumorvol.html. The program can use your data with the required inputs of PSA, gland volume, and Gleason score to calculate the PC volume. The necessity of having a reading of the Gleason score by an expert in PC pathology will be discussed in the section “Validating Critical Data Inputs.”

The Clinical Stage (CS)
The clinical stage is often misunderstood by both physicians and patients. CS refers to the clinical impression of the amount and extent of disease exclusive of pathology findings such as the results of biopsies or of radical prostatectomy. The clinical stage, as used today, essentially reflects the findings of the digital rectal examination (DRE) of the prostate; this is essentially the T stage. Understanding that the vast majority of the urologic world equates the clinical stage with the T stage of the TNM classification is important if we are to speak one medical language. Confusing the clinical stage with the findings after pathologic biopsy or RP leads to incorrect perceptions as to extent of disease and invalidates proper strategy. The clinical stage, as it relates to the T portion of the TNM classification, is described and illustrated in the April 2000 issue of PCRI
Insights.

The clinical stage is highly subjective and many physicians (including urologists, radiation oncologists and medical oncologists) do not have great skills in discerning pathology within the prostate gland. Thus, the clinical stage (CS) is the least accurate of the three basic assessments (PSA, Gleason score, and clinical stage) that are used most often in the initial evaluation of patients. Moreover, in at least 70% of men who are newly diagnosed with PC in the USA by physicians skilled in the art of DRE, the CS reveals no evidence of PC; these patients have a CS of T1c. This is a favorable prognostic finding when present. When the CS is more advanced, it reflects more PC that may be a factor in the outcome using therapies such as RT or Cryosurgery. Such therapies are considered to tumor-volume dependent. That is, a significant factor in the success of such treatment approaches relates to the amount of PC assuming the disease is organ-confined. Therefore, for at least 30% of men with PC, the CS still is hypothetically relevant in our strategy of how best to treat PC. (Editor’s Note: In contrast, RP is felt to be tumor extent dependent. If the disease is not confined to the surgical boundaries of the RP procedure the treatment will not be curative.)

Oncogenes
There are numerous other biologic factors that have been associated with a more advanced stage of disease. These include genes relating to tumors (oncogenes) that promote cancer cell survival. Oncogenes such as bcl-2 are associated with a more advanced clinical stage.16 In addition, growth factors such as plasma levels of transforming growth factor beta-1 (TGFß-1) have recently been reported to be associated with occult metastatic disease in patients with apparent clinically localized PC.17

However, in our initial strategy with a newly diagnosed patient with PC or for a patient with recurrent disease, we can use the basic biologic tests that are readily available and still enhance our strategic skills even if we do not have the ability to explore new studies.

Virtually all of these biologic expressions are disease manifestations as they reflect interaction between the host (the patient) and the malignancy. The PSA dynamics may relate to the rapidity of disease growth: is the disease slow-growing or fast growing? The DRE may reflect the amount of tumor volume as well as provide a clue that part of the PSA is benign-related in those men presenting with large prostate glands without DRE evidence of PC. When we use such tools we are listening to the biology of cancer and enhancing our strategy of success.

Step 2. Validating Critical Data Inputs

The Gleason Score (GS)
The GS is one of the most important biologic clues that allows us to profile PC aggressiveness or lack thereof. The potential downside of the GS is that an accurate reading of the GS cannot to be taken for granted. Medicine has become more complicated, and the skills of community pathologists and even academic pathologists vary significantly. Some pathologists are highly competent in evaluating a specific disease(s), while others are not. Observer disagreement occurs even among experts, albeit not that commonly. Disagreement on GS between community pathologists and recognized experts in the field, however, is significant. Therefore, validating the Gleason score with an acknowledged expert in the field of PC is a critical part of a successful strategy.18-21 The process of validating key biological “ inputs” involved in the prognostic equation is important. Certainly, we should optimize our evaluation of the biologic process by understanding the variable talents that exist everywhere and in every field. Obtaining a second opinion from an acknowledged expert in the field of PC pathology is a worthwhile investment. A listing of some of the internationally recognized experts in prostate cancer pathology can be found on the Prostate Cancer Research Institute’s website at: www.prostate-cancer.org/resource/special.html#pathology

Step 3. Establising a Baseline

In summary, a truer picture of the patient’s status evolves when we (1) listen to the biology of PC and utilize the valuable tools of PSA and its dynamics, (2) understand the use of the clinical stage and its limitations, (3) obtain the prostate gland volume and use the appropriate calculations to determine cancer-related PSA as well as tumor volume, and (4) keep in mind that the Gleason score, one of the most important biologic expressions of prostate cancer, must be validated by an expert in PC pathology.

The patient’s medical “story” is developing as more and more clues are revealed to help us solve the mystery. There is no exact order in these strategy issues, but a picture unfolds while we obtain information. This information is our baseline, or starting point. Years ago, the baseline would have been limited to the findings of the DRE and a pathology report. Now our baseline information has evolved to incorporate biological manifestations that tell us so much more; as Paul Harvey used to say, “and now for the rest of the story.”

These baseline studies are valuable because they depict the biologic reality of the individual patient, and also because they act as critical observation or comparison points to evaluate the patient not just at the initiation of therapy, but along the entire course of his illness. How can we know how much we have helped the patient if we have no basis for comparison? We need the means to objectify our results of therapy, and when we have such findings we should use them.

Core Percentage
The number of biopsy cores that exhibit PC at the time of the diagnosis of this disease is another baseline input of significant importance. Dividing the number of cores that show prostate cancer by the total number of cores sampled yields the core percentage involvement by PC. The core percentage reflects tumor density and also contributes to our sense of tumor volume. A core percentage involvement by PC of 50% or higher has been established as an adverse prognostic finding.22-32

DNA or Ploidy
Ploidy, in the context of PC, relates to the amount of DNA present in the PC cell population being studied. A normal ploidy status, or “diploid” state, occurs when the amount of DNA within the tumor cell is normal. This is equated with the tumor cell having the full complement of chromosomes e.g. 46, since the DNA or genetic material is found within the genes that are arranged on each chromosome. Cells are either “diploid” or normal in their DNA amounts or abnormal i.e. “aneuploid.” Diploid status is more commonly associated with tumors of a low to moderate Gleason score, whereas abnormal ploidy (aneuploid) status is more commonly associated with tumors of a higher Gleason score.
However, this is not a hard and fast rule.

Although DNA analysis or ploidy is often criticized as not being a useful prognostic factor in prostate cancer, there are far more compelling studies that would suggest that the DNA status of the tumor cell population tells us much about the aggressiveness of the individual patient’s PC.33-61 Ploidy analysis can be done on the diagnostic biopsy or from PC tissue obtained at the time of RP. Normal DNA or diploidy is associated with a better prognosis and a better response to androgen deprivation therapy. Abnormal DNA or aneuploidy is associated with a higher risk for PSA recurrence after RP in a large series from the Mayo Clinic (Table 2).47,48

Progression Within 5 Years of RP (Percent)
The "Lerner Analysis		Ploidy Status
PSA Level	Gleason Score	Diploid	Aneuploid
< = 10 ng/ml	5	8%	15%
	6	15%	30%
	7	30%	42%
	8-10	42%	61%
> 10 ng/ml	5	15%	30%
	6	30%	61%
	7	42%	61%
	8-10	61%	61%
Table 2: Risk Factors for Progression in Patients with Prostate Cancer Treated with Radical Prostatectomy with Apparent Pathologically Organ-Confined Disease (OCD) Using the PSA prior to RP, the Gleason score at the time of RP and the ploidy status of the RP specimen, the risk of any kind of disease progression (biochemical or clinical) also showed significant independent correlation with the ploidy status. Recent DNA analyses have shown an excellent correlation between ploidy analysis obtained from biopsy specimens and the subsequent RP specimens. Therefore, in the setting of what appears to be organ-confined PC, the use of DNA analysis is a valuable tool for the patient and physician. Modified after Lerner et al.47

In this paper, Lerner et al clearly demonstrated the importance of ploidy as an independent prognostic factor. The 5-year relapse rates in patients undergoing RP and having “apparent” OCD were analyzed with respect to PSA, GS and ploidy status. A significantly higher rate of disease relapse was seen in patients with non-diploid tumors.

A discussion of ploidy appeared in the January 2001 issue of the PCRI Insights newsletter which is available off the PCRI website at www.pcri.org by choosing the Newsletter link. Alternatively, you can click this link.

Figure 9: Pyrilinks-D or Deoxypyridinoline The Pyrilinks-D or Dpd test is an inexpensive laboratory examination that measures a fragment of the bone matrix that is excreted into the urine. In situations of excessive bone resorption or breakdown, the Dpd is elevated. In men, this is greater than 5.4 nmoL Dpd per nmoL urine creatinine. Excessive bone resorption at diagnosis is associated with a greater risk of occult metastatic spread of PC. Increased Dpd is also commonly seen as a result of the use of androgen deprivation therapy since a lack of testosterone favors osteoclast activity and promotes the breakdown of bone.

Pyrilinks-D (Dpd)
This inexpensive urine test is an important baseline assessment. Pyrilinks-D (deoxypyridinoline or Dpd) quantitates the amount of bone breakdown or resorption (Fig. 9). Excessive resorption is associated with a greater risk of osteoporosis; moreover, at the time of diagnosis, prior to any therapy, elevations in Dpd have now been shown to be associated with metastatic disease to bone. This is not an absolute, but it is a risk factor that is put into the equation of how we assess patients and how we counsel them to comprehensively evaluate the entire disease process.62-64 Nationwide laboratories for two patient service centers doing the Pyrilinks-D (Dpd) urine test include Quest Diagnostics , and LabCorp .
Information for additional laboratories may be obtained by emailing info@dpcweb.com. For links to Quest and LabCorp, see: http://www.prostate-cancer.org/resource/links.html#Anchor-Laboratorie-20530.

Please note that the Pyrilinks-D urine test requires a sample obtained from the second voided urine specimen upon arising out of bed. It does not require a 24-hour urine specimen.

We now have tools to improve the bone environment. These are the class of compounds called the bisphosphonates of which Fosamax ® , Actonel®, Aredia® and Zometa® are examples (Table 3).
Used in combination with bone supplements such as Bone Assure® (Life Extension Foundation) and Bone Up® (Jarrow Inc), we can stop bone resorption and hopefully decrease the spread of PC to bone. If we use tests such as Pyrilinks-D (Dpd) prior to, and during treatment with bisphosphonates plus bone supplementation, we have an objective means to ascertain that the treatment has accomplished its goal. Therefore, obtaining a baseline Pyrilinks-D is an important starting point to correct what needs to be fixed within the health of the patient.

Table 3: Bisphosphonate Potency and Structure These are the five major available bisphosphonate compounds in the world today. Clodronate, Alendronate (Fosamax) and Risedronate (Actonel) are oral agents and their bioavailability is affected by gastrointestinal absorption. Pamidronate (Aredia) and Zoledronate (Zometa) are administered intravenously. However, the the Pyrilinks-D test, used to monitor the status of bone resorption, provides an assessment of the efficacy of any bisphosphonate compound.

QCT Bone Densitometry
Not only does the status of the bone environment appear to be important in the potential spread of PC, but it also appears that bone loss is an epidemic disease in men with PC prior to the initiation of any type of PC treatment. Using the superior technology of quantitative CT (QCT) bone mineral density to assess bone loss, Smith et al showed that 31% of men diagnosed with PC had osteopenia and 63% had osteoporosis. In the same patients, the DEXA scan, the so-called “gold standard” used to assess bone density, indicated that 29% of men had osteopenia while only 5% had osteoporosis.65 Apparently, arthritic changes in the lumbar spine and hip, curvature of the lumbar spine, and/or vascular calcifications in either spine or hip area falsely elevate the DEXA bone density, thus understating the degree of bone loss. QCT bone densitometry is not compromised by these common conditions and thus more accurately assesses the bone density. Establishing a baseline using the superior technology of QCT bone density scanning prior to any kind of therapy may not only enhance the outcome of the PC patient if an abnormality is detected and corrected, but it may also prevent the complications of osteoporosis. Information on QCT bone density testing sites can be obtained from Mindways Software, Inc. (1-877-646-3929 or www.qct.com) and at Image Analysis, Inc. (1-800-548-4849 or www.image-analysis.com).

Testosterone Levels
Obtaining a baseline testosterone level is basic to an understanding of PC as it relates to treatment with ADT. Too often we see men receiving therapy targeted to deprive androgens such as testosterone, DHEA-S and androstenedione and note that the patient never had a pre-treatment testosterone level or one obtained after initiating ADT. PC patients presenting with low baseline testosterone levels at diagnosis have been found to have higher Gleason scores. Schatzl determined that the mean Gleason score averaged 7.4 in such circumstances versus 6.2 when the baseline testosterone levels were normal.66 Other investigators have found a correlation between low free serum testosterone at diagnosis and more extensive PC as well as a higher percentage of PC that shows a GS of 8 or greater.67 At the opposite extreme, pretreatment serum testosterone levels greater than 500 ng/dl have been associated with metastatic relapse in men with clinically localized PC treated with RT.68

Failure to monitor serum testosterone levels after initiation of therapy directed at lowering testosterone to castrate levels may lead to a misdiagnosis of androgen independent PC (AIPC). It should not be assumed that AIPC is present in the setting of either a rising PSA, or a failure of the PSA to drop to undetectable levels (e.g. < 0.05 ng/ml) unless a castrate testosterone level has been documented.69 We and others define a castrate testosterone as < 20 ng/dl (or < 0.69 nM/Liter).70,71 Moreover, such patients suspected to have AIPC and who do have confirmation of a castrate testosterone, should also have undergone antiandrogen withdrawal (AAW) to rule out a mutation in the androgen receptor before the healthcare team entertains a diagnosis of AIPC. These issues are discussed and illustrated in the October 2000 issue of PCRI Insights (page 3, “Understanding the Endocrinology of Prostate Cancer”).

Prostatic Acid Phosphatase (PAP)
Prior to the PSA, the major biomarker of prostatic cancer was the prostatic acid phosphatase, or PAP, which is a laboratory test obtained from the serum. Many physicians have discarded the PAP while many others still use it as a differential tool in their strategic analysis of the patient. In their experience, the PAP is an important baseline test since it has predictive value regarding the success or failure of RP or RT.72-74

In a study by Moul et al, values of PAP at baseline of 3.0 or higher were associated with more than a two-fold risk of PSA recurrence after RP, even if the baseline PSA was 10 or less.73 In a study by Han et al from Johns Hopkins, a striking relationship between baseline PAP using the enzymatic method of Roy and PSA recurrence post RP was seen. In the Hopkins study, freedom from biochemical recurrence at five and 10 years after RP was 87% and 77%, respectively, for those men with normal pre-RP PAP levels defined as <0.4. However, this dropped to 79% and 65%, respectively, in men with preoperative PAPs of 0.4 to 0.5 U/liter and even further to 63% and 44% in those with baseline PAP levels of > 0.5 U/liter. This is the third study to show the significance of baseline PAP testing in the outcome of men with PC (Table 4). In current times, when translational medicine is stressed so often, such findings should be routinely incorporated into the clinical care of men diagnosed with PC. Clearly, the importance of this baseline biomarker must be emphasized and utilized in an intelligent strategy to maximize a successful outcome for the PC patient.

PAP Roy Assay	Freedom from Biochemical Recurrence after RP
U per Liter	At 5 Years	At 10 Years	p Value
< 0.4	87% (84-89)	77% (73-81)	0.0001
0.4-0.5	79% (75-83)	65% (59-70)	0.0001
> 0.5	63% (52-72)	44% (30-57)	0.0001
TABLE 4: PAP and Freedom from Biochemical Recurrence After RP In a study from the Johns Hopkins Medical Institutions involving 1,681 men, PAP levels obtained prior to RP were predictive of patient outcome.74 In this study spanning the years 1982 to 1998, the PAP methodology employed was based on an enzymatic assay described by Roy et al75 in contrast to present-day methods which use immunoassays.73 In the original paper by Roy, the mean PAP for normal healthy men was 0.28 ± 0.09 U/liter with a range from 0.11 to 0.60. Table modified after Han et al.74

Step 4. Integrating Information

Using a Combined Variable Analysis
Integrating and analyzing clinical and/or pathologic data to enhance the generation of information that is more statistically significant has been termed “combined modality analysis” by Anthony D’Amico, MD. Such an approach incorporates various biological evaluations of the patient in order to project outcomes to be used as guides for further evaluation and treatment purposes. In essence, this is a deductive process of “Given these biological facts of known significance that are unique to the patient’s situation, what can we deduce is the reality for this patient insofar as the extent of his disease and the probability of success of various treatments that may be suggested” (see Fig. 10).

Figure 10: Status Level 1 of a Strategy of Success The essence of Level 1 involves the identification of biological inputs known to be statistically significant used in an analytic milieu that generates further information of even greater significance. Tools such as algorithms, neural nets, and nomograms are processing devices. Their focus should be to facilitate an objectified risk assessment for the patient, which the patient’s physician is able to use to fine-tune the management of the patient. This formalizes the analytic process and forces those involved in the patient’s care to look at “the facts Ma’am, just the facts.” This methodological process is of paramount importance since the nomograms, neural nets and similar tools that have been available utilize the inputs and outcomes of over 20,000 human lives in their generation of new data. This is not mouse, rat or hamster data, but the experiences of men with prostate cancer that can guide other men who come after them. Thus, Level 1 embodies the philosophy of Santayana: “ Those who cannot remember the past are condemned to repeat it.”

Physicians have been using a lower intensity form of this kind of approach by observing individual variables e.g. PSA, Gleason score, etc. What scientists like Partin and D’Amico and many others have done is to combine these variables and define riskgroups that relate to particular outcomes for various therapies. In other words, what treatment will be most successful for your given biological profile. The outcomes may relate to the findings at RP such as the probability of organ-confined disease versus the presence of extra-capsular extension, seminal vesicle or lymph node involvement, e.g. the Partin Tables, the Narayan data. The outcomes may be expressed as the risk for PSA recurrence after RP, RT or seed implantation, e.g. D’Amico analyses, Kattan nomograms. Many scientists are also using additional statistical methods that go beyond analysis of multiple variables. Their analytic approaches are now being published in large numbers of papers.76-79 Approaches such as artificial neural nets that can be taught to look for patterns associated with a specific outcome are very important advances. Some of the algorithms and neural nets that we have found helpful in integrating information (baseline and validated information) are shown on the PCRI website at www.prostate-cancer.org/tools/software/software.html. These are all available for free from the PCRI website.

The output of these mathematical analyses provides what we consider a refined risk assessment. This allows your doctor either to obtain additional studies to evaluate PC spread to areas that indicate a significant risk or to forgo studies where the yield of finding such pathology is negligible. This has been discussed in a pamphlet called “Predictive and Prognostic Information in the Counseling of Patients Recently Diagnosed Patient with PC,” by Stephen B. Strum, MD. You can call the PCRI at (310) 743-2110 to request this booklet.

This refined risk assessment profile, now developed specifically and individually for a particular patient, becomes a custom profile. Rather than pigeonhole patients into broad categories, it has presented the individual patient as the unique biologic entity that he is. In addition, as mentioned previously, the patient is now taking advantage of the past history and performances of other men in similar prognostic risk categories. This historical data is the essence of what Partin et al first presented in 199380, updated in 199781 and again recently updated; this is what we call the Partin Tables.82 The Partin Tables are the prototype of combined modality analysis.

Step 5. Synthesizing All This Data to Represent a “ Refined” Analysis Based on these tests and studies, the patient-physician team now has a much better sense of what prognostic group the patient is in, what further studies need to be done, and what studies can be excluded. If the validated Gleason score is less than 7 and the baseline PSA is less than or equal to 10, multiple papers confirm that there is little value in obtaining bone scans or CT scans. If the algorithmic outputs suggest a negligible risk of lymph node involvement, there is no indication that a ProstaScint scan is needed to rule out lymph node disease. There are published algorithms and neural nets using basic inputs that refine the patient’s analysis.24,76,83-85

Further inroads into such refined risk assessments are now being made using some of the new tools that include oncogene analysis such as bcl-2, mutated p53, proliferation indicators such as MIB-1, and growth factors such as transforming growth factor-ß1 (TGF-ß1), interleukin-6 (IL-6) and its soluble receptor (IL-6sR). Also in progress are evaluations of angiogenesis or new blood vessel development of the tumor by measuring vascular endothelial growth factor (VEGF) and using treatments to reduce this vascular growth stimulator.

Step 6. Presenting Strategies to the Patient Within the Context of His Situation

The strategies described in this article present a rational way to determine which treatment option(s) is(are) indicated. However, this indication is only useful to the patient with PC if it coincides with his personal wishes. Such personal wishes include what kind of therapy he is comfortable with, if the therapy fits into what he is financially able to afford, and if it also relates to his access to healthcare providers within his insurance plan (if this is relevant in his situation). Such considerations must be taken into account all along this journey. However, other issues of a medical nature must also be brought into this equation. The overall health of the patient and his mental status are clearly aspects of refined medicine that involve patient context (Fig. 11). I have seen patients with advanced Alzheimer’s disease who were subjected to RP, others who were told to have local therapies although their PSA values were in the 80s, and still others who were subjected to RT after they have failed RP although they were never candidates for any local therapy. We need to eliminate such examples of medicine gone astray.

Figure 11: Status Level 2 and Beyond in a Strategy of Success After the initial risk assessment has been obtained and discussed in depth with the patient, refinements of staging are performed (if indicated) to rule out PC extension of disease, or to detect features suggesting a more aggressive form of PC. These findings, if present (but ignored) will usually negatively affect the outcome of therapy. After such studies are done, other patient-oriented factors must be brought into the equation to ensure that the patient is getting personalized care. The context of the patient is critical and although this concept is introduced at this level of analysis, patient context must be brought into this strategic process from the onset. Issues of gland volume and the status of lower urinary tract symptoms (LUTS), patient preferences as well as fears about certain treatment modalities, non-prostate health issues and the financial status of the patient are important examples of “context” that are critical to a strategy of success. In the words of Sir Francis Weld Peabody: “One of the essential qualities of the clinician is interest in humanity, for the secret of the care of the patient is in caring for the patient.”

The selection of therapy(ies) as part of the increasing number of treatments for PC available today is a complex subject that is outside the scope of this article. However, it can be said that along this journey that involves prevention, early diagnosis, staging and treatment, the knowledgeable and supportive care of the patient by the physician and the entire healthcare team will maximize the probability of a successful outcome. The ingredients of this recipe for success must involve a conscious tactic, a methodology, a process, a strategy of success.

(References on next page)

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