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CAUTION: Some readers will find this protocol technically challenging. It is written for both the patient and the attending oncologist.

Proper "Staging" and Use of Hormone Blocking Therapy

The sections below are written by Stephen B. Strum, M.D., and Jonathan E. McDermed, Pharm.D., of the Prostate Cancer Research Institute (PCRI) in Los Angeles, California. Dr. Strum is on the Life Extension Medical Advisory Board. Drs. Strum and McDermed are proponents of a holistic medical strategy that combines peer-reviewed conventional scientific publications with new findings in the areas of nutrition and supportive care of the patient.

The Extent of Disease or Stage

Our current ability to assess disease is compromised by issues of resolution; what you see is not always what you have. The approach to "early stage" PC is confused by the fact that so-called "early stage" PC is frequently not early. In other words, what appears to be localized PC is often beyond the confines of the prostate gland. Our assessment of cancer extent (staging), in general, is often incorrect. That is, we underestimate the extent or stage of the cancer with the tools that we currently have available.

If we are to categorize PC as "early," we need to scrutinize men newly diagnosed with PC and optimally use the available staging tools. If PC is not confined to the prostate, then local therapies such as radical prostatectomy (RP) and radiation therapy (RT) will not eradicate or cure the disease. If PC is verified to be confined to the prostate (organ-confined) to the best of our ability, then a second important variable must be considered if local treatment is to be successful-the volume of the cancer. If the volume is too great, local RT-be it external beam RT, seed implantation, or cryosurgery-will not likely eradicate the disease. Therefore, two significant variables must be addressed for local therapy to optimally eradicate disease. These are:

• Extent of disease: Organ-confined versus non-organ confined.
  
• Volume of disease: Minimal tumor burden versus moderate-large tumor burden.

These basic tenets are true for the vast majority of malignancies, not just for PC. Determination of the extent of disease is called "staging." The determination of the volume of cancer is often incorporated into staging. However, the volume of the disease plays a very important role in the ability of local therapies such as RT (external beam RT or brachytherapy) and cryosurgery to cure a patient with PC (Bostwick et al., Urology, 1993; Babaian et al., J. Urol., 1995).

Basic Biological Principles

We believe staging involves a logical, stepwise approach that reflects an understanding of the important variables in the way a malignancy behaves. A malignancy expresses itself by virtue of a growth curve that is essentially logarithmic. This means that a tumor cell basically divides from one to two, from two to four, from four to eight, and so on. In reality, there are a certain number of tumor cells that are dying off during this process. Therefore, it is not exactly logarithmic, but close; the medical name for this growth curve is Gompertzian.

We measure proteins or antigens that are associated with malignant tumor cell growth. These proteins or antigens are called biomarkers, since they mark the biological activity of the tumor process. The most commonly used biomarker in PC is the prostate-specific antigen, or PSA. However, PSA is not the only marker of PC disease activity or aggressiveness.

PSADT, PSAV, and PSA

PSADT

PSA is currently the key antigen used in assessing PC. Measurements of PSA over time express a logarithmic pattern when PC is present. In this way, PC can be identified years before it may be suspected by an abnormal digital rectal exam (DRE). A calculated PSA doubling time (PSADT) provides the first clue to the presence of a malignant process. In cases of PC, the PSADT is shorter than 15 years (Stamey, Quebec City, 1995; Berry et al., J. Urol., 1984). Most PC tumors have PSADTs in the 4- to 10-year range. When a PSADT in this range is documented, the physician's burden of proof is to exclude the presence of PC.

PSAV

PSA rates of increase (PSA velocity or PSAV) of 0.75 ng/ml/year or greater reflect production of a cell product consistent with malignancy (Carter et al., JAMA, 1992). Therefore, the rate of increase of PSA and its doubling time can indicate the presence of malignancy. A PSADT of less than 6 months most often represents a rapidly growing malignancy consistent with systemic spread of disease; i.e., it is not localized to the prostate and is likely to have spread to the lymph nodes and/or bone marrow (Fowler et al., Surgery, 1994; Fowler et al., J. Urol., 1995). Software applications for determining the PSADT and PSAV are available for download at the PCRI Web site [http://www.prostate-cancer.org]. There are no charges for these and other programs.

Take-home Lesson 1 PC is often wider spread than believed at diagnosis. Is the PC organ-confined? Medical expertise currently underestimates the volume of cancer. Is the PC of low volume? The aggressiveness of cancer is significantly manifested in its growth rate. What are the PSAV and PSADT?

PSA

The amount of serum PSA is proportional to the tumor cell mass. There are modifying factors involved, however. These include PSA leak into the serum, which is related to Gleason score, and the contribution to the serum PSA from the benign component of the prostate. Therefore, additional ingredients to staging include the absolute PSA value, and the rapidity of PSA increase. PSA values at diagnosis of greater than 25 ng are more often associated with PC outside of the gland, involving seminal vesicle, lymph node, or bone. PSA values greater than 8 at diagnosis are associated with a lower percentage of cures using modalities such as RT or RP (Lattanzi et al., Int. J. Radiat. Oncol. Biol. Phys., 1997). Therefore, the PSA absolute value becomes an important discriminant regarding likelihood of organ-confined disease, and hence cure, with a local therapy. This basic information has to be taken into account in any discussion on the value of RP and RT as well as any comparison studies of RP with RT. The story gets more complex, but it is rational and understandable.

The Gleason Score

There are other variables that relate to cell behavior that must also be taken into account. The most important of these is reflected in the microscopic appearance of the tumor and is called the Gleason score (GS). The higher the GS, the more aggressive the tumor. For a detailed description of the GS, please visit the PCRI Web site [http://www.prostate-cancer.org]. The GS should be read by an expert in the pathology of PC to be most valid. The above Web site also has listings of expert pathologists in the field of PC. Paradoxically, with a GS of 8 to 10, there is less PSA leakage from the tumor cell into the serum (Aihara et al., J. Urol., 1994). This may result in a low serum PSA level despite a large volume of tumor. The table below relates the Gleason weighted grade to the PSA leak (Aihara et al., J. Urol., 1994).

Table 1: PSA Leak vs
Weighted Gleason Grade

Gleason grade (weighted)	PSA leak
5	1
4.5	1.5
4	2
3.5	3
3	4
2.5	6
2	10
1.5	15
1	20

To determine the weighted Gleason grade, you need to know the GS resulting from biopsies taken from areas of the gland that were positive for PC, assuming the GS from these areas was different.

If the GS was [3,2] from the right lobe, and 3 of 3 cores biopsied were positive, and if the GS was [3,3] for the left lobe, and 2 of 3 cores biopsied were positive, the weighted GS would = 5 (GS from right lobe) × 3 (# of cores positive) + 6 (GS from left lobe) × 2 (# of cores positive) divided by 5 (number of cores involved). Therefore, in this case the weighted GS would be (5 × 3 + 6 × 2)/5, or 27/5 = 5.4. The weighted GG is half of the weighted GS, or 2.7. The paper relating GG to PSA leakage into the serum unfortunately does not give us exact values for intermediate GG. Therefore, we can only estimate that the PSA leak for a weighted GG of 2.7 is halfway between that for 2.5 and 3.0, or 5. We use the gland volume determined at TRUSP to calculate benign-related PSA and cancer- specific (cs) PSA. This is shown below for a TRUSP volume of 60 cc and a PSA of 7.2 (D'Amico et al., Int. J. Radiat. Oncol. Biol. Phys., 1996; D'Amico et al., Urology, 1997; Marks et al., Urology, 1994).

PSAcs = cancer-specific PSA = PSAtotal - PSAbenign
PSAbenign = epithelial fraction × PSA/cm3 of

epithelial tissue × TRUSP volume

Values for epithelial fraction are 0.2 (after Marks et al.) and 0.33 for PSA per cm3 of benign tissue.

Therefore, if we have a TRUSP volume of 60 cm3, we multiply this by 0.066 (product of 0.2 × 0.33) to get PSAbenign = 3.96. Benign PSA values per TRUSP volume are precalculated below for your convenience.

Table 2: Benign PSA per Gland Volume

TRUSP volume	PSA benign
volume in cc or gm	ng/ml
20	1.32
25	1.65
30	1.98
35	2.31
40	2.64
45	2.97
50	3.3
55	3.63
60	3.96
65	4.29
70	4.62
75	4.95
80	5.28
85	5.61
90	5.94
95	6.27
100	6.6

 

The benign PSA is subtracted from the total PSA to give excess of PSA cs. The PSA cs = 7.2 - 3.96 or 3.2.

That is, for every 5 ng/ml of serum PSA for this particular patient with a weighted GG of 2.7, there is 1.0 cm3 of tumor tissue that relates to producing this value in the serum. Therefore, we divide the PSA cs by 5 to get the cancer volume. In this case it would be 3.2/5, or 0.64 cm3 of tumor.

Therefore, men with verified Gleason scores of 8 to 10 need to be aware that the PSA reading may be misleadingly low, and that, in some cases, there may be no PSA secretion of the tumor cell into the blood despite active disease of significant tumor volume. It is clearly essential in the evaluation and management of the man with PC that an accurate Gleason score be obtained. In most studies of PC, the GS is the most important of all clinical and pathologic variables relating to prognosis. A serious pitfall in our current evaluation of PC is a GS that is incorrectly read.

Take-home Lesson 2 The GS is the most important single variable in the natural history of PC. Always verify the GS by a second opinion with a PC pathology expert.

Clinical Stage (CS)

The other important variable, alluded to above, is the tumor volume or tumor burden. At diagnosis, the tumor burden is reflected in the PSA, the findings of digital rectal exam (DRE), the number of biopsy cores involved, and the extent of core involvement. The DRE findings are expressed in the clinical stage (CS). This is also discussed at the above Web site in the paper called "Treatment Options for Prostate Cancer Patients with Early Disease." We commonly see the patient and the physician confused when it comes to the CS. If the DRE does not reveal a palpable abnormality worrisome for PC, then the CS is T1c. If the DRE is abnormal and consistent with PC confined to the prostate, the CS is T2. Within the T2 category, the subset designations of T2a, T2b, and T2c reflect the extent of the abnormality palpated. If there is a palpable area of abnormality that is 50% or less of one lobe of the prostate, the CS is T2a. If there is more than 50% of one lobe involved by PC, the CS is T2b. If both lobes are involved, the CS is T2c. If the DRE reflects disease that is outside the prostate, the designation T3 is used. T3a CS means unilateral (one-sided) extracapsular extension, whereas T3b means bilateral extracapsular extension. T3c means seminal vesicle(s) involvement. Finally, T4a disease means that tumor invades the bladder neck, or external sphincter, or rectum, whereas T4b indicates that PC invades the levator muscles and/or is fixed to the pelvic wall. The clinical stage, or CS, is used in the Partin and Bluestein algorithms for assessing extent of disease. What are algorithms?

Take-home Lesson 3 Understand the jargon used in PC medicine. It is your link to a higher communication with your medical coaches. Communication of critical issues is essential to patient empowerment.

Algorithms: Tools for Risk Assessment

Clinical and pathologic variables interact with one another to give us additional information. Such a process where combinations of 2 or more variables yield information more significant than any one variable is called an algorithm. The algorithms are important buoys to help us navigate through the confused seas encountered in the staging of PC. A description of the process of using the algorithms to derive a risk assessment in the newly diagnosed patient is found in the paper entitled "Predictive and Prognostic Counseling in the Newly Diagnosed Patient with Prostate Cancer" at the PCRI website [http://www.prostate-cancer.org]. It is important to realize that data derived from these algorithms result from almost 13,000 human clinical experiences-not from mouse models of PC or studies of PC cell lines grown in petri dishes. Algorithms may involve the newly diagnosed patient, or they may relate to the patient anywhere in the natural history of the disease. In the setting of newly diagnosed men with PC, these authors statistically analyzed preoperative variables that could predict for final pathologic stage. They concluded that the combinations of preoperative variables were of greater value than any single variable. Most of these studies employed a statistical maneuver called multivariate analysis. These algorithms are usually published with tables or graphs. Below is a listing of some of the studies employing this concept involving over 12,000 human experiences!

Table 3: Patients Enrolled in Various Studies
Involving Predictive Algorithms

Senior Author: Institution	# of Pts	Reference
Partin: Hopkins, Baylor, MI	4,133*	JAMA 277: 14451451, 1997
Bluestein: Mayo	1,632*	J Urol 151: 13151320, 1994
Lerner: Mayo	904*	J Urol 156: 137143, 1996
Narayan: U of Florida	813*	Urology 46: 20521, 1995
Eastham: Baylor	766*	J Urol 157: 298, 1997
Partin (II): Hopkins	542	Urology 43: 649659, 1994
Pisansky: Mayo	500	Cancer 79: 337344, 1997
D'Amico: Harvard	480*	Cancer J Sci Am 2: 343, 1996
Dugan: Mayo	337*	JAMA 275: 288294, 1996
Huncharek: Mass General	300	Cancer Invest 13: 31-35, 1995
Bostwick: Mayo, Baylor, Wash U, Laval	186*	Urology 48: 4757, 1996
Oesterling: Mayo Clinic	852	JAMA 269: 5760, 1993
Powell: Wayne St, Michigan	369*	Urology 49: 726731, 1997
Kleer: Mayo Clinic	945*	Urology 41: 207216, 1993
Total	12,759
*Refer to studies involving 10,565 radical prostatectomy patients.

What does all of this lead to? It leads to a more accurate assessment of the patient's true status. Knowing where the PC may have spread gives direction to the patient-physician team to perform certain tests to exclude disease at those site(s). For example, if the algorithms show a high risk for lymph node disease, the staging process should include the monoclonal antibody scan called ProstaScint. If the risk is negligible for lymph node involvement, this study could be excluded. The same approach is used to evaluate disease at the different stations of involvement. Is there disease in the capsule of the prostate, the seminal vesicles, the lymph nodes, or the bones? If one finds a high probability of disease confined to the prostate, then local therapies such as RP, RT (external beam using 3D conformal techniques, or seed implantation or a combination of both), or cryosurgery can be used with a greater probability of success. However, there are caveats that relate to the successful use of these therapies as well.

Take-home Lesson 4 Algorithms involve human experiences of men who have gone before you. Take advantage of the information that others have provided you. Obtaining data from the algorithms is critical homework that must involve you and your medical coaches. Assessing your risk for PC spread to particular sites and evaluating those sites with special testing is an essential part of successful management of the man with PC.

Three Basic Ingredients of Successful Cancer Management

All treatments in cancer medicine are associated with a skill factor. In this respect, a treatment should be regarded as the "message," with the physician or technician performing them regarded as the "messenger" for that specific treatment or therapy. It is ignorant to believe that all urologists can do a radical prostatectomy with an equal degree of excellence, that all radiation oncologists have equivalent skills, or that all medical oncologists plan and execute chemotherapy treatments equally well. When we became superselective in our choice of consultants for RP, SI, and EBRT, the incidence of adverse side effects changed drastically. For example, the 40 to 50% significant incontinence rates that we had previously seen after RP became less than 1% when we directed patients to the very best urologists. Newer procedures such as cryosurgery have even fewer highly skilled physicians able to perform this treatment without a significant risk of leaving the patient with serious complications. I have heard physicians make derisive remarks about cryosurgery; in my experience with this modality, it is usually the ill-talented physician who has most of the complications as well as the poor anticancer results. Never get the message and the messenger confused.

The three basic ingredients that relate to the success of any treatment are (1) selection of the patient, (2) preparation of the patient, and (3) choice of a physician(s) to do the treatment(s).

It is important that the patient be aware of all these elements and that he network with support groups and his medical coaches to find the physicians involved in the therapy of PC. These physicians are needed to coordinate the selection, the preparation, and the definitive treatments of this disease. We need physicians to be graded according to skill and rewarded according to performance. Patient groups must push for societies of accredited physicians with credentialling at the highest levels.

Take-home Lesson 5 Not all men (or women) are created equal. Always look for the artist, be it the pathologist, the urologist, the radiation therapist, and/or the medical oncologist. Maintain a high level of communication among all health-care personnel involved with your life. Make sure you receive copies of all medical tests and consultations, and make copies for all your physicians. This is part of your mandate to optimize and maximize your chance for a healthy life.

Continuation of PROSTATE CANCER: EARLY STAGE