Prostate Cancer

INTRODUCTION TO DR. STRUM'S PROSTATE CANCER UPDATE

When I was diagnosed with advanced prostate cancer in September 1991, I thought my life, as I had envisioned it, was over. Instead, I have found a whole new universe of living and, in doing so, have come to terms with my own mortality.

Transformation is what is possible when we are faced with a life-threatening illness. When the unthinkable happens to us and we are faced with our mortality, we have an opportunity to transform our lives.

Acceptance of our situation is the first milestone we must pass before we can truly begin the process of healing. For me this translates into doing everything I can to understand the entire process of my illness and what I can do to become well. While I do not blame myself for my diagnosis, it has been valuable for me to take an introspective look at my life in relation to the kinds of stressors or environmental exposures that may have played a role. Sometimes it is not until we are on the reef that we realize it is there.

Fortunately for us, the cancer patient today has many more resources available than there were just a few years ago. What follows by Dr. Stephen Strum is an update of the treatment of prostate cancer. I have known Steve for over 10 years. He is one of the precious few who have brought a new and compassionate dimension to the patient/physician relationship.

Frederick Mills
Prostate Cancer Survivor
Founding Member of Educational Council
for Prostate Cancer Patients

PROSTATE CANCER UPDATE 2003

Stephen B. Strum, M.D., F.A.C.P.

GENERAL INTRODUCTION

In this, the year 2003 edition of Disease Prevention and Treatment, I will discuss prostate cancer (PC), using the metaphor of a military incursion--needing to have a focused, strategic approach, deployed in a systematic, problem-solving manner. The purpose of such a metaphor is to bring to the student of this disease a different perspective that will hopefully provide new insights that will lead to victories in our battles against this disease. The reason for such a departure from the conventional formal discussion of PC is that this latter academic approach is not being translated into winning strategies for the man with PC. The battle is being lost because we, the generals, are not translating what has been published in medical journals and discussed at national meetings into real-time preventive, diagnostic, evaluatory, and treatment tactics. Medical pragmatism--the art of being practical and using common sense--is not being practiced.

The battle to prevent this disease, to diagnose it earlier, and to treat it effectively is also not occurring at the proper pace largely because men are not taking an active role in winning this war. As we are learning in our war against terrorism, you defeat the enemy by recognizing their presence early (not late), preventing their buildup, learning their location, and eradicating them with the proper weaponry. There are too many men, already diagnosed with PC, who are not taking an active role in their own recovery. Many believe that because they are consulting a professional with a medical degree (who may also command a generous salary), all or part of this equates with getting the very best advice and treatment. Wrong. In today's world of rapid pace, where medicine is practiced with 15-minute office visits and where physicians are too busy to read and translate much of what is being published, the patient and his partner must not take a passive role and assume that all that can be done is being done.

My recommendations, therefore, either to patients with PC or to their loved ones, will be those of a counselor or guide, offering practical advice based on 20 years of working on the front lines of PC management. I do not hesitate in telling you that for the vast majority of men diagnosed with PC, a successful outcome can be realized. But the principles you are about to learn must become part and parcel of the strategic approach used by the patient/partner/physician (PPP) team. The patient and his partner have the most to gain as well as the most to lose when encountering PC. They must expend serious energy to win this particular war. In doing so, they learn the art of battle; they are brought closer together and evolve in their lives; and other intertwined health issues are brought to light and healed. This is the beauty of such an approach. Are you willing to invest in the time to help yourself? Are you worth it?

THE 2003 DISEASE PREVENTION AND TREATMENT EDITION

The most important take-home lesson that I can relate to you within the pages that follow relates to your ability to use concepts. It is through the use of concepts--the structural framework of our thinking--that we intelligently plan a strategy of success.

As stated in the introduction, defeating PC is a military campaign. Winning a military campaign, or a war against PC, involves concepts such as prevention, basic training, military intelligence (Intel), early recognition of enemy activity, assessment of the strength of the enemy, an understanding of the pros and cons of the weapons in our arsenal, stabilization of key areas of conflict, stopping supply lines to the enemy, supporting our troops, and other issues common to a military arena (see Table 1). A strategy for success, be it in a military war or a war against PC, simply involves adding factual information to a sound conceptual framework.

The approaches used in a winning strategy, whether for a military campaign or a medical battle, are superimposable. That which occurs in the life of a cell is reflected in society as well.1 Cellular battles are but a microcosm of what takes place on a more macromolecular level within the individual, his community, his country, the planet, and the universe. This is reflected repeatedly throughout the entire history of man.

1. PREVENTING WAR: PREVENTING PC

Most students of either campaign will maintain that prevention is the key to being truly victorious. There is no argument there. However, the desire to understand the principles and importance of preventive tactics does not appear to be a top priority for most people until the harsh reality of war or cancer is present. For example, the appreciation of terrorism in America was not brought home until September 11, 2001. This appreciation of the enemy may take the form of seeing the reality of cancer up close and personal when a father, brother, or other family member is diagnosed with PC or another malignancy. Otherwise, the motivation to learn and utilize prevention tactics does not seem to be part of human reality for the vast majority of us. What can we do to foster an appreciation of the value of preventing PC?

Hereditary PC: Risk Factors
Out of every 100 men diagnosed with PC, approximately 5 will have hereditary PC (HPC).2 HPC is presently defined by any one of the following three criteria:

• Three successive generations with members having PC
• Three first-degree relatives, for example, a father and two brothers, three brothers, or a father and two sons with PC
• Two relatives with PC diagnosed before age 55(3)

It is not surprising that the incidence of hereditary breast cancer is also about 5% of the total population of breast cancer patients--the same incidence as that of HPC.4

Genetic Transmission from Father to Son and Father to Daughter
HPC is transmitted by a gene from father to son and from father to daughter and then to her son. When HPC is present, nearly half the male offspring will have PC, and many of these will develop PC before age 55. In fact, HPC accounts for approximately 43% of PC diagnosed before the age of 55 years.3,5,6

Since the transmission of the gene may also occur from father to daughter and then to her son, a sound medical history includes information about the health of the maternal grandfather as well as maternal uncles and maternal cousins regarding any history of PC. Studies of PC within families show a stronger familial inheritance pattern than colon or breast cancer.

Value of Intensified Surveillance in High-Risk Situations
Most importantly, procedures to routinely test the first-degree relatives of those having HPC have yielded an eightfold higher detection of PC than that found in the general population.7 Soon, genetic testing for chromosomal abnormalities found in HPC may become commercially available. Patients' interest in testing HPC similar to that available for breast cancer, appears great when there exists a family history of such disease.8,9

Increased Risk of Male Breast Cancer and Colon Cancer in Male Offspring and Breast Cancer in Female Offspring
It should also be emphasized that men with a history of breast cancer (BC) in their family are also at greater risk for developing PC, just as women with a family history of PC are at greater risk for developing BC.10 Since both PC and BC share common genes, it is not surprising that men who are carriers of the gene associated with BC (BRCA1 or BRCA2) are at a greater risk for developing male BC in addition to PC and colon cancer.4,11-13

Therefore, greater vigilance is suggested when a history of PC or BC is present.

What Are the Tests for High-Risk Persons?
Currently, most physicians who focus on PC as their main specialty will recommend routine prostate-specific antigen (PSA) testing starting at age 40. This is important to establish objective findings that indicate a healthy prostate. In subsequent paragraphs, this will be shown to equate with a baseline PSA of less than 2.0 and often less than 1.0 ng/mL. In a population in which there is a family history of PC, such as has been described, PSA testing should be commenced at age 35 with yearly testing for a few years to establish a trend or profile. Then, if the PSA remains below 1.0 ng/mL, consideration for testing every 2-3 years can be considered. Vigilance on the part of the empowered patient, partner, and physician will also involve digital rectal examination (DRE) at reasonable intervals and tracking of the PSA over time. If any persistent PSA increase is noted, determinations of PSA velocity, PSA doubling times, free PSA percentage, and additional testing that will be discussed in subsequent sections must be done. Moreover, a baseline colonoscopy and stool testing for microscopic blood (Hemoccult) would be a reasonable consideration in such men starting at age 40 rather than at age 50.

General Preventive Measures
Besides laboratory testing, physical examination, and investigative procedures to rule out the presence of PC and other diseases, an action plan to prevent their development should be considered. These types of preventive measures are preemptive, or defensive, measures. The most apparent of these relates to what we eat and drink.

There is no doubt that what we put into our bodies relates to the health of our cells. It is obvious that food intake is associated with delights to our senses of sight, smell, and taste. However, on a survival level, food is the necessary fuel source for all the cells of the human body. The quality and quantity of the food, water, and air we put into our bodies clearly have serious ramifications. There are major parallels between human nutrition and a high-performance engine:

• The kind of fuel we add to high-performance engines
• The fuel-to-air ratios that occur within the combustion chambers
• The metabolic breakdown products resulting from internal combustion
• The wear and tear on the engine due to driving habits
• The preventive measures used to increase engine life

The human body is certainly no less of a high-performance engine than that of an airplane or car. Yet, although we appreciate the preventive maintenance that is part of the strategy of engine survival, we are inconsistent when we too often ignore the needs of our own bodies--that is, until we have signs of engine breakdown. As many of us love our cars and care for them, we must do the same with our bodies.

Lycopenes and Their Critical Role in Cancer Prevention
Of all nutritional literature currently in existence relating to PC, the relationship between lycopene ingestion and the health of the prostate is the clearest. Lycopene consumption been found to decrease not only the risk of PC in multiple studies,14-16 but also the risk of BC17 and pancreatic and stomach cancer,16 as well as lung cancer.18

Tomato-Based Products Are the Richest Sources of Lycopene
In these positive studies that correlated lycopene consumption with decreased risk of PC, the lycopene sources were tomato-based products. The richest sources of lycopene in the U.S. diet are ketchup, tomato juice, and pizza sauce; these account for over 80% of the total lycopene intake of Americans.19 In one study from Athens, Greece, the authors concluded that the incidence of prostate cancer in Greece could be reduced by about 40% if the population increased the consumption of tomatoes, reduced the intake of dairy products, and substituted olive oil for other added lipids.20

Lycopene Consumption Correlates with Blood and Tissue Lycopene Levels
The correlation between increased tomato-based consumption of lycopenes and the decreased risk of PC and other cancers is also found in the laboratory, where serum levels of lycopene are correlated with lycopene intake. The same holds true in studies in which tissue levels of lycopene have been studied in prostate pathology specimens.16,17

Lycopene concentrations in the serum of healthy men are typically 0.60-1.9 nmol/mL (nanomoles per milliliter).21 Biochemically, lycopene is composed of two main chemical structures or isomers: all-trans-lycopene and cis-isomers. Tomato sauce contains primarily all-trans-lycopene (83% of total lycopene). The ingestion of tomato sauce results in substantial increases in total lycopene levels in both the serum and prostate tissue and a substantial increase in all-trans-lycopene in prostate tissue but with relatively smaller increases in the serum.22 Serum lycopene levels are predominantly composed of the cis-isomer of lycopene, which represents 58-73% of the total serum lycopene, while the all-trans-isomer composes 27-42% of the serum lycopene.21

Among 72 studies identified, 57 reported that higher tomato intake or blood lycopene levels reduced the risk of cancer at a defined anatomic site; 35 of these associations were statistically significant.23 The evidence for a benefit was strongest for cancers of the prostate, lung, and stomach. Data were also suggestive of a benefit for cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix. The relative risk (RR) was determined, comparing high tomato intake or high lycopene levels with low tomato intake or low lycopene levels. In such comparisons, about half of the RR was close to 0.6 or lower.23 In another study, the odds of contracting aggressive PC were significantly lower when plasma lycopene levels were high. Plasma lycopene levels were divided into five quintiles. The highest level, the fifth quintile, showed an odds ratio (OR) of 0.56.14 These findings add up to about a 40% reduction in risk of being diagnosed with these cancer types for those with high tomato intake or the highest plasma lycopene levels.

The Proof of the Pudding Is Not in the Eating but in the Assimilation
The proof of the pudding, in the matter of dietary issues, relates more to how we assimilate what we have eaten rather than to just a history of having eaten something. It should not be surprising then that the correlation between serum or plasma lycopene levels and a lower incidence of PC is greater than the correlation between the oral intake of lycopenes and PC incidence. In a study by Lu et al., significant reductions in PC incidence were observed with higher plasma concentrations of the following carotenoids: lycopene, OR 0.17; and zeaxanthin, OR 0.22, when comparing highest and lowest quartiles.24 This translates into about an 80% reduction in PC incidence when the highest blood levels of either lycopene or zeaxanthin are achieved.

Lycopenes and Strawberries Lower Risk, Especially for Aggressive and Extra-Prostatic PC
A dietary history of significant lycopene and/or strawberry consumption correlated with a lower risk of aggressive and extra-prostatic PC.14 The lycopene source that was found to be most significant in most epidemiologic studies was the tomato, in the form of tomato sauce, stewed tomatoes, and pizza. In one large-scale study involving 812 new cases of PC over the years 1986-1992 with matched controls, of the 46 vegetables and fruits or related products significantly associated with lower PC risk, three of the four identified were related to lycopenes--tomato sauce, tomatoes, and pizza. In this study, the combined intake of tomatoes, tomato sauce, tomato juice, and pizza (accounting for 82% of lycopene intake) was associated with a reduced risk of PC for consumption frequency greater than 10 versus less than 1.5 servings a week. Lycopene intake was also associated with a 53% reduced risk for advanced PC (Stages III and IV). The other nonlycopene product identified with significantly lower PC risk was strawberries.15

The largest relevant dietary study, a prospective study in male health professionals, found that consumption of 2-4 servings of tomato sauce a week was associated with about a 35% risk reduction of total PC and a 50% reduction of advanced (extra-prostatic) PC. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study.25 These associations persisted in analyses controlling for fruit consumption, vegetable consumption, and olive oil use and were observed separately in men of Southern European or other Caucasian ancestry.26

Lycopene Inhibits Cancer Cell Growth by Gene Up-regulation of Connexin 43
Lycopene functions as a very potent antioxidant. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis (gene mutations) in the Ames test. Other mechanisms of lycopene action may be operative as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell-cycle progression--specifically in PC cells--without evidence of toxic effects or apoptosis of cells.27 Studies of human and animal cells have identified connexin 43, a gene, whose expression is up-regulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or up-regulation is associated with decreased proliferation.

Lycopene Is Synergistic with Vitamin D, Inhibiting Tumor Cell Proliferation and Enhancing Differentiation
The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on inhibition of cell proliferation, and differentiation, and an additive effect on cell-cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.18

Lycopenes Reduce Cardiovascular Risk Factors
Lycopene levels decrease with advancing age. However, in contrast to other carotenoids, they are not found to be reduced by smoking or alcohol consumption.16,19 Lycopenes also have an inhibitory effect on cholesterol synthesis and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene.19

Lycopene Levels May Be Associated with Decreased Insulin-like Growth Factor Levels
The consumption of cooked tomatoes was substantially and significantly associated with reduced insulin-like growth factor-1 (IGF-1) levels, with a mean change of -31.5% for an increment of 1 serving a day. The authors concluded that the strongest known dietary risk factor for PC (lycopene deficit, as reflected in a reduced intake of cooked tomatoes) is somehow related to an important endocrine factor (IGF-1) in the cause of this disease.28 However, in another study, IGF-1 was not associated with any dietary factor studied, such as total fat, carbohydrate, protein, dairy products, tomatoes, or calcium.29

Suggested Ways to Increase Lycopene Consumption and Plasma Levels
The easiest way I have found to combine a healthy intake of lycopenes into my diet is by using marinara sauce on various foods. For example, at breakfast, an egg-white omelet containing eggplant and bell peppers (ratatouille omelet) covered with marinara sauce is a healthy source of protein, contains a substantial fiber content, and is restricted in the amount of simple carbohydrates. Stewed tomatoes can be served as a vegetable side dish with lunch or dinner.

Dietary Fat Increases PC Growth Rates
There are studies that show that dietary fat increases tumor growth rates in an animal model of human PC. In a mouse model of PC involving androgen-sensitive human prostatic adenocarcinoma cells (LNCaP cells), mice fed a 40.5% fat diet had mean tumor weights more than 2 times greater than mice fed a 21% fat diet. The 40.5% fat diet approximates that found in the average American male diet, which has been determined to be 36%.30

The slower tumor growth associated with the low-fat diet occurred even after the formation of measurable tumors when the diets were changed from 40% fat to 21% fat. Serum PSA levels also were highest in the 40.5 kcal% fat group and lowest in another group fed only 2.3 kcal% fat.30

Reduction of Total Calorie Consumption Decreases Tumor Size by Decreasing VEGF, Angiogenesis, and IGF-1 and by Increasing Apoptosis
The emphasis on dietary fat, per se, has lessened our focus on the importance of caloric over-consumption. Fat excess, however, is linked to excessive calorie consumption, since fat contains twice as many calories, gram for gram, as protein or carbohydrate.

I believe that diet should be regarded as having serious biochemical relevance to the health of the individual. You are, for the most part, what you eat (or at least what you assimilate). Western societies, especially the United States, are consumers of excessive calories. Excessive caloric consumption, especially coupled with a sedentary lifestyle, is a significant factor that adversely affects longevity.

An important study demonstrated that energy intake (caloric intake) modulates the growth of prostate tumors in two animal models: the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human adenocarcinoma in severe combined immunodeficiency (SCID) mice.31 Specifically, decreasing calorie consumption (energy restriction) by 20-40% from the control animals fed ad libitum resulted in:

• Increased PC cell apoptosis (programmed cell death)
• A two- to threefold reduction in PC angiogenesis as measured by microvessel density
• A decrease in vascular endothelial growth factor (VEGF) expression
• A decrease in circulating levels of IGF-1
• A significant decrease in tumor size

Therefore, all of these findings were benefits observed in the calorie-restricted group. This study showed that the nutritional status directly or indirectly influenced interaction between tumor cells and local blood vessels by changing the expression of angiogenic growth factors. In the Dunning model, energy (calorie) restriction resulted in a striking inhibition of VEGF expression. In the LNCaP model, there was little baseline expression of VEGF. However, there was an almost threefold reduction from the baseline IGF-1 levels in blood samples from LNCaP-bearing mice that were subjected to energy restriction.

IGF-1 Levels Stimulate PC Growth, Up-regulate uPA, and Stimulate Angiogenesis
Higher IGF-1 levels are associated with a fourfold greater risk of developing PC.32 IGF-1 is a known mitogen (stimulator of cell division and tumor growth) for PC. IGF-1 receptors are found on the PC cell as well as on osteoblasts.33 IGF-1 stimulates the PC cell to make uPA (urokinase-type plasminogen activator), a cell product implicated in the invasiveness and metastasis of PC. The uPA receptors are on the PC cell and on osteoblasts. IGF-1 adds further insult by also acting as an angiogenic growth factor.34 A detailed illustration of these and other interactions is shown in Figure 1.

Gene expression of IGF-1 and its receptor are inhibited by 5-alpha-reductase inhibitors such as Proscar.35

IGF-1 and uPA Act Together to Increase Aggressive PC Growth
There are studies demonstrating that elevations of uPA and its receptor are associated with nonorgan-confined PC at radical prostatectomy (RP), disease progression with metastases, and a poorer overall survival.36 uPA works closely with IGF-1 and its receptors, cleaving IGF-1 from its binding proteins. uPA is also part of an autocrine pathway for the PC cell, allowing uPA to stimulate PC cell growth and make more uPA at the same time.

Good News! GLA and EPA Inhibit uPA
Of interest is the fact that uPA production is inhibited by gamma-linolenic acid (GLA) and eicosapentenoic acid (EPA).37 GLA and EPA, which are essential fatty acids, are among the important players in the prevention of disease and in maintenance of health. This is discussed by Barry Sears, Ph.D., in Omega Rx Zone.38 Sears beautifully presents the interconnection between restriction of calories, along with dietary adjustments of carbohydrate, protein, and fat intake, and the production of a class of fatty acids called eicosanoids. An understanding of these issues is fundamental to our ability to prevent disease and maintain or recapture health.

More Advantages to Caloric Restriction and Avoidance of Hyperinsulinemia
Sears stresses the importance of caloric restriction by means of limiting the intake of high-density carbohydrates such as bread, pasta, grains in most cereals, and starches such as those found in potatoes. This reduction of caloric intake by lowering high-density carbohydrate intake decreases the stimulation of the pancreas to make insulin and limits all the adverse side effects associated with increased insulin levels (hyperinsulinemia).

Caloric restriction has been shown to be an important factor in augmenting the immune system and improving longevity. It reduces free radical production, which if otherwise unchecked, damages DNA and oxidizes polyunsaturated fats. Caloric restriction increases levels of superoxide dismutase (SOD), glutathione, melatonin, DHEA, peroxidase, and catalase. The latter substances are important defense mechanisms in our body that are known to decrease with aging. Caloric restriction is instrumental in lowering the production of cortisol. Cortisol is associated with increased stress levels, and an imbalance in cortisol production leads to immune deficiency and bone loss through resorption, leading to osteopenia and osteoporosis, as well as muscle breakdown and aging of the skin.

Calorie restriction, as proposed by Sears and others, has been shown to also reduce advanced glycosylated end-products (AGE). These are carbohydrate-protein complexes associated with hyperinsulinemic states and with cardiovascular disease, Alzheimer's disease, kidney disease, and other degenerative states.

We need to rethink how much food we need to eat. Our ideal body weight should be taken seriously. If we were to do this alone, we would eliminate most cases of diabetes, hypertension, hypercholesterolemia, stroke, heart disease, and a significant amount of cancer from our lives and those of our loved ones. healthy people should consume 500 calories permeal and 100 calories persnack. Modifications of this are based on the level of disease activity, age, and body surface area. Nutritional software and nutritional counseling should be an integral part of our approach to good health.

Insulin-Stimulating Carbohydrate Is the Damaging Subcomponent of Carbohydrate If hyperinsulinemia is crucial to the development of many of our biochemical problems--from arthritis to neurodegenerative disease to cancer--then controllingthe carbohydrate loads we subject our bodies to should be a major tool in maintaining good health. Carbohydrates can be characterized by the amount of insulin-stimulating carbohydrate (ISC) that they contain. The ISC is the total carbohydrate content (in grams) minus the amount of fiber (in grams) it contains. An example is 1 cup of broccoli containing a total of 7 grams of carbohydrate, of which 4 grams are fiber. The difference between the two equals the ISC content or 3 grams. Fruits and vegetables, which are high in fiber, generally have a lower ISC content than do starches, grains, and pasta. Therefore, analogous to PSA (benign-related versus cancer-related) and to cholesterol (total cholesterol versus LDL versus HDL), any intelligent discussion on carbohydrates must specify the components in question.

High Density Carbohydrates Should Be Minimized
An important variable in nutrition relates to the quantity or volume of food that we eat at each meal. Therefore, we need to specify carbohydrate intake as a function of ISC per unit volume of food. A serving of mashed potatoes (1 cup) containing a total of 40 grams of carbohydrate, with 2 grams being fiber, would have the difference--38 grams--as ISC. The same serving of broccoli containing a total of 7 grams of carbohydrate, with 4 grams being fiber, would have 3 grams of ISC per serving. The ISC per unit serving, comparing mashed potatoes to broccoli is therefore 38 versus 3. Carbohydrates that deliver a high insulin-stimulating effect per unit serving are termed high-density carbohydrates. Carbohydrates that are proportionally higher in fiber and lower in ISC per unit serving are called low-density carbohydrates. In our PC analogy, PSA density would relate to carbohydrate density.

Glycemic Index Further Modifies the Concept of ISC Content: The Glycemic Load
Insulin release is also related to the rapidity of increase of the blood sugar after ingestion of carbohydrates. The concept of glycemic index is used to account for this variable. The glycemic index measures the rate of carbohydrate entry into the bloodstream. Factors relating to the glycemic index of a particular food include the following:

• • The amount of fiber it contains
• • The amount of fructose the carbohydrate contains relative to the amount of glucose
• • The amount of fat eaten with the carbohydrate

High fiber and increased amounts of fructose (sugar from fruits) both function to lower the glycemic index. Fat consumed with carbohydrates will also mollify the glycemic effect and lower the glycemic index. Sears ties this nicely together by using the concept of glycemic load (GL): the amount of insulin-stimulating carbohydrate multiplied by the glycemic index of the carbohydrate (ISC × GI).

Volume of Food Eaten
An additional factor that must also be accounted for is the volume of carbohydrate ingested. You might be looking intelligently at the total carbohydrate content, noting the fiber content and determining the grams of ISC. You might even be smart enough to have memorized the glycemic indices of many of the foods you eat to determine the GL. However, if you double or triple the volume of carbohydrate you eat, you can still be over-stimulating the production of insulin. These topics relating to balancing protein, carbohydrate, and healthy fats, are discussed in the Omega Rx Zone by Sears.

Eicosanoid Balance
Eicosanoids are hormones that are made within the cell membrane of each and every cell--all 60 trillion cells in the human body. Eicosanoids are 20-carbon structures. Eicosanoids have autocrine, paracrine, and endocrine effects. That is, they affect the very cell that produces the eicosanoid (autocrine effect), as well as nearby cells (paracrine effect) and distant cells (endocrine effect). As with every aspect of biology, balance is a critical issue relating to good health as well as the development and progression of various diseases. Likewise, eicosanoid balance plays a central role that puts this desired biological endpoint at the hub of the integrative medicine wheel. Eicosanoids, and the balance of good versus bad eicosanoids, can be seen as the heart and soul, muscle, bone, and sinew, literally and figuratively, of holistic medicine.

Clearly pertinent to a discussion of PC is the fact that the first eicosanoids isolated in 1936 by Ulf von Euler were prostaglandins--eicosanoids isolated from the prostate gland. Eicosanoids are the oldest hormones, tracing their origin back 500 million years ago to production by sponges. Hormones are messengers involved in communication between cells. A hormone is formally defined as a substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another to affect physiological activity, such as growth or metabolism. All of medicine--in fact, all of life--represents issues of communication and balance. Such is the case at every level of existence. This is true for the cell, tissues, an organism, a human individual, a family, a community, a society, a nation, a planet, and the universe. If there was ever a guiding principle that is truly holistic, it is the principle of communication and balance.

Arachidonic Acid Metabolites Increase PC Growth, Invasion, and Metastasis
Eicosanoid synthesis involves the release of arachidonic acid (AA) from cell membrane phospholipids by an enzyme called phospholipase A2 (PLA2). AA then undergoes metabolism by cyclooxygenases (COXs) and lipoxygenases (LOXs). AA is an omega-6 fatty acid that is known to generate free radicals and is considered an unfavorable eicosanoid. Specific metabolites of AA, for example, PGE2 and 5-HETE, are created through the actions of the enzymes COX-2, 5-LOX, 12-LOX, and 15-LOX. These metabolites are examples of bad eicosanoids and have been implicated in PC growth and metastasis.39,40 In a study of human PC in which 5-LOX and its metabolite 5-HETE were evaluated in both malignant and benign prostate tissue within the same patient, both 5-LOX and 5-HETE were significantly over-expressed in the PC tissue.41 In other words, specific eicosanoids are modulators of tumor cell interactions with certain host components within the context of cancer growth, invasion, and spread.

The administration of PGE2 to prostate, breast, and colon cancer cells resulted in increased cellular proliferation. Some studies have shown that stimulation of PC growth is related more to COX-2 and a resultant increase in angiogenesis than to PGE2.42

Inhibition of AA and Its Metabolites Causes PC Apoptosis
Laboratory studies have shown a significant reduction in cancer cell invasiveness by inhibitors of PLA2, as well as by general COX inhibitors such as ibuprofen (Motrin) and also by specific COX-2 inhibitors.43 In this particular study, the mechanism of action was related to a reduction in angiogenesis factors called matrix metalloproteinases (MMPs). Other studies have shown a significant role for COX-2 inhibition in PC with demonstration of reduction in microvessel density of the tumor related to a decrease in VEGF, a potent angiogenesis factor.44 Apparently, within the center of PC tumors a state of lower oxygen tension exists (hypoxic center) which stimulates VEGF. COX-2 inhibition seems to be able to prevent this hypoxia-induced up-regulation of VEGF and angiogenesis. An ibuprofen derivative called Flurbiprofen® inhibited PGE2 and reduced PC cell growth by inhibiting up-regulation of COX-2.45

Multiple papers have shown that inhibition of 5-LOX leads to PC apoptosis.46-49

EPA and DHA Lower PC Risk
EPA, an omega-3 fatty acid, has been shown to suppress AA formation by inhibiting the enzyme delta-5-desaturase.50 Some epidemiologic studies have shown that high intakes of EPA and DHA lower PC risk substantially.51 Other studies have shown a reduction in PC risk only with a decrease in the ratio of AA to EPA (AA:EPA).52 A combination of GLA and EPA administered to humans was shown to strongly increase serum EPA and DGLA levels and to reduce AA formation and AA metabolites such as leuko-trienes.50

Foods rich in EPA include coldwater fish such as tuna, sardines, herring, swordfish, and salmon. Commercially available pharmaceutical-grade fish oils also contain large amounts of EPA and DHA.

Selenium Prevents PC in Select Patients
Measures to prevent PC must be a routine part of the counsel that general practitioners and internists give their patients. Selenium intake of at least 200 mcg a day should be a consideration in the prevention of PC. Low plasma selenium is associated with a four- to fivefold increased risk of PC.53 In addition, levels of plasma selenium also decrease with age, resulting in middle-aged to older men being at a higher risk for low selenium levels. Ideally, baseline levels of selenium should be obtained before beginning routine selenium supplementation. It would make sense to begin such a micronutrient and mineral assessment at age 25 and perhaps every 10 years thereafter.

The studies of selenium supplementation and its role in preventing PC need continued clarification. In one study, selenium supplements provided benefit only for those individuals who had lower baseline plasma selenium levels.54 Other subjects with normal or higher levels did not benefit and had a slightly increased risk for PC. The studies by Clark et al. showed that selenium reduced the incidence of PC in men 63%.54,55 The mechanism of selenium anti-PC activity appears related to selenium's antiproliferative effect against PC. Selenium affects the cell cycle (see Figure 3) with up-regulation of cell-cycle regulators such as p21 and p27, resulting in a decrease in PC growth due to G1 arrest and up to an 80% reduction in the S-phase of PC growth.56

Selenium Enhances Cell Kill with Taxol and Adriamcyin Chemotherapy
Selenium also has been shown to have a significant antineoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation with selenium enhanced the chemotherapeutic effects of Taxol (paclitaxel) and Adriamycin (doxorubicin) in these cells beyond that seen when the chemotherapeutic drugs were used alone. In studies of the PC cell lines LNCaP and PC-3, the addition of Taxol or Adriamycin, in combination with selenium, caused small but significant inhibition of the PC cell growth. In the cited studies, the optimal inhibition of tumor growth occurred when the plasma selenium level was between 4 -40 ng/mL after 72 hours of treatment.57

Vitamin E Isomers Alpha- and Gamma-Tocopherol plus Selenium Combine to Reduce PC Risk
A large-scale study of almost 11,000 men in Maryland showed that the protective effects of high selenium levels, and similarly that of the alpha-tocopherol isomer of vitamin E, were only observed when the concentrations of the gamma tocopherol isomer of vitamin E were also high.58 In this study, the risk of PC declined with increasing concentrations of alpha-tocopherol, with the highest concentration associated with a 68% PC risk reduction. For gamma-tocopherol, men with levels in the highest fifth of the distribution had a fivefold greater reduction in the risk of developing PC than men in the lowest fifth (p = .002). The observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium suggested that combined alpha- and gamma-tocopherol supplements, used in conjunction with selenium, should be considered in future PC prevention trials.

Vitamin E Succinate Inhibits PC Cell Growth and PSA Expression
In another study, vitamin E succinate inhibited cell growth of PC cells in the LNCaP line by suppressing androgen receptor expression and PSA expression. The combination of Eulexin (flutamide) with vitamin E succinate resulted in a more significant inhibition of LNCaP cell growth.59 The same investigators demonstrated that selenomethionine also showed an inhibitory effect on LNCaP cell growth but that this appeared to be independent of androgen receptor or PSA pathways.

Vitamin E Reduces Incidence of PC in Smokers in Two Separate Studies
A study of over 29,000 male smokers in Finland, ages 50-69, disclosed a 32% decrease in the incidence of PC (95% confidence interval [CI] = -47% to -12%). This was observed among the subjects who had received 50 mg a day of alpha-tocopherol (n = 14,564) in contrast with those not receiving it (n = 14,569). Mortality from PC was 41% lower among men receiving alpha-tocopherol (95% CI = -65% to -1%). Among subjects receiving beta-carotene (n = 14,560), PC incidence was 23% higher (95% CI = -4% to 59%) and mortality was 15% higher (95% CI = -30% to 89%) compared with those not receiving it (n = 14,573). In this study, long-term supplementation with alpha-tocopherol substantially reduced PC incidence and mortality in male smokers.60

An important issue is whether this benefit of alpha-tocopherol, and possibly other tocopherols, is limited to smokers or those who have recently quit smoking. A report by Chan et al. (1999) showed significant benefit only to smokers or those recently quitting smoking in a study involving 47,780 U.S. male health professionals who received at least 100 IU of supplemental alpha-tocopherol. In this population, the risk of metastatic or fatal PC was reduced 56%. In the nonsmoking population, there were no beneficial findings of statistical significance.61 In a study on the relationship of green and yellow vegetable consumption to risk reduction in cancer development, a significant reduction was again found to occur only in smokers. The cancers studied included those of the mouth and pharynx, esophagus, stomach, liver, larynx, lung, and urinary bladder.62

Vitamin E Reduces VEGF Levels
A follow-up study involving the Finnish smokers compared VEGF levels in patients receiving alpha-tocopherol with those in the placebo group. There was an 11% reduction in VEGF levels in the alpha-tocopherol group as compared with a 10% increase in the placebo group (p = 0.03).63

Vitamin E Lessens Adverse Effects on PC Growth Due to Dietary Fat In vitro
Research studies have shown that vitamin E reduces growth rates of PCs resulting from a high fat diet. Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (the typical American diet). Tumors in animals fed 40.5%-kcal fat plus vitamin E were th same as those fed a 21.2%- kcal fat diet (an ideal fat level).64

One Recommendation for Implementing Some of the These Finding
Each Life Extension (LE) Booster softgel contains 210 mg of gamma-tocopherol plus 200 mcg of selenium in addition to 10 mg of lycopene. The full supplement facts on LE Booster softgels can be reviewed at http://www.lef.org/newshop/items/item00600.html. Combining one LE Booster softgel with one LE Vitamin E capsule containing 400 IU of d-alpha-tocopherol succinate, in conjunction with the dietary approaches detailed in previous paragraphs, should contribute significantly to both the prevention and active nutritional treatment of PC.

High Consumption of Dairy Products and Calcium Increase Risk of PC
A study in Sweden examined the relationship of dairy products, dietary calcium, phosphorus, and vitamin D with risk of total, extraprostatic, and metastatic PC. The results indicated that calcium intake was an independent predictor of PC [relative risk (RR) = 1.91] for calcium intakes of greater than or equal to 1183 mg a day versus less than 825 mg a day. This was especially the case for metastatic tumors with a RR equal to 2.64, controlling for age, family history of PC, smoking, and total energy and phosphorus intakes. The authors concluded that high consumption of dairy products was associated with a 50% increased risk of PC.65

A second study in the United States involved 1012 cases of PC among 20,885 men over an 11-year follow-up period. Men consuming greater than 2.5 servings a day of dairy products had a RR of 1.34 for PC after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming less than or equal to 150 mg calcium a day from dairy products, men consuming greater than 600 mg of calcium a day had a 32% higher risk of PC. The results support the hypothesis that dairy products and calcium are associated with a greater risk of PC.

Also noted was that at baseline men who consumed greater than 600 mg of calcium a day from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consuming less than or equal to 150 mg of calcium a day (71 compared with 85 pmol/L or 30.06 pg/mL compared with 35.64 pg/mL; p = 0.005).66

The RR for the diagnosis of advanced PC was noted to be 2.97 in men with daily calcium consumption of greater than or equal to 2000 mg a day versus intakes of less than 500 mg a day.67 The same was true for the risk of metastatic PC, but with a stronger RR of 4.57. (A RR of 4.57 means a 4.57 times greater risk of contracting PC.) Calcium from food sources and from supplements independently increased risk of PC.

High Fructose Consumption Decreases Risk of PC
In the same study referenced above, high fructose intake was found to be related to a lower risk of advanced PC (multivariate RR, 0.51). Fruit intake was associated with a RR of advanced PC (RR = 0.63; 5 versus %1 serving a day), and this association was accounted for by fructose intake. Nonfruit sources of fructose similarly predicted lower risk of advanced PC.67

Boron Consumption Lowers PC Occurrence
Men who ate the greatest amount of boron were 54% less likely to develop PC compared to men who consumed the least amount of boron. This information was presented in the annual Experimental Biology Conference in Florida in 2001. The study was led by Cui et al. from the UCLA Medical Center and compared dietary patterns of 95 men with PC with those of 5720 males without cancer. 67a The more boron-rich foods consumed, the greater the reduction in risk of being diagnosed with PC. Those men in the highest quartile of boron consumption had a 54% reduction in PC. Boron-rich foods include plums, grapes, prunes, avocados, and nuts such as almonds and peanuts. A serving of 100 grams of prunes (6 dried prunes) has 2-3 mg of boron and 6.1 grams of fiber.68

Diet and Supplement Studies Versus Cancer Risk: Confounding Findings Affecting Interpretation
The lifestyle characteristics of supplement users are certainly a potential bias in studies investigating the benefits versus risks of vitamins, minerals, and dietary habits. A study by Patterson et al. evaluated supplement users and found that, among men, supplement users had the characteristics detailed in Table 2.69

The health-minded nature of users of vitamins, mineral supplements, and dietary plans may well confound what we think we know about the relationship of such integrative health measures and investigations dealing with relative risks (RR) and odds ratios (OR) of diseases such as PC as well as other malignant and nonmalignant processes.

2. GETTING HELP TO UNDERSTAND BIOLOGICAL PRINCIPLES ABOUT PROSTATE CANCER

To master the tactical approaches and be victorious in your battle with PC is challenging. In such a context that involves a major crisis in your life, you need to have guidance in multiple shapes and forms.

Support Groups
If you belong to an interactive support group, this can be a great beginning. These are some of the largest:

• Us Too International, Inc., (800) 808-7866;
  www.ustoo.com
• Man-to-Man, (800) 227-2345;
  http://www.cancer.org
• Patient Advocates for Advanced Cancer Treatments,
  (616) 453-1477; http://www.paactusa.org
• Education Center for Prostate Cancer Patients,
  (516) 942-5000; www.ecpcp.org

I have attended many support group meetings, and the level at which each support group functions is highly variable. Some are informal meetings--more akin to chat groups relating personal experiences. Others are more scientific, with guest speakers involved in the diagnosis and treatment of PC. I hope that more support groups evolve into workshops that focus on each of its members--one at a time--using a scientifically objective approach with working forms. In such an idealized setting, an invited professional speaker would be asked to orient his or her talk around selected case histories (called clinical vignettes) pertaining to individuals in the support group.

Let's face it. Everyone at the support group meeting is there because of a perceived threat involving his or her life as it relates to PC. They are present because they are seeking answers to their problems. Therefore, every PC patient-oriented meeting should have patient outcome as the prime directive. Patients should understand that they learn about their particular problem through the understanding of concepts that, more often than not, also apply to them. When such lessons are taught as a story of an actual human being, the lesson is reinforced and becomes memorable. Such an approach translates science into practical issues of value that are more understandable to the individual man with PC and his partner.

Resolution of problems and prevention of problems unrecognized (or yet to develop) should be the prime directive of such organizations. Working together as a team (or army) to help one another is an effective way to teach all members of this platoon some valuable lessons about PC and hopefully about the spirit of human unity. Those that approach PC in such a manner will increase the likelihood that critical crossroads will now be approached in an intelligent fashion and crossed successfully. Instead of hearing about patients and physicians making the same mistakes repeatedly, we would hear more and more success stories. We do not want to fulfill the warning that the philosopher Santayana posed when he said:

Those who cannot remember the past are condemned to repeat it.

In my 20 years of counseling patients and physicians about PC, the same mistakes are made far too often. Using an objective format to gather data and presenting such data to your support group veterans should be the modus operandi of support groups. This will be discussed later in detail.

Also, and of great importance, working together elevates the individuals and the group. The mindset of the man with PC changes from "me against the disease" to "we against the disease." This fosters feelings of human unity. It is within this human unity, or humanity, that hope for mankind lies:

Our humanity lies in our human unity.

Without it, we are all individuals fighting a lonely battle. With it, we can conquer anything. Support groups, then, should elevate and evolve the individuals within them. Support groups should have a task force mentality, objectify patient information, and resolve critical issues for the individual, while at the same time accomplishing this for the group. How can this be done?

Field Guides
If we are striving to develop a group mentality and can pool our individual talents, we can now enter the phase of synergy. This can be facilitated by using the skills of those who can organize thought and details and share such organizational thinking with others. Manifestations of this are in books, medical articles written for the PC patient and partner, PC-specific newsletters, websites, and Internet-based tools. Suggestions for these elite materials, the field guides, are provided at the end of this protocol.

To summarize these points, a winning strategy for the individual soldier and his corps is to understand as much as possible about his situation in the context of the battle. His PC-fighting training, if you will, mandates his reading the manuals and doing his homework.

The only place where success comes before work is in the dictionary.

The concept of synergy empowers this foundational tactic. Therefore, the individual man with PC, his partner, and corps of patients in his support group must be working in the spirit of harmony. In essence, at this crossroads, the motivation for the patient and his partner is simply survival and quality of life. It comes down to the same old story: "We are only as strong as we are united, as weak as we are divided."70

A Key but Often Missing Link
There is no doubt whatsoever that the outcomes of patient longevity and quality of life can be changed for the better with the relatively simple first steps described earlier. The major drawback, as I see it, is bringing the professional healthcare team into the equation: the third element of PPP. There are reasons for this difficulty that are worthy of some speculation.

The education of the physician is based on competition for scholastic grades in college and in medical school. The ego--the unhealthy aspects of ego--is encouraged by repetitive challenges to the student, intern, resident, and junior staff regarding esoteric information and medical trivia. Individuals selected out of premedical candidates are often those who are accomplished at memorization of such material. The deans of medical schools are not accomplishing their mission in finding great numbers of outstanding physicians. This lies in the failure of not selecting more students who are driven by the passion to fix the individual and society. True physicians--sincere healers--all have a common denominator: a caring soul that is awed by the wonder of creation and the study of life. With such a constitution, these individuals have a passion to fix problems. This said, the fortunate patients are those able to find the real physicians.

Added to this demanding situation is another serious issue. A physician involved in the totality of cancer medicine cannot adequately cover the waterfront as it relates to all the different types of cancer. A physician must realize his limitations. In the first 10 years of my life as a general medical oncologist diagnosing and treating adult malignant conditions, I have strived to succeed in the impossible task of understanding how to best treat cancers of the breast, colon, lung, stomach, pancreas, ovary, head and neck, and brain, as well as sarcomas, lymphomas, and leukemias.

A man has got to know his limitations.

I should have realized from my medical school and postgraduate work on Hodgkin's disease that understanding one malignancy was in itself a formidable task. Becoming a master of 20 different malignancies is an impossible task that does not allow for an optimal outcome for the patient presenting with one particular type of cancer. How can this not be realized by the medical profession and the medical societies? It is as clear as day. Therefore, my advice to the man and his partner faced with a diagnosis of PC is to undertake the challenge of learning as much as possible about the disease, ideally in concert with a proactive and interactive support group and to do this while working with an M.D. copartner who is hopefully specialized in the management of PC.

What Specialist to Choose?
Patients and their partners routinely ask me, "Should I seek care under the aegis of a urologist, medical oncologist, or a radiation oncologist?" My initial response is to select an outstanding physician (no matter what his or her label or tag is) who manifests the characteristics of a real healer. With this said, I must be forthright in stating that there is a reality--in general--that the amount of time and focus spent on the patient will be such that the following ranking will most often be found to be true.

Medical Oncologist > Radiation Oncologist > Urologist

Medical oncologists and radiation oncologists are internists who have subspecialized in medical oncology and radiation oncology, respectively. Urologists are specialists in surgery. The nature of these specialties, their modus operandi, is quite different. During the junior and senior years in medical school, while we puzzled about which specialty to choose, one of the classic jokes was

Surgeons do everything, but know nothing.
Internists know everything, but do nothing.
Psychiatrists do nothing and know nothing.
Pathologists know everything and do everything,
but too late.

As silly as these stereotypes are, this joke always brings smiles to the faces of all physicians because there are inherent elements of truth present; surgeons are indeed oriented around operating--that is their modus operandi, literally and figuratively.

Therefore, in the best of all worlds, find a medical oncologist whois intensely focused on PC. Such a physician must have the patient's best interests at heart. This is the ideal teammate for the PC patient and his partner. To paraphrase Scott Peck, M.D., in A World Waiting to Be Born, a good act is that which appears good to an ideal observer, "a being who is more knowledgeable than you, more objective than you, yet who still cares."71

As with breast cancer care or any life-threatening illness, the primary intervention of the man diagnosed with PC or suspected to have PC should be with an objective, caring, and highly informed physician--the medical oncologist trained in the area of PC. He or she is the least biased concerning which treatment the patient should be considering. He or she has a broader scope of knowledge regarding oncology and internal medicine. He or she will spend more time dealing with concepts as they relate to PC rather than with procedures.

The good physician knows his patients through and through, and his knowledge is bought dearly. Time, sympathy, and understanding, must be lavishly dispensed, but the reward is to be found in that personal bond which forms the greatest satisfaction of the practice of medicine. 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.
- Sir Francis Weld Peabody, Lecture to Harvard Medical Students, 1927

Some of the statements made above will meet with disapproval by some of my colleagues. Nevertheless, they are true. In today's world, we desperately need more integrity.

Assuming that medicine evolves to a point where physicians specializing in areas such as PC become more plentiful, the PC patient and partner must find a like-hearted and like-minded physician.

The real challenge then is for the medical profession and society to foster an increasing population of physicians meeting these qualifications, for the number of such physicians is far too small to meet the demands of 170,000-200,000 men in the United States each year who are newly diagnosed with PC. An estimate of the number of men with PC in the United States today is somewhere in the 6-9 million range.

What Does This Mean for Patients?

• To win this battle, you must foster an understanding of the basic biological principles involved in PC. Just as a new recruit into the army becomes savvy by means of education from experienced field officers and fellow soldiers, the new patient with PC (the newbie) needs to obtain information from a supportive cast.
• The PC patient and partner must act as a team, reinforcing its growing understanding and, in time, sharing its knowledge with the community of other PC patients and partners.
• Reality is a tough concept, but an understanding of the limitations of the current medical care of the PC patient is mandatory to prevent major and minor casualties. The diagnosis and initial care plan is often made by the urologist and not a more integrative physician such as a medical oncologist focused on PC. To win a war, one needs a strategist familiar with all aspects of the battle.
• PC necessitates organizational thinking, with strategy and serious focus on biological events as they relate to tumor/host interactions. A successful military campaign requires sound military intelligence. Similarly, a successful medical campaign requires organizational thinking which is rooted in solid medical intelligence.

3. MILITARY INFORMATION (INTEL): THE IMPORTANCE OF THE MEDICAL RECORD

The Medical Record--The Key to Organizational Thinking
Ask a captain of any ship or airplane about the importance of a detailed log or ask a real physician about the crucial role of the medical chart or record and you will get the same response:

The Chart is a must to ensure the integrity of the Ship.

The medical record is the patient's story. More important than that, it is the chronology of medical events put to music, and the music is reflected in the biological expressions of the health and disease processes. It is simply a statement of whether or not the orchestra is in harmony or in discord.

The entire clinical story of the patient informs the listening physician; it provides clues to elucidate a fuller story--a closer approximation to the truth--as well as the caring and informed physician can understand it. This really is a manifestation of medical common sense. But, as Thomas Paine once said:

Common sense is not so common.

When the PPP team is involved in a logical and common sense approach to analyzing and resolving the patient's problem, a medical symphony evolves. This medical symphony has different movements to it. These movements are separate, and yet they overlap at the same time. The following discussion is described and illustrated fully in Appendix F (starting page F27) of A Primer on Prostate Cancer, The Empowered Patient's Guide (the Primer) by Strum and Pogliano. The Primer is available through Life Extension Foundation at 1-866-820-7457 or www.lefprostate.org, through Amazon.com, Borders, and Barnes & Noble. A review of the important movements is described below.

Basic Information
This is routine information to identify the patient. It is, in essence, name, rank, and serial number. It is very basic data that often fall into administrative details, for example, age, birthdate, full address information, spouse or significant other's name, and the names of physicians with their specialty and contact information. It should also include any medical diagnoses that are likely to have some interactive role with PC.

Prediagnostic History
When we talk about the diagnosis of any kind of cancer, we refer to the microscopic diagnosis obtained after a biopsy or sampling of tissue. Data in the prediagnostic category relate information about biological expressions of PC that precede the diagnosis of PC. Such information might include the dates and PSA values prior to a diagnosis of PC. It might also include results of the free PSA percentage, calculations of PSA velocity (PSAV), and PSA doubling time (PSADT).

Diagnosis and Staging
This movement relates key baseline information of prognostic significance. This includes the baseline PSA and PAP, the Gleason score, gland volume, core involvement, and clinical stage. The Gleason score must be validated by an expert in PC pathology. This section of the medical record also contains the critical biologic expressions that are used in the algorithm section. Examples of various medical inputs in this category are shown below in Table 3.

Therefore, to assess the reality of the military campaign, a good intelligence officer will gather information crucial to understanding the reality of the battle being faced. This part of the winning strategy overlaps with early recognition of the enemy and assessment of enemy strength (and weakness).

For example, in the clinical data shown in Table 3, the patient's baseline PSA (bPSA) of 35 already suggests that we have a minimal chance that the PC is confined to the prostate. The high level of PSA is equivalent with a large tumor volume. These findings are unfortunately reinforced by those of the DRE where the clinical stage was T3a (indicating extracapsular extension on one side of the prostate), along with the findings showing that of the six biopsy cores taken, all six showed PC. Moreover, the percentage of individual core involvement was also very high with one core showing 100% involvement of PC and the remaining five cores having a total of 220% involvement, for an average core involvement of these five cores of 44%.72 Again, this is indicative of a large tumor volume.

The Narayan stage assesses whether the microscopic findings of PC were limited to one side of the prostate gland (B1) versus both sides (B2). Again, the B2 Narayan stage reinforces our understanding of the enemy insofar as a larger tumor volume.73 This is clearly not going to be a situation where watchful waiting is a rational consideration or one where the first tactic would involve surgery, radiation therapy, or cryosurgery. The PAP blood test is above 3.0, and this finding would point to a high risk of failure from RP74 or of progression after radiation therapy, even with newer advances involving 3D Conformal Radiation Therapy (3DCRT) or Intensity Modulated Radiation Therapy (IMRT) with or without seed implantation.75

The gland volume (GV) has relevance to what therapy is selected, as does the American Urologic Association (AUA) symptom index--an objective scoring system that quantifies lower urinary tract symptoms.

The gathering of this medical informationallows a clearer understanding of what the patient's outcomeis. In a situation that is far more favorable than this one, a patient at the time of diagnosis of PC presents with a PSA of 9 ng/mL with a Gleason score of (3,3) that has been read by an expert in PC pathology. His clinical stage based on the DRE reveals nothing to suggest PC, i.e., T1c clinical stage. Moreover, he has a favorable percentage of PC core involvement with less than 50% of the biopsy cores sampled showing cancer.76

However, his GV is extremely large at 80 cc. Too often, at the time of the patient's diagnosis via transrectal ultrasound of the prostate, the GV is not recorded by the urologist. The patient's assessment is incomplete because the GV is a critical issue in PC diagnosis and management.77-80 The large GV in this example would adversely affect the outcome of the patient undergoing treatment with radiation therapy (external beam and/or brachytherapy) or cryosurgery.81-85 This would be especially true in the setting of an AUA symptom index greater than 20, a maximum urine flow of 10 mL per second or less, and even a GV greater than 40 grams or cc.86 However, controversy in this area does still remain.87

These data inputs are evolving as we understand more and more about the biological story and what is most important for a successful clinical outcome.

Data Used for Algorithms and Nomograms
The gathering of this medical information is important to supply at baseline prior to any treatment. This information is critical in the treatment strategy selected by the PPP team. The calculations involved in such algorithms have been simplified by the use of software programs such as PC Tools I and II on websites such as the PCRI (Prostate Cancer Research Institute) website at www.pcri.org and the Kattan nomogram site at http://www.mskcc.org.

The key baseline data necessary for many of the standard algorithms/nomograms currently in use include the data inputs mentioned in the Diagnosis and Staging section. Other data that may become available during the PC patient's course are applicable to additional algorithms involving PSA recurrence after surgery or radiation. This would involve Gleason score at radical prostatectomy (RP), ploidy (DNA analysis) at RP, presence or absence of lymph node involvement at RP, PSA velocity and PSA doubling time after RP, time to PSA recurrence after RP, history of use of ADT (androgen deprivation therapy), dose of RT employed, and other data. The risk assessment provided by the use of algorithms and nomograms is discussed in more detail in Section 5, Risk Assessment of the PC Patient.

A Detailed Clinical Chronological Review (DCCR)
In my opinion, this is the most important part of the medical record for the PC patient. This is because the DCCR represents an incorporation of all prior information into a medical story that is clear to the physician, the patient, and his partner (PPP). The DCCR uses a combination of a timeline and information relating to major events to present the key crossroads in the patient's history as it relates to PC. Treatments are designated as "Rx" and are bolded for emphasis.

Ideally, the patient and his partner as well as the physician add information to this part of the PC medical record, encouraging its use as an important navigational tool for the entire team. Using the DCCR as a means of conveying medical information focuses energy on areas of concern. This avoids generic suggestions, for example, operate, radiate, or do nothing, and thus it engenders the need for substantial evidence to support the choice(s) of particular evaluations and/or treatments. Such an approach would help to improve the outcome of the patient and ease his path to that outcome. This is the essence of good treatment strategy. You must do your homework. All of this is illustrated in the Primer.

Flow Sheets (A Powerful Graphic Tool that Warrants Emphasis)
Flow sheets are the Rosetta Stone in understanding the patient's response to treatment. Flow sheets, compulsively maintained, detail the treatment strategy and its response. The flow sheet, accurately kept by the physician, and ideally understood by the patient and his partner, is the nitty-gritty worksheet that conveys the success or lack of success of Treatment.

Flow sheets are critical to the management of any patient, no matter what illness the PPP may encounter. Unfortunately, the concepts involved with flow sheets although simple, are often totally missed by many doctors. The flow sheet employs the concept of time in relation to treatment and correlates this with parameters (indicators) of response.

Simply put, the flow sheet gives a timetable of the patient's medications and correlates them with laboratory and radiological studies (response parameters) to point out any changes reflecting either the presence or absence of the desired biological effect. At the same time, body system functions are monitored using laboratory tests. This monitors any developing drug toxicity or tissue damage that may be due to the treatment and/or the disease. An example of this would be John Doe treated with Flutamide and Lupron for metastatic PC. An example of his flow sheet is shown in part in Tables 4A and 4B (and in full on page F37 of the Primer).

Note how the flow sheet acts as a treatment record and how the columns show the time-related effects of therapy on the CBC (hematocrit dropping), which was due to androgen deprivation therapy (ADT). The desired therapeutic effect on the PSA is also clearly shown. The worsening liver function test (SGPT, a liver enzyme) is forecasting problems secondary to liver toxicity, which may be due to Flutamide. The flow sheet is declaring this in advance because the physician or the patient can see the test result going from low normal to high normal before entering the flagged abnormal range. Alkaline phosphatase (due to bone metastases) is showing a response to ADT and is falling from the initial 456 toward the normal range (= 125). Even after reaching the normal range, the alkaline phosphatase continues to drop lower. The concepts here relate to baseline, trends, the issue of changes within the normal range, and treatment versus response parameter.

The empowered patient and partner obtain hard copies of any laboratory data generated in the physician's office along with copies of any flow sheets. The team is encouraged to carefully review and to understand these forms. A true physician welcomes such a request. The same applies to all consultation reports.

Summary/Surveillance Sheets
Lastly, as part of medical event recording, an overall assessment of the patient's total health is needed. While the patient may be having a great response to his PC treatment, his bone mineral density may be worsening.88 If the medical campaign is to be successful, the battle needs to be won on all fronts.

Table 5 is an example of what I have used in medical practice to monitor patients. It makes little sense to put a patient through intensive treatment for PC if his cardiovascular status is deteriorating89 or if he has a second malignancy90 that has gone undiagnosed because of a tunnel-vision approach to the patient's care. Table 5 presents this concept of surveillance and reminds the PPP when the last such test was performed. The patient's flow sheets would show the actual results of such examinations.

What Does This Mean for Patients?

• To win the battle against PC, you must obtain information that is highly important in deciding the outcome of this biological interaction. Medical intelligence (Intel) is as important to the survival of the patient as military intelligence is to the survival of the soldier and the success of the campaign.
• The PC patient and partner must again act as a team, reinforcing each other with their growing knowledge. In time, for the paradigm to be fulfilled, they must share this newfound knowledge with the community of other PC patients and partners.
• Being aware of the importance of medical Intel gathering and how it is organized, the patient and partner can work together with their fellows to extend influence that will affect the nature of information gathering and record keeping done by physicians.
• In an enlightened world, and certainly in a society with today's technological advances, physicians should be graded on their care of patients. This should be carried out by an on-site task force that surveys the medical records and the actual hands-on care delivered by physicians to their patients in the medical office and in the hospital.

4. EARLY RECOGNITION OF ENEMY ACTIVITY: EARLY DIAGNOSIS OF PC

In the prior three sections, I have presented:

• The use of measures that have been shown to prevent PC
• Medical references for using preventive measures in PC
• The need for interactive assistance in obtaining basic medical comprehension and the associated reference tools that can provide this
• How an organized medical log ties all relevant information together in an integrative fashion

Given this groundwork, what can be said about an early diagnosis of PC?

It seems uncanny that in the year 2003 we are still debating the virtues of an early diagnosis of PC by means of PSA-associated tools and the DRE. I would chalk this up as a reflection of the old saying

Don't confuse the message with the messenger.

or its alternate expression:

Don't confuse the mission with the man.

The problem is not with the early diagnosis of this disease but with what we do with the realization of such a diagnosis in the following contexts:

The patient's overall biological setting

1. The skills and lack of skills of the medical professionals available to the patient
2. The constraints, if any, of the patient's personal finances or medical insurance

The patient's wishes in response to such a diagnosis
For example, if we were to discuss an 85-year-old man with far-advanced Alzheimer's disease, it makes no sense to pursue a diagnosis of PC unless we have reasons to believe that such a diagnosis would substantially benefit the patient. In a different situation, if a patient is diagnosed with PC and his biological findings, for example, PSA velocity and doubling times, indicate a very small tumor volume and stability of the biological process, then both nutritional and lifestyle changes can be suggested to slow the biological process. This often allows the patient to outlive the PC. We can use a strategy of watchful waiting (WW). WW does not mean ignoring biological parameters. Perhaps the term WW should have been replaced long ago with the term Objectified Ongoing Observation (OOO). Currently, more and more medical articles are pointing out the value of using a rational approach to OOO by listening to the biology of PC.91-97

We should not tell patients that making a diagnosis of PC is dangerous because of the morbidity and mortality of various invasive therapies when such therapies in the hands of the upper echelon of medical practitioners are not at all significantly associated with such adverse findings in the overwhelming majority of patients.98,99

One paradox of our modern times is the involvement of insurance carriers in the medical decision-making processes such as screening for PC, the staging of PC, and what treatment choices are available to the patient. It is not so surprising that the insurance companies wish to control this, but it is incredibly painful to observe that the physicians working for such companies would allow their professional training and judgment to be overridden by the economic needs of the insurance carrier. I believe that this reflects a conflict of interest on the part of those physicians. In my opinion, this conduct violates the Hippocratic Oath and is certainly a violation of human rights that is being tacitly accepted and therefore condoned in a supposedly sophisticated society.

Ironically, if the advisers to those insurance companies would read medical literature more carefully, they would be utilizing ways to prevent significant disease, diagnose disease early when present, and avoid the very expensive costs associated with a late diagnosis of PC and other diseases. I would attribute this to short-term vision and being "pennywise and poundfoolish." In my experience, the frightening aspect of this control over disease management by some insurance companies is that they are deferring active treatment until the patient is so far advanced that death often precedes any chance to do the patient good. I believe that the economics of the insurance carrier has invoked the pathological concept that "death is cost-effective." I have seen this too often to regard it as an aberration in dealing with organizations so motivated. Consumer advocacy and safeguarding are badly needed. The expression caveat emptor or "let the buyer beware" is operative here.

The patient's wishes--that is, the informed and educated patient and partner's wishes--must be taken into account. One unusual but true story that relates to this is that of a patient who was recently diagnosed with PC. His sex life was not at all important to him in comparison to the necessity of his feeling assured that the entire prostate gland and surrounding tissues were removed at the time of RP. Although he expressed this to his physician, and specifically his decision not to have a nerve-sparing procedure, the patient was disappointed and depressed when he realized that he had been subjected to a bilateral nerve-sparing procedure. This was not what the patient wanted. This is the only time that I have personally witnessed a man who was unhappy about having erections after a radical prostatectomy (RP). The patient's wishes had been discounted and ignored by the physician.

With all of these situations discussed, what relatively simple and inexpensive tools can be used to discern that PC might be present??

PSA Density Higher Than 0.15 ng/cc Should Raise Concern about PC
If a determination of the volume of the prostate has been made by ultrasound or some other radiological technique, we can calculate the PSA density (PSAD) or the amount of PSA (expressed in nanograms) for each cubic centimeter of the prostate volume. The PSAD is simply the serum PSA value divided by an accurate gland volume determination.

PSAD = Serum PSA ÷ Gland Volume (per TRUSP or Endorectal MRI)

Some physicians are incredibly astute in having the ability to estimate the gland volume within 10% of more objective gland volume determinations that are obtained using radiological studies such as transrectal ultrasound of the prostate (TRUSP), or endorectal magnetic resonance imaging (endorectal MRI). PSAD results of 0.15 ng/cc or greater are more consistent with a diagnosis of PC than if the PSAD is less than this.100-102 There is very little in medicine that is an absolute guarantee, a definite yes or no. Therefore, it is strongly suggested that a combination of modalities be used to enhance the accuracy of any kind of assessment. This combined modality analysis was the basis for the breakthrough approaches of Oesterling103 and Partin104 and the many subsequent analyses that we use in a comprehensive risk assessment for the individual patient.

PSAD of Transition Zone More Accurate Than PSAD for Diagnosis of PC
A recent improvement to the value of the PSAD is doing a PSAD of the transition zone (TZ) of the prostate; this is called PSAD-TZ. The zonal anatomy of the prostate was proposed originally by McNeal.105 He divided the prostate into three glandular zones: transition, central, and peripheral zones (see Figure 4). The PSAD-TZ has been shown to be more accurate than a simple PSAD of the entire prostate gland.

PSAD-TZ = Serum PSA ÷ Gland Volume
(per TRUSP or Endorectal MRI of TZ)

In a prospective study of 559 patients, 217 men with PC and 342 with histologically confirmed BPH were evaluated with PSA, PSAD, PSAD-TZ, and percent free PSA. Multivariate analysis and ROC curves showed that PSA-TZ and percent free PSA (f/t PSA) were the most powerful and highly significant predictors of PC. Areas under the receiver operating characteristics (ROC) curve for PSA-TZ and percent free PSA were 0.827 and 0.778, respectively (p = .01). The combination of f/t PSA with PSA-TZ [Area Under Curve (AUC) = 88.1%] significantly increased the AUC as compared to each of the other parameters alone as well as their combination (p = .02). The next best combinations were PSA-TZ + PSAD, PSA-TZ + PSA, and f/t PSA + PSA.

Note: Accuracy is measured by the area under the ROC curve. An area of 1 represents a perfect test: an area of .5 represents a worthless test. A rough guide for classifying the accuracy of a diagnostic test is the traditional academic point system:

.90-1 = excellent; .80-.90 = good; .70-.80 = fair;
.60-.70 = poor; .50-.60 = fail.

See review by Tape TG: Interpreting diagnostic tests, University of Nebraska Medical Center at http://gim.unmc.edu/dxtests/ROC3.htm.

With regard to an individual test, PSA-TZ followed by f/t PSA and PSAD were the most powerful single predictors of PC in patients having a serum PSA between 4-10 ng/mL. The f/t PSA plus PSA-TZ was the most effective combination.107 The same findings held true for PSA values of 2.5-4 ng/mL.108

PSA Velocity Reflects the Biological Activity of the PC Process
The PSA velocity (PSAV) is a statement of how fast the PSA is accelerating. It is the rate of change of PSA calculated per year of time. Therefore, if the PSA on 1/1/98 was 0.5 ng/mL and on 7/1/98 it was 1.0 ng/mL and then rose to 2.0 ng/mL on 1/1/99, the PSAV would be 1.5 ng/mL per year. The PSADT would be 6 months because the PSA is consistently doubling every 6 months. The faster the PSAV, the shorter the PSADT. Such PSA kinetics are additional inputs of information for the observant physician and/or the empowered patient and partner. Results of such tests should raise or lower suspicion about the presence of a pathologic process, that is, PC.109-111 It is important to emphasize that combining multiple sensory, or data inputs, enhances our understanding of the biology of disease. If it looks like a zebra, walks like a zebra, and has stripes, it probably is a zebra. The ability to manipulate multiple sensory inputs into an action plan for improved diagnosis and survival is a hallmark of higher-level thinking. Too often, in medicine or in life, we try to hang all of our hats on one hook. The PSAV has also been shown to be an important determinant in survival in patients with Androgen Independent PC (AIPC) or so-called hormone refractory PC.112

The more data points in these determinations and the longer the time period over which a trend is maintained, the greater the validity of such calculations.113,114 The important concept underlying the above is the persistent generation of PSA by the tumor cell population reflecting itself in the bloodstream and determined by repeated testing.

PSA Doubling Time Reflects Tumor Growth
The PSAV tells us how rapidly the PSA is increasing per year. The PSADT tells us the length in months it takes for the PSA to double in amount. All of the mathematical derivatives of serial PSA testing are expressing the biological process.115 The average PSADT of PC is approximately 48 months, or 4 years. Men with an absolutely healthy prostate gland do not have any appreciable PSADT; their PSA levels remain essentially flat over decades of observation. Men with BPH have very slow PSA doubling times--usually over 12 years.

Men presenting with historical data showing PSADT of less than 12 years must be presumed to have PC until proven otherwise.116 The PSADT in men with histologically established PC is a valuable tool in:

• The management of PC (watchful waiting versus active treatment).97,117,118
• The prediction of extent or stage of disease.119
• The correlation of PSADT with normal versus abnormal DNA (ploidy).120
• The probability of local recurrence and metastatic disease after local treatment.121-124

The same concept of the PSA doubling time paralleling the biological growth rate of the tumor may be applied to other biological markers of PC malignancy. Biomarkers such as PAP (prostatic acid phosphatase), CEA (carcino-embryonic antigen), CGA (chromogranin A), and NSE (neuron-specific enolase) may be expressed in PC variants that usually are associated with high Gleason scores, for example, 8-10.125,126 In such patients, the expression of PSA in the blood or serum may not be great. This has been referred to as the PSA leak.127 The PSA leak in high Gleason score PC is relatively low. For example, a Gleason score of 10 has a PSA leak of approximately 1.0 mg/cc versus 4.0 mg/cc for a Gleason score of 6.

Therefore, in patients with a Gleason score of 8-10, the PSA becomes less of a reliable marker of disease activity. Some tumors may show evidence of dedifferentiation and express relatively little PSA despite other findings of PC activity such as a progressive bone scan, bone pain, and elevations in alkaline phosphatase and lactic dehydrogenase (LDH) as well as other tests. This is uncommonly seen in newly diagnosed PC unless the disease has been diagnosed late and the chance of mutation affecting the PC population has occurred. Such patients with a late diagnosis often present with PSA levels greater than 20 and not uncommonly greater than 50. The probability of disease outside the prostate is greater in such patients, again reflecting the more aggressive nature of the PC cell population.

Therefore, we learn about a tumor based on the biological activity it manifests. The same principle involving biomarker kinetics has value in the monitoring of patients with various common malignancies (see Table 6). Important concepts in the use of biologic markers are to obtain blood at baseline after the diagnosis is established to see what markers the tumor is producing and to monitor the patient's course after treatment to ensure that any elevated marker(s) have returned to normal levels and that they remain there.128 This is the same principle used in the evaluation of PC and monitoring the response to all types of therapy. This is a simple tool that should be regarded as an excellent means of assessing biological activity.

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

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

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

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

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

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

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

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

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

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

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

The Dimension of Time--The Importance of Trends
The so-called prediagnostic history often provides laboratory information that when properly analyzed indicates a high probability that PC was already present but unfortunately not suspected or perhaps not pursued to establish an earlier diagnosis. We know, for example, that PSAV determinations of greater than 0.75 ng/mL a year should raise a red flag as to the presence of PC. For accuracy in analysis, such calculations should be made using one PSA assay, for example, Tosoh, DPC, Hybritech, Bayer, etc., which is being run in the same laboratory facility.

PSAV and PSADT determinations are most valid when the PSA testing interval selected for the analysis is approximately 6 months or more. However, what is important to stress in this context is the PSA trend or slope over time. Serial PSA values showing a progressive increase in PSA should always raise concern that a biological process is occurring. It is the rapidity of such an increase that will suggest if this is a malignant or a benign process.139

The PSA increases over time associated with a healthy prostate are tiny. They amount to average increases of less than 0.1 ng/mL a year (range 0.055-0.128) of PSA in the blood.140-142 Therefore, the use of PSAV thresholds of greater than 0.75 ng/mL a year is quite generous in raising concern about the presence of PC. Table 10 shows my PSA values over the course of 10 years.

The PSA trend or slope (also referred to as PSA kinetics or dynamics) is a far more important biological expression than any one PSA absolute value. Such kinetic values express active changes in the status of the PC patient over the dimension of time. Realizing that aberrations in laboratory testing do occur should mandate that, when a major change is found in a laboratory test result, repeat testing for validation purposes should be required until a definite trend is clearly seen. Too often, patients with PC are ready to make major changes in their evaluation or management based on one or two PSA changes. This also applies to other biomarkers such as PAP (prostatic acid phosphatase), CGA (chromogranin A), CEA (carcinoembryonic antigen), and NSE (neuron-specific enolase), which the physician may be using to monitor the PC patient.

TRENDS ARE IMPORTANT IN BOTH THE EVALUATION AND MANAGEMENT OF ANY ILLNESS--INCLUDING PROSTATE CANCER.

What Does This Mean for Patients?
In prior paragraphs, it was emphasized that first-time PSA levels of less than 2.0 are uncommonly associated with PC and that, in such patients, PSA testing can be done every 2-3 years. Patients with first-time values of PSA that are less than 4.0 ng/mL but at least 2.0 ng/mL should not be regarded as having a PSA within the normal range. The guidelines for a normal first-time PSA are up to 1.9 ng/mL.

It was also pointed out that the PSA and its derivatives, such as PSA velocity, PSA doubling time, PSAD (total gland and for transition zone), and free PSA percentage, are instrumental in our understanding of biological reality. It is akin to the story of the three blind men feeling different parts of one elephant and describing three entirely different animals. What is needed in the elephant story, in the management of PC and other health issues, in a military campaign, and in the management of any world challenge, is an integrative way of thinking, which fosters unified concepts and embodies principles of synergy and harmony.

We also presented new findings on the free PSA percentage; it can be done on PSA levels as low as 2.0. This finding, coupled with the information on first-time PSA readings being significant when the PSA is found to be 2.0 or higher, should lead to an earlier diagnosis of PC and greater probability of cure.

Additional reading on the subjects of free PSA, PSADT, and PSAV can be found in the Primer published by Life Extension Media and available either by telephoning (866) 820-7457 or on the Life Extension website at www.lefprostate.org . Software on free PSA percentage versus the diagnosis of PC, correction for PSA results if ejaculation has occurred within 48 hours of PSA testing, and calculators for PSAV and PSADT can be found on the PCRI (Prostate Cancer Research Institute) website at www.pcri.org . This software, PC Tools I and PC Tools II, was developed by Glenn Tisman, M.D., a medical oncologist in Whittier, California, who specializes only in PC.

5. RISK ASSESSMENT OF THE PC PATIENT

Once a diagnosis of PC is established by means of tissue biopsy and microscopic findings showing PC, the foundation of the medical record should have further information added to it to allow for an even greater understanding of the patient's true status. In this context, status refers to the actual extent of disease, or stage of disease. Is the PC really confined to the prostate gland or does it penetrate the capsule of the prostate or perhaps invade local surrounding tissues such as the seminal vesicles and nearby lymph nodes? Are there any clues that the PC has spread or metastasized to more distant lymph nodes or bone?

The orientation of most specialists will be toward recommending a local therapy to eradicate PC within the gland. This is the essence of the reasoning behind the surgical removal of the prostate--RP. The other approaches toward treating PC with curative intent may be slightly more regional, but most are still designed to primarily treat the prostate gland. For example, external beam radiation therapy (EBRT) will include not only the prostate gland itself, but also a margin around the gland to kill any tumor cells that may be in this area trying to escape and spread to more distant sites. The same is true for the iceballs created by cryosurgery.143 The critical concept here is that local measures treat local disease. The determination of the true extent or stage of the disease is one of the critical variables in the strategy of successful treatment of PC. For example, if the disease is present outside the prostate gland in tissues such as the seminal vesicle or nearby regional lymph nodes (the obturator or internal iliac lymph nodes), an RP will have a significantly diminished chance in curing the patient with PC. The same is true for RT or cryosurgery. For such therapies to have a great chance of cure, the cancer must be within the scope of the scalpel, within the boundaries of the radiation ports of therapy, and within the periphery of the iceball(s) created by cryosurgery.

An additional limiting factor for radiation therapy and cryosurgery is the amount of PC. The tumor volume has a bearing on the ability of RT or cryosurgery to destroy the entire tumor mass.78,144,145 This second variable in the equation may relate to the penetrating ability of the radiation particle used (photon < proton < neutron)146-148 or to the understanding that the core of a large tumor has a diminished oxygen supply (a hypoxic center) that confers resistance (called radioresistance) to the treatment.149,150 This actually may not be as critical a factor in cryosurgery as it is in RT. These aspects of RT are discussed and illustrated in detail in the Primer. The reader is recommended to review pages 90-127 of the Primer to better understand these concepts.

A third variable, one under-discussed with the patient for obvious reasons, is the variability in skill of the physician, regardless of the specialty. Some physicians are just plain outright talented artists, while others are average in skill and still others are below average.

Unfortunately, all physicians quote the outstanding literature on a particular treatment but very few present to the patient their own scorecard of performance statistics.

There are additional variables relating to diagnosis and staging. The number of these biological observations is increasing as we learn more and more about the cancer process. Some of these variables include the following:

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

Baseline PSA and Baseline PAP Are Keystones in Our Understanding of PC
The Primer goes into great depth on the importance of the baseline PSA and PAP. Let me make a few salient points. The PSA is a blessing. There are no other common malignancies that forecast their development through such a simple and inexpensive blood test as the PSA. But there are limitations to the PSA, as there are with everything in life.

Everything in life is a two-edged sword.

One major limitation of the PSA is that it is a laboratory test, which makes it subject to error and to conditions that elevate the PSA and possibly result in false alarms. However, one can state safely that a healthy prostate is one not subject to progressive or persistent elevations of PSA. In such situations, if PC is not the underlying cause, then prostatitis or BPH is the cause. These conditions significantly affect the quality of life of many men. Many scientists involved with PC research also believe that prostatitis may be a precursor to PC.151,152

In regard to the laboratory errors that may occur with PSA; these may occur with all tests. The rule of thumb is that if a test shows a reading at any time that is of concern, the test should be repeated and then repeated again after a short period of time to confirm whatever trend now seems apparent. It is this persistent trend that is so important in declaring the presence of biological conditions that should concern us.

PSA Leak Is Relatively Low in Undifferentiated PC
Another aspect of the PSA that may be misleading is in the setting of patients with a low PSA level that is associated with a high Gleason score, for example, (4,3) or higher. The problem here is that high Gleason score lesions, having a significant component of Gleason grade 4 or 5 PC, do not secrete as much PSA into the blood as lower grade lesions. This is called the PSA leak. Table 11 shows the PSA leak as a function of average (weighted) Gleason grade.

Here is where the Gleason score is very important in elaborating on the significance we give the PSA during the initial and subsequent evaluations of the patient. I have seen patients present with Gleason scores of 9 and 10 with low levels of PSA and yet they had large tumor volumes reflecting PC that was outside the prostate gland and not amenable to cure with local therapy.

A Microsoft Excel software program for tumor volume (which can be found on the PCRI home page at www.pcri.org ) shows the above relationships clearly. The program requires the b (baseline) PSA, gland volume, and Gleason score. The PSA leak is calculated from the weighted Gleason grade. The outputs of this program give you benign PSA, PC-related PSA, and calculated tumor volume. Additional integrated programs give you probability of organ-confined disease, probability of cure with RP, and likelihood of freedom from biochemical relapse at 20 months after RT.

Gleason Score Versus Gleason Grade
The Gleason score is composed of two grades: the primary grade and the secondary grade. The primary grade is the preponderant glandular pattern of PC as seen under the microscope. By definition, it composes a minimum of 51% of the picture and possibly as much as 95% of the picture. In contrast, the secondary grade must represent at least 5% and as much as 49% of the glandular architectural pattern.

The most common Gleason score seen in biopsies obtained during contemporary times is (3,3). Gleason scores of (4,4), (4,5), (5,4), and (5,5) make up about17% of all PC cases.153 The Gleason score of 7 is a special situation that has significant implications depending on whether the 7 is a (3,4) or a (4,3). This distinction is based solely on the amount of Gleason grade 4 PC that is present. As previously stated, a (3,4) could have as little as 5% Gleason grade 4 disease or as much as 49%. In contrast, a Gleason score of (4,3) must, by definition, have at least 51% Gleason grade 4 disease and possibly as much as 95% (since there must be at least 5% of Gleason grade 3 PC in a (4,3) lesion). A major difference in prognosis has been found for patients with a Gleason score of (3,4) versus (4,3) located within the RP specimen.154-156 The new Partin Tables for 2001 have different readings of risk assessment for Gleason score (3,4) versus (4,3) on the diagnostic biopsy specimen.157 This distinction is easily seen when using the PC Tools II software program developed by Dr. Glenn Tisman (available on the PCRI website at www.pcri.org ).

In the hands of expert pathologists, focused only on PC pathology, the Gleason score identification is one of the most important biological determinants of prognosis. I have suggested that the Gleason score be embellished with what I call the Gleason differential: a quantification of the amount (in percent) of Gleason grade 4 or 5 in the pathology specimen. Therefore, a patient with a Gleason score of 7 that is (4,3) might have 95% Gleason grade 4 and only 5% Gleason grade 3 to give the following Gleason differential: GS(4,3)[95/5]. In contrast, he might only have 51% Gleason grade 4 or a Gleason differential of GS (4,3)[51/49]. Evaluations of the diagnostic biopsy material that quantitate the amount of Gleason grade 4 or 5 disease may allow for a further enhancement in the prognosis of PC.

These variables are part of the equation to determine extent and amount of PC as well as the ability to deliver specific kinds of therapy with greater or lesser probability of disease progression after completion of such therapy. Pending this kind of input, the astute physician, empowered patient, and partner can determine what other tests should be considered or discarded. Additionally, with this foundational information at hand, the healthcare team can use history to develop a risk assessment for the patient that relates to outcome: What is the probability that your treatment will be successful? Again, the latter presumes that the therapist delivering the treatment is as talented as the physicians involved in the studies that were the basis for the risk assessment.

Cross One Bridge at a Time
A common path that patients and partners as well as physicians take after a diagnosis of PC is to immediately make the choice of a treatment option the main focus. Too often, a patient goes from a diagnosis to a bone scan, often a CT scan, and then to the discussion of treatment options. The medical detective work of assessing the patient's risk for organ-confined disease versus nonorgan-confined disease is just not done routinely.

The risk assessments involved with PC take the form of multiple inputs into a statistical evaluation in which the output has more statistical significance than any single input. In such a scenario, the whole is greater than the sum of its parts. These assessments are termed algorithms, nomograms, neural nets, etc.154,158-160 They look at data in terms of searching for meaningful variables and then combine these variables to provide a closer sense of the truth about a particular patient based on how other patients with the same variables fared in a large series of patients. This is the essence of what we call the Partin Tables.

Partin et al. looked at the findings of radical prostatectomy (RP) and noted whether or not the pathologic findings showed the PC to reflect OCD, and whether there was evidence of capsular penetration (CP), seminal vesicle (SV) or lymph node (LN) involvement.104,157,161 Statistical analysis was done to determine which presurgical findings would equate with a high probability of these RP findings upon pathological review of the surgical specimens. This is the essence of many of the tools we use to assess risk for the hypothetical patient. Everyone is unique in his or her biology, but a general statement of risk can still be presented to the patient.

Unfortunately, despite the availability of this tool and many others similar to it, perhaps only 5-10% of physicians go through the discipline of doing the Partin Table and/or other algorithmic calculations. Sitting down and inputting medical variables of known significance and doing the homework involved in the risk assessment of the PC patient is a very crucial step in a logical, rational approach to this disease. Not only the patient but also the physician should be crossing one bridge at a time. When this is done, the PPP team reaches a superior understanding of the disease process and attains a greater sense of what is likely to be the reality for a particular patient.

Appendix F in the Primer goes into great depth about these diagnostic and staging variables. The reader is referred to Appendix F for further information. In addition, the May 2001 issue of the PCRI Insights newsletter contains a comprehensive review of risk assessment algorithms by Glenn Tisman, M.D. This issue can be obtained online at www.pcri.org or by calling the PCRI at (310) 743-2110. The software section on the PCRI website also has risk assessment computer programs that can be downloaded without charge.

What does all 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 PPP 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. However, 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 (3D conformal radiation, IMRT, seed implantation, HDR, or a combination of these radiation approaches), 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.

What Does This Mean for Patients?
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 the successful management of the man with PC. Remember, if man does not learn from history, he is forced to repeat it.

6. KNOWING PROS AND CONS OF WEAPONRY: UNDERSTANDING PROS AND CONS OF TREATMENT OPTIONS

In winning a military battle, an understanding of the appropriate strategy for the situation at hand is critical for success. Military tactics, including the weapons used, must be matched intelligently to the circumstances that are present. The same is true for the management of PC and other illnesses. The most important aspect of this match is the realization that a local treatment will have its greatest chance of being curative if the biological expressions of disease suggest that it is likely that only local disease is present. Therefore, obtaining as many insights as possible into what constitutes a high probability of OCD is warranted.

The preceding sections have laid the groundwork, the reconnaissance so to speak, for the gathering of that information. The medical strategist takes these variables into account and builds a case for or against local therapy. The major algorithms such as the Partin 2001 Tables157 and the nomograms from Kattan et al.,162-164 D'Amico et al.,76,158 Narayan et al.,73 Bluestein et al.,165 Gilliland et al.,166 Lerner et al.,167 Pisansky et al.,168 and others72,109,154,159,160,169-180 should be used. These only take minutes to do and there is little to lose in seeing if a consensus is present for organ-confined disease.

If an assumption is made that a patient has a high probability of organ-confined disease and that there are no medical issues or financial issues that preclude any particular choice of local procedure to cure PC, the $64,000 question is this: "What procedure has the best track record?" Certainly, given the many publications on this subject over the last few years, one would have to state that overall there is no striking difference in success rates between any of the local therapies for PC--RP, RT of any type, or cryosurgery.181-183 The longest follow-up period after definitive local therapy relates to RP. However, it appears unlikely that the 10- and 11-year data following RT are going to suddenly deteriorate or that the 15-year data after RP are going to change. The follow-up data after cryosurgery are at most 10 years old with most of the modern-day approaches to this technique beginning in 1992 with the work of Onik and Cohen et al.184,185 The cryosurgery literature is more difficult to evaluate because in the last 10 years there have been major technological advances. These include the following:

• The use of temperature monitoring using thermo-couples143,186,187
• The use of double and triple freezing techniques143,186
• The use of Argon gas188-190 instead of liquid nitrogen to induce the freezing necessary for creation of the iceball
• The recent use of templates to guide the placement of the cryosurgery probes, similar to those used in brachytherapy191

The fine points of RP, RT, and cryosurgery are extensively dealt with in the Primer (now available through amazon.com, Barnes & Noble, Borders, and the Life Extension Foundation at (866) 820-7457).

The issue then is which of these local therapies, if any, does the patient choose. Assuming that the patient at risk is not a candidate for watchful waiting, any of these therapies might be a perfectly reasonable strategy to eradicate organ-confined or regionally confined PC. My recommendations to patients on this matter are based on the following differential factors:

• Age
• Overall medical status after a detailed examination
• Patient priorities
• Patient access to expertsin the selected modality of therapy
• Financial and insurance issues
• Lower urinary tract symptoms (LUTS) at the time of diagnosis
• Prostate gland volume
• History of scar formation (keloids) after any prior surgery
• Baseline PAP
• Baseline plasma TGF-b1, IL-6, and IL-6 soluble receptor levels
• PSA response to ADT (androgen deprivation therapy) after 3 months of therapy

In essence, a combined modality analysis of sorts is being employed. This involves variables that have not been interactively evaluated as part of an effort to define the best local therapy for an individual patient. Hopefully, a true nomogram or artificial neural net (ANN) looking at such additional variables can validate their significance for such an analysis.

Some of these issues have been discussed in prior sections. A short review of each of these topics is justifiable for this section.

Age
Traditionally, patients beyond age 70 are excluded as being candidates for RP. I believe that this decision should be individualized based on the patient's health, youthfulness for his age, and the other listed factors rather than using age as an arbitrary reason for excluding a patient. I have evaluated some men in their 50s who are much older in appearance and in biological status than their stated age. I have seen others in their late 70s who appear to be in their early 60s and who are healthier on examination than men in their 60s.

Overall Medical Status after Detailed Examination
This has been alluded to in the section on medical record-keeping and the use of summary and/or surveillance forms. Patients being considered for any invasive procedure should have a thorough physical examination. Factors that place them at much higher risk for morbidity after RP, RT, or cryosurgery should be candidly discussed with the patient and his partner.192 Cardiovascular disease, Type II diabetes, kidney disease, hypertension, and neurodegenerative diseases should be red flags that an invasive procedure may be associated with greater adverse effects.192,193 The evaluation of the patient's cardiac status with triglyceride/HDL ratios194,195 as well as the conventional LDL and total cholesterol levels, the use of hypersensitive C-reactive protein,196-198 and homocysteine levels are reasonable to do in this setting (discussions of these topics can be found in several other protocols in this volume).

The use of fasting insulin levels and the ratio of AA to EPA may be an excellent screening tool to evaluate the overall health of a patient considering any of these procedures.199-202 In addition to a very thorough internal medicine history and physical examination, the studies that I have found particularly revealing include a stress echocardiogram with calculation of the ejection fraction and electron beam tomography with coronary artery calcium scoring.196

A significant factor in patients having problems with RP, RT, or cryosurgery is small vessel disease due to diabetes or hypertension. Diabetic patients represent a great challenge because of the prolonged delay in return of urinary function after any local therapy. Tissue healing is not optimal in such a setting.

Patient Priorities
The patient's inclinations toward a particular therapy are often a product of decades of programming that will not be undone in a course of weeks or even months. Some men are adamant about having surgery, while others are exactly the opposite. Some feel that RT is the choice for them, while others are more comfortable with freezing. The poet Robert Frost may have encountered this same problem and reflected upon it in "Fire and Ice:"203

Fire and Ice
Some say the world will end in fire,
Some say in ice.
From what I've tasted of desire
I hold with those who favor fire.
But if I had to perish twice,
I think I know enough of hate
To say that for destruction ice
Is also great
And would suffice.

There are those patients who cannot decide between fire (RT), ice (cryosurgery), or surgery and who instead pursue objectified ongoing observation. But as my father used to tell me, "That's what makes horse racing."

Patient Access to Expertsin the Selected Modality of Therapy
I have no issues with any decision that a patient and his partner make if it has reasonable backing with biological data and the ability to involve physicians with gifted technical skills. Patients should interact with their fellow patients at support groups, asking about the details of experiences with local physicians in these fields. Patients and their partners should explore the Internet, looking for any listings of physicians considered to be outstanding in their skills.

Moreover, patients and their partners should have a formal consultation with the physician(s) that they are considering to see if there is rapport between all three parties and to witness the interaction of the physician with other patients in his or her medical office. The physician should be asked for names of patients who are willing to be telephoned by you and/or your partner. These should be patients who have undergone the procedure within the last year or two. Obtaining three such names would be appropriate--perhaps one that had the procedure 6 months ago, another who had the procedure 12 months ago, and a third who had it 1 1/2-2 years ago. You should not be embarrassed to ask the physician about his success rate or about the incidence rates of complications his patients have experienced. These should be his figures and not those cited in someone else's series of patients.

Financial and Insurance Issues
The choices being made are quality-of-life decisions that also can affect quantity of life. Some patients may elect to stay within their medical insurance plans and feel that this is adequate for them.

Lower Urinary Tract Symptoms (LUTS) at the Time of Diagnosis
LUTS will often adversely affect the quality of life of a patient undergoing RT of any kind or cryosurgery. The physiological interaction is likely related to radiation urethritis due to RT or thermal (cold) injury to the urethra from cryosurgery.

LUTS can be quantified with the AUA symptom index score.84,204 Patients should consider scores of 10 and higher as a relative negative risk factor in choosing RT or cryosurgery as a local therapy. A more powerful argument can be made for baseline AUA scores of 15 to 20 and higher. A relatively recent study used a combined modality assessment to determine what findings are most significant for predicting bladder outflow obstruction. A combination of an AUA symptom index of greater than 20, a prostate gland volume of 40 grams or more, and a urine flow of 10 mL or less per second, when present, predicted for obstruction 100% of the time.86 Urine flow rate was determined using uroflowmetry.

The prophylactic and long-term use of alpha blockers (Flomax, Cardura, or Hytrin) to reduce LUTS prior to, during, and after brachytherapy has been reported to reduce the time to return to baseline urinary function.84

Prostate Gland Volume
Often, but not invariably, men with LUTS will have prostate gland enlargement due to BPH. The large gland volume is another confounding factor affecting potential radiation or cryotherapy-related injury to the urethra, rectum, and bladder. Options for the patient in such a situation include the use of ADT to reduce the gland size prior to local therapy. Usually, within 3 months of starting ADT, the gland volume will be reduced by as much as 40%. After 6 months of ADT, the gland volume may be reduced 60% or more from baseline. The proper use of ADT with monitoring of the serum testosterone using the goal of less than 20 ng/dL may be a factor in why some men have dramatic reductions in gland size with ADT and others do not. The use of three-drug ADT involving an anti-androgen plus Proscar or possibly another 5-alpha reductase inhibitor Avodart (dutasteride) in conjunction with an LHRH-agonist like Lupron, Zoladex, or Trelstar LA has provided me with excellent results in both prostate cancer reduction and prostate gland volume reduction.

In men who are reluctant to receive ADT and/or do not have a dramatic response to alpha-1-blockers, choosing an RP is an excellent way to eliminate LUTS and restore urinary function to a high level. The urologist is essentially providing the patient with a new urethra, without the adverse effect of compression of the urethra by an enlarged prostate. Urinary flow in such patients is restored to that of a young man. This presumes that the operating urologist is skilled in the RP procedure and has an impeccable track record with a complication rate for gross incontinence at less than 2%, but total continence rates in the order of 92-95% with no need for protective pads of any kind, and anastomotic stricture rates that are less than 5%.

History of Scar Formation (Keloids) after Any Prior Surgery
If we could identify patients most likely to develop complications, we could direct them to other therapeutic strategies. An investigation that comes close to this was done by Park et al.205 This study correlates the probability of developing a narrowing or stricture after RP to a patient history of excessive scar formation from the actual RP or evidence of such scarring in prior surgical procedures. This study spanned a 5-year period and involved 753 radical retropubic prostatectomies performed by a single surgeon. The overall incidence of stricture at the anastomosis or connection of the bladder neck and distal urethra (anastomotic stricture) was 4.8%. The only significant finding that predicted the development of such a stricture was the maximal width of the abdominal scar resulting from the skin incision made at the time of RP.

In other words, the patient's reaction to surgery at a skin level was reflected in the tissue healing at the site of union (anastomosis) between the bladder neck and membranous urethra joined together after the excision of the prostate and prostatic urethra (see Figure 5). Men with a maximal scar of greater than 10 millimeters (mm) were 8 times more likely to develop strictures than men with smaller scars. The percentage of men who required protective pads 1 year following radical retropubic prostatectomy in the stricture group was 46.2%, while the figure for those without a stricture was 12.5%.

The authors of this study speculated that prior history of excessive scar formation may have implications in the adverse outcomes of other surgical procedures such as coronary bypass grafts, angioplasties, bile duct operations, etc. This is highly provocative, and the potential implication is that a history of excessive scar formation after any of the latter procedures may be a warning for those men considering a RP as a possible choice of local therapy.

Baseline PAP
The importance of the baseline PAP blood level has been published in three major papers.74,75,206 These papers are referenced in detail in the Primer. The routine use of the PAP as part of our understanding of the biology of PC, its relation to the tumor cell population, and the probability of disease progression after RP or RT (with or without seed implantation) appears to be justified.

Baseline Plasma TGF-b1, IL-6, and IL-6 Soluble Receptor Levels
Molecular biomarkers relate the mechanisms of biologic behavior, function, and cell-to-cell interaction that add to the profile of the PC cell population. This has been known for PAP and PSA as well as CGA (chromogranin A) and NSE (neuron-specific enolase). Many physicians, however, are not aware of the functionality of biomarkers. For example, PSA has major activity as an enzyme--a kallikrein-like serine protease to be exact. PSA is a normal component of the seminal fluid component of the ejaculate and helps to keep the ejaculate liquid. However, as stated earlier, everything in life is a two-edged sword.

PSA produced from malignant prostate cells functions to break down specific proteins. These glycoproteins are found within the basement membrane of the microscopic glandular architecture. Simply, they are the ground substance to which the basal cells of the prostate glands are anchored. PSA degrades these proteins (fibronectin and laminin) and facilitates invasion by the PC cells. Thus, PSA made by the PC cell population is not only a biomarker of disease activity, but also a functional protein that is important to the survival of the cancer cell. Reducing PSA is therefore not only a good sign that a therapy is working, but also that one is reducing a substance that facilitates spread of the disease.207 In another publication, PSA was shown to suppress T-cell mediated immunity.208 This functional activity of PSA may be mediated by TGF-b1 production from the prostate cell.209

That cell products that we identify as biomarkers may have function appears to be the case for virtually every cell product identified. They have function as well as form. Another enzyme produced by both benign and malignant prostate cells is uPA. uPA was discussed earlier in this review (see the section on General Preventive Measures). uPA is stimulated by IGF-1 and inhibited by GLA and EPA. uPA is believed to play a key mechanistic role in PC invasion and metastasis.210

TGF-b1 is a growth factor produced by the prostate cell as well as by cells of the bone matrix. Interleukin-6 (IL-6) is a cell product, or cytokine, that is made essentially by the primary tumor as well as by osteoblasts. IL-6 facilitates bone resorption by acting on IL-6 receptors located on the osteoclast and osteoclast precursor cells. This incredible cascade was illustrated in Figure 1 of this chapter. Studies recently published by Shariat et al. show a very strong positive correlation between higher plasma levels of pre-RP TGF-b1 and findings at RP of ECE (extracapsular extension), seminal vesicle involvement, and lymph node involvement.211 In this study, preoperative plasma TGF-b1 median levels of approximately 15 ng/mL was significantly associated with lymph node and bone metastases. Healthy noncancer controls and men with RP findings not indicating extra-prostatic involvement had median levels of TGF-b1 of 4.7-4.8 ng/mL.

In a subsequent study involving 302 men with clinically localized PC, the same investigators evaluated preoperative and postoperative plasma TGF-b1 levels, and also IL-6 and its soluble receptor (IL-6sR), to determine correlations with disease progression. Of the study participants, 88.8% of the men had PSA progression-free survival at 3 years and 85.1% remained progression-free at 5 years post-RP. Cancer progression occurred in 43 of the 302 men (14%), with average postoperative follow-up of 50.7 months. Of the 43 men with PC progression, 19 were categorized as having nonaggressive progression postoperatively because they had complete responses to salvage RT or because their PSA doubling times postoperatively were equal to or greater than 10 months.

The remaining 24 men had aggressive progression because of positive lymph nodes found at RP (n = 6), because of positive metastatic workup on bone or ProstaScint scan (n = 6), because their PSA doubling times were less than 10 months (n = 23), or because they failed to respond to salvage RT (n = 14). What Shariat and colleagues found were significantly higher pre- and postoperative TGF-b1 levels and higher preoperative IL-6 and IL-6sR levels in men with "aggressive progression" versus those with "nonaggressive progression." These findings are summarized in Table 12.

This laboratory testing is allowing us to use the biology of the patient's tumor cell and host interaction to declare the probabilities of organ-confined disease versus nonorgan-confined disease. These findings are nicely in keeping with the Lerner algorithm from the Mayo Clinic in Rochester, MN. In that large-scale study, 904 men with apparently pathologically organ-confined PC were found to have PSA recurrences within 5 years based on the RP Gleason score, baseline PSA, and whether or not the PC at surgery had a normal DNA amount (diploidy) or abnormal amount (aneuploidy). Even in the best of circumstances, with baseline PSA values of less than 10 ng/mL, a Gleason score at RP of 6, and diploidy, the data still show a biochemical failure rate of 15% within the first 5 years. If the RP specimen was aneuploid, this increases the failure probability to 30%. It would be of interest to see whether the TGF-b1 status of the patient is independent of the ploidy status. Evolving algorithms using these kinds of inputs will clarify our recommendations to patients and their partners.

PSA Response to ADT after 3 Months of Therapy
Michael Zelefsky of Memorial Sloan Kettering (New York City) a radiation oncologist, published a paper about the predictive value of the PSA after 3 months of ADT.212 The purpose of his study was to identify prognostic variables that predict for improved biochemical and local control outcomes in patients with localized PC who had been treated up-front with ADT, which was then followed by three-dimensional conformal radiotherapy (3D-CRT).

Between 1969-1995, 213 patients with apparently localized PC were treated with 3 months of ADT before 3D-CRT. The ADT consisted of leuprolide acetate and flutamide (ADT2). The purpose of ADT was to reduce the preradiotherapy target volume in order to decrease the dose delivered to adjacent normal tissues and minimize the risk of morbidity from high dose RT. The median pretreatment PSA level was 13.3 ng/mL (range of 1-360 ng/mL). The median 3D-CRT dose was 73.6 Gy (range of 64.8-81 Gy), and the median follow-up time was 3 years (range of 1-7 years).

The significant predictors for improved outcome identified by multivariate analysis included a pretreatment PSA level less than or equal to 10.0 ng/mL (p < 0.001), an ADT-induced preradiotherapy PSA nadir of less than or equal to 0.5 ng/mL (p < 0.001), and a clinical stage less than or equal to T2c (p < 0.04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels less than or equal to 10 ng/mL, 10-20 ng/mL, and greater than 20 ng/mL, respectively (p < 0.001). Patients with preradiotherapy nadir levels after 3 months of ADT2 that were less than or equal to 0.5 ng/mL experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (p < 0.001). The incidence of a positive biopsy among 34 patients pretreated with ADT was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (p < 0.001).

Zelefsky and colleagues concluded that, in settings of PC treated with ADT2 and high dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with PSA nadir levels greater than 0.5 ng/mL after 3 months of ADT2 are more likely to develop biochemical failure after radiotherapy and may benefit from more aggressive therapies. A summary of these findings is shown in Table 13.

What Zelefsky et al. have done is to use the biological response of the tumor to indirectly gain insight into the tumor biology in order to help assess the probability of successful outcomes with radiation therapy. A low probability of success should prompt the PPP team to discuss different treatment strategies.

The reduction of PSA to a lowest point or nadir is the same principle used in our study on intermittent androgen deprivation (IAD) to identify men with a high probability of PC that most likely reflects a homogeneous tumor cell population of androgen-dependent cancer cells.213 In our study, we used an ultrasensitive PSA and required a threshold of less than 0.05, 10 times more than the threshold of acceptability in the Zelefsky study. It is quite conceivable that the use of the PSA nadir is identifying a number of biological events that would equate with a better prognosis or response to therapy in general.

For example, the ability to drop the PSA to very low levels suggests that androgen-independent PC (AIPC) is not present. If it were, the efficacy of androgen deprivation would not decrease the PSA to the very low levels determined with an ultrasensitive PSA assay such as the Tosoh or DPC Immulite Third Generation assay. AIPC represents PC that has undergone mutation. It is associated with more aggressive PC that is also more likely to have left the prostate. If so, then RT would be less effective in preventing biochemical recurrence manifested by a persistently rising PSA after RT is completed. This may be one of the operative factors in the Zelefsky study.

Additionally, resistance factors to RT may have also developed in a setting of mutated tumor. This might be related to an increased amount of the antiapoptosis protein bcl-2, which confers radiation resistance. It could also be attributed to elevated levels of mutated p53.214-216 Lastly, in a study by Rakozy et al. on the use of up-front (neoadjuvant) androgen deprivation with RT, it was shown that levels of mutated p53 in PC tissue biopsied from patients failing RT were significantly increased in patients who had not received neoadjuvant ADT compared to those who did receive ADT (82% versus 38%, respectively).217 bcl-2 and mutated p53 are adverse biochemical findings because they protect the cancer cell from undergoing apoptosis.

PSA also reflects tumor volume. RT is a volume-dependent modality. It is also reasonable to consider that the PSA threshold of 0.5 or less after 3 months of ADT2 required in the study reflects a significantly diminished tumor cell volume. This would enhance the efficacy of any form of RT because the target volume is smaller. ADT also decreases angiogenesis by reducing VEGF.218 A major stimulus to increase VEGF and angiogenesis occurs in the centers of large tumors where oxygen tensions are low and cells cannot extract as much oxygen. This is called tumor hypoxia, and its occurrence is associated with resistance to radiation. If ADT is decreasing the size of the tumor, the probability of tumor hypoxia is less and also the ability of the tumor to nourish itself or spread via new blood vessel growth (angiogenesis) is less, again due to the effect of ADT.218 Therefore, the Zelefsky publication is a landmark paper because it stimulates much thinking as to what explanation exists for its findings. It should also prompt others to test the many hypotheses that are implicit in this study.

All of the biological events above are pertinent to translating the findings of the patient's clinical situation into a real-time medical strategy. They should direct the team to select a particular tactic(s) pending the biological feedback obtained because, in biological reality, all of these tests are reflections of the tumor-host interaction. Therefore, in all six steps discussed so far, we are investigating biological indicators--medical gauges or LEDs--to help us obtain true information about the enemy and how our soldiers will likely fare in a particular medical-military tactic. This is the essence of Lewis Thomas's The Lives of a Cell, the foundation of Eastern philosophy that the microcosm reflects the macrocosm (and vice versa) and the truth behind optimizing outcomes for any issue vital to life.

Hormone Therapy in Advanced PC
Hormone therapy may be used in advanced PC (Stage 3) or cancer that spreads beyond the prostate (Stage 4; metastasis often to the bones). Hormone therapies such as anti-androgens and estrogens (e.g., ethinylestradiol) are used to reduce testosterone levels (androgen ablation therapy). Hormone analogues are also used as anti-androgens, i.e., to interfere with the action of androgen.

A number of selective somatostatin analogues have been developed for clinical use in the treatment of PC. Somatostatin was first found in hypothalamic extracts and identified as a hormone that inhibited secretion of growth hormone. Somatostatins are regulatory hormones produced by neuroendocrine, inflammatory, and immune cells in the central nervous system and in most major peripheral organs. Somatostatin can act as an endocrine hormone; can participate in paracrine/autocrine regulation; or can act as a neurotransmitter. And when activated, many tumor cells produce somatostatin (Abrahamsson et al. undated).

Changes in PSA levels are commonly used to monitor response to PC therapy. A PSA value that declines by more than 50% is considered to indicate an objective clinical response to therapy in hormone-refractory disease. Often, measurement of another marker, chromogranin A (CgA), is required to accurately monitor response to treatment and to identify some patients with advanced disease who do not have elevated serum PSA (Deftos et al. 1996).

A study reported in the Journal of Urology evaluated whether a combination therapy of ethinylestradiol and somatostatin analogue can reintroduce objective clinical responses in patients with metastatic androgen ablation refractory prostate cancer. The test subjects (10 patients with stage D3 PC disease and bone metastases) had disease progression despite an initial response to combined androgen blockade and subsequent failure to anti-androgen withdrawal. The combined androgen blockade was discontinued and the patients were given 1 mg of oral ethinylestradiol daily and 73.9 mg of intramuscular lanreotide acetate (a somatostatin analogue) every 4 weeks. Serum PSA, CgA, the Eastern Cooperative Oncology Group (ECOG) Performance Status, and bone pain scores were monitored (median, 18 months; range, 10–24 months).

Although the number of patients in the study group was small, results were encouraging when combination therapy was used: 90% of the patients experienced an objective clinical response and an improvement in symptoms. In 9 of 10 subjects, PSA decreased greater than 50% and in 3 subjects PSA normalized (less than 4 ng/mL). All subjects had significant improvement in bone pain (median duration 17.5 months) and ECOG Performance Status (median duration 18 months) without major treatment-related side effects. There was also a statistically significant decrease in serum CgA during administration and at the response to therapy (median 38.4%, range 28.6% to 64.9%) that was not increased at relapse. Although two patients died secondary to prostate cancer, all of the other patients were without disease progression (Di Silverio et al. 2003).

Note: The ECOG Performance Status is used to assess disease progression, to assess how the disease affects the patient’s daily activities, and to determine appropriate treatment and prognosis. The Status has Grades 0 to 5: 0, fully active, no physical restrictions; 1, physical restrictions, but ambulatory and able to do light work; 2, ambulatory, can care for self, active more than 50% of waking hours, but unable to perform any work activity; 3, self-care is limited, in bed or chair more than 50% of waking hours; 4, completely disabled, no self-care, confined to bed or chair; 5, deceased.

7. UNDERSTANDING ENEMY VULNERABILITY: LEARNING PRINCIPLES UNDERLYING TUMOR GROWTH

To understand the weakness and vulnerability of an enemy in military battle, one must first try to understand his apparent strengths. The analogy of the tumor or cancer cell being the societal equivalent to a terrorist is a strong one. What we learned and are still learning from September 11, 2001, is that we did not understand the strengths of the enemy. Hence, we were not successful in deterring a successful incursion by the terrorists on September 11. If we do not learn from this historical event, we will see history repeated. The same remarks about cancer are true.

What are the characteristics of malignancy that justify a metaphor with terrorists? First of all, both arenas often share common terminology. Some comparable words include "disorderly," "inflammatory," "primitive," "network," "radical," "invasive," "instability," "hits," "cells," "resistance," "surveillance," "eradication," "preemptive," "checkpoints" and "survival."

Every cancer, including prostate cancer, is a disordered and abnormal cell growth. Cancer cells have lost the ability to network and communicate in the way that normal cells do, and they no longer function as intended in the overall framework of body chemistry. Such cells take on a demeanor of juvenile delinquents, with no respect for parental direction. Attempts to restrict disruptive or nonproductive behavior are ignored. Such disruptive cells are usually censored and expelled by regulatory monitors--guardians of the genome, proteins such as p53, p21, and p27, which normally identify and biologically excise such maladapted cells. In malignant conditions, these regulatory proteins lose control for largely unknown reasons.

In one study involving the development of malignancy of the esophagus, antibodies to p53 were found in 4 of 36 (11%) premalignant lesions of the esophagus and in 10 of 33 (30%) of those with cancer of the esophagus. In two of the esophageal cancer patients, the p53 antibodies were detected prior to a clinical diagnosis of cancer.219 Therefore, the cellular counterparts of terrorists are finding a way past one of the surveillance mechanisms (p53) that usually stand guard to detect DNA damage and halt the machinery of the cell cycle in G1 or G2 when DNA defects are found (see Figure 3). In a later section, another mechanism that tumor cells and viruses use to get past the surveillance system will be discussed.

The development of malignancy results from a combination of hits on the cell--repeated insults. Initial factors that lead to cancer production (carcinogenesis) are shown in Figure 6. Ongoing promotional and progression events eventually lead to premalignant changes such as prostatic intraepithelial neoplasia (PIN), then to noninvasive cancer, and finally to invasive cancer. If not diagnosed early and eradicated, metastatic cancer may eventually develop.

Malignant tumors develop multiple genetic abnormalities that accumulate progressively in individual cells during the course of tumor evolution. For example, abnormalities involving p53 generally occur early in the development of invasive breast cancers.220 What biological situation(s) or conditions allow p53 or other DNA repair proteins, the guardians at the gate, to become mutated enough to allow such expressions? If we know what steps are involved in this process(es), we can avoid or reduce them and prevent initiation or promotional events.

The conditions favoring the above appear to include inflammatory situations that are associated with metabolic products that favor the development of dysplasia and neoplasia. These biologically inflamed situations are characterized by the production of reactive oxygen species (ROS) that damage cell membranes, that is, free radicals. For example, we know that ROS, or free radicals, cause oxidative damage to LDL cholesterol to eventuate in atheromatous plaques that are major factors in coronary artery disease. ROS damage the lipid membranes of the cell by means of an oxidative reaction called lipid peroxidation. The cell membrane is critical to the cell's integrity; are involved in the selective entry and exit of substances (ligands) that interact at the membrane border by means of a chemical reaction with docking sites called receptors.

Damage to structures like the cell membrane allows the tumor cell access to vital cell functions. Tumor cells, or what causes them, along with viruses, inactivate other parts of the surveillance mechanisms of the healthy organism. The interferon-signaling pathway (ISP) is often knocked out by tumor cells because interferons are molecules that actively patrol against viruses and cancer cells. In situations where cancer has developed, the ISP is often damaged or inactivated. Therefore, tumor-promoting situations are ones in which there is vulnerability of the organism due to inflammatory conditions incited by events that lead to damage of the surveillance mechanisms and result in access to vital cell functions.

What is all this leading to? In earlier sections, the importance of the eicosanoids was discussed. These are the oldest hormonal substances known to scientists. Every cell membrane in every cell in the human body generates eicosanoids. This occurs via pathways that lead to a major metabolic crossroad--di-homo GLA (DGLA), a 20-carbon omega-6 fatty acid. DGLA is further metabolized to AA and its illness-producing metabolites (bad eicosanoids) or away from AA production and metabolized to good eicosanoids (see General Preventive Measures, Eicosanoid Balance). This balance is crucial to the maintenance of health and prevention of illness (see Figure 7).

Since eicosanoids are the oldest hormones, with origins that can be traced back to 500 million years ago, perhaps they are also the ones most likely to be vital keys in the initiation of malignancy and the perpetuation of cancer growth. Studies have shown that the essential fatty acids, linoleic acid (LA) and AA, and the AA metabolite PGE2 stimulate tumor growth. In contrast, oleic acid (OA) and the omega-3 fatty acid, EPA, inhibit growth.221,222 In cell cultures of the human prostate cancer cell line PC-3, expression of the c-fos gene and the early COX-2 gene is increased within minutes of adding AA. This expression is dependent upon the amount of AA present, that is, it is dose-dependent.221 We also know that PGE2 is associated with the stimulation of vascular endothelial growth factor (VEGF) and thus with angiogenesis and tumor growth (see Figure 7). These findings have huge implications for medical strategies.

Further insight into this strategy to decrease AA production comes from studies showing that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the incidence of malignancy. Both of these agents have in common the ability to antagonize the enzyme COX-2, which converts AA to PGE2. High doses of Celebrex (celecoxib), a more selective COX-2 enzyme inhibitor, have been shown to prevent precancerous adenomatous polyps from progressing to overt colon cancer.223 More drugs are being identified that act selectively on the COX-2 pathway. Agents such as silymarin (milk thistle), a known protector of liver cells (hepatocytes) against oxidative damage, have been shown to selectively inhibit the enzymes COX-2 and lipoxygenase (LOX) and also to down-regulate interleukin-1 (IL-1). All of these are implicated in cancer initiation and growth.224

Another study of prostate cancer showed a significant degree of 15-LOX in PC biopsy specimens and correlated this with mutated p53 immunostaining in the same specimens. The findings of 15-LOX and mutated p53 were highly correlated with each other and with the Gleason score. In only five of 48 patients did normal tissue adjacent to cancerous foci display staining for 15-LOX-1. No staining for mutated p53 was observed in any of the normal tissues. In contrast, in prostate cancer foci, robust staining was observed for both 15-LOX-1 (36 of 48; 75%) and mutated p53 (19 of 48; 39%). Furthermore, the intensities of expression of 15-LOX-1 and p53 correlated positively with each other (p < 0.001) and with the degree of malignancy as assessed by Gleason grading (p < 0.01).225

Therefore, with an understanding that the AA-COX-2-PGE2 pathway is a major sequence associated with inducing and perpetuating malignancy and inflammation, we now have some additional means to undo pro-inflammatory and promalignant situations. Understanding how the tumor cell is initiated and perpetuated provides methods for us to prevent or lessen the events that result in tumor growth. The Sears approach emphasizes the importance of carbohydrate restriction to prevent insulin surges (hyperinsulinemia), along with the incorporation of healthy fats into the diet and the use of highly purified fish oil to supply EPA and DHA. These are all directed to push the eicosanoid imbalance that is so characteristic of illness back toward the direction of health. In Figure 7, the pathway between di-homo gamma-linolenic acid (DGLA) and AA is shown with an arrow and bar blocking the pathway. This pathway is stimulated by insulin, but inhibited by EPA and DHA. With dietary measures, we can implement the concepts of COX-2 and LOX inhibition.38

The interferon-signaling pathway (ISP) was mentioned earlier as one of the defensive pathways that healthy cells use against the development of malignancy and against invasion by viruses. In response to a cancer cell or to a virus, the body produces interferon. Interferon communicates with the cell through interactions at the surface membrane (a lipid membrane) via interferon receptors. This interaction initiates a chain of communications involving a number of intracellular pathways whose end functions involve the following:

• Immune modulation
• Cell differentiation or maturity
• Apoptosis
• Changes in the cell cycle

All of these functions (and others) represent some of the security systems within the cell that are intended to prevent or to halt tumor growth. The very same processes also serve to protect normal cells from viral invasion. However, as part of tumor evolution, the selective pressure of mutations results in faults in this security system--the ISP. The paradox is that the defects in the ISP that may lead to the development of cancer cells may at the same time leave the very same cancer cells vulnerable to viral invasion. In this manner, biology represents a two-edged sword, not just for the normal cell, but also for the cancer cell. What has allowed the normal cell to become a cancer cell due to disruptions in the ISP at the same time leaves the cancer cell vulnerable to lethal attack by viruses.

A new arena of anticancer activity involves the use of viruses that kill tumor cells (oncolytic viruses). Vesicular stomatitis virus (VSV) is an RNA virus that may infect cattle to cause a temporary lip blister similar to cold sores in humans. In studies of human tumor cells, VSV destroys an impressive array of tumor types while leaving normal cells unharmed.226,227

Intravenously administered VSV has shown evidence of anticancer activity in tumor cells that have lost their interferon-induced antiviral response.228 VSV has demonstrated oncolytic activity against tumor cells lacking normal p53. Other studies have shown that tumor cells expressing a protein called large T antigen along with PKR, a protein kinase molecule, lack an antiviral response and may be sensitive to VSV oncolysis.226,229,230 (A discussion of oncolytic viruses with illustrations appears in the December 2002 issue of the Prostate Exchange published by the Educational Council for Prostate Cancer Patients (ECPCP). Their website is http://www.ecpcp.org and their telephone number is (516) 942-5025.

Other activities that disclose the modus operandi of the cancercells include the recruitment of raw materials from native resources to use as part of their weaponry. This includes the utilization of iron to initiate and further tumor cell growth. It is known that ferric iron (Fe+++) is reduced by a vital cell guardian--superoxide dismutase (SOD)--to ferrous iron (Fe++). In the process of this reaction, a hydroxyl free radical [OH-] is produced that causes DNA damage by DNA strand breaks, crosslinking, and point mutations.231 These mutations are often clustered at apparent hot spots, many of which are similar to sites seen using iron to generate oxygen radicals.

These results suggest that human cells are able to produce oxygen radicals in response to tumor promoters and that this might play a significant role in the generation of tumors.231 There are many publications on the decline of SOD with age. There is also much written about the association of malignancy and other degenerative processes with SOD deficiency states.232 What appears critically important in this and all discussions throughout this volume is the balance of free radicals and free radical scavengers and the defense measures to combat the imbalance resulting in oxidative stress. In fact, in established malignancies, we are using chemotherapies and other approaches that employ the generation of free radicals to kill the very cancer cells that may have arisen from an imbalance of reactive oxygen species (ROS). As stated earlier, biology is a two-edged sword. All of biology relates to balance and communication.

Table 14 lists characteristics of societal terrorism and compares these with cellular terrorism. Possible antidotes for the latter are suggested. Perhaps in solving one problem, we solve multiple problems.

8. ANTI-ANGIOGENESIS TREATMENTS, DIETARY CHANGES

Much of this has already been discussed in previous pages. The survival of the tumor cell population requires that the nutritional needs of the tumor cell be met. This may relate to the supply lines to the tumor--the vascular pathways that carry oxygen and amino acids, sugars, and fats required by the tumor for growth and function--or to the supplies themselves. Vascular pathways or blood vessels specifically arise through the process of angiogenesis, or new blood vessel growth. The major stimulant for that growth is hypoxia, or low levels of oxygen in the tissue. —Hypoxia, which stimulates new blood vessel growth is also identified as a major factor relating to failure of radiation and chemotherapy protocols.

Tumor hypoxia has been shown to be an independent prognostic indicator of poor outcome in prostate, head and neck, and cervical cancers. Recent laboratory and clinical data have shown that hypoxia is also associated with a more malignant phenotype (observable physical or biochemical characteristics of an organism) as well as increased instability of the genome, resistance to apoptosis, increased angiogenesis and a greater propensity to metastasis.234 In a study of the effect of hypoxia on radiation dose needed for tumor cell killing, the dose of radiation had to be increased by a factor of 2.6-2.8 if the tumor cell population contained an average of 20% hypoxic cells.235

Because tissue hypoxia or lower partial pressures of oxygen are found more frequently in tumor cells compared to normal cells,236 consideration of therapies to reduce hypoxia and to reduce angiogenesis are reasonable strategies for clinical trials. The use of a Zone approach to calorie input (eating), according to the writings of Sears, has the potential to profoundly affect angiogenesis. This is because PGE2, a major metabolite of AA, is known to stimulate VEGF and hence angiogenesis.42,237 A carbohydrate-restricted diet focused on preventing hyperinsulinemia and the use of highly refined fish oil supplementation containing EPA to shift the pathway from AA to favorable eicosanoids has been mentioned previously, but must be strongly reinforced as a simple, inexpensive foundation to lowering VEGF levels. This certainly should be studied in a clinical trial.

In a study by Fosslien et al., the induction of the COX-2 enzyme was associated with an increase in TGF-b1 and VEGF. Of interest is that these three agents favoring the growth of the cancer cells were co-localized.237

Measures to reduce angiogenesis could involve not only reduction in PGE2 production, but also the use of antiangiogenesis agents such as ADT, which decreases androgen levels and reduces VEGF.218 Other therapies to reduce angiogenesis are shown in Table 15.

Docetaxel and Management of Androgen-Independent Prostate Cancer
Androgen hormones are produced in the adrenal glands and testis. These hormones facilitate the growth of prostate cancer cells (testosterone in particular). Hormone therapy targeted at lowering testosterone levels can be an option when prostate cancer spreads beyond the prostate gland to other parts of the body, or if it comes back after being treated before, or if it is advanced and surgery and radiation are not good treatment options for a patient. Effective hormone therapy lowers PSA levels an indicator of the amount of cancer in a patient’s body.

Although hormone therapy (ADT) can lower androgen levels, it does not cure prostate cancer. It is a management strategy which can shrink the cancer or cause it to grow more slowly. Over time, prostate cancer can become androgen independent. Androgen-independent prostate cancer (AIPC; also hormone-refractory prostate cancer) does not require androgen hormones to grow. If prostate cancer becomes androgen-independent or hormone-refractory, effective treatment options are very limited, leaving the patient with an extremely poor expected outcome (ACS 2001). However, use of docetaxel, a chemotherapy drug, has shown promise in AIPC patients (Khan et al. 2003).

Docetaxel (Taxotere®) is a drug from the taxane family of medicines that is used in chemotherapy for some types of advanced cancers. It is synthesized from an extract of European yew needles (Taxus baccata) (Beer et al. 2003b). Taxotere was approved by the FDA on June 22, 1998 for locally advanced or metastatic breast cancer that had progressed during anthracycline-based treatment or had relapsed during anthracycline-based adjuvant therapy. On December 23, 1999, Taxotere received FDA approval for locally advanced or metastatic non-small cell lung cancer after prior platinum-based chemotherapy failed.

Docetaxel has shown promising results in the management of AIPC (Beer et al. 2003a,b; Khan et al. 2003). Used as a single agent, docetaxel had an overall PSA response rate (reduction) of 42% in four Phase II studies (Beer et al. 2003b). Even more impressive were the results of docetaxel in combination with other chemotherapy drugs (Beer et al. 2003a; Khan et al. 2003). A review of clinical trials investigating docetaxel used alone or in combination with other agents found that when docetaxel was combined with other agents, it consistently demonstrated a palliative response.

The docetaxel-based regimens were moderately well tolerated and PSA decreased by 50% or more in over 60% of patients, indicating a decrease in measurable disease and suggesting improved survival (Khan et al. 2003). Close patient monitoring is required because Taxotere can cause allergic reactions, decreased red and white blood cells, and liver damage. Studies are ongoing to determine if docetaxel-based therapy will have a beneficial impact on overall survival rates (Hitt 2003; Smith 2003; Susman 2000).

9. STABILIZING KEY ARENAS OF CONFLICT: FOCUS ON BONE INTEGRITY, BIOMARKERS, ETC

The old expression of "cross one bridge at a time" is valuable in approaching life's problems. In the various arenas encountered by the patient, partner, and physician in dealing with prostate cancer, this philosophical approach is sound advice. The crux of integrative or holistic medicine is the realization that fixing one aspect of health affects multiple areas--everything is interconnected. This is especially true for PC-related issues.

Bone Integrity Affects the Natural History of Prostate Cancer
Bone integrity in a man with PC is often ignored until the patient is symptomatic. Not until recently have the issues of osteoporosis and its relationship to PC come to the medical forefront. Not only is bone integrity of vital consequence in the matter of PC spreading to the bone, but also in the realization that bone loss through resorption can lead to bone pain, compression of the bones of the vertebral column, and fracture of a weight-bearing bone in the hip or other bones affecting function. Such complications demand immediate attention and the need for surgical and/or radiation treatment. Frequently, the patient requires strong pain-killing medications. Such adverse occurrences clearly detract from the quality of life of the PC survivor, his family, and friends. Putting out this new fire also diverts attention away from the primary issues of control and eradication of the PC.

We know that the main danger in PC is its ability to metastasize to the bone. The bone is a favored place when PC cells metastasize. Stephen Paget discussed this in 1889 in his essays on The Seed and the Soil:247

When a plant goes to seed, its seeds are carried in all directions; but they can grow only if they fall on congenial soil.

Paget recognized this inclination for cancer of the breast to spread to the bone. The same proclivity is found in PC. PC and breast cancer are brother/sister diseases, strikingly alike in a multitude of ways. Most physicians consider the bone a static tissue, but it is exactly the opposite. The bone is constantly undergoing change in a process called remodeling. Bone tissue is formed and lost in the processes of bone formation and bone resorption (see Figure 8). This remodeling of the bone tissue occurs every 100 days.

The dynamic nature of the bone tissue has been described in medical literature in thousands of peer-reviewed publications. Many patients and physicians are surprised to learn that the bone is extremely rich in growth factors. These growth factors have been implicated in PC growth and metastasis. Therefore, it should come as no surprise that prostate cancer cells consider the bone a haven or sanctuary--congenial soil, to use the words of Paget. The rationale of current therapies in prostate, breast, and other cancers is to stabilize the bone microenvironment so that these bone-derived growth factors (BDGF) are not made readily available to nurture PC growth, invasion, and metastasis.

The Difference Between Evaluation of Bone Status Using QCT Versus DEXA
Emphasizing the importance of the bone microenvironment in PC appears justified because there is a strong correlation with osteoporosis and osteopenia, as determined by bone mineral density examinations, at the time of diagnosis of PC.

In a report by Smith et al., osteoporosis was present in 63% of men at the time of diagnosis of PC, prior to any therapy. An additional 32% of men, in this same study population, had osteopenia.248 In this landmark paper, the investigators evaluated DEXA bone mineral density testing and compared it to quantitative computerized tomography (QCT) bone mineral density testing in the same patients. A significantly greater percentage of men were found to have osteoporosis using the QCT methodology than the DEXA approach. DEXA bone mineral density evaluation picked up osteoporosis in only 5% of men. Therefore, using QCT technology, abnormalities in bone density were found in 95% of men compared to 34% of men with DEXA.

Studies done by Strum and Scholz have confirmed the results of Smith et al. (see Table 16). We found either osteoporosis (50%) or osteopenia (50%) in 100% of the men we studied with QCT. In the same men, using DEXA, we found only 5% with osteoporosis and 50% with osteopenia.249 A reasonable question is "why are there such differences in the two techniques?" The DEXA scan may read degenerative changes involving bone and joint tissues and calcium deposits within blood vessels as bone density.250-254

The T Score Determines Your Status and Risk of Fracture
The definitions used in the bone mineral density reports that are valid for men or women relate to the T scores. These reports are confusing even to radiologists who are experts in this field. The Z score is often relayed to patients and physicians in the radiology report as the final diagnosis or impression. The Z score compares the findings of the bone density exam, be it QCT or DEXA, with an age-matched population. This is of little actual value because what we are doing is comparing possible pathological findings in a patient with known problems with osteoporosis or osteopenia in a general population of similar age. If I were 70 years old, I would not feel reassured that I am like most other 70-year-olds (who may also have osteoporosis or osteopenia) and therefore I am considered to be normal. I want my bone density to be compared to that of someone with healthy bone tissue that is not likely to fracture, or to release BDGF (bone derived growth factors), which may initiate prostate cancer, stimulate its growth, or have a permissive action on bone metastases.

Therefore, it is the T score that is, or should be, the benchmark in bone mineral density (BMD) evaluations. The T score is based on World Health Organization (WHO) population studies that indicate how your bone density compares to that of a healthy 30- to 35-year-old (woman). There have been no T score determinations set up for men. If the BMD is exactly 1 standard deviation below that which is considered to be normal bone density for a 30- to 35-year-old woman, the patient's T score is minus (-) 1.0. If the BMD is one half of a standard deviation above what is considered normal for a 30- to 35-year-old, the T score is +0.5. More than 1 standard deviation below normal is considered to be the cut-off level to define abnormality. Therefore, if you have a T score of -1.1 or less, you have at least osteopenia. If the T score falls between -1.1 and -2.5, you are still in the range of osteopenia. Once below -2.5, the patient falls into the category of osteoporosis. The fracture risk doubles for each standard deviation below the normal T score.255 Therefore, a person with a T score of -2.0 has twice the chance of fracturing a bone compared to a person with a T score of -1.0.

Osteoporosis is rampant in men newly diagnosed with PC. That is clear from previously cited studies. In light of the knowledge that bone loss occurs during treatment with any therapy that lowers male hormone, the PC patient undergoing almost all forms of ADT is in jeopardy of having abnormal bone density and a serious risk of osteoporosis. Add to this knowledge the fact that bone loss through the process of resorption may be stimulating the PC, and the issue of bone integrity becomes paramount.

In the context of prostate cancer (PC), the bone tissue has to be regarded as a strategic area and must be stabilized, fortified, and brought to the status of a stronghold if we are to optimize our care of the PC patient.

Resources for QCT Testing
Improving bone integrity mandates that we first assess bone integrity status to obtain a baseline. BMD evaluation and the value of the QCT technique has been emphasized in the preceding paragraphs. Since QCT technology is not readily known to most physicians, it is important that patients and partners share these new findings and seek out radiology facilities that have QCT bone densitometry equipment. Two references for sources of QCT testing are Mindways, Inc. and Image Analysis. Telephone numbers and websites for these nationally based organizations are Mindways, (877) 646-3929 (www.qct.com), or Image Analysis, (800) 548-4849 (www.image-analysis.com). For further information on maintaining bone integrity, refer to the protocol Cancer Treatment: The Critical Factors.

Importance of Bone Integrity Extends to Cardiovascular Risk and Possibly Alzheimer's Disease
Studies have shown a relationship of abnormal bone density with an increased risk of cardiovascular disease.256,257 It has been the observation of many that the loss of bone matrix detected by measurements of bone mineral density appears to relate to the deposition of calcium in arteries such as the coronaries, aorta, and femoral arteries. The loss of calcium from the bone matrix is a characteristic finding during excessive bone resorption. Hypothetically, it is reasonable to consider that calcium lost from the bone matrix may be pathologically deposited in blood vessels as well as associated with calcifications elsewhere, such as kidney stones, gall stones, and prostatic calculi. In fact, correlations between osteoporosis and an increased risk for kidney stone development have been reported.

An improvement in bone density with treatments that are designed to prevent kidney stones have likewise been reported.258,259 Studies have shown that bisphosphonate compounds [such as alendronate (Fosamax®)] not only improve bone mineral density but also decrease a substance known as osteopontin, which has been implicated in kidney stone development.260 Other studies have presented this unifying concept and have even linked bone loss and kidney stones with hypertension (high blood pressure).261

A biological marker involved in PC, especially androgen-independent PC, is interleukin-6 (IL-6).262-264 IL-6 is a cell product that stimulates the maturation of osteoclasts, the cells that are major players in the breakdown (resorption) of bone. IL-6 is produced by osteoblasts265 and stimulates the mature osteoclasts to break down bone. IL-6 has been identified as an inflammatory cytokine that is likely to play a major role in Alzheimer's disease (AD). Therefore, the emphasis on bone integrity is of potentially great magnitude. Maintaining bone integrity can now be seen to play a role in the following:

• Prevention and treatment of osteopenia or osteoporosis
• Decrease in cardiovascular disease
• Reduction in kidney stone formation
• Minimization of release of bone-derived growth factors that can stimulate prostate or breast cancer
• Prevention of Alzheimer's disease

This again points out that a holistic approach to medicine is vital to our understanding of unifying concepts involved in both health and disease. The hip bone is connected not only to the thigh bone, but also to the heart, kidneys, prostate, breast, and brain.

AD is considered to be an inflammatory disease of the brain associated with the deposition of beta amyloid material. In prior discussions, the importance of the eicosanoid pathways was detailed and the role of the inhibition of AA formation and the prevention of metabolites of AA such as PGE2 and 5-HETE by dietary changes and by the use of EPA and DHA were stressed. COX-2 inhibitors that prevent AA metabolism to PGE2 have been shown to be associated with a decreased incidence of AD. Even nonselective COX-2 inhibitors such as ibuprofen (Motrin) are now shown to have a protective effect against the development of AD.

There are studies that show that all of these pathways are integrated in PC. COX-2 expression and PGE2 secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. An up-regulation of PGE2 by IL-6 in a human cell line of PIN has been demonstrated. PGE2 further stimulates IL-6 soluble receptor release and other complex intracellular functions (gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity).266 These events, induced by PGE2, lead to increased PIN growth. Conversely, the use of a selective COX-2 inhibitor (e.g., Celebrex) decreases cell growth. Moreover, PIN cell growth stimulated by PGE2 was nullified by adding antibodies to IL-6. The authors concluded that increased expression of COX-2/PGE2 contributes to PC development and progression via activation of the IL-6 signaling pathway. Refer to the following sections in the protocol entitled Cancer: Gene Therapies, Stem Cells, Telomeres, and Cytokines: Suppressing Pro-Inflammatory Cytokines, Measuring IL-6 Levels (see TNF-a, IL-8, IL-1b), and the Cytokine Panel.

It should therefore come as no surprise to find that a study of animals fed diets varying in the ratio of AA to EPA reported that (1) higher AA-EPA-ratio diets led to findings of increased PGE2 production in the bone; (2) higher PGE2 in the bone was associated with increased bone resorption; and (3) lower AA-EPA ratios (reflecting higher intake of EPA) were associated with bone formation and decreased PGE2 concentrations.201

There is no doubt that the signaling pathways of communication between a PC tumor cell and bone (with osteoblasts and osteoclasts) are multidimensional. A conceptualized graphic of some of these interactions was shown in Figure 1 on page 1390.

Clinical Aspects of Bone Integrity in the Treatment of PC Patients
Many of the salient points relating to the evaluation and treatment of bone integrity can be found in the protocol entitled Osteoporosis. In addition to numerous articles written by me in the PCRI newsletter Insights, there is also a PowerPoint presentation on this subject that can be downloaded without charge. An update on this topic also appears in the Primer (available at www.lefprostate.org). In general, the main issues that still need a greater focus of attention include the following:

• Every man with PC and most likely every apparently healthy man aged 45 or over should be evaluated for osteoporosis and osteopenia. (Refer to the Osteoporosis protocol.
• Significant bone loss in PC patients is underestimated by the use of DEXA scanning and should be evaluated with QCT bone density study instead.
• Bone resorption, and its correction, are easily evaluated by using a sensitive biomarker, as a biological endpoint (BEP), the (runin to text)

the Pyrilinks-D (free deoxypyridinoline or free Dpd). Dpd levels can be obtained from the second urine sample of the patient's day. This test is inexpensive and is an excellent tool to monitor the biological endpoint of bone resorption activity. In men, a normal value for Dpd is less than or equal to 5.4 (nanomoles Dpd/nanomoles creatinine) using the Metra Biosystems assay and up to 6.6 using the assay from Quest Laboratories.

In men, if the free Dpd exceeds the upper limit of normal, it is indicative of excessive bone resorption. This finding may be secondary to underlying PC in the bone or secondary to increased bone resorption due to ADT or illnesses such as diabetes, hyperthyroidism, Paget's disease of the bone, or hyperparathyroidism.

If the Pyrilinks-D level is abnormal, it should be corrected with the use of combination therapy employing a bisphosphonate compound, a calcium-containing bone supplement, and Rocaltrol (synthetic vitamin D). The most active oral bisphosphonates are Fosamax and Actonel. The bone supplement is best taken in the evening between dinner and bedtime. Studies have shown that the administration of calcium in a bone supplement will reduce bone resorption by up to 20%, but only if it is administered in the evening.269 This is apparently due to a circadian rhythm involving bone formation and bone loss.

The use of Rocaltrol (calcitriol or 1,25-dihydroxy vitamin D3) requires a prescription. It is not to be confused with ordinary vitamin D3. There are an increasing number of articles relating to the use of standard dose270 or high dose calcitriol,271 used either alone or with chemotherapy such as Taxotere272 in combination with bisphosphonates to slow the doubling time of PSA and dramatically reduce PSA levels. This holds great promise for the PC survivor.

When bone resorption is halted, and the net effect favors bone formation, it is critical that not only sufficient calcium be available to restore bone density, but also other ingredients necessary for healthy bone formation. These include magnesium, boron, and silica, as well as vitamin K. The nature of the calcium salt used in these preparations is also of major significance, because calcium carbonate is not well absorbed in older patients when gastric HCL production is decreased.

Calcium citrate, bisglycinate, and microfine calcium hydroxyapatite should be used preferentially. Two excellent comprehensive bone supplements include Bone Assure from Life Extension Foundation and Bone Up from Jarrow. It is important for the PPP team to understand the importance of these substances in bone physiology and their interactions with other cellular processes. A detailed description of these issues can be found in the Primer.

10. SUPPORTIVE CARE OF THE PATIENT

A military campaign is never successful unless the troops are supported in their efforts. Great military strategists win their battles because they realize the value of generous support for their soldiers. This is true in all endeavors; it is critical to invoke this principle in the support of the patient as he faces challenging crossroads in pursuit of quality and quantity of life. This is the essence of outstanding medical care and goes hand-in-hand with the physician-scientist whose prime directive is a strategy of success for the patient with whose life he is entrusted. This is an incredible opportunity for physicians, given the immediate intimacy with patients and their partners facing life-threatening illnesses. But what does supportive care mean?

Supportive care of the patient involves the fine-tuning needed to maximize efficacy while minimizing adverse effects. This is the basis for the concept of Therapeutic Index.

Therapeutic Index (TI) = Benefits of Therapy ÷ Adverse Effects of Therapy

Supportive care of the patient must be a conscious up-front concern with every aspect of the physician/patient encounter. The list below details some of the main supportive care issues that the PC patient may encounter. This is not an exhaustive list because an itemization of every supportive care measure (SCM) would involve numerous pages of text.

Supportive Care Measures Involved in the Diagnosis, Evaluation, and Treatment of Men with Prostate Cancer

Diagnosis
(1) DRE (digital rectal examination): This must be done gently, and with ample lubricant. The patient's rectal sphincter should be given time to adjust to the initial palpation of the gloved finger. This should not be a "ram job" that is too often described by traumatized patients. No patient should be reaching for the chandelier during a DRE. There may be an uncomfortable sense of fullness, an awkward feeling that there may be some leakage of seminal fluid, but if the physician is adept at doing a DRE, the patient should not be fearful of another such examination.273 I have found that if I describe to the patient what I am doing, and feeling, during the entire procedure, the patient is more focused on listening to what I am saying than on any minor discomfort he may be experiencing.

The physician's notes concerning the DRE should be detailed. An estimate of the gland volume, a notation of any areas suspicious for PC, and if present, their extent regarding size, should be clearly entered in the medical record. The use of descriptors such as moderately enlarged or 1+ enlarged is worthless. The physician should commit to an estimate of the gland volume in cubic centimeters. A T-stage designation, essentially equivalent to the clinical stage of the disease, should also be routinely recorded.

After the DRE is complete, the physician should have tissues available for the patient to wipe himself and allow him to use the restroom to clean himself up further and wash his hands. The patient should not spend the rest of the day sliding around on lubricant left over from the DRE. This may seem to be an excessive amount of words to spend on this subject, but this is one of the first physically intimate interactions the physician has with the patient. It should create a sense of trust that the physician is sensitive to this embarrassing and awkward situation.

(2) Venipuncture (blood drawing): This is something that the physician's staff does, but it is also so potentially traumatizing that some discussion is necessary. Assuming a good-sized vein is found and the R.N. or laboratory technician has had no problem in obtaining blood, a gauze pad should be placed over the vein as the needle is withdrawn. The patient should be told to apply firm pressure with his fingers over this gauze pad and to hold it for a few minutes.

What I have seen too often is that the needle is withdrawn and almost immediately a Band-Aidtm is applied to cover the venipuncture site. No mention is made for the patient to apply pressure for at least 3-4 minutes. It is as if the covering of the needle exit site with a Band-Aidtm will eliminate the chance of bleeding after venipuncture. Too often, the patient is left with blood on his clothing, a hematoma at the site of the venipuncture, possible loss of use of that vein, and emotional stress the next time he has blood drawn. These two interactions are very simple, yet often poorly done.

(3) TRUSP (transrectal ultrasound of the prostate) with biopsies: The procedure should be discussed in advance with the patient and his partner. The importance of avoiding drugs such as aspirin and NSAIDs for at least 10 days prior to prostate biopsies should be mentioned. Given the commonality of bleeding into the prostate and blood in the urine or semen after TRUSP with biopsies,274,275 I believe it would be reasonable for physicians to do an in-office template bleeding time (TBT). This is a cheap and easy test to rule out a drug effect on the platelets that would be associated with an increased risk for prolonged bleeding after multiple biopsies.

The Surgicutt TBT normal range is less than 9 minutes. Surgicutt is available through ITC, Inc. at www.itcmed.com. The U.S. customer service number is (800) 631-5945. Secondly, a urologist or other physician planning to do the biopsies should, as a matter of routine, check the patient's CBC (complete blood count), absolute platelet count, PT (prothrombin time), and the APTT (activated partial thromboplastin time). If the platelet count is normal (over 150,000) and the PT, PTT, and TBT are all within normal limits, then any potential risk for significant hemorrhage from TRUSP with biopsies as a result of a blood-related problem(s) would be excluded.

If bleeding is persistent after TRUSP with biopsies, Proscar at a dose of 5 mg a day should be considered. Even in the face of coagulation abnormalities, as mentioned above, a report by Kearney et al. showed a marked decrease in gross bleeding (hematuria) with the use of Proscar. Note that this study involved men with BPH and the bleeding that occurred was unrelated to prostate biopsies.276 Critical to the results of this study are additional reports indicating the key role that androgens such as testosterone and dihydrotestosterone (DHT) play in increasing VEGF.218,240,277 It should come as no surprise that Proscar and/or other inhibitors of DHT formation would have the ability to decrease bleeding due to the hypervascularity of tissue known to occur in BPH and in PC.278

As part of the supportive care of the patient, physicians should employ such pharmacologic strategies in patients with persistent bleeding after TRUSP with biopsies. This intervention would take into account that the use of drugs such as Proscar or other 5-alpha-reductase inhibitors such as Avodart® (dutasteride) are effective at reducing angiogenesis by virtue of decreasing VEGF within prostatic tissue.

Additionally, other studies in breast cancer patients have shown that the COX-2 enzyme is up-regulated in breast cancer tissue and that this is associated with an increase in tumor blood vessels (microvessel density) and VEGF.279 We know that many PC patients will also have over-expression of COX-2 and this should suggest treatment by COX-2 inhibition, be it via dietary manipulation or by drugs. Therefore, in the management of persistent bleeding from prostate tissue or any tissue that may have an increase in blood vessels due to the activation of the COX-2 ? VEGF ? angiogenesis pathway, these measures are reasonable options to discuss with your physicians.

Not only is the bleeding complication of biopsy traumatic for the patient, but it also interferes with the interpretation of other investigational studies due to the effects of hemorrhage within the prostate. For example, if PC is diagnosed and an endorectal MRI is suggested for evaluation, the occurrence of any significant intraprostatic bleeding will complicate the interpretation of the MRI because cancer and hemorrhages both demonstrate the same low signal intensity.280 It will take a minimum of 8 weeks for the postbiopsy hemorrhage to clear sufficiently to allow the endorectal MRI to be done under optimal conditions.

The patient's preparation for the TRUSP with biopsies should include a 1-day course of prophylactic antibiotics (Cipro, Floxin, or Levaquin) and a Fleet's enema to clear the rectal chamber.281-283

The patient should receive some type of pain medication prior to the actual biopsies.284,285 It is amazing that a dentist will routinely give Novocain to fix dental cavities, but men going through 6-13 biopsies of their prostate gland have been offered local analgesia only for the last 5-6 years. Studies showing efficacy in reducing pain from the biopsy procedure have utilized injections of lidocaine (1%) into the tissue surrounding the prostate285-288 or have used lidocaine gel (2%) as a lubricant for the insertion of the transrectal probe in order to provide analgesia during the biopsy procedure.289,290 It is sad testimony that such studies were not done 10-15 years ago and that currently less than 50% of patients undergoing biopsy are offered periprostatic analgesia or some other approach to lessen their pain.281,291,292

Although not as distressing to the patient as a TRUSP with biopsies, the use of an endorectal probe during an endorectal MRI study can cause discomfort and pain. All along the road of diagnosis, evaluation, and management, the caring physician should be sensitive to any emotional or physical misery the man with PC may encounter. The road should be smoothed and the journey thus made easier. Insertion of an endorectal probe and inflation of the balloon surrounding the probe can be an unpleasant surprise. I have heard this from many men caught unaware. It is very simple to inform a patient who is planning this procedure about the possible discomfort and to propose workarounds.

Perhaps a complete liquid diet the day before and a Fleet's enema until clear on the morning of the endorectal MRI will lessen the discomfort because the rectal vault will be empty. The patient's primary physician may also prescribe Valium 5 mg and Vicodin ES, with 1 tablet of each medication to be taken about 30 minutes prior to the procedure. If the patient has not had prior experience with these drugs, his physician could prescribe a few extra tablets of each so that the patient can experience how he feels after taking this combination. Of course, the patient should not consume alcoholic beverages or drive when these drugs are taken. This kind of approach can change the patient's experience from one characterized by anxiety and pain to one of assuredness and acceptable discomfort.

(4) LUTS (lower urinary tract symptoms): In the course of the above evaluations leading to a diagnosis of PC, it is not uncommon for the physician to encounter men having problems with LUTS. Symptoms relating to slowness of urinary stream, difficulty in initiating urination, intermittent flow of the stream, dribbling of urine near the end of urination, getting up at night to urinate (nocturia), and other symptoms are cataloged objectively by the AUA symptom index score. This is described in detail in Appendix F (Forms) of the Primer.

Out of these problems come opportunities for the physician focused on supportive care. He can not only lessen the problems caused by LUTS, but also implement a pharmacological strategy that has an anti-PC effect. The efficacy of multitasking relates to the fact that, more often than not, our therapies, if chosen carefully, can elicit multiple benefits. Clearly, if LUTS is treated with finasteride (Proscar), we also are initiating the following biochemical effects:

• Inhibition of 5-alpha-reductase Type II, blocking conversion of testosterone to DHT
• Reduction in epidermal growth factor (EGF), especially in the periurethral zone293
• Reduction in both glandular and stromal elements within the prostate gland294
• Decrease in VEGF
• Decrease in microvessel density
• Decreased expression of basic fibroblast growth factor (bFGF)295
• Down-regulation of androgen receptor (AR) expression296
• Decrease in IGF-1 gene expression in BPH patients35
• Increased programmed cell death of PC epithelial cells297

To add compliment to benefit, agents (alpha-1-blockers) that improve urine flow by affecting periurethral smooth muscle have been shown to be synergistic with Proscar in causing prostate cell apoptosis.297 These effects are not restricted to the benign prostate cell population of BPH, but are also operative in PC. In the study by Glassman et al., terazosin (Hytrin), an alpha-1-blocker used in treating LUTS, was shown to cause apoptosis of prostate cells and to be synergistic with Proscar. In our supportive care of PC patients, we can choose drugs that have multiple modes of biological action and by doing so improve the outcome for our patients. In other words, we can treat LUTS and improve the quality of life for men with these symptoms, while at the same time having a beneficial effect against PC.

Table 17 lists some of the literature citing activity of alpha-1-adrenoreceptor blocking agents in causing programmed cell death to prostate cells, both benign and malignant. Of the alpha-1-blockers used in the United States today to treat LUTS, two are in the piperazinyl quinazoline class. These are Hytrin (terazosin) and Cardura (doxazosin). These agents cause apoptosis of PC cells. The third agent, Flomax (tamsulosin), an alpha-1-blocker in the sulphonamide class, does not have the apoptotic effects of either Hytrin or Cardura.

LUTS also has another potential role in the supportive care interactions between PC patients and their physicians--the choice of the primary PC treatment. The currently accepted choices of primary therapy include:

• RP
• RT of any kind, such as

3D-conformal RT,

• Conventional brachytherapy,
• High-dose rate brachytherapy,
• Proton beam RT,

Neutron beam RT;

• Cryosurgery;
• ADT;
• Watchful waiting.

In the setting of significant lower urinary tract symptoms that are not responsive to available therapies, RP, done by a surgeon, will resolve the issue of LUTS. In contrast, RT will usually aggravate LUTS and not occasionally cause problems with urinary retention necessitating TURP (transurethral resection of the prostate). What an RP accomplishes in this respect is the removal of the prostatic urethra--the site of compression by tissue of the transition zone of the prostate. The transition zone is the portion of the zonal anatomy of the prostate gland that is significantly increased in men with BPH, a problem that commonly occurs in association with PC (see Figure 4).

It is reasonable to consider, in this respect, the use of ADT3, which combines an LHRH-agonist agent such as Lupron, Zoladex, Trelstar LA, or Viadur with an antiandrogen such as Eulexin, Casodex, or Nilandron and a 5-alpha reductase inhibitor such as Proscar or Avodart, as well as an alpha-1 blocker in light of the data presented in Table 17. If the ADT3 plus alpha-1-blocker is given with other supportive care measures, the patient has numerous ways to use this therapy with both therapeutic and prognostic strategies. This is especially true in men not physically fit enough to undergo an RP or in those with risk factors that would suggest that RP is not likely to be curative. This will be discussed in a later section.

Evaluation
(5) Choice of Diagnostic Studies to Evaluate Stage in Newly Diagnosed Men with PC: Supportive care of the patient also involves a physician knowledgeable enough about PC to know when not to use healthcare dollars in ordering tests of negligible yield in the workup of a PC patient. This decreases the costs to patients, minimizes exposure to ionizing radiation, and reduces the workload on healthcare personnel when tests inappropriate to the patient's biological status are not needed.

This is especially true for CT scans of the pelvis and abdomen. Such studies done shortly after diagnosis are rarely abnormal. Eliminating such expensive procedures could better direct medical funds to more productive testing or treatment. In newly diagnosed PC patients with Gleason scores of less than (4,3)--validated by an expert laboratory or pathologist--a CT scan is not indicated unless the PSA exceeds 20 ng/mL. In a study of 425 PC patients, the authors concluded that in asymptomatic patients with newly diagnosed, untreated prostate cancer and serum PSA levels of less than 20 ng/mL, the likelihood of positive findings on abdominal/pelvic CT is extremely low (< 1.0%).303

The same is also true of the bone scan in newly diagnosed patients with a baseline PSA of 10 ng/mL or less--assuming that the Gleason score is less than 7.304 A study by Chybowski et al. concluded that the negative predictive value for a positive bone scan given a serum PSA of less than or equal to 20 ng/mL was 99.7%. Only 1 patient out of 306 with a PSA of less than or equal to 20 (PSA = 18.2) had a positive bone scan. Of the 207 patients with PSAs of less than or equal to 10 ng/mL, none had a positive bone scan and only 1 of the 99 patients with a PSA of greater than 10 and less than or equal to 20 had a positive bone scan. It therefore appears reasonable to forego bone scanning in newly diagnosed, untreated prostate cancer patients who have PSAs of less than or equal to 10 ng/mL.305 In another study, Oesterling et al. reported that only one abnormal bone scan out of a total of 200 bone scans (0.5%) would be missed if the requirement for performing a bone scan was a PSA greater than 10 ng/mL.306

In light of the fact that more and more men are being diagnosed with PSA levels of < 10, the impact on the healthcare economy when physicians order these tests in a reflex fashion is disastrous. Assuming that 180,000 men are newly diagnosed with PC each year in the United States and that at least 70% of them will have PSA levels at diagnosis below 10 ng/ml, and a negligible number will have PSA levels greater than 20 ng/mL, the healthcare financial waste is staggering (see Table 18).

Given that the average cost of a bone scan, CT scan of the pelvis, and CT scan of the abdomen is $600 per test, the waste in healthcare dollars is approximately $300 million dollars each year! If we add to this a pelvic MRI study (not to be confused with an endorectal MRI), the cost could total $400 million a year. These sums represent flagrantly wasted economic resources, misused technician time, unnecessary radiation exposure to patients, and inconvenience to patients. Most importantly, think of what some of this money could do in areas truly needing economic support, be it from private insurance carriers or in the United States to the taxpayer.

The major exception to the above is in the case of a patient with a Gleason score of (4,3) or higher at diagnosis. In such a setting of a high Gleason score, characterized by significant amounts of Grade 4 and/or Grade 5 disease, for example, (4,3), (4,4), (4,5), (5,4), and (5,5), the PSA leak phenomenon must be taken into account.127 Such patients may have low PSA levels, not uncommonly less than 5, yet have metastatic disease to bone. However, it must be emphasized that such patients have Gleason scores of 8-10 at the time of diagnosis or on the occasion that they are rebiopsied due to findings suggesting active PC.

Treatment
(6) Testosterone Deprivation Therapy and Its Far-Reaching Implications: If there is any area of PC management that necessitates a comprehensive understanding by the physician, it is in knowing the spectrum of effects of ADT on male physiology. A lack of such understanding deprives the patient of available supportive care that can mean the difference between success and failure in the patient's life. This not only relates to preventing or minimizing side effects due to treatment, but also to the patient's compliance with therapy--whether he will remain on the medications used in ADT or stop them due to adverse effects.

In the early 1980s, I began treating PC patients using anti-androgen therapy in combination with an LHRH agonist as one of the first American collaborators working with Fernand Labrie. My observation of patients taught me a great deal about the effects of an accelerated and intensified male menopause. The lowering of serum testosterone to castrate levels, defined as less than 20 ng/dL (less than 0.68 nM/L), resulted in a spectrum of possible signs and symptoms that varied from man to man.

Some of these symptoms occurred acutely, while others developed over time. However, all were potentially troublesome, if not aggravating, for the patient. If not treated in a preventive manner, such signs and symptoms can have a negative impact upon the patient's overall health.

Except for hot flashes and impotency, many symptoms resulting from androgen deprivation have been discounted by physicians as being due to old age or due to medical problems such as arthritis or heart disease. However, this constellation of clinical and laboratory abnormalities quickly develops in younger men or older men in otherwise good health after the initiation of ADT. This clearly suggests that these symptoms are not due to "old age" but are characteristics of the androgen deprivation syndrome (ADS).

ADS symptoms are directly or indirectly due to the drop in testosterone level that occurs following orchiectomy or use of an LHRH agonist (LHRH-A) such as Lupron, Zoladex, Trelstar LA, or Viadur. In essence, men who are medically or surgically castrated undergo an accelerated and intensified form of male menopause that leads to many of the same symptoms that are seen in women going through female menopause. Patients treated with combined ADT (LHRH agonists or orchiectomy plus an antiandrogen such as Eulexin, Casodex, or Nilandron) may have more severe ADS symptoms than those treated with an LHRH agonist or orchiectomy alone. This is because the additional use of an antiandrogen also helps to block residual testosterone from interacting at androgen receptor sites located throughout the body. LHRH agonists or orchiectomy suppress testicular androgen and not androgen synthesis from the adrenal glands. In fact, orchiectomy will result in increased production of adrenal androgen precursors due to a reflex stimulation of the hypothalamic-pituitary tract. This causes an increased production of LH along with an overflow stimulation of ACTH, which increases production of adrenal androgen precursors (see Figure 9).307

As mentioned in the section on LUTS (on page 1433), the addition of Proscar will result in a further lowering of androgen effect. This is due to Proscar's ability to block the enzyme 5-alpha-reductase (Type II), which converts testosterone to DHT. DHT is therefore a metabolite of testosterone and is five times more potent than testosterone in stimulating cell growth. In addition to this, Proscar also down-regulates the expression of the androgen receptor. Therefore, it should not be surprising that ADT3, as described previously, would have the greatest potential for side effects due to androgen deprivation, but would also have a higher probability to have a greater anti-tumor effect on the PC cell population for the very same reason. If we were to routinely add the use of an alpha-1-blocker such as Hytrin or Cardura, we should have even greater effects against the PC population due to a decrease in microvessel density, down-regulation of bcl-2, and enhanced apoptosis (as discussed in the section on LUTS and shown in Table 17).

In fact, the designation ADT4 could indicate the addition of a piperazinyl quinazoline compound of the alpha-1-blocker class to the standard ADT3 regimen of LHRH-A, antiandrogen, and 5-alpha-reductase inhibitor.

Androgen deprivation with four agents or ADT4 would involve the routine use of an agent of the quinazoline class of alpha-1-blockers such as Hytrin or Cardura. These agents will not only improve urinary flow, but also act to enhance the effects of ADT3. Therefore, the typical ADT4 regimen would include:

• • LHRH-agonist: Lupron, Zoladex, Trelstar LA, or Viadur
• • Antiandrogen: Eulexin, Casodex, or Nilandron
• • 5-alpha-reductase inhibitor: Proscar or Avodart
• • Alpha-1-blocker: Hytrin or Cardura

As emphasized earlier, there is a spectrum of side effects that may be seen with the use of ADT. These untoward effects are highly variable from man to man. Some men have no significant clinical symptomatology associated with the use of ADT, while others state they cannot function with a reasonable quality of life. The supportive care of the patient by the physician in using ADT is vital to the acceptability of this very important modality used in the treatment of prostate cancer. We can improve the therapeutic index of ADT by finding solutions to the problems that may occur as part of the androgen deprivation syndrome, or ADS.

Signs and symptoms that are part of the spectrum of ADS are shown in Table 19. These are divided into systems or tissues affected and the nature and onset of the symptoms, that is, acute and chronic. Again, it is of vital importance to understand that there is significant variability from patient to patient regarding frequency of occurrence and timing of all such findings.

To assess the significance of common ADS symptoms, we evaluated 177 hormone-naïve PC patients consecutively treated with an LHRH-agonist and an antiandrogen between 1994-1997. We asked patients to grade the frequency and severity of ADS as absent (Grade 0), occasional (Grade 1), frequent or bothersome (Grade 2), or requiring drug therapy (Grade 3). Other than loss of libido and impotence, Figures 10 and 11 depict the most commonly reported acute and chronic symptoms. Only Grade 1, 2, or 3 findings are shown.

Finally, the incidence and the intensity of bone loss are affected by the duration of ADT. This assumes that the patient on ADT is not receiving concomitant therapies to prevent bone resorption, e.g., a bisphosphonate plus a bone supplement in conjunction with an exercise program. The mechanism of progressive bone loss during ADT relates to the fact that androgens are known inhibitors of osteoclast function. During ADT, this inhibition is lost and osteoclasts are activated, allowing for promotion of bone loss (resorption). Testosterone, therefore, is an anabolic steroid for bone, muscle and other tissues. The deprivation of androgens pushes the balance towards catabolism or breakdown.

Clearly, a comprehensive care plan that takes the overall health of the PC patient into account must look at the impact of each and every ADS-related finding. Prevention of the undesirable consequences of ADT equates with a higher therapeutic index, which in turn means a higher quality of life for the PC survivor. Therefore, the intelligent use of ADT, as with any therapy, should take into account the

• Therapeutic purpose of ADT
• Nature of ADT (neoadjuvant, intermittent, or continuous treatment)
• Age and overall general health of the patient
• Degree of tolerance by the patient of the various ADT side effects
• Prevention or resolution of any signs and symptoms of ADS
• Net picture of pros versus cons

For example, the duration of neoadjuvant ADT rarely exceeds 1 year in patients who are candidates for potentially curative local therapies with RT or cryosurgery. Therefore, such patients have the potential risk for the typical acute ADS symptoms, but they will not experience chronic ADS symptoms to any significant extent. Patients who may be involved in this scenario include those with large-volume PC within the prostate with extracapsular extension (ECE). Such patients fare better when ADT is used up-front (neoadjuvant therapy), prior to the RT or cryosurgery, to decrease both the cancer volume as well as the gland volume. In the Primer, Physician's Note #5 relays such a story in the case of patient GB. The patient completed IMRT over 3 years ago and his PSA remains flat at 0.4 ng/mL.

Even with a highly responsive physician who is knowledgeable about ADS, acute ADS-related symptoms invariably compromise the lifestyles of healthy and active prostate cancer patients. This mandates that certain changes be made in the patient's diet, exercise, and work habits during ADT.

Chronic ADS symptoms are much more prevalent in PC patients treated with ADT than are currently recognized, and some are nearly inevitable in patients treated for longer than 1 year. For such patients, specific treatment strategies must be implemented to minimize or prevent the development of chronic ADS. Left untreated, chronic ADS is progressive with ongoing ADT and often leads to other medical complications. Useful preventive or active strategies against acute ADS-related symptoms are shown in Table 20, and chronic ADS-related symptoms in Table 21.

In the past, patients who were not candidates for local therapy were typically treated with continuous androgen blockade. Armed with our current knowledge about the signs and symptoms of acute and chronic ADS, we prevent or correct these findings with one or more of the therapies listed in Tables 20 and 21.

Another approach that avoids symptomatology attributable to chronic ADT is through the use of intermittent androgen deprivation (IAD). Depending on the required duration of ADT, individually determined for patients, IAD may be a reasonable alternative approach. This is an example of how therapy should be individualized to the patient's biological constitution. (A discussion of IAD with graphs indicating outcomes using ADT2 versus ADT3 can be found in the Primer.)

Supporting the patient through measures such as some of those discussed relates to the fine-tuning that is characteristic of outstanding medical care. This is the essence of holistic medicine. There are other issues of supportive care that relate to the settings of pre- and postoperative care for a patient undergoing RP, cryosurgery, RT, and even watchful waiting. Some of these issues and possible resolution therapies worthy of your review and subsequent discussion with your physician are outlined in Table 22.

(7) Supportive Care for PC Patients Undergoing Chemotherapy: A comprehensive review of this topic is a book in itself and such a treatise is being considered. Due to limitations of space and time, this topic is not discussed at this time. The reader is advised to log on to the Prostate Chemotherapy protocol that can be accessed at www.lefprostate.org

11. BOOSTING MORALE OF THE TROOPS: FOSTERING A WILL TO LIVE, EMPOWERING THE PATIent

The previous 10 sections have presented strategic issues that need to be addressed in our battle with prostate cancer. And, make no mistake, it is a battle--but one that can be won. There is much to be gained, by many people in viewing this medical confrontation using a military metaphor. Such tactical thinking undoubtedly plays a pivotal role in achieving an optimal outcome for any life-endangering encounters.

However, all the good science and all the outstanding medicine in the world will not achieve its true goal of healing without the presence of spirit. This may not seem relevant to the man feeling the immediate threat of prostate cancer because of its philosophical orientation. But, I assure you, over the course of your journey, at some important crossroad in your life, it will be seen as the take-home lesson for all that has been written here. Your spirit, your will to live fully, is the crust of the holistic pie of life. Without this esprit, it is unlikely that you would have accepted the challenge of reading this chapter.

Out of the night that covers me, black as the Pit from pole to pole,
I thank whatever gods may be for my unconquerable soul.
- from Invictus by William Ernest Henley

The basis for any victory must therefore involve morale--a state of spirit of a person or group as exhibited by confidence, cheerfulness, discipline, and willingness to perform assigned tasks. Morale, as defined in this fashion, and in the context of a war against prostate cancer, is embodied in acts reflecting empowerment of the patient and his partner.

Empowerment in this context becomes a process by which people assert control over factors that affect their health. This comes as a result of sharing resources and collaboration, which in turn lead to a more complete understanding of all aspects of a health issue.308 My perspective developed through thousands of patient encounters each year with prostate cancer is that the empowered patient is better able to decide on treatments, and better able to choose physicians to guide him on his medical journey. The empowered patient is less anxious and more secure about his clinical course.309 Empowerment, by its very nature, links people with resources.310

The empowered patient will explore options, look for new trials, participate in adjunctive or complementary therapies to enhance treatment outcomes, and be interactive in support groups. The empowered patient will take a politically active stance to increase funding, research, and awareness of the disease. The empowered patient is the purveyor of his medical records. The empowered patient views the physician as co-navigator, companion, and friend on his medical journey. An empowered patient expects bidirectional communication with his medical team to be the rule and not the exception.

In the process of opening channels of learning to the patient, we foster his empowerment and that of his partner, and that in turn encourages further learning. This extension of the physician as educator to the patient at a time of need is a manifestation of love. From this love comes wisdom in many walks of life.

How do you choose to learn love?
How do you choose to learn authentic empowerment--
through doubt and fear, or through wisdom?
- Gary Zukav

Those of you with prostate cancer are focused on your lives--your life is in jeopardy and what you took for granted before is no longer guaranteed to be there in the years to come. But

Out of crisis comes opportunity.
- Old Chinese saying

or

A smooth sea never made a skilled mariner.
- English proverb

During this crisis of prostate cancer, you will be provided multiple opportunities to overcome many obstacles. This is part of the lesson of life, of living, and of evolving. Remember that there are many out there without prostate cancer who will live their lives, day after day, without the appreciation to see the beauty of a tree or a sunrise; to say I love you; to smell the flowers; to marvel at the innocence of children; and to appreciate the uniqueness of your humanity. But this journey you are on should not be just an appreciation of life at a time of crisis, which is conveniently forgotten once the crisis is over. There are lessons here, crucial to your well-being and to that of your family, friends, community, and to all life forms.

Life is the ultimate prize and it takes on ultimate value
when suddenly we discover how tentative and fragile it can be.
The essential art of living is to recognize and savor its preciousness when it is free of imminent threat or jeopardy.
- Norman Cousins

Louis Armstrong said: "It's a wonderful world." The creation is wonder-full. We are part of that creation. We are also the caretakers of this wonderful world. Prostate cancer should change your life; it should make you aware of this creation--not just the natural wonders, but the wonder of you and your fellow humankind--all are linked together in a system longing for balance and communication. This is the essence of health for all biological systems. This is the heart of all that has been discussed in this chapter and throughout this book.

Our humanity lies in our human unity.
- Strum

This statement is not a political one. It is a sociobiological expression of what should be the underlying theme of virtually all life forms. On a biological level we are multicelled organisms that seek to achieve and maintain high levels of communication to remain in balance. It is a restatement of yin and yang. On every level of existence, from that of cellular interactions to the complexity of the individual human being to societies and governments, the call is the same: communication and balance. Without this, our health declines. Without this, our world dies.

My vision is for an empowered patient, who now enters the new millennium with an ability to use technological enhancements that provide the patient/physician team with far-reaching insights into the natural history and treatment of disease. At the same time, this empowerment embraces human unity--humanity--a realization that we are all in this together. The empowered patient shares his newfound understanding with others. He leaves the world of "I" and enters the world of "we."

The objective of this chapter on prostate cancer has been to provide specific and critical data that are an integral part of the comprehensive care of a patient with prostate cancer. The use of military metaphor has not been used simply as a literary tool, but more as a unique perspective--a different way of looking at things--that may yield new approaches in thinking about what tactics we could employ in our war against cancer. What may surprise the reader is the enormity of published information that is not routinely incorporated into the prevention and active treatment of prostate cancer. Much of this involves an understanding of what encourages tumor growth and what enhances its rate of growth and its ability to metastasize. The reader is encouraged not to look for a paragraph or two that summarizes all of what has been presented here; this is not realistic. Instead, read one section at a time and ask yourself: "Is this applicable to my situation?" If so, then take this information to your physician(s) and provide him with the appropriate references. Providing information in this manner improves your situation and that of all patients under the care of such physicians.

The first part of this chapter dealt with prevention. This is of importance not only to family members (and others) concerned about contracting prostate cancer, but also to patients seeking to slow disease progression and enhance the odds of a successful long-term outcome. As was discussed, many of the lifestyle changes that reduce prostate cancer risk also interfere with existing cancer cell proliferation.

Understanding the biological principles of the disease is crucial to understanding why such meticulous attention should be paid to keeping an accurate medical record of all test results, lifestyle changes and therapeutic interventions. The medical record provides a basis for determining the status of the disease and what therapeutic modalities should be considered if adequate control of the disease has not been achieved.

By precisely assessing all of the measurable individual risk factors, a prostate cancer patient can better decide on the treatment options that offer the greatest opportunity for long-term control or cure, while minimizing potential side effects.

The knowledge base of how prostate cancer cells propagate and what can be done to interfere with these processes is colossal. This is good news for a prostate cancer patient who seeks a comprehensive scientific approach to eradicating his disease. Contrast this with a pancreatic cancer patient, who has little hope of survival beyond 12 months.

Prostate cancer can easily be diagnosed at an early curable stage. Recurrence of existing disease can also be readily monitored. This is different from other cancers, in which a patient often waits for a dreaded physical symptom before learning the cancer has occurred or recurred. The bottom line is that a prostate cancer patient can exert a tremendous amount of control over his disease. What has been written here provides a systematic guide to taking advantage of the many technologies available today.

The Life Extension Foundation has identified an extensive array of integrated prostate cancer therapies based on published scientific findings and the clinical experience of practicing oncologists. While this protocol provides information in a practical format, the cooperation of the attending physician is crucial.

WHERE TO GO FROM HEre

While this chapter on prostate cancer provides an abundant quantity of life-saving guidance, many patients will need additional information to address their particular type and stage of disease. A special website has been established (www.lefprostate.org) to provide comprehensive updates, along with information specific to different stages and treatment options. The following reports were posted on this website as of the writing of this protocol:

• Prostate Cancer: Early-Stage
• Prostate Cancer: Late-Stage
• Prostate Cancer: Chemotherapy
• Prostate Cancer: Adjuvant Therapy
• Prostate Cancer: PSA Parameters and Heredity
• Prostate Enlargement: Benign Prostate Hypertrophy

For specific information about implementing some of the adjuvant drug therapies discussed in this chapter, refer to the Cancer Treatment: The Critical Factors protocol in this book. Please remember that everything that is read should be done so with the conscious thought of how this could apply to the current situation.

Those who have prostate cancer are urged to log on to www.lefprostate.org to read in-depth discussions that pertain to their stage of the disease and the different therapeutic modalities to consider.

Nutritional Aspects of Prostate Cancer

GLOSSARY OF TERMS

3DCRT (3-Dimensional Conformal Radiation Therapy):
An approach to radiation treatment planning that focuses on directing the radiation energy to the tumor target while sparing surrounding normal tissues.

5-ALPHA REDUCTASE (5-AR):
The enzyme that converts testosterone to dihydrotestosterone (DHT).

ADENOCARCINOMA:
A form of cancer that develops from a malignant abnormality in the cells comprising a glandular organ, such as the prostate. Almost all prostate cancers are adenocarcinomas.

ADVANCED PROSTATE CANCER:
Prostate cancer that is no longer organ-confined; systemic prostate cancer, sometimes with metastases to lymph nodes, seminal vesicles, bone, or vital organs of the body such as liver and/or lungs. Advanced prostate cancer is treated with systemic therapies currently in use such as androgen deprivation and chemotherapy.

AGONIST:
A chemical substance, such as a drug, capable of combining with a receptor on a cell and initiating a reaction or activity. In PC, the LHRH agonist is also called LHRH-A. The most commonly used LHRH-As are Lupron and Zoladex. Either of these agents interacts with the LHRH receptor and forms a complex that results in a decrease in the release of LH over a period of 2 weeks and hence a lowering in serum testosterone.

ALGORITHM:
In prostate cancer, one of a group of systems whereby the human experiences of a number of patients are statistically or numerically analyzed to produce data that can be generalized to predict the probable disease status of patients who have not yet been treated and therefore have no empirical data of their own on which to base judgments regarding their disease status. Examples include the Partin Tables, Narayan Stage, and Kattan Nomograms.

ALPHA-1 BLOCKERS:
Oral medications prescribed to improve urine flow by relaxing periurethral smooth muscle tissue; those of the quinazoline class (Hytrin and Cardura) have been shown to be synergistic with Proscar in causing programmed cell death in prostate cells, both benign and malignant.

ALPHA-TOCOPHEROL ISOMER:
A component of vitamin E.

AMERICAN UROLOGICAL ASSOCIATION (AUA) SYMPTOM INDEX SCORE:
A series of subjective questions used by physicians to evaluate the extent of existing lower urinary tract symptoms.

ANASTOMOSIS:
In prostate cancer, the surgical connection made between the bladder neck and the remaining urethra after the prostate is removed.

ANASTOMOTIC STRICTURE:
In prostate cancer, a narrowing at the site of the anastomosis between the bladder neck and urethra after radical prostatectomy.

ANDROGEN:
A hormone produced primarily by the testicles, but also in the cortex of the adrenal glands, that is responsible for male characteristics and the development and function of the male sexual organs and also affects muscle and bone mass, emotional stability, cognitive function, skin and hair, and so forth.

ANDROGEN-DEPENDENT PC (ADPC):
Prostate cancer cells that depend on androgens for continued growth and vitality.

ANDROGEN DEPRIVATION SYNDROME (ADS):
A constellation of symptoms directly or indirectly due to the drop in testosterone that occurs following surgical castration or the suppression of testicular and adrenal androgens by the use of medications.

ANDROGEN DEPRIVATION THERAPY (ADT):
A prostate cancer treatment that is based on blocking the amount of available androgen to the prostate cancer cell.

ANDROGEN-INDEPENDENT PC (AIPC):
Prostate cancer cells that do not depend on androgen for growth.

ANDROGEN RECEPTOR:
A structural entity that is essentially a docking site for androgen to communicate with the cell and affect cell function. The substance interacting with the receptor is called a ligand. The interaction of ligand and receptor is a major mode of biochemical communication in all life forms.

ANEUPLOID:
Cells that have an abnormal number of sets of chromosomes. Aneuploid cancer cells tend not to respond as well to androgen deprivation therapy.

ANGIOGENESIS:
Relating to the formation of blood vessels.

ANTAGONIST:
A chemical that acts within the body to reduce the physiological activity of another chemical substance.

ANTIGEN:
A substance that elicits a cellular-level immune response or causes the formation of an antibody.

APOPTOSIS:
Programmed cell death due to an alteration in a critical substance or chemical necessary for cell viability. For example, the lack of male hormones causes apoptosis of androgen-dependent prostate cancer cells.

ARACHIDONIC ACID (AA):
An omega-6 fatty acid that is known to generate free radicals and is considered an unfavorable eicosanoid. AA is metabolized via enzymes of the COX and LOX family to generate prostaglandins, thromboxanes, leukotrienes, hydroxylated fatty acids, lipoxins, and 5-HETE compounds that are implicated in cancer, inflammatory disease, immune dysfunction, and degenerative disorders. Organ meats and egg yolk are rich in AA.

ARTIFICIAL NEURAL NET (ANN):
An approach to analyzing data that uses statistical analysis of historical data to produce systems that can predict probabilities of future outcomes based on inputted variables.

BASELINE PSA:
The PSA level before a new treatment has begun; used to establish the efficacy of a therapy based on response of the PSA to treatment.

BENIGN:
Not malignant; noncancerous.

BENIGN PROSTATE HYPERPLASIA OR HYPERTROPHY (BPH):
A noncancerous condition of the prostate that results in the growth of both glandular and stromal (supporting connective) tissue, enlarging the prostate and potentially leading to obstructive symptoms relating to urine flow (see American Urological Association Symptom Index Score).

BILATERAL:
Both sides; for example, a bilateral nerve-sparing radical prostatectomy is one in which the nerves on both sides of the prostate are left intact.

BIOMARKER:
An indicator of biological activity of cells or tissues that can be used as a means to monitor a state of health or disease. PSA is one of the most useful biomarkers in medicine.

BIOPSY:
Sampling of tissue from a specific part of the body in order to check for abnormalities such as cancer.

BISPHOSPHONATES:
A class of compounds that stops bone loss (resorption) by actions directed against the osteoclast.

BONE SCAN:
An imaging technique using a radioactive isotope that is selectively taken up by bone tissue to identify abnormal or cancerous growths within bone such as metastases.

BRACHYTHERAPY:
A form of radiation therapy in which radioactive seeds or wires are used to deliver the radiation dose close to the site of a tumor. Seeds can be permanently implanted or radioactive wires can be temporarily introduced and then withdrawn after the radiation dose is delivered.

CANCER:
The growth of abnormal cells in the body in an uncontrolled and disordered manner, invading surrounding tissues and sometimes spreading to distant sites within the body via the bloodstream and/or lymphatic system.

CARCINOEMBRYONIC ANTIGEN (CEA):
A biomarker of prostate cancer that may be expressed in prostate cancer variants associated with higher Gleason scores, for example, Gleason scores 8-10 may indicate that androgen-independent cells are present.

CASODEX:
Brand name of an antiandrogen medication that functions by occupying and therefore blocking the androgen receptor, thus preventing natural androgens from stimulating cell growth.

CAT or CT SCAN (COMPUTERIZED AXIAL TOMOGRAPHY):
An imaging method used to identify abnormalities by combining images from multiple X-rays under the control of a computer to produce cross-sectional or three-dimensional pictures of internal structures.

CBC (COMPLETE BLOOD COUNT):
Complete blood workup including white blood count, hematocrit, and platelet count.

cc (CUBIC CENTIMETERS):
Used as a measurement of prostate gland volume or amount of prostate cancer; cubic centimeters are equivalent to grams (g) in determinations of prostate gland volume.

cGy (centiGray):
A unit of measurement of radiation dose; 1 cGy equals the energy absorbed from ionizing radiation equal to 1 joule (a unit of energy) per kilogram.

CHEMOTHERAPY:
The use of pharmaceuticals or other chemicals to kill cancer cells. In many cases these agents may also damage normal cells in the process of killing cancer cells, resulting in various adverse side effects.

CHROMOGRANIN A (CGA):
A biomarker of prostate cancer that may be expressed in prostate cancer variants associated with higher Gleason scores, that is, Gleason scores 8-10. Progressive increases of CGA in the blood indicate an aggressive clone of prostate cancer is present that exhibits an increased tendency to metastasize to lymph nodes, liver, and lungs. CGA is produced by the neuroendocrine cells associated with androgen independent PC.

CLINICAL STAGE:
The TNM (tumor, nodes, metastases) system of classification for communicating extent of disease in a specific patient based on all available information. This system has largely replaced the older Whitmore-Jewett staging classification system.

CORE INVOLVEMENT:
Expressed as a percentage; indicates the amount of biopsy cores involved by prostate cancer divided by the total number of cores that have been sampled. If 12 cores of tissue were obtained and 6 showed PC, then the percentage core involvement would be 50%.

COX-2 (CYCLOOXYGENASE 2):
The enzyme that converts arachidonic acid to prostaglandin E2. Inhibition of COX-2 is now an important approach to reducing the production of unfavorable eicosanoids implicated in the cause and progression of malignancy and inflammatory disorders.

CRYOPROBES:
The hollow probes used to freeze tissue during a cryosurgery procedure.

CRYOSURGERY:
The use of liquid nitrogen or argon gas circulated through cryoprobes to freeze and kill tissue, including any cancerous tissue.

DEDIFFERENTIATION:
Relatively more primitive in appearance and function than well-differentiated cells that, by contrast, are mature and able to function properly. As the disease progresses, cancer cells become more dedifferentiated (i.e., primitive) than normal cells, losing the characteristics that normal cells possess.

DEXA SCAN:
An imaging procedure used to evaluate bone mineral density and evaluate the status of bone integrity as regards a diagnosis of osteopenia or osteoporosis. The DEXA may understate the true extent of abnormality by attributing unrelated conditions such as arthritis and vascular calcifications to normal bone density.

DIAGNOSIS:
The evaluation of signs, symptoms, and tests to determine physical and biological causes of these signs and symptoms and evaluate whether a specific disease or disorder is involved.

DIGITAL RECTAL EXAMINATION (DRE):
The use by a physician of a lubricated and gloved finger inserted into the rectum to feel for abnormalities of the prostate and rectum.

DIHYDROTESTOSTERONE (DHT):
A male hormone five times more potent than testosterone; DHT is converted from testosterone within the prostate and in other tissues by the enzyme 5-alpha-reductase.

DIPLOID:
Cells having one complete set of 46 normally paired chromosomes, that is, a normal amount of DNA. Diploid cancer cells grow relatively slowly and usually respond well to androgen deprivation therapy.

DNA (DEOXYRIBONUCLEIC ACID):
The basic biologically active chemical that defines the physical development and growth of nearly all living organisms; a complex protein that is the carrier of genetic information.

DOWNREGULATING (DOWNREGULATION):
Turning off a mechanism of action in the body at the biochemical level.

DUTASTERIDE (AVODART):
A 5-alpha-reductase inhibitor that prevents the conversion of testosterone to the five times more potent dihydrotestosterone (DHT). Unlike Proscar, which blocks only 5-alpha reductase Type II, dutasteride also blocks 5-alpha reductase Type I.

EICOSANOIDS:
Hormones made within the cell membrane of every living cell in the body controlling every physiological function. Eicosanoids have opposing actions operating as a check-and-balance system. Therefore, a balance of these opposing actions is essential for optimal health.

EICOSAPENTENOIC ACID (EPA):
An omega-3 fatty acid that has been shown to inhibit the formation of AA by inhibiting the enzyme delta-5 desaturase, which converts DGLA to AA.

EJACULATION:
The release of semen through the penis during orgasm.

ENDOCRINE GLAND:
Any of various glands producing hormonal secretions that pass directly into the bloodstream. Examples of endocrine glands include the thyroid, parathyroids, anterior and posterior pituitary, pancreas, adrenals, pineal, and gonads.

ENDORECTAL MRI:
Magnetic resonance imaging of the prostate using a probe inserted into the rectum.

ENZYME:
Any of a group of chemical substances that are produced by living cells and cause particular chemical reactions to happen while not being changed themselves.

EPITHELIAL CELL:
A cell type in the prostate gland that lines the ducts and functionally secretes substances such as PSA into the bloodstream or into the duct openings or lumens.

EULEXIN:
The brand name of an antiandrogen that blocks the androgen receptor and prevents testosterone and/or DHT from stimulating cell growth.

EXTERNAL BEAM RADIATION THERAPY (EBRT):
A form of radiation therapy in which the radiation is delivered by a machine directed at the area to be radiated as opposed to radiation given within the target tissue, such as brachytherapy.

EXTRACAPSULAR EXTENSION:
A disease status in prostate cancer in which the cancer has penetrated the outer shell or capsule of the prostate and extends into the periprostatic tissue.

FINASTERIDE (PROSCAR):
An inhibitor of the 5-alpha-reductase Type II enzyme, which converts testosterone to the five times more potent dihydrotestosterone (DHT); used to treat BPH and PC.

FOLLICLE STIMULATING HORMONE (FSH):
A hormone produced in the pituitary gland that, in males, stimulates cells (Sertoli cells) in the testicles to make sperm; may be a factor in prostate cancer growth because FSH receptors have been identified on prostate cancer cells.

FREE PSA:
PSA unbound to any major protein; free PSA relates to benign prostate growth. The percentage of free PSA is one indicator of whether or not prostate cancer is likely present.

FREE RADICALS:
Substances that damage cell membranes and disrupt the integrity of the cell; reactive oxygen species (ROS).

GAMMA-LINOLENIC ACID (GLA):
One of the building blocks of eicosanoids that is metabolized to DGLA. The pathway that is taken after metabolism to DGLA is either toward AA and the unfavorable eicosanoids or toward the production of good eicosanoids such as PGA1 and PGA2.

GAMMA-TOCOPHEROL ISOMER:
A component of vitamin E.

GLAND:
A structure or organ that produces a substance that may be used in another part of the body.

GLAND VOLUME:
The volume of the prostate gland in cubic centimeters or grams. (Both units of measurement, cubic centimeters and grams, yield the same result.)

GLEASON GRADE:
After Donald Gleason, M.D. who developed the Gleason grading system as a tool to profile the aggressiveness of prostate cancer. A number from 1 to 5 that describes one of the two most predominant tissue patterns seen in the microscopic analysis of glandular architecture. The primary grade is the most predominant pattern, comprising 51% to 95% of the specimen, while the secondary grade comprises 5-49%.

GLEASON SCORE (GS):
The two Gleason grades, represented as (primary grade, secondary grade). An example of a high Gleason score would be (4,4) or (5,4) compared to a Gleason score of (3,3), the most common Gleason score at the time of diagnosis of PC.

GLYCEMIC INDEX (GI):
A measurement of the rate of carbohydrate entry into the bloodstream.

GLYCEMIC LOAD (GL):
The amount of insulin-stimulating carbohydrate multiplied by the glycemic index of the carbohydrate.

HDR:
See High-Dose Rate Brachytherapy

HEREDITARY:
Traits inherited from one's parents and from earlier generations via their DNA.

HIGH-DOSE RATE (HDR) BRACHYTHERAPY:
Involves inserting iridium wires into the prostate gland through hollow plastic needles that are placed under transrectal ultrasound guidance. Once the radiation dose is delivered, the wires are withdrawn from the prostate.

HORMONE:
Substances that are produced in the body that act as messengers, communicating information between cells. Usually peptides or steroids, they are produced by one tissue and delivered via the bloodstream to another tissue to affect physiological activity such as growth or metabolism.

HYPERINSULINEMIA:
A state of high insulin levels in the blood that can be caused by disproportionate consumption of simple or complex carbohydrates in the diet in proportion to dietary proteins and fats.

HYPOXIC CENTER:
The center of a prostate cancer tumor in which a state of lower oxygen tension exists. This stimulates VEGF, a substance that stimulates the blood vessel growth necessary for the nourishment of the tumor.

IMAGING:
A radiology technique or method allowing a physician to see something that would not ordinarily be visible. Imaging studies include X-ray examinations, CT scans, bone or other nuclear medicine scans, and MRI and ProstaScint studies.

INTENSITY MODULATED RADIATION THERAPY (IMRT):
An approach to external beam radiation therapy delivery using sophisticated computer planning to specify the tumor target dose and the amount of radiation allowable to nearby tissues and to modulate the intensity of the radiation as the delivery system rotates around the patient, thus minimizing damage to normal tissues.

INTERFERON:
A molecule that is active against viruses and cancer cells.

INTERLEUKIN-6 (IL-6):
A cell product made by the primary tumor as well as by osteoblasts that facilitates bone resorption and promotes osteopenia and osteoporosis by stimulating mature osteoclasts to break down bone.

INTERFERON-SIGNALING PATHWAY (ISP):
One of the defensive pathways that healthy cells use against the development of malignancy and invasion by viruses involving the interaction of interferon, which is produced in response to an invader.

KATTAN NOMOGRAMS:
Various algorithms named after Michael Kattan that present probabilities of response to therapies, such as radical prostatectomy, external beam RT, and seed implantation based on a combination of biological inputs such as PSA, Gleason score, and clinical stage.

KELOID:
Excessive scar tissue at the site of a surgery or an internal procedure. A history of this type of scar tissue formation may indicate the probability of the development of anastomotic stricture after radical prostatectomy.

LACTIC DEHYDROGENASE (LDH):
Elevated levels of this substance are associated with high Gleason score prostate cancer. LDH used to be routinely included in the standard chemistry panel and was considered an excellent overall tumor marker. For reasons unclear, LDH has been omitted from the standard panel.

LHRH ANTAGONIST:
An agent that blocks the LHRH receptor by pure antagonism without the initial release of LH, which is responsible for causing a testosterone surge seen with LHRH agonists; Abarelix (Plenaxis) is an example of an LHRH antagonist.

LIGAND:
A protein or an enzyme that combines with its appropriate binding site or receptor. The interaction of a ligand and its receptor initiates a biochemical reaction leading to the synthesis of other substances, often proteins, hormones, or enzymes. Almost all reactions in the human body involve ligands interacting with their appropriate receptors.

LNCaP:
One of the many prostate cancer cell lines. LNCaP is an androgen-dependent cell line.

LOWER URINARY TRACT SYMPTOMS (LUTS):
Urinary difficulties including slow stream, urinary urgency, difficulty in starting urination, and incomplete emptying of the bladder. These symptoms are quantified in the AUA Symptom Index or Score.

LUPRON:
Brand name of one of the drugs acting as an LHRH agonist.

LUTEINIZING HORMONE (LH):
A pituitary hormone that stimulates the Leydig cells within the testicles to produce testosterone.

LUTEINIZING HORMONE-RELEASING HORMONE (LHRH):
Hormone from the hypothalamus that interacts with the LHRH receptor in the pituitary to release LH which in turn stimulates Leydig cells in the testicles to make testosterone.

LYMPH NODES:
Small glands occurring throughout the body that filter out bacteria and other toxins, including cancer cells. During the process of metastasis, they are one of the first sites of involvement when the cancer leaves the primary site of origin.

MAGNETIC RESONANCE:
Absorption of specific frequencies of radio and microwave radiation by atoms placed in a strong magnetic field.

MAGNETIC RESONANCE IMAGING (MRI):
Use of magnetic resonance with atoms in the body tissues to produce distinct cross-sectional or three-dimensional images of internal structures.

MALIGNANCY:
A growth or tumor composed of cancerous cells.

MALIGNANT:
Cancerous; tending to become progressively worse and to result in death; having the invasive and metastatic (spreading) properties of cancer.

METASTASIS (pl. METASTASES):
Secondary tumor formed as a result of a cancer cell or cells from the primary tumor site traveling to a new site and growing there.

MICROVESSEL DENSITY:
An objectified measurement of angiogenesis.

mL (MILLILITER):
Unit of volume equal to one-thousandth of a liter.

NARAYAN STAGE:
Part of the algorithm developed by Perry Narayan that assesses if the microscopic findings of prostate cancer were limited to one side of the prostate (Narayan B1) or both sides (Narayan B2).

NERVE-SPARING:
A technique used in radical prostatectomy in which the erectile nerves are left intact by the surgeon.

NEURON-SPECIFIC ENOLASE (NSE):
A biomarker of prostate cancer that may be expressed in prostate cancer variants associated with higher Gleason scores, that is, Gleason scores 8-10.

ng (NANOGRAM):
Unit of measurement that is one-billionth of a gram.

NOMOGRAM:
A graphic representation, often used in analyzing data, consisting of several lines marked off to scale. Specific variables such as PSA, Gleason score, clinical stage, etc. are given point values. The sum of all the points equates with the prognostic outcome.

OBJECTIFIED ONGOING OBSERVATION:
A more appropriate term than watchful waiting that indicates that a patient not undergoing a definitive procedure using surgery or radiation or other treatments will be objectively monitoring his biological status in a consistent ongoing fashion.

ONCOGENES:
Genes relating to tumor growth.

ONCOLOGY:
The branch of medical science dealing with tumors. Oncologists study cancer and treat patients who are afflicted with cancer.

ONCOLYTIC VIRUS:
A virus that can kill tumor cells having defects in the interferon-signaling pathway or by other mechanisms.

ORGAN:
A group of tissues that work in concert to carry out a specific set of functions in the body.

ORGAN-CONFINED DISEASE:
Prostate cancer that is apparently confined to the prostate as determined either by clinical findings or, in the case of radical prostatectomy, by pathological findings; prostate cancer that has not penetrated the prostate capsule.

OSTEOBLAST:
A cell type within bone that promotes bone formation.

OSTEOCLAST:
A cell type within bone that promotes breakdown of bone or bone resorption.

OSTEOPENIA:
A condition of bone that indicates that an imbalance between bone formation and resorption is compromising bone integrity. Osteopenia indicates that the degree of bone loss is more than 1 standard deviation from the WHO definition of normal, but not more than 2.5 standard deviation below that level.

OSTEOPOROSIS:
A reduction in bone mineral density that is more that 2.5 standard deviation below the normal level defined by the WHO.

PARTIN TABLES:
Tables constructed based on results of the PSA, clinical stage, and Gleason score and associating those values with the findings at radical prostatectomy. Data involving thousands of men with PC used to predict the probability that the prostate cancer has penetrated the capsule, spread to the seminal vesicles or lymph nodes, or has remained confined to the prostate. The tables were developed by a group of scientists at the Brady Institute for Urology at Johns Hopkins Medical Center.

PATHOLOGICAL STAGE:
The extent of disease as determined by a pathologist's microscopic analysis of tissue removed at the time of surgery.

PERIPROSTATIC:
Pertaining to the soft tissues immediately adjacent to the prostate gland.

PLOIDY:
DNA analysis to establish whether normal or abnormal numbers of pairs of chromosomes are present in a cell.

PROCTITIS:
Inflammation of the rectum; may be an adverse effect of radiation therapy used to treat prostate cancer.

PROSCAR:
Brand name of finasteride, a 5-alpha-reductase inhibitor that blocks the conversion of testosterone to DHT.

PROSTAGLANDIN:
An eicosanoid isolated from the prostate gland that acts locally, metabolizes rapidly, and has a hormone-like effect, stimulating target cells into action.

PROSTAGLANDIN E2 (PGE2):
A major metabolite of arachidonic acid, known to stimulate vascular endothelial growth factor (VEGF) and hence, angiogenesis.

PROSTASCINT:
A monoclonal antibody (mAb) tagged with a radioactive isotope that is used to detect prostate cancer, particularly within lymph nodes. The ProstaScint mAb is directed against the prostate-specific membrane antigen (PSMA). PSMA is associated with androgen-independent PC. A few centers are using the ProstaScint scan to identify PC in the prostate gland.

PROSTATE:
The gland surrounding the urethra and immediately below the bladder in males.

PROSTATE CANCER:
Adenocarcinoma of the prostate gland.

PROSTATECTOMY:
Surgical removal of part or all of the prostate gland. If the entire gland is removed, a radical prostatectomy has been performed. Transurethal resection of the prostate (TURP), performed to improve urinary difficulties, is an example of removal of part of the gland.

PROSTATE-SPECIFIC ANTIGEN (PSA):
A protein secreted by the normal epithelial cells of the prostate gland as well as by prostate cancer cells if they are present. Elevated PSA levels in the blood can be due to benign or malignant causes. After diagnosis of prostate cancer, this biomarker is typically used to monitor disease progression and/or response to therapy.

PROSTATIC ACID PHOSPHATASE (PAP):
An enzyme or biomarker secreted by prostate cells that is associated with a higher probability of disease outside the prostate when pretreatment levels are 3.0 or higher. PAP elevations connote that the disease is not organ-confined disease.

PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN):
A pathologically identifiable condition believed to be a possible precursor of prostate cancer; broken down into high-grade PIN or PIN 2 and PIN 3 versus low grade PIN or PIN 1. High grade PIN is associated with having PC.

PROSTATITIS:
Infection or inflammation of the prostate gland that can be treated with medication and/or prostate massage.

PSA ASSAY:
The means by which a blood sample is analyzed to determine its PSA content. Various assays can result in different in readings from the same sample; therefore, it is wise to use the same assay for each subsequent PSA test. Very sensitive assays that measure PSA down to two or three decimal points are called hypersensitive or ultrasensitive PSA assays. These assays play a major role in early detection of relapse after radical prostatectomy or in the assessment of the tumor cell population in response to ADT.

PSA DENSITY (PSAD):
The amount of PSA (expressed in nanograms) for each cubic centimeter of prostate volume; the serum PSA value divided by an accurate gland volume determination.

PSA DOUBLING TIME:
The length of time in months that it takes for the PSA to double in amount.

PSA LEAK:
The secretion of PSA from the cells into the blood. Low levels of serum PSA are often associated with higher Gleason scores, as an expression of less PSA leak because more aggressive prostate cancers lose the ability to secrete PSA. Thus, PSA is an unreliable marker of disease progression in high Gleason score prostate cancer, e.g., Gleason scores 8-10.

PSA RECURRENCE (PSAR):
Elevated PSA following treatment of prostate cancer, signaling that cancer cells are still present and that monitoring for disease progression is indicated.

PSA RELAPSE-FREE SURVIVAL:
Survival of the patient that relates to no evidence of a progressively rising PSA.

PSA TREND:
The slope that a series of PSA readings over time would exhibit on a graph.

PSA VELOCITY:
A statement of how fast the PSA is accelerating; the rate of change in PSA calculated per year of time.

PYRILINKS-D (Dpd):
Deoxypyridinoline, or Dpd, is a laboratory test to monitor the biologic endpoint of bone resorption activity obtained by analysis of the second-voided urine of the day.

QCT SCAN:
Quantitative CT bone densitometry; a superior way to evaluate bone density compared to the DEXA scan because it is uninfluenced by unrelated conditions such as arthritic changes and/or vascular calcifications. (Telephone numbers that may be helpful in finding QCT sites near you: Mindways, (877) 646-3929 ( www.qct.com ), or Image Analysis, (800) 548-4849 ( www.image-analysis.com ).)

RADIATION THERAPY (RT):
The use of X-rays and other forms of radiation to destroy malignant cells and tissue.

RADICAL PROSTATECTOMY (RP):
Surgical removal of the entire prostate gland and seminal vesicles.

RECEPTOR:
A docking site on the cell membrane in the cell cytoplasm or in the nucleus that interacts with a ligand. All cells have multiple receptors.

RECURRENCE:
The reappearance of disease manifested by clinically based findings, either upon physical examination or by the results of laboratory findings such as a rising PSA.

RESORPTION:
Loss of bone caused by an imbalance in the dynamics of bone formation by osteoblasts or bone loss due to breakdown of the bone by osteoclasts.

RISK ASSESSMENT:
An analysis of probabilities related to a specific patient's case, obtained by analyzing medical variables of known significance and used to derive an overall impression of how different disease management options would impact an optimal or suboptimal outcome for the patient.

SCREENING:
Evaluation of populations of people who have no symptoms of the disease for which they are being evaluated in an effort to diagnose disease in its early stages.

SEED IMPLANTATION (SI):
A treatment for prostate cancer in which radioactive seeds encased in titanium shells are permanently implanted into the prostate gland.

SELENOMETHIONINE:
A substance that shows an inhibitory effect on certain prostate cancer cell lines that appear to be independent of androgen receptor or PSA pathways.

SEMINAL VESICLES:
Glandular structures located above and behind the prostate that secrete and store seminal fluid. Seminal fluid is one component of ejaculate.

STAGE:
See CLINICAL STAGE, PATHOLOGICAL STAGE.

SYSTEMIC:
Throughout the whole body; in prostate cancer, cancer that is no longer organ-confined.

TESTOSTERONE (T):
The male hormone or androgen that comprises most of the androgens in a man's body. Chiefly produced by the testicles, testosterone is essential to virtually every male function from the brain to toenails.

THERAPEUTIC INDEX (TI):
Treatment benefit divided by treatment side effects.

THERMOCOUPLES:
In relation to prostate cancer, devices used during cryosurgery to monitor the temperature achieved by cryoprobes, thus helping to improve the therapeutic index of the procedure.

TRANSFORMING GROWTH FACTOR BETA-1 (TGF-b1):
A growth factor produced by prostate cells, as well as by cells of the bone matrix. Elevated plasma levels of TGF-b1 obtained at baseline are associated with distant disease involving bone and/or lymph nodes.

TRANSRECTAL:
Through the rectum (as in transrectal ultrasound of the prostate).

TRANSRECTAL ULTRASOUND OF THE PROSTATE (TRUSP OR TRUS):
A method that uses the echoes of ultrasound waves to image the prostate by inserting an ultrasound probe into the rectum.

TRANSURETHRAL:
Through the urethra. See Transurethral Resection of the Prostate.

TRANSURETHRAL RESECTION OF THE PROSTATE (TURP):
A surgical procedure to remove prostate tissue obstructing the urethra.

T SCORE:
A designation used in evaluation of bone mineral density that relates the patient's bone density to that found in a population of healthy women of approximately 30 years of age. The T score is in contrast to the Z score, which relates the patient's bone density to a pooled population of an age similar to the patient. The T score is the desired test result. (No T score levels have been ascertained for men as of the end of 2002.)

TUMOR:
An excessive growth of cells caused by uncontrolled and disorderly cell replacement that can be either benign or malignant.

TUMOR VOLUME:
The amount of tumor measured in cubic centimeters.

ULTRASENSITIVE PSA ASSAY:
PSA assays that are able to measure very small amounts of PSA in the blood sample, reliable to the hundredth or even the thousandth of a nanogram per milliliter of blood. Tosoh and DPC Immulite Third Generation assays are examples of ultrasensitive PSA assays.

UPREGULATING (UPREGULATION):
Turning on or increasing a mechanism of action at the biochemical level in the body.

UROKINASE-TYPE PLASMINOGEN ACTIVATOR (uPA):
A substance believed to play a role in prostate cancer invasion and metastasis that is stimulated by IGF-1 and inhibited by GLA and EPA.

UROLOGIST:
A surgically trained physician who specializes in disorders of the genitourinary system.

VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF):
A substance known to stimulate blood vessel growth or angiogenesis and hence to stimulate PC growth.

VIADUR:
Brand name of an LHRH agonist that is implanted under the skin and releases medication over the course of one year.

VITAMIN E SUCCINATE:
Substance that inhibits the growth of prostate cancer cells of certain cell lines by suppressing androgen receptor expression and PSA expression.

WATCHFUL WAITING:
Objective ongoing observation and regular monitoring of a patient with prostate cancer without actual treatment or invasive therapies.

ZOLADEX:
Brand name of one of the LHRH-agonists.

Z SCORE:
A designation of bone mineral density that relates the patient's bone density to that of a pooled population of similar age. See T Score.

SUGGESTED READING

Those seeking additional information may order a copy of A Primer on Prostate Cancer, the Empowered Patient's Guide. The Primer reflects the synergistic efforts of Stephen B. Strum, a medical oncologist involved with PC since 1983, and Donna Pogliano, a partner of a PC warrior. The Primer is in full color with many graphic images, clinical vignettes, and a comprehensive appendix replete with material that is the essence of top-of-the-line health care as it relates to PC. The Primer is a working manual and companion tool to this protocol. The Primer is to be regarded as required reading for those serious at winning the war against PC. It is your basic field guide--but much more so. The Primer is available through Life Extension at (866) 820-7457 or on the Life Extension website at www.lefprostate.org . You may fax an order to the United States at (954) 761-9199. The Primer is also available through amazon.com, the Prostate Cancer Research Institute, Us Too!, the Educational Council for the Prostate Cancer Patient, Barnes & Noble, and Borders.

ADDITIONAL READING

Books About PC

• Patrick Walsh, M.D., Janet Farrar Worthington.
  Dr. Patrick Walsh's Guide to Surviving Prostate Cancer
• Sheldon Marks, M.D.
  Prostate & Cancer. A Family Guide to Diagnosis, Treatment & Survival

Medical Journals Focused on PC

• Urology
• Journal of Urology
• Prostate
• Prostate Cancer and Prostatic Diseases

PC Newsletters

• Prostate Cancer Research Institute's PCRI Insights
• Dr. Snuffy Myers's Prostate Forum
• ECPCP's (Education Center for Prostate Cancer Patients) Prostate Exchange
• PAACT's (Patient Advocates for Advanced Cancer Treatments) Cancer Communication

Internet Websites

• PCRI (www.pcri.org)
• Don Cooley (http://www.cooleyville.com/cancer/)
• Robert Young (http://www.phoenix5.org)
• PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi)

Internet-Based Tools (Software)

• PC Tools I and II (www.pcri.org)
• Kattan Nomograms (http://www.mskcc.org/mskcc/html/10088.cfm)

PRODUCT AVAILABILITY

High potency genistein extracts, lycopene, gamma-E tocopherol, curcumin, selenium, silymarin, Life Extension Booster, Mega EPA/GHA, Super GLA/DHA, Vitamin E Succinate (natural), Mega GLA, Super Max EPA, PectaSol, vitamin D3, TriBoron, Bone Up, Bone Assure, vitamin K, Calcium Citrate w/Vitamin D3 and other supplements discussed in this protocol can be ordered by telephoning (800) 544-4440 or by ordering online.

STAYING INFORMED

The information published in these protocols is only as current as the day the book was sent to the printer. This protocol raises many issues that are subject to change as new data emerge. Furthermore, cancer is still a disease with unacceptably high mortality rates, and none of our suggested treatment regimens can guarantee a cure.

The Life Extension Foundation is constantly uncovering information to provide cancer patients with more ammunition to battle their disease. A special website has been established for the purpose of updating patients on new findings that directly pertain to the cancer protocols published in this book. Whenever Life Extension discovers information that points to a better way of treating cancer, it will be posted on the website www.lefcancer.org.

Before utilizing the cancer protocols in this book, we suggest that you log on to www.lefcancer.org to see if any substantive changes have been made to the therapeutic recommendations described in this protocol. Based on the sheer number of newly published findings, there may be significant alterations to the information you have just read.