A Strategy of Success in the Treatment of Prostate Cancer
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PCRI Insights July, 2002 vol. 5, no. 1
By Stephen B. Strum, MD, FACP

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In August, 1999 at age 69, GB was diagnosed with PC. His baseline PSA was 4.2, and the Gleason score was (3,4). The digital rectal exam (DRE) revealed the entire right lobe to be hard consistent with a clinical stage of T2b. Four of six biopsy cores indicated PC. The gland volume per ultrasound was 29 cc. GB was offered radiation therapy (RT). After doing much investigation on his own, GB obtained further consultation with a team of physicians fully focused on PC. Repeat DREs raised a concern for extra-capsular involvement at the right base and midgland more consistent with a clinical stage of T3a. The pathology slides were sent for review by one of the experts in PC pathology, David Bostwick MD, who confirmed a Gleason score of (3,4). Bostwick estimated the Gleason grade 4 component to be 20% (out of a possible range of 5% to 49%).

Analysis of the above data using the available algorithms, e.g. Partin, Narayan, Bluestein, Lerner, D’Amico and others indicated a low probability of organ confined disease and a substantial risk for extracapsular extension (ECE) as well as a risk for seminal vesicle and lymph node involvement. (Editor note: Algorithms are described in the May 2001 issue of PCRI Insights and available on our Software page. For additional information, contact the PCRI Helpline.)

Further analysis of the pathology tissue blocks by Bostwick Laboratories indicated the DNA ploidy analysis to be diploid. Oncogene analysis of the PC tissue for Bcl-2 and mutated p53 indicated good results with both studies being negative. A PAP blood test was normal at 2.0. Other tumor markers, such as CGA, NSE and CEA were also within normal limits. A baseline Pyrilinks-D (Dpd) urine test for bone resorption was 5.4 (normal is = 5.4). A ProstaScint scan showed uptake in the prostate and was suspicious for disease in both seminal vesicles. No lymph node uptake was seen. An endorectal MRI with spectroscopy at UC San Francisco indicated a gland volume of 35 cc. It also showed bilateral disease but did not reveal ECE nor did it confirm seminal vesicle involvement.

After discussion with his consulting physicians, GB began androgen deprivation therapy (ADT) in 11/99 with three drugs: Flutamide, Proscar and Lupron (ADT3) to reduce the PC volume and gland size prior to RT. After three months of ADT3, the PSA had dropped to 0.2 and by five months it was 0.092. After six months of ADT3, the DRE showed only slight firmness at the right base. On 7/12/00, after eight months of ADT3, an undetectable PSA (<0.05) of 0.02 ng/ml was attained and the DRE had completely normalized. A repeat endorectal MRI with spectroscopy showed the gland volume reduced to 24 cc, and the MRI and spectrographic findings suggested no significant PC activity.

After further reviewing all his options, GB elected to receive intensity modulated radiation therapy (IMRT) between 8/31-10/24/00 with BAT (B-mode acquisition and targeting) guidance under the supervision of radiation oncologist David Beyer MD. This was begun in 8/00. ADT3 was stopped on 1/11/01. GB has done well and at 20 months after completion of IMRT his PSA has remained stable at 0.3 ng/ml. His testosterone level returned to normal 10 months after ADT was stopped. GB selected experts in the field of PC. He was properly prepared for the chosen treatments, and he decided upon therapy that was appropriate to the biological manifestations of his disease. He was guided by a Process, a Methodology, a Tactical Plan – a Strategy of Success.

Empowerment - What a Concept Figure 1: Empowerment–What A Concept Many men totally delegate to their wives decisions about what to do after a diagnosis of prostate cancer. These men do not enter the empowerment process and do not optimize their chance of a successful outcome. They also miss the opportunity to bond with other men and women and the ability to not only receive guidance but also to give it to others in return.

After a diagnosis of prostate cancer has been made and the initial shock of a life-threatening diagnosis has begun to lessen, the thoughts of the patient almost invariably focus on “What should I do to get rid of this disease?” Family and friends reinforce this mental set as well as add to the anxiety of the situation by asking, “ What are you going to do?

However, no patient is magically transformed into a PC expert upon being diagnosed with this disease. Life is not that simple. Amazingly, there are patients who rise to this threatening opportunity and educate themselves to a degree that many physicians find astoundingly impressive. Many other men delegate this empowerment process to others – especially their wives or their partners (Fig. 1).

Few men employ a team approach, working together with their wives or partners, their family and friends, and in co-partnership with their physician(s), devouring literature, searching the Internet, attending support group meetings and becoming involved with email lists focused on PC. These empowered patients are involved in a Strategy of Success (Fig 2).

A Strategy of Success Figure 2: A Strategy of Success.

The intent of this article is to share my views on how to achieve a successful outcome for men with prostate cancer. As a medical oncologist focused on this disease, it has become clear to me that a successful strategy does not equate with one or another particular therapy but instead with an understanding that listening to the world of biological expressions of health and disease of a particular human being within his personal context enables the patient and physician to climb to new heights of understanding that equate with a strategy of success.

The items bolded in green in this article indicate positive, proactive statements while those items in red indicate areas that should be regarded with caution by the patient-physician team.

The Importance of Extent of Disease (EOD)

After a diagnosis of PC, most physicians in the United States suggest an evaluation of the EOD. Surely, we cannot advise a man to have a local treatment with curative intent with therapies such as radical prostatectomy (RP), seed implantation (SI), external beam radiation therapy (EBRT) or cryosurgery if cancer has spread beyond the scope of the scalpel, beyond the boundaries of the radiation field, or beyond the periphery of the cryosurgical iceball.

This concept of staging, i.e. the determination of the extent of disease, is a basic principle of cancer medicine. Until we have a universal “antidote” or cure for cancer(s), we need to individualize the treatment based on what works best for the particular stage of disease the patient is found to have. This is a sound concept; unfortunately however, the way the extent of disease is currently determined is overly simplistic.

Staging
Virtually every patient newly diagnosed with PC is referred for a nuclear medicine bone scan, along with a computerized tomography (CT) scan of the pelvis and of the abdomen. This particular approach to staging PC had relatively greater value 10 to 20 years ago in the days before PSA testing was routine and in the early years after PSA testing was approved as a critical tool in the diagnosis and evaluation of PC. In those times, it was not uncommon to find at diagnosis an abnormal bone scan, CT scan of the pelvis and sometimes of the abdomen, and a digital rectal examination which revealed bulky PC. Indeed, all of these staging tests reflect the volume of cancer as well as the extent of disease; the two usually go hand-in-hand.

However, PSA testing in the USA has dramatically changed the profile of the newly diagnosed man with PC. Annual PSA testing has caused a “stage migration” with the result that advanced disease at diagnosis is a rarity; today, we mostly see advanced PC in men who have not undergone periodic PSA testing due to their own neglect or that reflecting medical and economic policies of certain so-called “Health Maintenance Organizations (HMOs).”

The most common history now associated with the diagnosis of PC in the United States is that of a rising PSA or of an absolute PSA value that raises concern for PC being present. The migration from an advanced stage at diagnosis to an earlier stage manifests itself clearly in the fact that abnormal digital rectal examinations suspicious for PC are found in only 25% of men at diagnosis today, compared to 60-75% or higher percentages from twenty years ago. Again, this reflects a tumor volume that is so much smaller that the DRE raises no concern that PC is present; the volume of the disease is below the threshold of the examining finger. This impact of PSA screening is akin to the change in breast cancer where diagnoses of this disease are most commonly made via mammography rather then by a woman or her doctor feeling a suspicious lump in her breast. We can thank the use of the PSA for the change in the nature of presentation of PC we see in the USA today.

To all of this, most physician-scientists would say “Elementary, dear Watson,” This is simply a matter of earlier discovery using higher resolution tools. It is merely improving our ability as detectives by using a magnifying glass(es) of sorts. A good MD is therefore, in this setting, a great Medical Detective, a Sherlock Holmes, MD, so to speak (Fig. 3).

Doing Your Homework Figure 3: Doing Your Homework. All of us have to put in the hours and try to understand the problem at hand. In today’s world of medicine, this also means the patient. The Internet and its powerful tools of learning are of monumental importance to the PC patient and his family. The full circle of patient-familyfriends- physician should be involved in this learning process. This photograph is actually one of historic nature. This is Dr. Oscar Vivian Batson, discoverer of the venous plexus that surrounds and runs parallel to the spinal column with countless anastomoses to the sinusoidal structure of the vertebral marrow and epidural venous channels which appears to account for the spread of metastatic disease of prostate cancer to the bones.1 Photograph is courtesy of his grandson Eric Batson, M.D., Ph.D.

There is a Catch 22 that comes with all of the above. The hypothetical patient diagnosed with PC today, James Potter for example, presents with a PSA level of less than 10, no palpable abnormality on DRE (T1c clinical stage) and most commonly with an average degree of aggressiveness upon microscopic review, i.e. a Gleason score of (3,3). He will have a normal bone scan and, 99% of the time, a normal CT of the abdomen and of the pelvis. When Mr. Potter is told of these results, he assumes the PC is confined to the prostate, and he, his family, and friends breathe more easily. They assume that the situation is controlled and most likely curable. All of this scenario usually transpires within a week or two after the diagnosis of PC has been established. Again, the patient focuses on “What treatment should I have to cure me of this disease?” Family and friends again ask, “What therapy have you decided to select?”

To summarize the foregoing, the man diagnosed with PC has been through a PSA (or multiple PSAs) and a DRE. He has also probably undergone a transrectal ultrasound of the prostate (TRUSP) which enables the urologist or radiologist to visualize the prostate gland, determine the gland volume, and perhaps see some of the abnormalities within the gland and/or at its borders. Most urologists use the TRUSP primarily as an imaging tool to direct the needle biopsies of the prostate gland and thereby to establish the diagnosis of PC. In addition, some physicians might also have obtained a free PSA percentage to heighten or lessen their concerns that the nature of the PSA is, or is not, most likely related to PC. Again, once the diagnosis of PC has been confirmed upon microscopic review and a Gleason score has been assigned to the PC, the patient is most often advised to have a bone scan and CT scans to “resolve” the issue of whether or not the PC is confined to the prostate.

For the patient, his family, and the physician, the time has come to decide upon a definitive treatment. This is the state of the art of PC medicine in the United States in 2002.

Despite this being a far more favorable process in the USA than elsewhere in the world, even with all of the tools we currently have available, we still are not listening to the biological expressions of PC to optimize our assessment of the individual man with this disease. The staging of disease often remains limited in scope and is unsophisticated in its understanding of the biology of this heterogeneous group of diseases called prostate cancer. How can this be? It is because of a lack of a coherent process, a strategy that optimizes success.

It has been said that the only place where “success” comes before “work” is in the dictionary. Successful strategies in virtually every aspect of medicine and life in general involve work; this is especially true in PC. The work being referred to is strategy – developing a plan of action intended to accomplish a specific goal. Strategy implies analytic skill and process; it involves science and art. Strategy is derived from the Greek “strategia”, meaning the office of a general; the root word is “strategos”, or general. This is a military strategy as it applies to eradicating the enemy, or at the very least controlling the enemy (Fig. 4).

Strategy Implies Tactical Skill Figure 4: Strategy Implies Tactical Skill Strategy implies a process of logical thought and rationale. This is the key to the successful outcome of virtually every problem faced by humankind. “ Strategy” is derived from the Greekword “strategia”, meaning the office of a general. This is George C. Scott portraying General George S. Patton, Jr., one of the great military strategists of modern times and a faithful student of the history of military strategy dating back to the saga of the Greek and Roman epic heroes.

After counseling thousands of men and their families from all over the United States and abroad for over the last twenty years, a strategy associated with a successful campaign against cancer became apparent. The characteristics of such a strategy of success basically involve the following six steps:

1. Listening to the biology of cancer.
2. Validating critical data inputs.
3. Establishing a baseline.
4. Integrating information with combined variable analysis.
5. Synthesizing all of the above data to represent a “refined” analysis.
6. Presenting strategies to the patient within the context of his situation.

Strategy to Enhance the Outcome in the Man with Prostate Cancer

Step 1. Listening to the Biology of Cancer

The biology of cancer is the expression of life forces; it relates to everything we know about health and disease. It is the essence, the underlying dynamic that is behind the chronicle of the cancer patient. Biology, the science of life, is ubiquitous. For the man with cancer, some expressions of biology involve genetics, social and occupational exposures involved with cancer development, stress and dietary factors, and nutritional deficiencies. Scientists relate these manifestations and their understanding of them in various forms: the history and physical examination of the patient, laboratory test results, and radiologic images that may involve x-rays, nuclear medicine scans, CT, MRI and spectroscopy, to name a few. If we can conceive that all the complex-sounding medical terms and issues that so often are confusing to the cancer patient are simply reflections of biological interactions, the understanding becomes easier and the anxiety of the patient lessens as well.

At the current level of what is commercially available to the patient-physician team dealing with PC prevention and epidemiology,
we have some basic inputs that reflect such biological forces. Is
there a family history of prostate cancer– especially in the first-degree relatives such as the father or brother(s) of the man suspected
of having PC? If two such relatives have a history of PC, the risk of PC is 4.9 times greater, and if three then the risk of PC is 10.9 times greater and the chance of developing PC earlier in life (less than 55 years of age) is more likely.2 Does the patient’s nutritional status relate to his risk of developing PC? Low plasma selenium levels, for example, are associated with a 4 to 5-fold increased risk of PC development.3 Studies by Clark et al showed that selenium supplementation at 200 mcg per day reduced the incidence of PC in men by 63%.4 A high boron consumption has now been associated with a 64% decreased likelihood of developing PC (Fig. 5).

Boron Lowers Risk of PCFigure 5: Boron Lowers Risk of PC.  Boron is an element found in nuts and fruits such as plums, prunes and grapes. Three and a half servings of boron-rich fruit per day plus one serving of nuts per day lower the risk of PC by 64%. After Zhang et al, personal communication.

In addition, there is a 32% decreased incidence of PC and 41% lower mortality in men taking synthetic vitamin E.5 Basic research studies have shown that vitamin E reduces growth rates of PC tumors that were transplanted into mice and stimulated by a high fat diet.6 Moreover, a recent study published in the Journal of the National Cancer Institute determined that statistically significant protective associations for high levels of selenium and alpha-tocopherol (vitamin E), were observed only when gamma-tocopherol (the gamma isomer of vitamin E) levels were high.7 The underlying mechanisms or processes behind such discoveries are forthcoming.

Most of the aforementioned studies reported a reduction in the incidence of PC. Although the prevention of PC is of prime importance, the theme of this article is the concept of strategy and the realization that it is a logical and rational step-wise process which leads to the successful treatment of men with an established diagnosis of PC (Fig. 6).

A Strategy of Success in PC

Figure 6: A Strategy of Success in PCIn the world of the prostate cancer patient, this is a roadmap that works. It involves the six basic steps in the Strategy of Success. The left side of the “roadmap” shows the conceptual aspects of this strategy of success, while the right side gives concrete examples.

Within this latter setting or context, we can learn to listen to the biology of PC at a more astute level then that which is generally being done. We can use basic inputs like PSA, clinical stage and Gleason score and increase the value of such inputs by a number of easy maneuvers.

(Continued on next page).

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