What We Should Have Learned About Prostate Cancer (PC) in the Past 10 Years
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by Stephen B. Strum, MD, FACP
Medical Oncologist and PCRI Co-founder
Ashland, OR

Edited from PCRI Insights February, 2008 v 11.1

 

Overview

The goal for this article is to present my views on the current status of the everyday care of the PC patient. This communication thus serves as a State of the Union message developed from the actual hands-on care of a medical oncologist who has specialized in PC for 25 years. This experience has involved (1) the care of many thousands of PC patients between the years 1983-2000, (2) additional communication with 600-800 PC patients from all over the world since 1995 via detailed interactions utilizing Internet services such as CompuServe, Prodigy, and Prostate Pointers; and (3) additional in-depth experience with 400+ patients who have been or continue to be part of my consultation practice since I left California and relocated in Oregon in 2003.

This review will concentrate on the wealth of information covered in the last 10 years in Insights, but it will not be strict in its limitation to Insights or to the 10-year time span. I will endeavor to make this discussion as straightforward as possible. It is my nature to shoot from the hip and veer away from the platitudes so often presented to PC patients and their families. I want each reader to truly understand where we are in today’s world of PC – and where I believe we should be as seen through the eyes of a frontline physician involved in the care of his fellow men, who are faced with the challenge of PC. For the individual PC patient, an accurate assessment of status (what is going on in all spheres of the patient’s health) must come before any discussion of strategy (what further studies and/or treatment should be considered). Thus, STATUS begets STRATEGY for the individual PC patient. Clearly, the same is true for the community of PC patients at large. As a group, it is mandatory that you understand where we are today in order to go forth (hopefully forward) in the most meaningful fashion.

Introduction

This issue of the PCRI’s Insights commemorates its tenth birthday. Insights was created as a serious newsletter – one that would focus on crucial concepts – medical messages that would alter the course of lives of men with PC and their extended families and associates. As the chief editor of Insights during those formative years, I aimed to also bring attention to philosophical issues that are inherent to the key approaches that change lives, and that would leave mental footprints that could be applied to almost all of life’s challenges. The name “Insights” was thus selected for a number of reasons, and was very much likened to the philosophy of Plato when he defined it as “gymnastics for the body, and music for the soul.” The hard scientific issues – what I refer to as the didactics – are for the body, and the philosophical insights, those usually attending life-altering events, are for spiritual growth. Both are fundamental to the welfare of humankind, and both are intimately interwoven – or should be. For those of you who have not read those early issues (1997-2003), I suggest you access the PCRI website (www.pcri.org) and read these philosophically oriented articles since they meld humanity with the basic science of PC.

The Need to Expedite Translational Medicine

Ten years of PC advances do not represent a long time period for medical advances. In fact, in my 45 years of experience in the arena of cancer medicine, I would estimate that on the average it takes approximately 20 years for a highly significant finding in peer-reviewed publications to reach clinical use. Given the lethal nature of many cancers, this “latency” period is unacceptable. The reasons for such protracted delays in translating significant advances to the patient (from the laboratory bench to the bedside) are many. They can be enumerated as follows:

(1) an FDA advisory panel that is ultra-conservative and still fearful about approving a drug or device that on follow-up may prove to be related to one or more serious adverse effect(s),

(2) a highly litigious American public that sues anything that moves coupled with a legal system that allows any Tom, Dick or Harry to file frivolous suits without any obligation to pay damages when such a suit is dismissed; and most importantly,

(3) a lack of empowerment of the PC community in uniting its membership (or even identifying its membership) to the goal of resolving issues #1 and #2 and thus bringing new advances to its constituency.

This is an indictment of both the medical and lay communities. Unless we change our nature from AIL (apathy, indifference, and lack of unity) to ACT (action, commitment, and togetherness) we will continue to lose families and friends to PC and other life-threatening illnesses obstructed by the same issues. As Martin Luther King once stated, “Our lives begin to end the day that we become silent about things that matter.

The Importance of Unity to Effect Change

In essence, we have dealt ineffectively, or perhaps not at all, with the philosophy of “drastic diseases doth require drastic measures.” We – mankind at large – also promptly forget history. Churchill said that “what man learns from history is that man learns nothing from history.” A specific example relates to the awe-inspiring accomplishments of the AIDS community in altering the FDA approval of new anti-HIV agents. This expression of human unity, channeled through true patient empowerment, effected the most dramatic change that I have seen in my entire medical career. Hospital wards of horrendously sick AIDS patients could be emptied and eventually closed, and the survival statistics and quality of life of HIV-infected patients in the USA and elsewhere surged upward. The AIDS community and its supporters should have shared in a Nobel Prize in medicine for this magnificent contribution.

That’s the good news. However, the PC community and its support groups (Us Too, Man-to-Man, PAACT, PCRI), as well-meaning as they are, and despite some substantial contributions, have failed to learn from the historical lesson that the saga of AIDS should have taught. The fault, dear Brutus, is actually with those people who have the most to gain and the most to lose – the PC community, which has yet to realize the power of a united front within individual organizations and between the organizations. If and when that power is realized, the changes in the prognoses of men with PC will be exponentially enhanced, other organizations will follow suit, and the entire course of healthcare will then evolve. Until then, we will continue on with the status quo uphill battle to make translational changes requiring 10- 20-year intervals. Pioneers embrace new ideas; others, who fear to know, strain to maintain the status quo.

My Early Involvement with PC

So what can be said about the actual changes in the management of prostate cancer in the last 10 years? Have they been substantial? Have they altered the “genealogy” of PC: prevention – diagnosis – staging – treatment – supportive care – end of life services? I believe I am in a unique position to honestly and critically answer such queries in this commemorative article.

My work in PC started back in 1983. In 1983, I joined forces with Fernand Labrie (Figure 1) in the first Canadian-American collaboration that studied the effects of an LHRH agonist (d-tryp-6, now Eligard®) in combination with an anti-androgen (euflex®, now flutamide or Eulexin®).

labrie

Figure 1: Dr. Fernand Labrie, a pioneer in modern prostate cancer treatment.

 

In 1989, I began investigating the use of the 5-alpha reductase inhibitor finasteride (Proscar®) as part of the ADT (androgen deprivation therapy) of PC. My initial work on Intermittent Androgen Deprivation (IAD) was eventually published in 2007 in an article in The Journal of Urology. The senior author of this article is Mark Scholz, MD. Mark joined me in 1995 and purchased my medical practice when I left in 2000 to work at the PCRI as its first full-time medical director. My work in collaboration with Drs. Scholz, Richard Lam, and Glenn Tisman extended to 2007 and led to publications on various key issues facing men with PC. These included:

(1) the anemia of androgen deprivation (AAD) resulting from ADT,

(2) the correction of AAD with EPO (erythropoietin),

(3) the use of ketoconazole as an effective agent in treating Androgen Independent PC (AIPC),

(4) Intermittent Androgen Deprivation (IAD) and the importance of using a 5-alpha reductase inhibitor to significantly prolong the time off (intermittent or maintenance) phase of therapy, and

(5) the significance of the PSA nadir on ADT as it relates to PC specific mortality and the development of bone metastases.

During the above collaborations, significant advances occurred as a result of the development of software tools (PC Tools I, PC Tools II) by Glenn Tisman, MD. I made additional smaller contributions in this venue with programs like Tumor Volume Calculator, BMI (Body Mass Index) and BMD (bone mineral density) and Renal Function Calculators. Such tools utilized the technical advances in the world of computers – still sorely underused by the medical profession – to help patient evaluation and decision-making. Nevertheless, the ability to objectify a patient’s risk or to get a sense of the volume of cancer were major contributions that for the most part are given lip service by community and academic physicians alike. I would estimate that of all the PC patients whom I have seen in my lifetime who have undergone prior evaluations by other doctors, less than 1% have been evaluated using ANY scientific form of calculation relating to the extent of PC, the probabilities of what is expected at the time of radical prostatectomy (RP), or the projected results of therapies such as RP or radiation therapy (RT). This failure to use combined variable analysis, emphasized by Partin, D’Amico, Kattan, and others, continues to be a major factor in the mismanagement of men with PC.1

Service

Nevertheless, additional real contributions were seen as a result of a long-term relationship with Arthur Lurvey, MD, who acted as the medical director of Medicare in Southern California for many years. Largely through Dr. Lurvey’s efforts, Medicare in Southern California approved cryosurgery, Aredia and later Zometa (for bone loss), and Taxotere for the chemotherapy of PC. Paradoxically, the medical insights that led to Medicare approval served to help Dr. Lurvey after he was later diagnosed with PC; he benefited from the very drugs that he had helped to secure Medicare approval. Philosophically, this brings to mind a quote from Jack London:

“It is so simple a remedy,
merely service.
Not one ignoble thought or
act is demanded of any
Of all men and women in the world
to make fair the world.
The call is for nobility of thinking,
nobility of doing.
The call is for service,
And such is the
wholesomeness of it.
He who serves all,
best serves himself.”

An Explosion in Peer-Reviewed Papers

Lastly, a number of excellent articles published in Insights were mailed to all members of ASCO (American Society of Clinical Oncology), AUA (American Urological Association) and ASTRO (American Society for Therapeutic Radiology and Oncology). They included such subjects as: Intensity Modulated Radiation Therapy (IMRT), magnetic resonance imaging (MRI) and m magnetic resonance spectroscopy (MRS), high-dose ketoconazole (HDK), and nomograms. The articles discussed the importance of expert pathology review and the chemotherapy of PC during the early years, and they helped to bring all of these advances into the clinical realm of patient care. That’s good news. But where are we, overall, in seeing these articles and the significant peer-reviewed publications on PC being translated into patient advances in prevention, diagnosis, staging, treatment, and quality-of-life issues in men with PC throughout the world?

As shown in Table 1, there is an exponential increase in the number of peer-reviewed papers on PC written in the last five years. Back in 1983, it was almost possible for a physician to obtain a grasp of the available PC literature then available. In the last five years, conversely, a physician would have to devote full time to read and assimilate the 12.4 new papers about PC being published each and every day (4,528.6 papers per year)!

Time Periods Interval (Years) Peer-Reviewed Publications per PubMed
1/1/83 to 12/31/92 10 9191
1/1/93 to 12/31/02 10 24254
1/1/2003 5 22643

Table 1: The Explosion in Peer-Reviewed Papers on PC.
In the past 25 years, the publications on PC in medical journals have risen exponentially. This table shows results obtained from a simple PubMed search using the key words “prostate cancer”. The PubMed url is www.pubmed.gov

Unfortunately, despite the plethora of new information, I have not seen significant clinical manifestations of heightened care being provided to the PC patient. Telling you the way I see it and shooting from the hip, I believe that we are utilizing but a tiny fraction of the established “new” information about PC. It appears that physicians are spending less time reading and translating new findings to treatment of PC patients under their care. I will point this out in the sections to follow in my attempt to generate sufficient controversy to alter this sluggish pace and thereby bring the “tactical to the practical“, the “bench to the trench“, and the “mission to the man“.

PC PREVENTION: What We Should Have Learned.

Many peer-reviewed publications show that specific dietary and life style changes as well as the usage of certain vitamins and supplements will reduce the incidence and/or the aggressiveness of PC. Fundamental to these findings is the basic concept that inflammation and its associated biological processes go hand-in-hand with all malignancies; PC is no exception. The inflammatory process involves the oldest hormonal system – the eicosanoid pathways. This hormonal system is found within the cell membrane of all cells. The production of what are termed “bad eicosanoids” is significantly affected by the quantity and quality of the foods we eat – especially insulin-stimulating carbohydrates – and whether or not we have a healthy intake of omega 3 fatty acids. If this metabolic “road” of bad eicosanoids is chosen, it is a bad detour since it increases the level of pro-inflammatory cytokines, tumor growth factors and activation of lines of communication (signal transduction pathways) that turn on tumor cell growth, invasion, angiogenesis and metastases (see Figure 2).

 

Figure 2: The Arachidonic Acid (AA) Pathways: AA is found in animal-derived meats, egg yolk and in dairy products. A precursor of AA, linoleic acid, is very high in most of the cooking oils used in the American diet. Without attention to factors that lead to reducing the traffic on this pathway, multiple medical problems are exacerbated due to the adverse effects of AA metabolites such as thromboxane A2 (TA2), prostaglandin E2 (PGE 2), leukotriene B4 (LTB4), and 5-HETE.

A basic knowledge of these facts leads us to understand the vital importance of the fuel we use to feed our cells – whether they are normal cells or malignant ones. Most of the civilized world is cognizant of the use of proper fuel to run machines such as automobiles and airplanes, but we ignore the very same concept in regard to the human machine. What have we learned or not learned about this?

  • The only way to increase longevity is via caloric restriction.
  • In the civilized world, especially the USA, there is an epidemic of diabetes mellitus that includes grade school children. The term adult onset diabetes mellitus (AODM) must be renamed because large numbers of children and teenagers are now being diagnosed with this type of diabetes (also called Type II diabetes mellitus).
  • The factors that underlie the development of AODM are carbohydrate excess, caloric excess and a sedentary lifestyle. The same factors lead to cardiovascular disease and neurodegenerative disease.
  • The typical diet in the Western world is overloaded with high glycemic foods (foods that stimulate insulin), which in turn stimulate the production of omega 6 fatty acid (e.g. arachidonic acid or AA). The breakdown of AA to its metabolites (see Figure 3) leads to cancer growth, inflammation, immune dysfunction, cardiac disease, and neurologic illnesses such as the dementias – essentially all the calamities that may befall mankind.
cellularLines

 

Figure 3: An Example of the Close Connection of All Cellular Lines of Communication Involved with Health and Disease. This graphic after Izzo et al2 shows the integrative nature of the various signals that involve all cellular growth – normal or malignant. Arachidonic Acid is acted upon by the cyclooxygenase enzymes to form PGG 2 which is converted to PGH 2. PGH 2 can be further metabolized to five different prostaglandins (PGs). The ones shown in dark blue have pro-malignancy effects. We know that PGE 2 is greatly involved with angiogenesis. What Izzo et al have importantly shown here is that PGE 2 also interacts with the PG receptor on the cell membrane. This further interacts with epidermal growth factor receptor to turn on the signal transduction pathways such as phosphatidylinositol-3′-kinase (PI3K) and akt. These lead to downstream pathways involved in tumor growth, invasion, and metastasis.

Our animal-protein-oriented society not only contributes inappropriately to global warming, but it also is a major source of AA, as well as total body acidification. The latter leads to bone loss with an associated release of bone-derived growth factors, a release that favors the acceleration of malignant growth, and every other malady mentioned above.

There has been little or no emphasis on changing the predominant way we eat to a plant-based diet. There has been essentially no utilization of alkalinization to alter bone physiology and improve bone density while decreasing bone loss and preventing calcification in blood vessels (coronary arteries, aorta); tissues (kidney, prostate); and bladder stones and gallstones. There has been miniscule use of QCT (Quantitative Computerized Tomography) to evaluate bone density in an aging population. Instead the dominant method used is still DEXA bone density measurement, which detects such calcifications as well as degenerative joint disease and osteoarthritis and misinterprets them as actual bone density. We are publishing papers like crazy but the information is being tucked away in the proverbial Al Gore lockbox – not to be used for decades, and possibly not at all. We have to change our medical path and do it soon.

There is compelling literature that we can decrease the incidence of PC as well as presentations of aggressive PC through the proactive use of selenium, vitamin E forms such as d-alpha tocopherol succinate, and gamma tocopherol, lycopene and boron.3-6 Despite this, it is rare to see men newly diagnosed with PC who have used a comprehensive dietary and/or supplement approach to avoid the entire problem of PC. Either the patient community requires a lot more education or the healthcare profession and the associated media need to do a lot more public relations work on this matter. To add to the above, you would think that long before the year 2008 we would have:

* Laboratory testing to see what the serum or plasma levels of the above mentioned vitamins and supplements are to ensure adequate bioavailability.

* Independent testing to verify the accuracy of supplement labeling. What you see on the label is not necessarily what you get.

There is no doubt whatsoever that there is a wide variation in quality of nutriceuticals (vitamins, minerals, supplements, and other healthcare products). How do we know whose products are really that well absorbed? How many milligrams of lycopene are really in that supplement? Can a multibillion dollar industry be so poorly regulated? Clearly the answer to that last question is yes. The only organization I am aware of that independently tests the quantity of a supplement and its purity and publishes its results is IFOS (International Fish Oil Standard) located in Toronto, Canada. IFOS has analyzed a handful of fish oil products and provides detailed results on its Internet site at http://www.nutrasource.ca/ifos_new/index.cfm. Why are there not specific companies that exist solely to assure the consumer and the physician that the quantity and the quality of a particular product ARE what the label says they are? Kudos to IFOS; at least there is one.

The PCPT (Prostate Cancer Prevention Trial)

Now on to key advances to date, essentially ignored in the prevention of PC.

There have been extraordinary advances in the prevention of PC that have not been adopted into practice. A remarkable case in point was the effective jettisoning of the landmark findings of the comprehensive Prostate Cancer Prevention Trial. The PCPT findings were published five years ago in the New England Journal of Medicine, and the findings were reported in the February 2004 issue of Insights. They involved a study of finasteride (Proscar®) versus placebo to determine if finasteride could reduce the incidence of PC. This report should have made headline news but today less than 0.1% of the world’s population is remotely familiar with the findings. A seven-year follow-up shows a 25% reduction in the incidence of PC. This is the most impressive reduction in a common malignancy via a one-capsule-a-day medication in the history of cancer medicine. Consider the remarkable findings summarized in the following paragraphs summarized here from the initial landmark paper by Thompson et al.7

In the PCPT, 18,882 men 55 years of age or older with a normal DRE and a PSA level of 3.0 ng/ml or lower were randomly assigned to treatment with finasteride (5 mg per day) or placebo for seven years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng per milliliter or if the DRE was abnormal. The schema for this study is shown in Figure 4.

 

Figure 4: Schema for the PCPT (Prostate Cancer Prevention Trial)
This landmark study was activated in 1993 and involved a seven-year follow-up of almost 19,000 men. This trial showed that finasteride (Proscar®) has the ability to dramatically decrease the occurrence of PC by 25%.

Prostate cancer was detected in 803 of the 4368 (18.4%) men in the finasteride group, and in 1147 of 4692 (24.4%) men in the placebo group, for a 24.8% reduction in prevalence of PC over the 7-year period. The statistical chance of this occurring by accident is less than one in a thousand. Moreover, there is a 95% probability that the statistical results might range from as low as 18.6% reduction in PC prevalence to a high of as much as a 30.6% reduction. These are earth-shattering findings. They should have been seized upon and applied throughout the prostate cancer community to be an effective tool PC patients had never had before.

But despite the enormous potential of this new tool, the widespread use of finasteride never happened. There appeared to be a fly in the ointment. In the initial report, a higher incidence of finding Gleason score 7-10 PC was reported in those men receiving finasteride (6.4%) who were diagnosed with PC compared to men receiving placebo (5.1%). The significant results of the PCPT have been downplayed, and in essence ignored, because of the this slight and unexplained increase in the incidence of high-grade PC (HGPC), i.e. Gleason score 7-10, in the finasteride arm compared to the placebo group.8,9

Initially, many experts in the pathology of PC explained that this finding was an alteration in the microscopic appearance of the biopsy specimen due to finasteride’s effect as a form of androgen deprivation therapy. They concluded that the finding of increased biopsies showing HGPC was simply a differential effect of the androgen deprivation caused by finasteride.10-19 Relatively recent studies that compared the histologic features of PC in finasteride-treated men versus those treated with placebo who subsequently underwent radical prostatectomy concluded that the androgen deprivation effect of finasteride appeared not to be the explanation for the findings of increased HGPC.20 Additional personal communications with additional prominent PC pathologists indicated a consensus that the relatively increased HGPC in the finasteride treated  men is not due to an ADT effect.

Properly explained, the biopsy findings within the PCPT can confirm that finasteride does not initiate HGPC. What might be the impact on human life by using finasteride as an agent to prevent PC? Unger et al estimated the number of person-years that would be saved assuming a 24.8% reduction in the incidence of PC for five years among United States males age 55 years old or older. The results indicated that 316,760 person-years would be saved due to finasteride use for the chemoprevention mode in the treatment of PC in the United States alone. But still most physicians are reluctant to use finasteride for PC. They seek an iron-clad explanation why finasteride is safe and effective for PC use.

More about “What We Should Have Learned About PC in the Last 10 Years”

There is an explanation, and it can and should lead the PC community to a more rational approach in advising men about using finasteride to prevent PC. Part 2 of this article presents this explanation in detail, and extends this thesis beyond prevention of PC to also discuss the status of diagnosis, staging, treatment, supportive care, and end-of-life services for men with PC. In toto, I hope to clarify for PC patients where we are today, where we could have been, and where we have the ability to go in our campaign against prostate cancer.

REFERENCES

1. Strum SB, Scholz MC, Lam R, et al: Optimized imaging in prostate cancer (PC) is absent 95% of the time at diagnosis or PSA recurrence 2nd Annual Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San Francisco, California. Abstr 68:167, 2006.
2. Izzo JG, Ajani JA: Thinking In and Out of the Box When It Comes to Gastric Cancer and Cyclooxygenase-2. J Clin Oncol 25:4865-4867, 2007.
3. Ansari MS, Gupta NP, Hemal AK: Chemoprevention of carcinoma prostate: a review. Int Urol Nephrol 34, 2002.
4. Djavan B, Zlotta A, Schulman C, et al: Chemotherapeutic prevention studies of prostate cancer. J Urol 171:S10-3; discussion S13-4, 2004.
5. Thompson IM: Chemoprevention of prostate cancer: agents and study designs. J Urol 178:S9-S13, 2007.
6. Cui Y, Winton MI, Zhang ZF, et al: Dietary boron intake and prostate cancer risk. Oncol Rep 11:887-92, 2004.
7. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215-24, 2003.
8. de Vere White RW: Finasteride for chemoprevention of prostate cancer: why has it not been embraced? J Clin Oncol 25:2999-3000, 2007.
9. Lippman SM, Lee JJ: Reducing the “risk” of chemoprevention: defi ning and targeting high risk–2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res 66:2893-903, 2006.
10. Andriole GL, Humphrey P, Ray P, et al: Re: effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. J Urol 173:1434-1435, 2005.
11. Bostwick DG, Qian J, Civantos F, et al: Does fi nasteride alter the pathology of the prostate and cancer grading? Clin Prostate Cancer 2:228-35, 2004.
12. Canby-Hagino E, Hernandez J, Brand TC, et al: Looking back at PCPT: looking forward to new paradigms in prostate cancer screening and prevention. Eur Urol 51:27-33, 2007.
13. Civantos F, Soloway MS, Pinto JE: Histopathological effects of androgen deprivation in prostatic cancer. Semin Urol Oncol 14:22-31, 1996.
14. Guinan P, Didomenico D, Brown J, et al: The effect of androgen deprivation on malignant and benign prostate tissue. Med Oncol 14:145-52, 1997.
15. Hellstrøm M, Haggman M, Brandstedt S, et al: Histopathological changes in androgen-deprived localized prostatic cancer. A study in total prostatectomy specimens. Eur Urol 24:461-5, 1993.
16. Montironi R, Magi-Galluzzi C, Fabris G: Apoptotic bodies in prostatic intraepithelial neoplasia and prostatic adenocarcinoma following total androgen ablation. Pathol Res Pract 191:873-80, 1995.
17. Montironi R, Pomante R, Diamanti L, et al: Apoptosis in prostatic adenocarcinoma following complete androgen ablation. Urol Int 60 Suppl 1:25-9, 1998.
18. Tran TA, Jennings TA, Ross JS, et al: Pseudomyxoma ovariilike posttherapeutic alteration in prostatic adenocarcinoma: a distinctive pattern in patients receiving neoadjuvant androgen ablation therapy. Am J Surg Pathol 22:347-54, 1998.
19. Vailancourt L, Ttu B, Fradet Y, et al: Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study. Am J Surg Pathol 20:86-93, 1996.
20. Lucia MS, Epstein JI, Goodman PJ, et al: Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial. J Natl Cancer Inst, 2007.