INTERMITTENT ANTIANDROGEN MONOTHERAPY IS OUR SIGNATURE PROSTATE CANCER TREATMENT
Ronald E. Wheeler, M.D., Urologist & Medical Director of The Prostatitis and Prostate Cancer Center
Recently, I was asked to consult with a 60 year-old male who only 10 days prior had received the shocking news that he had been diagnosed with prostate cancer. A successful businessman in the prime of his life, this man was told to have his answer regarding prostate cancer treatment in two weeks. The recommendation was made by his Urologist for Radical Prostatectomy based on his age and the lack of predictability for disease aggressiveness. His PSA was 11 ng/ml while his digital exam was non-diagnostic. The pathology showed a Gleason pattern 4+3/7 and a stage T2b. No ploidy (DNA analysis) was requested as the surgeon's plan was to remove the prostate.
The Risk of "Definitive" Prostate Treatment Failure is High
While it is tragic for any man to hear the four words, "you have prostate cancer", the far greater tragedy is the evolution of a group of men who represent the next wave or epidemic of treatment failures. This scenario plays out everyday across the USA. Ever present is a group of stoic and dogmatic physicians who fail to identify any group of patients who fail to qualify for some procedure. Allan Partin's data from Johns Hopkins provides the statistical edge for prediction of clinical failure in the decision making process. Basically, if your total PSA is greater than 10 ng/ml with a diagnosis of prostate cancer, you have a 50% risk the disease process is already outside the prostate capsule (extracapsular). Why remove a diseased organ when there is high likelihood the disease is no longer confined to the prostate? Good question - you shouldn't! If the odds do not favor success, you should look carefully at all other options. Our ability to predict with accuracy exactly where the cancer process lives amounts to nothing more than an educated guess. Any combination of Prostascint Scan, AMAS test, PSA, Gleason Score, MRI, CAT Scan, Ploidy, Prostatic Acid Phosphatase, NMP-48, Kallikrein assay or any other diagnostic test fails to adequately improve the sensitivity and/or specificity to make the case for organ confinement.
Prostate Cancer may be Systemic at the Time of Diagnosis
Validation that prostate disease cannot be accurately and dependably staged is noted through a recent Toronto Study. 49 patients scheduled for Radical Prostatectomy (presumably based on the ability to cure) underwent a bone marrow cellular aspirate to look for prostate cancer cells. After adequate tissue nourishment, 87% of patients were found to have prostate cancer cells metastatic to the bone marrow at the time of surgery. While there should always be an at attempt at scientific understanding of this phenomenon, the best interpretation is that all patients are at risk for local spread beyond the capsule at the time of diagnosis regardless of the best surgical opinion rendered. Thus, patients are at far graver risk of quality of life reduction with a failure of Radical Prostatectomy to cure than living with the disease with the benefit of other successful modalities including Intermittent Hormone Blockade (IHB) or selecting a less morbid procedure in an attempt at cure. Less morbid definitive treatment options include seeds (Brachytherapy) with or without External Beam Radiation or Cryosurgery. None of this should suggest that Radical Prostatectomy is obsolete although changes in the treatment paradigm should be considered. While many physicians endorse this thought, I subscribe to using Radical Prostatectomy in a select group of patients who qualify by age, low total PSA, and a Gleason Score of 6 or less. Obviously other treatments would qualify for this same group of patients as well.
Patient Case Reports
Just as I have supported the possible role for Radical Prostatectomy in a select group of patients, I am reminded of a case that supports the need for a less dogmatic approach to prostate cancer treatment. I received a desperate call from a 51 year-old male from New York who was told by his Urologist that Radical Prostatectomy was his only option for cure with a total PSA of 35 ng/ml and a Gleason pattern 8. This opinion came from a very prominent Urologist at a major New York University Hospital. While this case represents a blatant mismatch of surgical skill versus prostate disease and in my opinion has a greater chance for failure than success, the argument of questionable judgement cannot be overlooked. Even cases that should be a slam-dunk cure fail. In a representative case, I received a call from a 55 year-old male from Virginia who was diagnosed with a Gleason 8 in association with a PSA total of 6.5 ng/ml. Seeking the advice of a highly skilled referral Urologist in the Washington D.C. area, the patient became convinced that the only real option remaining for him was a Radical Prostatectomy. Following the surgery, the patient was given "the thumbs up" sign by his Urologist that all cancer had been removed. Within 3 months his PSA had risen to 1.5 ng/ml indicative of the failure to be cured. This type of scenario is all too common with Radical Prostatectomy recipients. People often ask me, how can this be? Quite simple is my reply. Either cancer was inadvertently left behind at the time of surgery or the cancer was already extracapsular. The issue here is generally not our skill level in removal of the prostate, but rather our misjudgment of the disease process at the time of presentation. In other words, the system we use to qualify men for this procedure is flawed and/or obsolete. These cases bring to light the uncertainty that goes along with the gamble for cure. As long as we, as surgeons, see the opportunity to seize success in the face of predicted failure, the group of prostate disease failures will rise. Why take the risk? I frequently tell patients that if a curative procedure looks good today, it will likely still look good in 6 months. If no Urologist can guarantee success with Radical Prostatectomy (and we do not) with 20 plus years of training and experience, how can you, the patient, make your most important health decision in two weeks or less? Truth is, you cannot and should not! Currently, there are excellent educational resources available that will allow you to get up to speed on prostate disease decision-making. PCRI, PAACT, The Prostate Forum, our website at www.TheProstateCenter.com, and others will provide the essential data and/or information that will serve as a foundation from which your decision will ultimately come. Patients are reminded that prostate cancer support groups located throughout this country provide an additional educational resource. The patient survivors in these groups often speak quite candidly in the form of a testimonial on all issues of life after treatment failure. The fact that these groups are growing should create national concern and suggest that there has to be a better solution associated with the theme of prostate cancer cure. While I am not trying to come between you and your physician, the inability of your physician to speak effectively to all viable options and/or delay his treatment option of choice in deference to your educational needs, will ultimately cause you to lose confidence.
Treat Prostate Cancer as a Chronic Disease
While the population across the United States of America is littered with our prostate surgical and radiation therapy failures, I continue to remind patients that if we can't get it right with Arnold Palmer at one of this country's most prestigious Institutions, what makes you think that you'll succeed at an Institution you select? The alternative to treatment failure is to avoid definitive treatment altogether. The late William Fair, M.D., noted Urologist from Memorial Sloan Kettering may have said it best when he suggested, "based on everything we know about prostate cancer in the year 2000, I am not certain that it (the disease) shouldn't be treated as a chronic disease". We should all learn from one so noble and honored in the field of Urology.
Our Prostate Disease Protocol
At the Prostatitis and Prostate Cancer Center, all of our prostate cancer patients are offered all viable treatment options. Following a lengthy dialogue including a question and answer session, patients most frequently select Intermittent Hormone Manipulation or blockade. This therapeutic approach represents the least invasive, least traumatic, yet equally effective format of disease suppression. Using the PSA as a guide, action points are selected, whereby patients understand the parameters of when to begin therapy and when to discontinue. Generally, an antiandrogen is selected as the initial format of care once side effects have been addressed thoroughly. The protocol generally allows for all quality of life issues to continue unchanged. Examples of antiandrogens used as a first line of therapy include Casodex (Bicalutamide), Eulexin (Flutamide) or Nilandron (Nilutamide). Regardless of the form of therapy selected, an Intermittent application of therapy is the standard of care implemented. Critics argue that Intermittent therapy has not shown a benefit in overall survival. While this may be true, we don't have validated data to suggest it doesn't. Furthermore, the more important take home message is that continuous therapy (antiandrogen alone, or in combination with an LhRh analogue) will fail to respond in 2.5 years on average. Therefore, continuous therapy predicts disease refractivity or lack of responsiveness and should generally be avoided. With Intermittent therapy, it is not infrequent for a patient to be on a therapeutic agent for a month to six weeks and then remain off of therapy for many months at a time. Critical to this approach is the patient responsibility to make lifestyle changes. Prostate cancer is not felt to be a stand-alone disease but rather reflective of a series of unintentional (less than favorable) habits throughout life.
Defeating Prostate Cancer is More Complex than Radical Prostatectomy Alone
In an effort to make a difference, I believe that a multi-faceted protocol must be initiated that includes proper diet, appropriate nutrition, adequate exercise, stress reduction, and continued education. Beyond this, a plan is crafted that is patient specific and consistent with the most precious of quality of life issues. We expect our patients, as example, to remain sexually active throughout their treatment course.
While our prostate cancer management program is successful, I am never quite satisfied. The only way to decrease the incidence of treatment failures is through education. Prostate cancer survivors, therefore, are urged to step forward and promote their message as a living legacy to all men who cross their path. Without this proactive approach we cannot make headway versus the ignorance that currently dominates the traditional treatment arena.
As I have previously stated, when prostate cancer is diagnosed, I minimally recommend an intermittent application of Hormonal Manipulation or Intermittent hormone blockade (IHB). This allows for a cooling off period so that the patient does not feel undue pressure from family, physician, or friends to make a decision he is not capable of making. This is also a time to develop the infrastructure for the decision that will be made later. This decision requires the knowledge of the positives and negatives associated with all options considered. Patients are reminded that all viable treatment options should theoretically be considered at this point. It is only through the comprehensive evaluation and understanding of all treatment risks and benefits that quality of life issues can be preserved while in many cases must be preserved. Minimally, this period of consideration and/or education should last no less than 6 months. Obviously, patients who have more extensive disease at the time of diagnosis do not fit this model and should respond immediately with Intermittent Hormonal Blockade using PSA action points to guide the future course. In my opinion, patients do not need to die from prostate cancer any longer. With an improved awareness program, prostate disease will be diagnosed earlier giving all men many more viable options for future care. Medically, any good coaching staff has the tools with which to suppress the disease activity for an as yet undefined period of time. In the past 5 years, I have had no patient die from prostate cancer given the ability of the patient to afford the treatment program proposed. This group includes a man with a PSA of 1265 ng/ml and many others with bone metastases. Obviously this pattern of survival will not continue unblemished, however we now have the momentum through knowledge and clinical experience that cancer management can be successful without definitive therapy such as Radical Prostatectomy. With that said, Quality of Life Issues, important to all of us become the focus of attention as we live together with the disease. Using this methodology, patients may find that their disease is non-aggressive and may not need to be treated at all.
Patient Case Report
I am reminded of a 70 year old male from New Hampshire who had prostate cancer diagnosed in association with a PSA of 6.4 ng/ml and a Gleason 4+3/7. Recommendation, by his Urologist for Radical Prostatectomy, was made as he was in fairly good health without evidence of life limiting disease such as heart disease, hypertension, and/or diabetes. Given the fact, the patient was ready to leave on his usual winter trek to Florida, the gracious Urologist suggested a Second Opinion with a Florida Urologist would be in order. After an intensely comprehensive visit at my office, I suggested that we consider diet alone with our Patented Prostatitis formula PEENUTS as Plan A. In the event this very conservative approach failed, based on a progressive rise in PSA, Plan B would incorporate the addition of an antiandrogen as a monotherapy. His PSA action points were arbitrarily set at 8 and 1, suggesting the point where the disease treatment would begin and the point where treatment would discontinue respectively. I recommended that the patient get his PSA at monthly intervals to establish disease volatility and/or stabilization. If the PSA remained quiescent, we would go to a 3-month PSA schedule. In 13 months the patient returned for follow-up. The expressed prostatic secretion (EPS), the diagnostic test for prostatitis, showed significant improvement from his initial visit, while his PSA had lowered to 4.2 ng/ml without the need for the antiandrogen. Realizing that this patient controlled his prostate cancer using basic lifestyle change, highlighted by diet adjustment and a prostate nutrient product, I asked the patient what his Urologist back home thought of the success of his conservative measures? His Urologist concurred with his noted success by stating, "I guess you no longer need the Radical Prostatectomy". A victory had been achieved for all who cared for this patient through the desire to remain conservative. Thus, the patient avoided the threat of incontinence, impotency and possibility of disease recurrence. He was in effect, living with his disease in a suppressed or non-advancing biologic state. Additionally, he was not threatened by bone loss, muscle wasting, hot flashes, impotency, weight gain and lethargy from taking drugs that would have been inappropriate at this time. This patient now counts his success versus prostate cancer at three-month intervals with the PSA blood test. Our coaching process allowed for the patient to understand the risks and benefits of all pertinent therapies realizing that the best therapy for him was associated with no definitive therapy at all.
Awareness Fails when We do not Understand the Application and Significance of PSA
The battle versus prostate disease does not always turn out so well. I recently heard of a 65 year-old gentleman from Nebraska who had realized the benefit of yearly PSA screening. For the previous 5-6 years his PSA had held stable in the range of 3.5 ng/ml. His digital exam was non-diagnostic according to his physician. The medical statement was made to him that his PSA was within normal limits and that a yearly PSA should continue. A year following this encouraging news and a month after he retired, his PSA was recorded at 29 ng/ml! The biopsy of the prostate revealed the obvious. He had prostate cancer! Not only did he have prostate cancer but he had cancer that had aggressively invaded his bones. Despite an orchiectomy (removal of the testicles) to wipe out virtually all of the testosterone that fed this cancer, he died within two months of the diagnosis. In this case, the healthcare system had failed to prevent the loss of a patient who understood the words: "proactive and awareness". He became an unwitting pawn on the chess board of prostate disease and lost his life. He was misinformed on what the normal PSA level really was. He merely followed directions and lost because he thought his doctor knew best. Regardless of what the healthcare system says, patients are advised to get the PSA, know the number and keep reading. I am presently in the process of trying to get the "so-called normal value of PSA" lowered to less than one. This life may have been spared if this information, were known by his health care providers.
Prevention makes Sense
The only paradigm to adequately complement patient survival from prostate cancer treatment and management of treatment failures is to implement an aggressive attempt at prostate cancer prevention through awareness. The interpretation of the PSA, "the barometer of prostate health", must be enhanced significantly to identify more disease in a more timely fashion. Historically, the 0-4 ng/ml range has been associated with 20-30% of all prostate cancer cases. Despite this, we have been telling patients since 1986 that 0-4 ng/ml is normal. Most notable to this group of "so-called normal" patients is the former Gulf War General, Norman Schwartzkopf. He was diagnosed with prostate cancer with a PSA of only 1.2 ng/ml. As a medical profession, we must stop representing as normal something that is far from normal. Patients are losing options and time to treat as PSA rises consistent with a greater aggressiveness of disease (prostatitis and/or prostate cancer). Despite what critics have said, the PSA blood test has excellent sensitivity and specificity for detection of prostatitis but does not fare as well when matched versus prostate cancer.
The True Meaning of PSA
In data I reported on at the NIH in 2000, I demonstrated that a PSA of 1 ng/ml or greater indicated prostatitis in virtually 100% of patients (N=177). This was validated with the EPS (expressed prostatic secretion), the diagnostic test for prostatitis. Thus PSA is a surrogate marker for prostatitis. In even more disturbing data released by Johns Hopkins in March of 2002, Ballantine Carter, M.D., demonstrated the significance of a PSA of 0.6-0.7 ng/ml. If a male in his 40s or 50s has a total PSA of greater than 0.6-0.7 ng/ml, he has a 3-4 fold increased incidence for prostate cancer within the next 20 years. This is a wake up call that adds credence to the Detroit Autopsy Study that showed 30% of 30 year olds had prostate cancer. We have only seen the "tip of the iceberg" on the devastating disease associated with this organ. The real epidemic is the new generation of prostate cancer patients disguised today as prostatitis patients. Therefore, if we don't recognize disease earlier and/or offer proactive options to the unwitting public, we will pass the baton of disease ignorance from one generation to another. Without an improved algorithm on prostate health, future generations of men will stand in front of a new generation of physician with the same level of dogmatism, arrogance, and failure to cure perpetuated over and over.
Understanding Prostatitis may be the Key to Prostate Cancer Resolution
While there are many theories for the evolution of prostate cancer, there is no one factor that can be isolated as the etiology of the disease process. While the component parts are multi-factorial, the most glaring and least understood element to me is the oxidative damage/destructive process of prostatitis or inflammation. Understanding the role of glutathione may hold the key to unlocking the pathogenesis of prostatitis to prostate cancer. While much work needs to be done to conclusively validate the cause and effect of the inflammation to the cancer, no one will dismiss that inflammatory disease leads to other cancers and that prostatitis and prostate cancer coexist at the time of prostate cancer diagnosis. While my thoughts on the role of prostatitis to prostate cancer are more clearly outlined in the April 1999 PAACT article, there is no doubt in my mind that the inflammation associated with prostatitis is causative to prostate cancer. This opinion is corroborated by a group of leading edge research specialists including doctors: Bostwick, Leiberman, Issacs, Nelson, Moon and others. These experts recognize a disruptive cell pathway that leads to prostate cancer. In this model prostate cells become atypical and then dysfunctional through a process affected by chronic inflammation called proliferative inflammatory atrophy. Subsequent cellular change or mutation creates PIN (prostatic intraepithelial neoplasia) that ultimately evolves into a prostate cancer cell.
Clearly, the evolution of prostate cancer and response to therapy varies from patient to patient and is based on many as yet unrecognized factors. Every patient should recognize that the fear of cancer must play no role in the decision process. Additionally, patients are encouraged to get educated with a physician coach who will guide them using an unbiased approach, even if the best approach doesn't include Surgery, Radiation or Cryosurgery. We must not abandon our patients if they choose a less than definitive approach. Through our efforts, we will empower the patient with education, experience, and knowledge to know what is best. The lack of data to prove adequate and predicted success with definitive treatment options speaks loudly and clearly for change. What we know at this point with prostate cancer is an inexact science where physician judgement and surgical operative skill are divergent and minimally related. The only way to blend judgement and skill is to realize that we have limitations to cure. Specifically, we must let go of the belief that everyone can be cured with something. We must give up the "one size fits all" mentality as well as treat only the best candidates using improved realistic guidelines for qualification. Only in this manner, can the profession restore a modicum of integrity to the treatment paradigm. The influence from this thought pattern will push awareness toward earlier evaluation and diagnosis and therefore, hopefully yield greater success in a smaller group of qualified participants for longer periods of time.
It is often said, sometimes, the more we learn, the less we know. It is only through vision and acceptance of our outcome data that we will realize that maybe the late William Fair, M.D., was right when he recognized that prostate cancer is far too complex to subject to any single procedure or process. Maybe it is finally time to treat all prostate cancer as a chronic disease.
1. Carter,B,: The Johns Hopkins March Newsletter, 2002
2. Richie,JP: Antiandrogens and Other Hormonal Therapies for Prostate Cancer. Urology Supplement Vol.54, Number 6A, 15-18,1999
3. Crawford,ED Et al: Overview: Hormone Refractory Prostate Cancer. Urology Supplement Vol. 54, Number 6A,