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Life Extension Magazine December 2013
As We See It  

Prostate Cancer Prevention Controversy

By William Faloon

A More Rational Approach

A More Rational Approach  

Most prostate tumors are very sensitive to their internal environment or what we prefer to call their “biological milieu.” We know this because when androgen-deprivation therapy is properly administered, PSA levels can drop to near zero and prostate cancer cells die through the process of programmed cell death, a.k.a. apoptosis.124,125

However, it is not uncommon for prostate cancers to eventually find other growth factors to fuel their continued proliferation and the anti-proliferative and pro-apoptotic effects of androgen-deprivation therapy wear off, as evidenced by a continuously rising PSA that was once brought down to below 0.05 ng/mL by adequately suppressing testosterone.36-42,125

When a diagnosis of prostate cancer occurs in the setting of a rising PSA in the lower range (below 4 ng/dL ideally), Life Extension views this as an opportunity for early intervention that might result in one’s body regaining control over tumor expansion.

We know that the drug Avodart® (dutasteride) lowers PSA levels by inhibiting the formation of dihydrotestosterone (DHT).126 Avodart® and its less potent cousin Proscar® (finasteride) are 5ARIs (5-alpha reductase inhibitors).127 5-alpha reductase is the enzyme that converts testosterone to DHT.127 The effect of DHT on prostate cancer cell growth is five times greater than that of testosterone.128 By blocking DHT, drugs like Avodart® and Proscar® provide a unique opportunity to suppress tumor growth. At the same time, comprehensive adjunct protocols can be initiated that are designed to deprive tumor cells of growth factors or fuels, further inhibiting cancer growth and/or invasion.

A More Rational Approach

For example, a recent study found that men taking finasteride for prostate cancer prevention were far more likely to benefit if they had lower estrogen levels prior to initiation of treatment with finasteride.129 This study clearly showed high concentrations of estrogen to be associated with increased cancer risk. So much so that the elevated estrogen neutralized the prostate cancer prevention impact of finasteride. Life Extension has repeatedly warned aging men about the critical need of achieving estrogen balance. One reason was our continued observation of high estrogen levels in newly diagnosed prostate cancer patients. Men can easily suppress elevated estrogen levels with aromatase-inhibiting therapies.130

So in response to a rising PSA and/or other indicators of prostate disease, men have a range of diagnostic options to assess whether there is underlying malignancy and if there is, what may be helping to fuel it (such as elevated DHT or estrogen).

If non-invasive diagnostics indicate malignancy, a color Doppler ultrasound-guided biopsy can indicate whether it may be high-grade (Gleason score over 7 that requires treatment) or low-grade (Gleason score under 7 that may be controlled with comprehensive surveillance/intervention).

Some Life Extension members choose to attack a rising PSA as if there is already low-grade prostate cancer present, especially if they suffer urinary symptoms relating to benign prostate hyperplasia (enlargement). In consultation with their doctor, they may choose to take 0.5 mg of Avodart® daily (though it may not need to be taken every day) and simultaneously introduce an arsenal of mechanistic approaches to restrain benign and/or tumor cell propagation and induce benign and/or tumor cell apoptosis.

The use of Avodart® or finasteride can shrink prostate gland volume by 25% thus relieving benign symptoms, improve the accuracy of a needle biopsy if this diagnostic procedure is needed, and deprive tumor cells of one growth promoter, i.e. DHT.131,132

A comprehensive arsenal of mechanistic approaches might involve healthy eating, high doses of specific nutrients (at least temporarily), hormone adjustment aimed at reducing DHT, insulin, prolactin and estrogen (but maintaining free testosterone133 in youthful ranges), and drugs like metformin and aspirin. If prolactin levels are elevated, the drug Dostinex® (carbergoline) can be used to suppress this cancer stimulating pituitary hormone.
 
I know this paradox has troubled aging men for decades, but according to a number of observations and some published studies, low levels of testosterone seem to predispose men to prostate cancer, including more high-grade Gleason score tumors. One explanation is that only low levels of testosterone are needed to convert into excess dihydrotestosterone (DHT).125 When prostate cells are deprived of their free testosterone, they may mutate to over-respond to other growth vehicles such as estrogen, insulin-like-growth factor, and DHT.129
 
Genetic Tests for Men Undergoing Prostate Biopsy

About half of US men diagnosed with prostate cancer are classified as low-risk by use of conventional measures such as Gleason score (a form of tumor grading), the prostate-specific antigen test (PSA), and a physical exam.135 Nonetheless, nearly 90% of these low-risk patients will choose to undergo immediate aggressive treatment such as radical prostatectomy or radiation even though there is less than a 3% chance of deadly progression.135

A new test called Oncotype DX is now available to physicians and their patients. It measures the level of expression of 17 genes across four biological pathways to predict prostate cancer aggressiveness.135

Test results are reported as a Genomic Prostate Score (GPS) ranging from 0 to 100; this score is assessed along with other clinical factors to clarify a man’s risk prior to treatment intervention.135 This multi-gene test can be used in conjunction with the needle biopsy sample taken before the prostate is removed, thereby providing the opportunity for low risk patients to avoid invasive treatments. According to the principal investigator of the validation study, “Individual biological information from the Oncotype DX prostate cancer test almost tripled the number of patients who can more confidently consider active surveillance and avoid unnecessary treatment and its potential side effects.”135

The advantage of this test for those who choose the comprehensive surveillance program utilized by Life Extension members (which involves the use of several drugs, targeted nutrients, and adherence to healthy dietary patterns) is to provide greater assurance the right course of action is being followed.

For information about the Oncotype DX test, log on to www.oncotypedx.com.

Prolaris® is another genomic test developed to aid physicians in predicting prostate cancer aggressiveness in conjunction with clinical parameters such as Gleason score and PSA.136

Prolaris® measures prostate cancer tumor biology at the molecular level. By measuring and analyzing the level of expression of genes directly involved with cancer replication, Prolaris may be able to more accurately predict disease progression.136

Prolaris® is a tool designed to measure the aggressiveness of a patient’s cancers to better predict and stratify an individual’s relative risk of disease progression within ten years.136 It may enable physicians to better define a treatment/monitoring strategy for their patients.

Prolaris® claims to be significantly more prognostic than currently used variables and provides unique additional information that can be combined with other clinical factors in an attempt to make a more accurate prediction of a patient’s cancer aggressiveness and therefore disease progression.136

Prolaris® has been shown to predict clinical progression in four different clinical cohorts, in both pre and post-treatment scenarios.136

In the treatment of prostate cancer, Prolaris® is prognostic at the point of diagnosis and in the post-surgery setting.136

At diagnosis, Prolaris® can help to identify patients with less aggressive cancer who may be candidates for active surveillance. In addition, Prolaris® can define patients who appear clinically low-risk but have a more aggressive disease that requires more aggressive treatment.

Prolaris® testing is also well suited for use in post-prostatectomy patients that have higher risk features after surgery to better estimate their risk of disease recurrence and therefore adjust the level of monitoring or add additional therapy.

For more information about Prolaris®, log on to the company website: www.myriad.com


The Development of Benign ProsTaTic bPH with a HyPerPlasia 

How Life Extension Differs From the Mainstream

A common approach to dealing with biopsied-confirmed low-grade prostate cancer is called “watchful waiting.” Under this scenario, PSA tests are performed at reasonable intervals and treatment decisions based on indicators of disease progression (or regression).

In the presence of persistently rising PSA and other markers, the patient and their doctor discuss wide ranges of treatment options ranging from surgical removal of prostate gland, different forms of radiation, cryoablation, and/or androgen ablation to temporarily reduce PSA and buy more time. All of these treatment modalities have side effects to consider.

Instead of merely “watching” a PSA rise until risky therapies are required, we at Life Extension view a low-grade prostate cancer (or even a biopsy that reveals no cancer) as an opportunity to intervene aggressively with a multitude of non-toxic approaches that benefit one’s overall health. Success or failure is measured by monthly PSA testing, along with other tests to ensure that other growth factors like insulin, estrogen, DHT, and prolactin are being adequately suppressed.

To clarify the point about a no cancer diagnosis, the accuracy of typical initial needle biopsies today is only around 75%.134 So if your urologist tells you he has good news, i.e., the biopsy showed no tumor cells in your prostate gland, there may be a 25% chance you do have tumor cells, thus making the kinds of comprehensive intervention that benefits your entire body a rational choice.

So rather than “watchfully wait,” as your underlying disease may progress, we suggest comprehensive intervention. The objective is to take away every route that enable tumor cells to propagate and escape confinement within the prostate gland.

For those who require a prostate biopsy, there are new (and expensive) genetic tests (described above) that may more accurately predict which tumors are aggressive and likely to metastasize and those that are so indolent that only minimal changes may be needed to keep control over them. If these genetic tests prove themselves in the clinical setting (outside the bias of company sponsored clinical trials), intelligently using the results of these tests can spare many men from needless treatments and provide information about genetic mutations to target in prostate cells may enable better long-term control.

Enhanced Diagnostic Procedures

What patients should understand is the diagnosis of prostate cancer per ultrasound-guided biopsies is also related to the skill of the physician performing the procedure, as well as the nature of the ultrasound (gray-scale versus color Doppler). CDU (color Doppler ultrasound) also indicates the degree of vascularity (angiogenesis) of the cancer, which if present is a factor associated with tumor aggressiveness. The more vascular the cancer the more aggressive it is. Dietary approaches, supplements, and medications to reduce angiogenesis should be considered in the arsenal of how we prevent the emergence or evolution of clinically significant prostate cancer.

An additional emerging area that may allow a better understanding of clinically significant prostate cancer and clarify the issue of risk of high-grade prostate cancer with 5-alpha reductase inhibitor drugs like Avodart® and Proscar® involves replacing the transrectal ultrasound of the prostate (TRUSP) with MRI utilizing parameters such as DWI (diffusion weighted imaging) and the associated grading of DWI using the Apparent Diffusion Coefficient (ADC). Studies indicate a much higher specificity for the diagnosis of prostate cancer than TRUSP when DWI and ADC are used together.154,155

Our Enlarging Prostate Glands

Aging results in a proliferation of prostate cells that is technically referred to as benign prostatic hyperplasia (BPH).137 The graphic on page 18 depicts an advanced case of BPH with a constricted urethra that would impede or block urine flow.

Illustrations on page 20 show a normal prostate gland compared to an extreme case of BPH.

Symptoms associated with BPH include frequent urination and urinary hesitancy that can be especially troublesome at night.137 In severe cases obstruction of urine flow requires insertion of a catheter into the bladder via the penile urethra.

A major culprit involved in the benign over-proliferation of prostate cells is dihydrotestosterone (DHT).138 Drugs such as Avodart® (dutasteride) or Proscar® (finasteride) reduce DHT levels and shrink the size of an enlarged prostate gland, which reduces BPH symptoms.139 These drugs also lower PSA levels by almost 50%, which may reflect the mechanism(s) that explain why men taking these drugs have reduced overall prostate cancer risk.140-142 In two large studies, men taking Avodart® or Proscar® had about a 24% reduced risk of prostate cancer.143,144

case of bPH
with a constricted urethra  

Men should know that testosterone is not the culprit behind prostate problems. Numerous studies suggest that youthful levels of testosterone do not increase prostate cancer risk.145-150 What happens in the aging man’s body, however, is that testosterone converts to estrogen and DHT, and these two testosterone metabolites have been shown to be involved in benign and malignant prostate disease. Fortunately, there are low-cost methods available to suppress DHT and estrogen in aging men, while maintaining youthful ranges of free testosterone.

Recall that PSA is not just a marker of prostate cancer, but functions as a tumor promoter by degrading barrier structures in the prostate gland that may contain isolated tumor cells.

What troubles Dr. Walsh and some other experts is that some of the men taking Avodart® or finasteride who do contract prostate cancer have been shown in two studies to develop more aggressive forms of the disease. They are so concerned that they warn men not to use these drugs for the purpose of prostate cancer prevention, as does the FDA.

Obstruction of urine flow

On the flip side are proponents of these drugs who point out that Avodart® as well as Proscar® (finasteride) reduce prostate gland volume by such a degree that the ability to identify high-grade tumors via prostate biopsy is improved. So it does not appear that Avodart® or Proscar® causes more high-grade tumors. Instead, these drugs facilitate earlier detection of such cancers, which is another reason to consider taking them.

A frustration with needle biopsies is that they miss as many as 20-30% of prostate cancers.134,151,152 The larger one’s prostate gland, the easier it is to have the biopsy miss those sites that are malignant. The illustration on page 4 depicts a 12-core biopsy to show why a larger prostate gland makes it more difficult to detect malignant cells. So an advantage of shrinking one’s prostate gland using drugs like Avodart® or Proscar® is that if a needle biopsy is required, it may more accurately detect underlying malignancy.153

As you’ll read in the article in this issue titled The Avodart®-Proscar® Debate, there is compelling evidence that these drugs may reduce high-grade prostate cancer risk.

Another virtue to using 5-alpha reductase inhibitors (like Avodart® or Proscar®) is that in the presence of prostate cancer, PSA levels don’t decrease as much after these drugs are initiated.140-142

Physicians using 5-alpha reductase inhibitors should take into account the PSA-lowering effect of these agents by doubling the PSA lab value.156 Given that PSA decreases less in the presence of prostate cancer, the doubling of PSA will result in a higher value of PSA and will trigger the need for diagnostic investigations sooner.

What doctors have observed is that drugs like Avodart® or finasteride suppress PSA levels more effectively in men with benign prostate enlargement or low-grade prostate cancer. When PSA levels drop then start raising again, this indicates that the 5-alpha reductase inhibitor is reducing low-grade cells of questionable clinical significance but is not affecting higher grade malignancies.131 This finding is another plus for using a 5-alpha reductase inhibitor as it can increase the sensitivity of the PSA test to reveal which men need aggressive diagnostics such as needle biopsies.