"SECOND LINE HORMONAL THERAPY" Dr. Charles Myers

Dr. Myers began this lecture by pointing out the rapid rise in number of scientific publications dealing with prostate cancer that are published annually. For instance, in 1987 some 687 such papers were published.

In 2003 the number had jumped to over 4,000! And in the first five months only of 2004 there were 2,003 papers published. Extrapolating this data would imply that by year end 2004 perhaps 5,000 papers would have been published.

Dr. Myers point was to illustrate the problem physicians have keeping up with all this new information. Attendance at National and International Conferences is also essential for a doctor to stay current with all the new data coming out.

He made another important point early: that is, that hormonal resistance develops in 18 months. Myers claimed that this is true for only a small minority of patients! MD Anderson data was quoted reporting that some 5+ years was needed to develop hormonal resistance if a single lymph note was involved at the time of surgery.

He also referred to some Mayo Clinic data that only 64% of men had developed hormonal resistance after 10 years with only one LN involved.

His point was that the time to develop hormonal resistance is highly variable and depends greatly on the specific parameters of the individual’s disease. Generalizations are not useful.

Because of earlier detection today, metastatic PC is not normally encountered until after some years following a failed primary therapy. Wide spread bone mets are no longer encountered at time of dx.

He concluded that “the risk of developing hormone resistance during the first five years is low for most patients”. Overall he claimed that the risk of recurrence is < 50% after ten years following RP or radiation therapy.

Myers then discussed the possible mechanism(s) that contribute to the development of hormone resistant PCa. His argument related to the so-called androgen receptors on the cell surface. Cancer cells can grow, he said, with as little as 1/100th to 1/1000th the normal testosterone levels in a man’s system.

He suggested that there was a dramatic increase in the expression of androgen receptors on the cell and these receptors had an enhanced potency to bind testosterone.

During HB treatment, T should be measured and a castrate level of < = 20 ng/dl should be maintained. If this is not achieved, the LHRH being used should be re-examined and causes explored. Myers indicated that there are batches of counterfeit drugs in circulation. Also, if Eligard is the chosen drug it must be stored in cold conditions to maintain its effectiveness.

Dihydrotestosterone is another form of T that Myers claims is 10X “more potent than T”. It can remain high even in the face of low T. It should be maintained below 10 ng/dl (but can be as high as 250 ng/dl

(Ed. Note: Dr. Myers did not make clear why this wide range was OK).

He reported that he now routinely administers Proscar® or Avodart® with Lupron®. Dr. Myers then went into a discussion of Intermittent Hormonal Treatment (IHT). Continuous hormonal blockade therapy can have some very undesirable side effects; hyperinsulinemia, obesity, diabetes, and hypertension among others can occur. Systolic hypertension can result from increased arterial stiffness.

IHT used carefully and under continuous monitoring can minimize the risks of these SEs. But both CHB and IHB can increase the risk of stroke, heart attacks, and kidney failure.

Myers claimed that IHT “appears to lower the risk of developing hormonal resistance. He reported on an animal study that led to a 50% increase in survival compared to CHB. He also referred to some good results from an IHT program in Vancouver, BC.

The protocol included 102 pts with a median follow-up of 4.2 years. Some 28% had progressed with a median of 3.7 years, with 18% dead with a median time of 5 years.

He went on in some depth citing other published results showing advantages for IHT in extending survival. Essentially Dr. Myers made an argument strongly in favor of using IHT instead of continuous hormonal blockade therapy. He did say that the best method and the best medications are still to be determined.

For those experiencing rising PSA after primary TX, Dr. Myers came down strongly in favor of IHT.

To discuss SECOND LINE HORMONAL TREATMENT he began by discussing how to determine when the first course of HB treatment has begun to fail. This is manifested by a rising PSA that no longer responds to the administration of the Lupron or Zoladex or other LHRH agonist.

He offered the suggestion of first measuring the level of DHT and if it is high then add Proscar® or Avodart® to the mix. Diethylstilbesterol is also coming back into use because it can be administered by means of patches that finesse the thrombosis issue from IV injection.

Ketoconazole, an anti-fungal product, is reportedly effective in reducing PSA when hormonal resistance begins to occur with Lupron, et. al. It is highly interactive with many other drugs therefore the administering physician must establish the patients entire drug inventory before using Ketoconazole.

In addition to the above, he discussed the use of Leukine® as an immune system enhancer that increases production of granulocyte macrophage colony population. This is a blood component believed to help attack and scavenge tumor cells. It is important to determine what your physician’s experience has been with this relatively new drug. Careful monitoring of pts on Leukine is essential.

The new PROVENGE® vaccine shows some promise in treating PCa after primary TX failure and rising PSA. He cited the results of a Phase III trial with this vaccine in which the drug delayed the time to progression of metastatic disease some 16 weeks compared to 10 weeks for the placebo arm.

[Ed. Note: Again we see a “new product” enter the market for anti-cancer drugs with only a limited gain in time to disease progression. This is the “classic” pattern, it would appear, in new, anti-cancer drug development]

Dr. Myers went into some pts clinical histories involving the use of Leukine®. He described its use in combination with other drugs such as ketoconazole, Zometa, misc. chemo drugs, etc. It appeared that he continues to experiment with the drug because not very much data exist for its use.

[Ed. Note: Medical oncologists must reach for those drugs that are available and in too many cases determine for themselves the advantages and disadvantages of each. Given the multiplicity of drugs available to them, the possible combinations become very great. Therefore medical oncology is largely an empirical exercise in “cut and try” to find combinations that will reduce elevated PSAs or increase the effectiveness of other drugs or create a synergy with some chemo drug or another.]

To further illustrate the above point, Dr. Myers listed more “new drugs” such as: thalidomide, Celebrex, Candesartan, Phenylbutyrate, Atrasentan, Captopril, Accutane, Vesanoid, Avendia, and Actos.

To find useful data regarding their use against prostate cancer is a major challenge. Then to find data for these drugs in combination with other drugs becomes an almost impossible talk. Each time a new hypothesis is developed about cancer mechanisms, the drug industry begins a program to develop drugs that implement (hopefully) the potential advantage. This results in ever-longer lists of drugs with side effects in the general population yet to be identified.

[Ed. Note: The writer recently received a catalog from the Pharmaceutical Manufacturer’s Association proudly identifying over 600 new anti-cancer drugs! Consider how a typical practicing oncologist can deal with this much overload. He will depend on the maker’s rep to fill him in on its usage and value. If and when he reaches for one of these new drugs to try on a patient it becomes a trial and error practice. Before accepting any new drug as part of his or her treatment plan, a patient should make every effort to learn the history of the drug and what its real benefits and risks have been shown to be]

Myers concluded his lecture by introducing (re-introducing is a better term) the “Mediterranian Diet” as the best overall diet for a healthy prostate. He reported a study by J. Saxe that showed an increase in doubling time for a post surgery failure patient from 6.4 months to 17.7 months. To achieve an almost tripling of psa doubling time from diet alone is a remarkable result.

He included the “usual suspects” of Lycopene and soy isoflavone as useful anti-prostate cancer dietary components. Dr. Myers also suggested that natural products like: sylimarin, curcumin, reservatrol, and melatonin have a place in PCa management.

He summed us his presentation as follows:

“Hormonal therapy is more durable than generally thought”

Multiple options exist for second and third line treatment

Effective Treatments Include:

Intensify androgen blockade

Augment immune response via GMCSF (Leukine)

Use nutritional programs that slow PCa progression

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