Using Hormonal Blockade

Definitions: Hormonal Ablation Therapy is sometimes called Hormonal Treatment (HT), Androgen Deprivation Therapy (ADT), Androgen Blockade, Combined Androgen Blockade (CAB), Androgen Ablation (AA) and others.

Lupron Depot®(leuprolide acetate) and Zoladex® (goserelin acetate implant), are LHRH agonists. (Luteinizing hormone-releasing hormone (LH-RH) agonists are hormone therapy drugs that lower the production of testosterone in a man's body.

Casodex® (bicalutamide) or another antiandrogen Eulexin® (flutamide) are anti-androgen (They usually works by blocking the appropriate receptors in the cancer cell so the cell cannot utilize the testosterone).

Combined Androgen Blockade (CAB) consists of Lupron or Zoladex, together with Casodex or Eulexin® (flutamide).  Some may use Proscar® (finasteride) or Avodart® (dutasteride) as part of CAB.

Non-Steroidal Anti-Inflammatory Drugs (NSAID) The most prominent members of this group of drugs are aspirin, ibuprofen (Advil®), and naproxen (Aleve®), partly because they are available over-the-counter in many areas.

Testosterone (T) steroid hormone from the androgen group. In mammals, testosterone is primarily secreted in the testes of males and, in a much smaller amount, in the ovaries of females.

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Some doctors in the prostate cancer field have thought that a testosterone level of 20 ng/dl is castrate level (the level of testosterone when a man is surgically castrated). Some have used 50 as the level for the purposes of giving Hormonal Ablation Therapy (Hormonal Therapy). The reason this is important is that we try to reduce the testosterone as much as possible because it is the testosterone that feeds the cancer. If we can lower the testosterone the cancer stops its growth until it adjusts and no longer depends on the level of testosterone for food.

Many in the field have thought that a testosterone level of 20 or below and a PSA level of 0.05 or below is important to those on Hormonal Ablation Therapy. These levels should be reached within 3 to 6 months. The longer it takes to achieve these levels the shorter the duration of effectiveness of the HT. Now we find the same is true for the level of T. If the testosterone does not get down to below a level of 32 there will be a shorter duration of the effectiveness of Hormonal Ablation Therapy.

In "Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy"  it was found that those men who had been medically (chemically as with an LHRH agonist) castrated the lowest testosterone castration level with clinical relevance in medically castrated patients with prostate cancer was 32 ng/dl. And "Maximal androgen blockade might benefit medically castrated cases of prostate cancer with breakthrough increases of more than 50 ng/dl." In this study they define "Maximal androgen blockade" as 150mg of Casodex.

Let us assume, that the taking of Lupron or Zoladex (in any form) is chemical castration and will eliminate some 90% to 95% of the Testosterone that is produced by the body. This leaves a possibility of 5% to 10% of the Testosterone as active in feeding the cancer. This is where a anti-androgen (Casodex) will keep the blockade for a longer period of time.

However the studies are mixed as to whether a Combined Androgen Blockade is more or less effective than just mono Lupron or mono Casodex. Some studies show it has a higher biochemical relapse free rate compared to castration or a anti-androgen alone. Some studies show that CAB have a slightly lower overall survival rate. So a doctor really has his choice of either Lupron, Casodex, castration and can justify it by studies.

In this paper I want to look at it in a little different way. Most doctors will give Lupron to a patient that has failed his original treatment and has a rising PSA. The length of time this is given will depend on which study the doctor reads or as determined by the Insurance policy of the patient. Depending on the studies they have read, some doctors will prescribe Lupron for relatively short periods of time (say 3 months) while others will prescribe it for longer (say 2 years). Usually when the shorter period is chosen, the doctor will include another treatment along with the Lupron. This could be an initial treatment but it also could be a salvage treatment after treatment failure. I believe we have lots of evidence that the longer Hormonal Therapy is given the more time we have before the growth of the cancer.

Let us assume that a doctor has decided to give Lupron to a patient. Some believe that the Lupron should be given until the treatment fails - however long it may take. Others believe in a intermittent type of therapy. This might range from 6 months on and 6 months off to 2 years on and off until a rising PSA. Again the studies are mixed.

Let us assume that this doctor, for whatever reason, does not believe in CAB and so he gives just Lupron and sends the patient home. Many doctors feel this is adequate care, fewer feel that CAB should be given from the beginning. We have found that it is almost impossible to convince a doctor to give CAB when he thinks Lupron alone is the treatment of choice. Therefore we need a way that will convince these doctors that at some point in time CAB may be a viable treatment,

In using the study above if the PSA does not get down to 0.05 or below and the testosterone does not get down to 20 or below within 3 to 6 months then a different approach may be appropriate. At this time maybe we can convince the doctor to add the anti-androgen Casodex to the treatment while continuing Lupron. Maybe we add 150 mg of Casodex a day. We should get a reduction of the PSA a this point in time. At the same time we should always be taking a testosterone blood test to see how effective the treatment has been in reducing the level of the testosterone. I would want a PSA and a testosterone at least monthly during this period of time.

Is this more effective than giving Lupron and Casodex from the beginning? We really don't know but I believe it is better than giving Lupron alone.

Once the CAB fails, the patient stops the Casodex and he may then see a temporary drop in his PSA. This is called an Anti-Androgen Withdrawal Response (AAWR). I am not sure this is indicative of anything but it always looks good to see the PSA drop. Actually the cancer may continue to grow during this period of time. The studies use PSA as a measurement and not the growth of the tumor itself. It is important, therefore, to use scans to verify any noticeable change in tissue or bones at least as a baseline with which to compare future scans.  FDA approved "Trials", on the other hand, do not use PSA at all as a measurement of the disease.

I have not considered the use of the third agent in CAB - principally Avodart. Most doctors will not consider it at all, those few that do would add it to a CAB at the very beginning. The studies show a very small gain, if any, in its use. I believe a very small gain is better than no gain at all. If we go the route of Lupron until a rising PSA then add Casodex I would add the Avodart at the same time as Casodex.

For years I personally have believed and recommended that a patient should take an NSAID as soon as he is diagnosed and continue it for as long as possible. (This could be as simple as Aspirin or Ibuprofen or in case of a prescription drug Celebrex). This is not a commonly acceptable practice to any but a very few doctors. However we are beginning to see some studies that may show this to be a positive in terms of prostate cancer. A recent study suggested this combination - "A new prostate cancer therapeutic approach: combination of androgen ablation with COX-2 inhibitor" 

This paper does not consider the side effects of any of these treatments - just the effect of the treatment itself. Nor does it go into Chemotherapy but many believe that the continuation of Lupron should be included in any Chemotherapy treatment - again a controversial subject.