A Patient's Guide to Managing Hormone-Refractory Prostate Cancer  

Chapter 10.  The First Treatment is to Continue Hormone Therapy

Why? 

To begin at the beginning, Huggins reported in 1941 that androgen withdrawal alleviates the symptoms of advanced prostate cancer. Hormone blockade was developed as an alternative to orchiectomy. That’s pretty much the entire history of treatment development for advanced prostate cancer. As it did then, the disease still progresses to a hormone-refractory stage, and that’s where we are today, more than 60 years later.

There are of course chemotherapy and surgery in the short list of treatments for prostate cancer. But hormone blockade is as important today as it was for Huggins in 1941.

Now, logic tells us that, once the disease becomes hormone refractory, there should be no further reason to continue hormone therapy. As usual, logic is trumped by experience. Men with HRPCa seem to benefit from continued hormone blockade. And, in a further challenge to easy logic, some men experience a drop in PSA when one component of the hormone therapy—the anti-androgen--is halted.

In cancerous and non-cancerous situations, the testosterone (a signaling molecule) moves through the blood stream, carried by a fat molecule—either albumin or SHBG—sex-hormone binding globulin. Eventually it makes its way to a prostate cell, where it can slip through the cell membrane. Inside the cell, an enzyme called 5-alpha-reductase causes the testosterone to convert chemically to dihydrotestosterone (DHT). Then DHT finds an androgen receptor—free floating in the cellular cytosol or attached to the nucleus. As a result of the contact, the androgen receptor gives off a “second messenger” that informs the nucleus to do one of two things: (1) generate those proteins that cause the individual to look and act like a male or (2) initiate the mitosis of the prostate cell.

About 90% of the androgen (testosterone) that reaches the prostate cells comes from the testes. The other 10% comes from the adrenal glands, not as testosterone, but as androstenedione and DHEA (dehydroepiandrostenedione). These adrenal androgens also find their way into the prostate cells, where they convert chemically to testosterone, which then enters the same process as above.

Studies over the last five years or so have shown that testosterone stimulation of cancer cell proliferation continues even during what we call “HRPCa”! There are biological explanations for these phenomena.

These studies describe a process called “gene amplification,” in which hormone blockade actually seems to cause an increase in the number of genes that produce the androgen receptors. The amplification is an aberrational increase in the number of those genes within the DNA of cancerous cells. The result is that the number of androgen receptors increases six-fold in the prostate cancer cells. Now the scene is set to enable cell mitosis, even though there is not enough androgen to support normal cell function. The smallest amount of androgen—even that from the adrenal glands—is sufficient to support proliferation of these mutant cancer cells! Thus, our prodigious efforts with LHRH agonist are insufficient for control of HRPCa.

To make this situation even worse, recent studies have shown that treatment with anti-androgen results in a significant mutation that causes some cancerous cells to actually use anti-androgen to stimulate proliferation! It is as though the firemen’s water supply has been turned to gasoline! Flutamide (Eulexin) seems to be more of a problem than bicalutamide (Casodex), but even that can turn to a cancer stimulant. Thus, anti-androgen is a potentially dangerous therapy for HRPCa.

It gets worse. Some of the cells subjected to hormone therapy become, in the terms of one researcher, “promiscuous.” They start reproducing with a host of different agents. Some will even be stimulated to reproduce by estrogens! And we commonly use estrogens to fight HRPCa!

This clearly locates us “between a rock and a hard place.” The good news, however, is that this knowledge finally makes it possible to start understanding some of the tough questions facing us with this disease. With this discussion in mind, let’s evaluate the approach to hormone therapy on HRPCa.

Lupron or Zoladex

The cancer cells in HRPCa are commonly a mixture of androgen-sensitive and androgen-insensitive cells. The hormone therapy has driven down the population of androgen-sensitive cells to the point that they are not a significant concern. However, it is unlikely that you have killed off the entire population of those cells. Thus, it is important to continue with this form of hormone blockade to prevent of androgen-sensitive cells from regaining their dominance. How long you continue on this treatment is an issue to discuss with your PCa expert. It would seem that a time would come when there would be no more androgen-sensitive cells.

Stay on Lupron. If you have stopped it, resume that treatment. If you have had an orchiectomy, you are still on hormone blockade and don’t need Lupron.

You should have a serum testosterone test while you are on Lupron to ensure that the dosage is adequate (i.e., therapeutic) to suppress the androgen and constitute a cancer-stopping treatment. The level of T should be below 20 ng/ml to meet that standard. Some doctors believe that a level as high as 50 is low enough. In either case, you want to satisfy yourself that the Lupron dosage is doing an adequate job. If the T level is too high, you should work with your PCa expert and your onco to increase the Lupron dosage to a therapeutic level.

One of the important things about Lupron is that it is a systemic treatment. HRPCa is a systemic disease, not a local disease; therefore, the effective therapies are going to be systemic. Surgery and most external beam radiation (EBRT) are of limited use in fighting this cancer; both are local treatments. One study also suggests that Lupron has a direct suppressive effect on the cancer.

Lupron is available in a 22.5 mg “depot” form that is injected for slow release over 3 months (84 days). This is more convenient than a monthly shot. If you are new to this drug, discuss the side effects with your physician.

Anti-androgen (Casodex, Eulexin, and Nilandron)

There is usually no need to consider an anti-androgen or finasteride if they have already been used and have failed. (After flutamide has failed, bicalutamide may still yield a response.)

Even when the testicular androgens have been shut down, some adrenal androgens can stimulate the prostate cell androgen receptors. Therefore, it is also important to block the androgen receptors themselves; the pharmaceutical tool to accomplish this is an anti-androgen.

Quite likely your previous hormone therapy included Casodex (bicalutamide) or Eulexin (flutamide) or Nilandron (nilutamide). As you have seen in the discussion above, flutamide carries a significant risk of leading to cell mutations in which the flutamide becomes a stimulant of proliferation. Therefore, it is best to avoid this drug. There is less risk of this mutation with Casodex, but it is still there. Casodex also has a significantly greater affinity for the androgen receptor than Eulexin. Additionally, Casodex has been shown to work even after Eulexin has failed.

What about Casodex? You will want to work this strategy out with your PCa expert. Casodex can be used with Lupron to complete the suppression of the androgens. So long as the PSA is dropping—or even remaining stable—Casodex would seem to be beneficial as a treatment.

Once the PSA begins moving upwards, it is possible that enough androgen receptors have mutated that they are now being stimulated by the Casodex instead of being blocked. You will need to stop the Casodex immediately to see if you achieve the benefit of the anti-androgen withdrawal response (AAWR). In this case you should persist as long as the PSA continues dropping or remains stable.

Casodex is dosed at low and high levels. The low level is 50 mg daily, with or without food. Studies showed that Casodex (50 mg/day) and Lupron are an effective combination. The most common side effect was diarrhea; however, care should be given to watching for all side effects. (Remember to check these drugs in the PDR for details of side effects.)

High doses up to 200 mg/day have been evaluated with positive results; however, those tests have been done using Casodex as a monotherapy, not in combination with Lupron. This treatment should be evaluated with your PCa expert.

Nilutamide has been used as a second-line hormone therapy (see also Chapter 13) following treatment with flutamide or bicalutamide. The authors of a recent study suggest that the different anti-androgens are not necessarily cross-resistant. (Desai, A. et al., Urology, 58(6), 1016-1020, 2001) A response rate of 50% was identified in a retrospective review of 14 patients who had failed on one or two previous anti-androgens or on an anti-androgen plus chemotherapy. Time to progression ranged from one to 28 months.

This tactic should not be overlooked by people fighting HRPCa. Drugs in the same family are not necessarily cross-resistant. Chemical logic would suggest that similar drugs would function similarly and have similar problems. But we are seeing that one drug may work even when another drug of the same chemical family has failed. Thus, we gain additional time. Even the same drug, when given a vacation of several months to a year, may regain its efficacy for an additional—if shorter—period.

Proscar (finasteride)

Proscar is the third part of the CHT3 regimen (with Lupron and an antiandrogen). It inhibits the enzyme (5-alpha-reductase) that enables the conversion of testosterone to dihydrotestosterone. Studies on this drug mostly focus on its use in treating BPH. Logic says that this drug may be useful against cancer, but there is no evidence that it is effective against HRPCa. There is, however, some evidence that it is effective against advanced—not yet hormone-refractory—PCa.

Use of this drug would seem to make most sense in conjunction with an anti-androgen—Casodex. The risks of side effects with finasteride appear to be slight. The dose is 5 mg q.d. Once again, if the PSA were to increase during treatment with this drug, it would be best to stop immediately.

One further thought

Prostate cancer cells have to be stimulated into proliferation by something, even if that something is produced in the cells themselves. We have blocked the chemical—testosterone—that is known to feed prostate cell development and growth. We have been able to shut down adrenal production of other androgens that serve the same purpose. And, finally, we have blocked the androgen receptors that are the gateway to proliferation. However, we now know that those receptors mutate during hormone blockade, the very process we thought to employ against the cancer.

We now know that other chemicals can slip into the process to replace androgens. Our new adversaries in this problem are vascular endothelial growth factor, epithelial growth factor, insulin growth factor, fibroblast growth factor, and estrogen.

Why are these mutations prompted by androgen blockade? What other enzymes, genes, and growth factors are to be implicated in this puzzle? What we do know is that all cells—cancer included—have the potential for survivability mutation. What we don’t know, is how to stop it.