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

Chapter 13.  Second-Line Hormone Therapy

What does “second-line” mean

Quite simply, “second-line hormonal therapy” is an attempt to shut down residual testosterone effects after the first round (Lupron) has failed to stop the progression of the PSA. The fact that second-line hormone therapy works is more than anything a recognition that first-line hormone therapy is not complete, nor is it thoroughly understood.

To review…first-round hormone therapy—CHT3, for combining hormone therapy with three agent includes:

(1) Lupron, that shuts down the production of testosterone by
the testes;

(2) Casodex or Eulexin, anti-androgens that prevent testosterone (formed from adrenal androgens) from having an effect by blocking the androgen receptors on the prostate cells; and

(3) Proscar, an inhibitor of 5-alpha-reductase—an enzyme that metabolizes testosterone to DHT (dihydrotestosterone) a more active form of testosterone that works inside the cell to stimulate proliferation.

The concept is that cancer cells—HRPCa in particular—gain a huge number of androgen receptors in the process of becoming hormone-insensitive. Consequently, it takes but the slightest amount of androgen to stimulate proliferation of HRPCa cells. This was originally interpreted as the cancer cells’ not being sensitive to hormone blockade; however, current, understanding says that those cells are actually hypersensitive to minuscule amounts of testosterone. Thus, we need to go after that residual quantity with a “second line” of hormone blockade.

Enter the subject of adrenal androgens. Androgens are endocrines (signaling molecules), produced in the endocrine system. There are two adrenal glands, located atop the two kidneys. About 10% of the body’s androgens (not testosterone) is produced in the adrenal glands; thus, this is the target of second-line hormone therapy. The androgens produced in the adrenal glands are DHEA and androstenedione. These convert to testosterone in the cancer cells. Ketoconazole shuts down adrenal gland production of androgens and steroids.

Since the adrenal glands also produce corticosteroids required by the body, it may be necessary to supplement any such treatment with a steroid, such as hydrocortisone.

As another approach to second-line hormone therapy, estrogens (DES) and estrogenic compounds inhibit the release of gonadotropins from the pituitary gland in the brain. The gonadotropins stimulate the functions of the testes. One of these gonadotropins is a luteinizing hormone, such as that released by the LHRH agonists (Lupron). Lupron stimulates the release of the LH, and estrogens inhibit the release. Interestingly, the ultimate effect is the same—testosterone production is shut down.

You may have to try several of these treatments to find one that is effective in reducing your PSA.

Low-dose/high-dose ketoconazole

Ketoconazole (Nizoral) was actually developed as an antifungal agent. It shuts down adrenal gland production of hormones and steroids. It also inhibits the cytochrome P450 enzyme. High doses can cause fairly severe side effects (fatigue, nausea, liver damage), so it is often taken at a low dose. Even if the intention is to take a high dose, it is prudent to begin this drug at a low dose.

Recognize that different doctors have different dosing approaches, and the numbers presented here, may be somewhat different from what your own physician recommends.

According to the PDR, testosterone levels are “impaired with doses of 800 mg/day and abolished by 1,600 mg/day.” The Prostate Forum (Vol. 6, No. 4, April 2001) reports that 400 mg taken every 8 hours (1,200 mg/day) shuts down the production of the male sex hormone. Either of those numbers would be a high dose.

A recent paper described the regimen for low-dose (LDK) and high-dose (HDK) ketoconazole with hydrocortisone (Harris, K.A. et al., The Journal of Urology, 168, 542-545, Aug. 2002). They compared the results for patients given 200 mg t.i.d. with the HDK results. Side effects were similar, but the response rate was 46%, as compared with 63% for the HDK.

Whether you choose the high or the low dose, it is the experience of some of the members of the HRPCa support group that the side effects of nausea and fatigue can be minimized if you start at the low dose and move up gradually. Let your response to the drug be your guide in how low to start and how fast to move up.

The pills must be taken on an empty stomach, and they may be supplemented with an acidic drink (Coca Cola and most fruit juices ok; do not use grapefruit juice) to promote dissolution and absorption.

Ketoconazole shuts down the adrenal gland production of some glucocorticoids (steroid hormones) that are required. It is possible to get along at the dose of 400 mg t.i.d. without supplemental steroids. However, a mild deficiency of glucocorticoids will result in nausea and fatigue. Under severe stress, such a deficiency can become life threatening. The Prostate Forum recommends 20-40 mg of hydrocortisone b.i.d. (with food) to minimize the side effects. At the end of the treatment, it is important to taper off the hydrocortisone, reducing the daily dose, each day, by 5 mg. Be sure to monitor for possible liver damage. (See Chapter 18 for the pertinent diagnostic tests.) It is beneficial to take milk thistle extract to protect the liver.

Ketoconazole may also cause the strange side effect of “sticky skin.” This is apparently just annoying, not harmful. In general, individuals who have had difficulty with this drug have been able to resolve the problems by going temporarily to a lower dose.

Ketoconazole has a number of significant benefits in fighting HRPCa. It is reported to shrink tumors that are compressing the spinal cord. It will also reverse cancer-induced blood thinning. It suppresses cytochrome P450 in the liver; this chemical detoxifies drugs passing through the liver and reduces their efficacy. The implication of this is that if you are taking the oral drug Emcyt, for example, cytochrome P450 would destroy part of this drug as it passes through the liver. But with ketoconazole, the P450 enzyme is inhibited, and the drug operates at full strength. Ketoconazole also blocks the action of the MDR-1 gene, which causes much drug resistance in chemotherapy.

The actions of ketoconazole can be a two-edged sword. For example, the suppression of detoxifying cytochrome P450 helps drug effectiveness, but removes one of the body’s protective mechanisms against ingested toxins. You and your doc should examine this treatment and its potential carefully to get the most from it, while minimizing side effects.

Estrogenic compounds – DES, phytoestrogens

DES (diethylstilbestrol) is a synthetic estrogen. A recent review suggests a dose of 3 mg/day to suppress testosterone (Oh, W., First International Prostate Congress, June 27-30, 2001). A higher dose may result in cardiotoxicity. Due to the risk of blood clotting, DES would normally be administered with Coumadin, or another blood thinner.

DES, as a treatment for advanced prostate cancer, was first reported in 1941. In the 1980’s it was replaced by the LHRH agonists. With the continued efforts to fight HRPCa, DES has been rediscovered as an agent that will achieve responses even after the failure of CHT. The above review suggests that the discovery of a second estrogen receptor in prostate cells, as well as the high cost of LHRH agonists, is driving the renewed interest in DES. The same review reports response rates of 43, 66, and 79% for three studies (DES—1 and 3 mg--and Fosfestrol) with HRPCa patients.

The herbal remedy PC SPES is mentioned here only because it has been so widely used in the past. It contained phytoestrogens and was often effective in obtaining responses in PSA in HRPCa. It is no longer on the market, and no replacement has been identified at this time. Suffice it to say that phytoestrogens seem to have the ability to help suppress HRPCa.

Cytadren and Arimidex

Cytadren (aminoglutethimide) and Arimidex (anastrazole) are inhibitors of aromatase enzyme. This enzyme enables the conversion of androstenedione to testosterone in the prostate cells. And, of course, androstenedione is an androgen supplied by the adrenal glands. Thus, Cytadren and Arimidex have both been considered for second-line hormone therapy.

Although Arimidex seemed to have advantages over Cytadren, the referenced Prostate Forum reports on a study in which Arimidex was tested on HRPCa patients; they found “no meaningful anti-cancer activity.” Thus, Arimidex is eliminated from consideration.

In tests with HRPCa patients, responses were obtained for 20-30% in studies of aminoglutethimide administered with hydrocortisone. Since aminoglutethimide is ineffective at reducing the testosterone, the drug mechanism may be due to blocking of estrogen or even to the activity of the hydrocortisone.


Anti-estrogens

As we discussed earlier, cancer cells that become androgen-insensitive, may also become mutants that are stimulated by estrogens, instead of suppressed by them. In such a case, an anti-estrogen may be effective. If you should try an anti-estrogen and the PSA should continue to rise, it would be prudent to stop the drug quickly.

Anti-androgens

It has been shown that the anti-androgens may work a second time around, even after failing the first time. Look at the discussion of anti-androgens under Chapter 10, especially nilutamide (Nilandron).

Continue with Chapter 14