Hormone Therapy: Earlier is Better than Later

BY MARK SCHOLZ, MD

Prostate cancer is by far the most hormonally sensitive cancer. Practically all other types of cancer, except breast cancer, are totally immune to testosterone blockade. Just as normal cells need oxygen, prostate cells, cancerous or otherwise, depend on testosterone. Cells originating in the prostate are by nature very sensitive to testosterone blockade. This sensitivity can be exploited as a treatment. When a cancer cell is deprived of testosterone it initiates a suicide sequence called apoptosis. Low testosterone is acting like a signal, sending a biochemical message to the cell, telling it to release destructive intracellular enzymes, causing it to die.

Within a few months of blocking testosterone, cancer regression is usually dramatic. For example, one study used Zytiga prior to surgery. The surgically removed prostate glands were fine-sliced and examined under a microscope.  Some men showed no residual cancer in their prostates.

The testosterone inactivating pharmaceuticals (TIP) that block testosterone are listed below in order of ascending potency:

 

1.    5-alpha reductase inhibitors: Avodart (dutesteride), Proscar (finasteride):

2.    Anti-Androgens: Casodex (Bicalutamide), Eulexin (flutamide), Nilandron (nilutamide)

3.    Orchiectomy: Surgical removal of the testicles

4.    LHRH agonists and antagonists: Lupron, Zoladex, Eilgard, Firmagon

5.    Estrogen: Works basically the same way as #3, by suppressing luteinizing hormone (LH). In addition, however, there also may be some direct anticancer effects from estrogen.

6.    Cyp17 Inhibitors: Zytiga (abiraterone), Nizoral (ketoconazole):

7.    Multimodality androgen receptor inhibition: Xtandi (enzalutamide)

While categories 6 and 7 are clearly the most potent, as yet there is no conclusive evidence that either of these two categories is more potent than the other. However, a variety of studies have demonstrated that a combination of agents is more potent that agents used by themselves.

 

Also, a number of studies have shown that men live longer when they are treated with TIP at an earlier stage—that is, at the time of diagnosis—rather than at the time of relapse when the disease has become more entrenched:  In August 1997, The New England Journal of Medicine published a study comparing two groups of 200 men each, all of whom were treated with radiation for high grade prostate cancer (Gleason 8, 9, or 10 or a large tumor felt on digital rectal exam). The five-year death rate from prostate cancer was reduced by 80% in the men who received radiation plus TIP compared to radiation alone.

 

A study published in the British Journal of Urology in February 1997 looked at immediate TIP vs. starting TIP after the cancer was causing symptoms.  Two groups of 400 men were evaluated and compared. Mortality was 25% lower in the group that had early treatment.  A third study was published in the Journal of Urology in June 1998 in which ninety-one men were randomized between radiation alone and radiation with TIP.  The mortality rate was 50% less in the men that were treated with TIP.

 

Another famous study in New England Journal of Medicine authored by Dr. Messing in 1999 looked at the value of starting TIP right after surgery in a 100 men, all of whom had cancer confirmed to have spread into their lymph nodes. Half were randomly allocated to start TIP right after the operation.  The other half started TIP when they had disease recurrence and evidence of progression.  Seven years later the men treated with immediate TIP were eight times less likely to have died of prostate cancer: Two men treated with immediate TIP died of prostate cancer whereas 17 men treated with delayed TIP died of prostate cancer.

 

In this last study TIP was continued for life. Since we know that TIP has more side effects when administered over a longer period, one can’t help but wonder if the same survival advantage could have been achieved with a shorter treatment period, say for two years?

 

The side effects of TIP can indeed be troublesome, especially the lowering of libido.  In our experience 70% of men under age 60 and 90% of men over age 65 lose sexual desire completely—particularly if they are treated with drugs in category three or higher. Category two and category one drugs cause loss of libido in about 50% and 25% of men respectively.

 

It is important to make one thing clear: Libido is not a euphemism for getting an erection. Viagra is powerful enough to restore erections in most men on TIP. Loss of libido means undergoing a loss of sexual interest. After TIP is stopped, younger men recover libido quite nicely though a minority describe their libido as persistently diminished. Some men, particularly the older ones, are more likely to have a persistent reduction in libido.

 

The list of potential side effects from TIP (besides libido problems) is long. Most of the side effects are manageable with expert supervision. Please inquire about a copy of Preventing the Side Effects of TIP for further details. Using a category two drug like Casodex is one way to reduce TIP’s side effects. However, using a less potent agent raises another concern: Some studies have shown reduced anticancer efficacy. Clearly treatment selection depends on weighing the intensity of potential side effects against the expected survival benefit. In some cases, slightly diminished anticancer efficacy may be an acceptable tradeoff if side effects can be substantially reduced.

 

Prostate cancer’s Achilles heel is that it can’t survive without testosterone. While anti-testosterone medications have remarkable anticancer efficacy they can also cause notable side effects. Treatment intensity and timing needs to be varied in accordance with each patient’s individual characteristics.