Introduction to Hormone Therapy for Prostate Cancer

BY MARK SCHOLZ, MD

Testosterone is the primary male hormone. It comes mostly from the testicles and to a lesser degree, from the adrenal glands. Testosterone causes the common male characteristics such as bigger muscles, facial hair growth and increased sex drive. Testosterone is also essential for prostate cancer to grow.

 

Why Blocking Testosterone Kills Prostate Cancer

The prostate gland, located near the bladder, makes semen. Prior to puberty the gland is only the size of a peanut. However, when the testicles begin making testosterone, the prostate comes to life and grows to the size of a walnut. The cells of the prostate, therefore, require testosterone to proliferate. Since prostate cancer originates from the prostate gland, the cancer also depends on testosterone.

 

Hormonal therapy works by blocking testosterone. When prostate cancer cells are deprived of testosterone they commit suicide in a cell death process called apoptosis.  The amount of cell death in early-stage prostate cancer is usually dramatic.  Not uncommonly, when men are pretreated with potent forms of hormonal therapy, there is no residual cancer after surgery. More typically, there is a dramatic reduction in the number of cancer cells, but not total elimination of the cancer.

 

The mechanism for testosterone to stimulate cancer growth occurs through the activation of a multifaceted protein called the androgen receptor.  Before binding with testosterone the androgen receptor is inactive. Once the receptor comes into contact with testosterone, the activated androgen receptor is transported into the nucleus of the cell where it stimulates DNA.  As a result, a plethora of cell-growth-enhancing proteins are synthesized that stimulate cancer growth and progression.

Hormone Therapy Comes in Many Form
Prior to the advent of modern medications, hormone blockade was accomplished by surgical castration. These days, testosterone is blocked with shots or pills. Agents that block testosterone by inhibiting the pituitary gland are Lupron, Zoladex, Firmagon, Eligard and Trelstar.  Medications that work by interposing themselves between testosterone and the androgen receptor to block its activation are Casodex, Nilutamide or Flutamide.  A third milder type of hormonal agent, the 5-alpha-reductase inhibitors, such as Avodart and Proscar, work by inhibiting the chemical conversion of testosterone into its more potent form, dihydrotestosterone (DHT).

Recently the FDA approved two new, and more potent, hormonal agents, Zytiga and Xtandi. Their increased anticancer efficacy was demonstrated through prolonged survival in men whose cancer became resistant to Lupron. Zytiga and Xtandi work by different mechanisms. Zytiga inhibits cancer cells from making their own testosterone. Xtandi works by blocking the activity of the androgen receptor.

The Nitty Gritty of Treatment Selection
The most potent anticancer action is achieved through complete blockade with agents from different functional classes administered together for a prolonged period of time. Therefore, the variables that affect the intensity of hormone blockade treatment are:  1. the type of medicine; 2. how many medicines are used; and 3. how long the medications are continued.  Of course, medical skill and experience is required to fine-tune the selection and duration of therapy.  Nevertheless, here is a brief presentation of some rough guidelines.
 

1.    A short course, say three to four months, to shrink the prostate or to improve cure rates in men with intermediate-risk disease (Teal Shade of Blue) undergoing radiation

2.    A short course of four months to improve cure rates with radiation in men with intermediate-risk disease (Teal Shade of Blue)

3.    An intermediate course (6-12 months) for treatment for intermediate-risk disease (Teal Shade of Blue) as a sole form of therapy

4.    A long course (18-24 months) to improve cure rates in men with high-risk (Azure Shade of Blue) prostate cancer undergoing radiation

5.    An intermediate to long course in conjunction with radiation to improve cure rates in men with a rising PSA after surgery (Indigo Shade of Blue) who are undergoing salvage radiation

6.    Intermittent use to suppress a rising PSA after surgery or radiation (Indigo Shade of Blue)

7.    Intermittent or continuous use to treat men with metastatic disease (Royal Shade of Blue)

8.    Salvage treatment with Xtandi or Zytiga to control disease in men on Lupron who have progressive disease (Royal Shade of Blue) 

Over the last ten years the medical community has been roiled by the discovery that some forms of prostate cancer are truly harmless, raising a serious concern about men receiving surgery and radiation they don’t need. However, overtreatment with hormone therapy also occurs. The overriding goal is to use a hormone therapy approach that achieves a maximum anticancer benefit while minimizing side effects as much as possible. Treatment always has to be personalized so the intensity and duration of treatment is appropriate for each individual’s specific situation.