Are there different types of hormone therapy Do I need to have my testicles removed

Hormone therapy is a form of prostate cancer treatment designed to eliminate the male hormones (androgens) from the body. The most common androgen is testosterone. Androgens are primarily produced by the testicles, under control of various parts of the brain. A small number of androgens are produced by the adrenal glands, which are small glands located above the kidneys and produce many important chemicals. Prostate cancer cells may be hormone sensitive, hormone insensitive, or hormone resistant. Cancer cells that are hormone sensitive require androgens for growth. Thus, elimination of the andro-gens would prevent the growth of such cells and cause them to shrink. Normal prostate cells are also hormone sensitive and also shrink in response to hormone therapy. Prostate cancer cells that are hormone resistant continue to grow despite hormone therapy.

Hormone therapy is not a curative therapy because it does not eliminate the prostate cancer cells; rather, it is palliative in that its goal is to slow down the progression, or growth, of the prostate cancer. Hormone therapy for patients with metastatic disease may work effectively for several years; however, over time, the hormone-resistant cells will emerge, and the cancer will grow.

Hormone therapy may be used as a primary, secondary, or neoadjuvant therapy. Hormone therapy is often used as a primary therapy in older men who are not candidates for surgery or radiation therapy and who are not interested in watchful waiting. It is also used in men who have metastatic disease at the time that their prostate cancer is detected. Men who experience a rise in their PSA after radical prostatectomy, radiation therapy, or

Testosterone

The male hormone or androgen that is produced primarily by the testes and is needed for sexual function and fertility.

Neoadjuvant therapy

The use of a treatment, such as chemotherapy, hormone therapy, and radiation therapy, before surgery.

Hormone therapy is often used as a primary therapy in older men who are not for surgery or radiation therapy and who are not interested in watchful waiting.

cryotherapy are given hormone therapy to slow down the growth of the recurrent prostate cancer. Lastly, hormone therapy may be given for a period of time before radical prostatectomy or radiation therapy to shrink the prostate gland and make the procedure easier to perform (neoad-juvant therapy). It is unclear whether this type of therapy affects the time to disease progression or survival. However, neoadjuvant therapy has a significant impact on the pathology, such that it is very difficult for the pathologist to grade the cancer cells after 3 months of hormone therapy.

In men with recurrent prostate cancer after EBRT or radical prostatectomy or in those who do not have organ-confined prostate cancer at the time of diagnosis, the time at which hormone therapy should be started is not clear. For this reason, one must weigh the potential benefits and side effects of hormone therapy. Hormone therapy may delay disease progression, but its effect on survival does not appear to be significant. In one study in men with prostate cancer, delaying hormone therapy for 1 year was associated with an 18% increase in the risk of death due to prostate cancer. Although this was a large study, it is still only one study, and more information is needed.

Many different forms of hormone therapy exist, both surgical therapy and medical therapy. The surgical approach

Orchiectomy is a bilateral orchiectomy, whereby the main source of

Removal of the androgen production, the testicles, are removed.

testicle(s).

Bilateral orchiectomy is performed in men with prostate cancer to remove most of the testosterone production. Typically, this procedure can be performed as a minor surgical procedure under local anesthesia.

The advantages of bilateral orchiectomy are that it causes a quick drop in the testosterone level (the testosterone level drops to its lowest level by 3 to 12 hours after the procedure [average is 8.6 hours]), it is a one-time procedure, and it is more cost effective than the shots, which require several office visits per year and are more expensive. The disadvantages of orchiectomy are those of any surgical procedure and include bleeding, infection, permanence, and scrotal changes. In men who have undergone bilateral orchiec-tomy and are bothered by an empty scrotum, bilateral testicular prostheses may be placed that are the same size as the adult testes. Most men who undergo bilateral orchiectomy lose their libido and have erectile dysfunction after the testosterone level is lowered. Other long-term side effects of bilateral orchiectomy, related to testosterone depletion, include hot flashes, osteoporosis, fatigue, loss of muscle mass, anemia, and weight gain.

Medical therapy is designed to stop the production of androgens by the testicles. The three types of medical therapies are luteinizing hormone-releasing hormone (LHRH) analogues, antiandrogens, and gonadotropin-releasing hormone (GnRH) antagonists. These prevent the action of testosterone on the prostate cancer and on normal prostate cells (antiandrogen), or prevent the production of adrenal androgens.

Luteinizing Hormone-Releasing Hormone Analogues

The brain controls testosterone production by the testicles. Leuteinizing hormone-releasing hormone analogues are chemicals that stimulate the production of the luteinizing hormone, which tells the testicles to produce testosterone. Initially, when a man takes an LHRH analogue, there is an increased production of LH and of

Flare reaction

A temporary increase in tumor growth and symptoms that is caused by the initial use of LHRH agonists. It is prevented by the use of an antiandrogen one week before LHRH agonist therapy begins.

testosterone. This superstimulation tells the brain to stop producing LHRH and, subsequently, the testicles stop producing testosterone. It takes about 5 to 8 days for the LHRH analogues to drop the testosterone levels significantly. The increase in testosterone that sometimes occurs initially with LHRH analogues may affect patients with bone metastases, and there may be a worsening of their bone pain, which is called the flare reaction. Such men with metastatic disease will be given an antiandrogen before starting the LHRH analogue to prevent the flare phenomenon.

LHRH analogues are given as shots either monthly, every 3 months, every 4 months, every 6 months, or yearly. There are six forms of LHRH analogues: leuprolide acetate for intramuscular injection (Lupron Depot), triptorelin pamoate suspension for intramuscular injection (Trelstar Depot and Trelstar LA), leuprolide acetate for subcutaneous injection (Eligard), leuprolide acetate subcutaneous implant placement (Viadur), histrelin acetate for subcutaneous implant (Vantas), and goserelin acetate implant (Zoladex). They work in essentially the same way but differ in how they are given (Table 8). The advantage of this form of therapy is that it does not require removal of the testicles; however, it is expensive and requires more frequent visits to the doctor's office.

Intermittent hormone therapy is an alternative to standard hormone therapy. With intermittent hormone therapy you are treated for a period of time, usually until your PSA drops to a certain level, then the hormones are stopped until your PSA rises to a certain level. The idea of intermittent hormone therapy is that the prostate cancer cells that survive while you are on hormone therapy (hormone insensitive) become hormone sensitive again when they are exposed to androgens.

Table 8 Commonly Used Antiandrogens, LHRH Analogues and Antagonists

Agent

Dose

Route of Administration

Action

Side Effects

/O

Lupron Depot (leuprolide

7.5 mg/mo

IM

LHRH analogue

Impotence, decreased libido,

acetate for depot injection)

22.5 mg/3 mos

osteoporosis, anemia, hot

30 mg/4 mos

flashes, weight gain, fatigue,

o

flare phenomenon

Eligard (leuprolide acetate for

7.5 mg/mo

sa

LHRH analogue

Same as Lupron

^

injectable suspension)

22.5 mg/3 mos

30 mg/4 mos

45 mg/6 mos

s

Trelstar Depot/LA (triptorelin

3.75 mg/mo

IM

LHRH analogue

Same as Lupron

OO

pamoate injectable suspension)

11.25 mg/3 mos

CO

Vantas (histrelin acetate

50 mg/yr

sa

LHRH analogue

Same as Lupron

O

implant)

S

Viadur (leuprolide acetate)

65 mg/yr

SQ_implant—requires

LHRH analogue

Same as Lupron

incision for placement

Zoladex (goserelin)

3.6 mg/mo

sa

LHRH analogue

Same as Lupron

10.8 mg/3 mos

('Continued)

Table 8 Commonly Used Antiandrogens, LHRH Analogues and Antagonists (Continued)

Agent

Dose

Route of Administration

Action

Side Effects

Firmagon (degarelix)

240 mg given as two injections of 120 mg each as initial dose followed 28 days later by maintenance dose of 80 mg Q28 days

sa

LHRH antagonist

Injection site reactions, hot flash, impotence, weight gain, fatigue, increase in transaminases, HTN, chills

Eulexin (flutamide)

750 mg/day

PO

Antiandrogen

Breast tenderness and enlargement, hot flashes, diarrhea, anemia, abnormal liver function

Nilandron (nilutamide)

300 mg/day 3 3 1 mo

PO

Antiandrogen

Same as with Eulexin. Also, reversible lung disease, alcohol intolerance, decreased night vision

Casodex (bicalutamide) comb rx

50 mg/day

PO

Antiandrogen

Same as with Eulexin

Abbreviations: mos, months; PO, orally; SQj subcutaneously; comb rx, combination treatment; IM, intramuscularly.

Abbreviations: mos, months; PO, orally; SQj subcutaneously; comb rx, combination treatment; IM, intramuscularly.

Possible advantages of intermittent androgen suppression include preservation of androgen sensitivity of the tumor, possible prolonged survival, improved quality of life because of recovery of libido and potency and improved sense of well-being, decrease in treatment costs, increased sensitivity of the prostate cancer to chemotherapy, and the fact that it can be used to treat all stages of prostate cancer. Intermittent hormone therapy appears to affect bone mineral density loss at 6 years.

The long-term effects of intermittent hormone therapy are not well known. The duration of the hormone therapy, the best time to restart hormone therapy, how to tell whether the disease is progressing, and who is the ideal patient for intermittent hormone therapy are not well defined. One potential way to give intermittent androgen suppression therapy (androgen blockade) is shown in Table 9.

LHRH analogues often are used alone as primary, secondary, or neoadjuvant therapy. Over time, the PSA level may increase. When the PSA increases, your doctor may check your serum testosterone level to make sure that the LHRH analogue is dropping the testosterone level to almost undetectable levels. In some cases with use of the LHRH analogue on an every-3-to 4-month basis, the testosterone suppression may not be adequate, and switching to a more frequent dosing interval, such as an every 28-day formulation, may be more effective. When a man is receiving hormone therapy, the testosterone level should be < 20 ng/dL. When the PSA increases despite LHRH analogues, the LHRH analogues are continued, and another medication, an antiandrogen, is added. This combined therapy is called

100 QUESTIONS AND ANSWERS ABOUT MEN'S HEALTH Table 9 Intermittent Androgen Blockage

Continue on therapy for an average of 9 months

Discontinue medications

Watch until PSA increases to mean of 10-20 ng/mL

Resume total androgen blockade

Continue cycling until regulation of PSA becomes independent of total androgen blockade

Ellsworth, P. 100 Questions and Answers About Prostate Cancer, 2e. Jones and Bartlett Publishers, LLC, 2009.

total androgen blockade and is often effective in treating the prostate cancer for 3 to 6 months.

Antiandrogen

Drugs that counteract the action of testosterone.

Antiandrogens

Antiandrogens are receptor blockers; they prevent the attachment of the androgens, both those produced by the testicles and those produced by the adrenal glands, to the prostate cancer cells, thus preventing them from acting on these cells. Because these chemicals do not actually affect testosterone production, the testosterone level remains normal or may be slightly elevated if they are used alone. Thus, these medications do not affect libido or erectile function when used alone. However, antiandrogens are more commonly used in combination with LHRH analogues. One antiandrogen, bicalu-tamide (Casodex) is approved for use as a monotherapy in Europe but has not been approved by the FDA.

There are three commonly used antiandrogens. bicalu-tamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron) (Table 8). As with all medications, these have side effects, which are listed in Table 8. When antiandrogens are used in combination with LHRH analogues, this is called total androgen blockade. Total androgen blockade is used for individuals whose PSA increases significantly while they are taking LHRH analogues.

Newer Therapies

Aberelix is a GnRH antagonist. Unlike the LHRH agonists, the GnRH antagonist does not initially cause an increase in testosterone level. Instead, it works to decrease testosterone more quickly. Aberelix can cause serious and life-threatening allergic reactions and therefore it is no longer available for use in the treatment of prostate cancer. Patients who have been previously prescribed by doctors enrolled in a special program, the Plenaxis PLUS Program, can continue to receive Aberelix as long as they continue to do well with the medication.

Degarelix is an LHRH antagonist which has been demonstrated in clinical trials to rapidly decrease serum testosterone (within 3 days) and is not associated with the initial surge of testosterone and risk of flare that is seen with LHRH agonists. It has been recently approved by the FDA. The starting dose is 240 mg given as two subcutaneous injections of 120 mg, then maintenance doses of 80 mg as one subcutaneous injection every 28 days. Phase III studies have demonstrated that degarelix is at least as effective as leuprolide (Lupron Depot®) in sustaining castrate levels or lower of testosterone and had a statistically significant faster decrease in testosterone levels.

Total androgen blockade

The total blockage of all male hormones (those produced by the testicles and the adrenals) using surgery and/or medications.

GnRH antagonist

A form of hormone therapy which works at the level of the brain to directly suppress the production of testosterone without initially raising the testosterone level.

Degarelix is an LHRH antagonist which has been demonstrated in clinical trials to rapidly decrease serum testosterone (within 3 days) and is not associated with the initial surge of testosterone and risk offlare that is seen with GnRH agonist.

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