Intermittent Androgen Deprivation Therapy for Treatment of

Intermittent Androgen Deprivation Therapy for Treatment of Prostate Cancer – What are the Benefits?

Release Date: 08/05/2011

Expiration Date: 08/05/2014

FACULTY:

Juli Aistars, RN, MS, AOCN, APN Prostate Nurse Navigator, Northwest Community Hospital Arlington Heights, IL

FACULTY AND ACCREDITOR DISCLOSURE STATEMENTS:

Juli Aistars has no actual or potential conflict of interest in relation to this program.

ACCREDITATION STATEMENT:

Pharmacy PharmCon Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Program No.: 0798-0000-11-052-H01-P Credits: 1 contact hour, 0.1 CEU

Nursing

Pharmaceutical Education Consultants, Inc. has been approved as a provider

of continuing education for nurses by the Maryland Nurses Association which is

accredited as an approver of continuing education in nursing by the American

Nurses Credentialing Center’s Commission on Accreditation.

Program No.: N-682

Credits: 1 contact hour, 0.1 CEU

TARGET AUDIENCE:

This accredited program is targeted to pharmacists and nurses practicing in hospital and community pharmacies. Estimated time to complete this monograph and posttest is 60 minutes.

DISCLAIMER:

PharmCon, Inc does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources.

Program Overview:

To provide Pharmacists and Nurses with an understanding of Androgen Therapy and its relation to Prostate Cancer treatment.

OBJECTIVES:

After completing this program, participants will be able to:

1. Review the etiology and epidemiology of prostate cancer.

2. Outline the types of androgen deprivation therapy

3. Describe androgen deprivation therapy to include mechanism of action, side

effects and means to mitigate the side effects

Aistars – Androgen Therapy Page 1

Intermittent Androgen Deprivation Therapy for Treatment of Prostate Cancer –

What are the Benefits?

Juli Aistars, RN, MS, AOCN, APN

Prostate Nurse Navigator, Northwest Community Hospital

Arlington Heights, IL

Mr. Q is a 74 year old man with a history of prostate cancer diagnosed 2 years ago after his PSA

increased from 5.67 to 11.6 over one year. It was high-grade with a Gleason of 5+4 present in

both lobes and with extracapsular extension (locally advanced). He has a history of coronary

artery disease and atrial fibrillation. After a bone and CT scan were negative for metastases, he

received intensity modulated radiation therapy to the prostate, seminal vesicles and adjacent

pelvic nodes. He was also started on post-radiation androgen deprivation therapy (ADT). He was

exercising daily before treatment but has decreased that to two days a week because of the

fatigue. He experienced the side effects of fatigue, weight-gain, hot flashes, and decreased libido

from ADT. He had done his own research and wanted to know if he was a candidate for

intermittent ADT to decrease side effects and decrease his out-of-pocket cost. He had missed his

last ADT injection because he was considering stopping it altogether because of how it was

affecting his life. In this paper, the questions below will be addressed and related specifically to

Mr. Q’s situation.

1. What are the indications for ADT in prostate cancer?

2. What are the possible side effects of ADT?

3. Can side effects be mitigated with intermittent androgen deprivation therapy (IAD)?

4. Is adherence to ADT increased with IAD?

5. Is long-term survival compromised with IAD?

Introduction

About 230,890 new cases of prostate cancer will occur in the US alone during 2011. The number

of deaths predicted in 2011 is 33,720, making it the second leading cause of cancer death in men.

Besides skin cancer, it is the most frequently diagnosed cancer in men.1


Because prostate cancer is being detected earlier with the advent of the PSA test in the 1990s,

more men are surviving prostate cancer. In North America, there are approximately 2 million

men who are surviving after a diagnosis of prostate cancer. Of these, 700,000 are either

chemically or surgically castrated (suppression of testosterone). At the current rate of detection

of prostate cancer, it is possible that as many as 4% of Caucasian men may eventually be treated

with chemical or surgical castration.2 The focus on quality of life in these men is becoming

increasingly more important, since they may be living with the side effects for many years.

Surgical castration is removal of the testicles to interrupt the production of testosterone.

Chemical castration, which is the focus of this paper, is accomplished by various forms of

androgen deprivation therapy. This treatment can be used continuously or intermittently (on-

again, off-again). The idea behind intermittent therapy is the potential for delaying progression to

androgen independence (hormone resistant prostate cancer), as well as improving quality of life.

There is some evidence that Intermittent Androgen Therapy can reverse anemia and also reduce

the risk of diabetes and cardiovascular disease caused by continuous androgen deprivation

therapy.3

Definition of Androgen Deprivation Therapy (ADT)

Prostate cancer growth is dependent on androgens (male hormones). In men, androgens are

produced by the testes and by the adrenal glands. The testes are the main source of testosterone,

while the rest of the androgens produced by the adrenal glands are precursors that are converted

to testosterone and dihydrotestosterone in prostatic and peripheral tissues. Hormone therapy for

prostate cancer does not mean adding hormones but depriving the cancer of androgens so that

growth of the cancer is slowed down.4

Mechanism of Action

There are various means of chemical castration, the most common being suppression of the

release of luteinizing hormone from the anterior pituitary. Other hormonal interventions for


prostate cancer cause depletion of androgens by inhibition of adrenal androgen synthesis. The

mechanism for suppression is by direct inhibition of the androgen receptor, 5 alpha reductase,

which converts testosterone to dihydrotestosterone (DHT).

Indication for ADT in Prostate Cancer

ADT, either surgical or medical, is the frontline treatment for advanced prostate cancer to slow

down the spread of cancer cells to distant sites (secondary or adjuvant therapy). It can be carried

out by surgical or medical castration as outlined above. Medical ADT may be used in localized

prostate cancer to shrink the prostate and the tumor before a procedure to reduce the likelihood

of spread or as an adjunct to radiation therapy for high-risk localized disease (neoadjuvant

therapy) and to ease pain caused by the spread of cancer (palliative). Of the 2 million men with

prostate cancer in the United States, over one-third have received ADT treatment.5

Types of ADT6

Surgical castration

Orchiectomy – surgical removal of the testicles, where more than 90% of the androgens,

mostly testosterone, are produced. Most prostate cancers will stop growing and shrink

once the source of androgens is removed. An orchiectomy is an outpatient procedure and

is the least expensive type of ADT. The disadvantage is that it is permanent, and it is

psychologically difficult for most men.

Chemical castration

Luteinizing hormone-releasing hormone (LHRH) analogs, also called LHRH agonists or

GnRH agonistsThese agents are expensive and require more frequent physician visits.

The advantage is that the testicles will remain in place, although they will shrink over

time. These agents interfere with the release of follicle-stimulating and luteinizing


hormone from the pituitary gland and reduce the production of testosterone from the

testes.

LHRH analogs are injected or placed as small implants under the skin. They can be given

from once a month up to once a year. The agents available in the U.S. are leuprolide

(Lupron®, Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®), and

histrelin (Vantas®). When treatment is started, testosterone production increases or flares

briefly before falling to low levels. This effect is called a tumor flare. It can cause

complications like increased bone pain or spinal compression, depending on if bone

metastases are present. Flare can be mitigated with drugs called anti-androgens given for

a few weeks when starting treatment with LHRH analogs.

Luteinizing hormone-releasing hormone (LHRH) antagonists

Degarelix (Firmagon®) was approved in 2008 to treat advanced prostate cancer. It is

administered as a monthly injection subcutaneously, and it rapidly reduces testosterone

levels. It directly inhibits gonadatropin releasing hormone activity which leads to

decreased testosterone production.

Anti-androgens – block testosterone production by the adrenal glands but do reduce the

patient’s testosterone level.

Flutamide (Eulexin®), bicalutamide (Casodex®) and nilutamide (Nilandron®) are pills

taken orally on a daily basis. These agents have not typically been used alone, but anti-

androgen monotherapy is being studied since this agent does not have as many side

effects as some of the other types of ADT and can be just as effective. An anti-androgren

may be added if orchiectomy or an LHRH analog is no longer effective. It can also be

given for just a few weeks when an LHRH analog is first started to prevent a tumor flare.

It can also be combined with orchiectomy or LHRH analogs as first-line hormone therapy

(combined androgen blockade or CAB). There have been some studies evaluating the use

of anti-androgens alone. The results have shown no difference in survival rate or a slight

disadvantage.


Other androgen-suppressing drugs include ketoconazole (Nizoral®) and

aminoglutethamide (Cytadren®). These agents prevent testosterone from binding to its

receptor rather than reducing the testosterone level. Since they decrease cortisol levels,

hydrocortisone is taken along with these two agents to prevent the side effects caused by

low cortisol levels.

An estrogen-like drug called Diethylstilbestrol (DES) was used formerly in hormone

blockade. Its use was discontinued because of severe side effects.

CAB or Combined Androgen Blockage – An LHRH agonist is combined with an oral

anti-androgen.

Potential Side Effects

ADT is associated with several possible side effects. The decline in testosterone that is

accomplished by ADT is accompanied by a decrease in serum estrogen because testosterone is

converted to estradiol by the enzyme aromatase in peripheral tissue. Estrogen also serves a

distinct function in male physiology. The decrease in both of these hormones is responsible for

the side effect profile. The known adverse effects are as follows:7

Decreased testosterone is mainly responsible for the following effects:

Increased fat mass and decreased lean body mass

Insulin-resistance/diabetes

Loss of libido/erectile dysfunction

Decreased estrogen is responsible for the following effects:

Decreased bone density and fracture risk

Altered lipid profile and cardiovascular risk

Vasomotor symptoms similar to the postmenopausal state in women such as hot

flashes

Gynecomastia


Other reported symptoms include:

Fatigue

Anemia

Cognitive Dysfunction

Depression

The above adverse effects can range from a minor annoyance to more serious symptoms that can

decrease quality of life. They can also be life-threatening, such as increased risk of

cardiovascular disease. A recent study by Keating et al8 and Saigal et al

9 used retrospective data

to show that LHRH agonist use was associated with a 16% and 20% risk of cardiovascular

morbidity, respectively. A meta-analysis by D’Amico et al,10

found that 6 months of ADT in

men over age 65 was associated with about a 2 year earlier onset of fatal myocardial infarction

compared with men of the same age who were not treated with ADT. Other studies have not

supported this conclusion.11

By suppressing testosterone levels, lean body mass is decreased and fat mass is increased within

months of starting treatment. These side effects, along with insulin-resistance, and increased

serum cholesterol and triglycerides can be grouped under the entity called “metabolic

syndrome”. Metabolic syndrome is associated with an increased risk of developing diabetes,

cardiovascular disease, and fatty liver. There have been a number of studies, as summarized by

Jefferies et al,11

that have supported the association between ADT and these adverse effects.

History and Evolution of ADT and Intermittent Androgen Deprivation Therapy (IAD)

ADT is not a new treatment for prostate cancer. It has been one of the main treatments used in

the clinical management of prostate cancer patients for more than 60 years. In 1941, surgical

castration was first shown to improve prostate cancer outcomes. Luteinizing hormone-releasing

hormone agonists (LHRH) also known as gonadotropin-releasing hormone agonists (GnRH),

which reduce testosterone to castration levels, were discovered in 1971 and introduced in the

1980s. Nonsteroidal antiandrogens were developed after the 1980s. A combination of surgical or


medical castration and oral antiandrogens is another treatment approach that developed since the

1980s.4,12

Because of the cost and toxicities that come with long-term androgen deprivation, hormone

therapies with less negative impact on body composition and quality of life would benefit

patients. Some of the novel treatments that have been developed are antiandrogen monotherapy

and intermittent androgen deprivation therapy (IAD).

IAS was developed with the goal of delaying hormone resistance, decreasing side effects and

enhancing antitumor efficacy. IAD alternates androgen blockade with stopping treatment to

allow hormonal recovery between cycles. It can be viewed as an on-again, off-again treatment.

ADT continues until PSA reaches a low point, is then discontinued, allowing serum testosterone

to increase to normal levels. Once PSA rises to a predetermined level, treatment is restarted.

Men are being diagnosed with prostate cancer at younger ages, which is the main impetus for

investigating IAD. If ADT is part of their treatment, they could be exposed for many years. The

short and long-term side effects and risks associated with ADT can have a significant impact on

quality of life. Early studies provide some evidence that sexual dysfunction could be improved

with no adverse effects on survival. IAD has potential advantages over ADT.12

Basic Review of Research Evidence

The first study on IAD was published in 1986. Twenty patients who wanted to discontinue ADT

agreed to IAD as an alternative. They were treated with diethylstilbestrol, an agent that is no

longer used because of the severity of side effects. They received diethylstilbestrol for a time

period ranging from 2 months to 5 years. Therapy resumed when there were signs of disease

progression since there was no PSA test at that time. The disease progressed after a median

period of 8 months and 9 of 10 patients who were impotent due to DES resumed sexual activity

during the period off ADT.13


In a comprehensive review of phase II and III studies evaluating IAD, Abrahamssom13

reviewed

19 phase II and eight phase III studies. ADT was well tolerated in the phase II studies with

decreased side effects and improved quality of life during the off-treatment period of time.

Improvement of sexual activity was noted in several studies. Two of the studies found no

significant improvement in quality of life factors on or off treatment. These trials have shown

potential benefits of IAD in various patient groups, but they did not answer questions about

survival, percentage of responders and which patients are most likely to benefit from IAD.

In the Abrahamsson review, the key conclusions cited from the phase III trials evaluated are:

Data was too limited to draw conclusions about cycle length.

In both phase II and III trials, the PSA level at which treatment was stopped was usually

< 4 ng/ml, and reinitiated either at >10 or >20 ng/ml.

One meta-analysis showed that reinitiation of therapy at <15 ng/ml had a significant

positive impact on 5-year survival and androgen independence compared to reinitiation at

> 15 ng/ml.

Early phase III results evaluating survival benefits are limited and inconsistent.

Early phase III results suggest a better tolerability profile and improved quality of life

with IAS than with continuous therapy, especially sexual function.

There is insufficient data to show that IAS can prevent or reverse the long-term

complications of ADT.

At the 2011 Genitourinary Cancer Symposium in Orlando, Florida, Dr. Laurence Klotz MD

reported that in a Phase III study of about 1,400 men, the median overall survival time of 9.1

years for those treated with continuous hormone therapy was not significantly different than the

8.8 year overall survival for men randomized to IAD. Dr. Klotz is Chief of Urology at

Sunnybrook Health Sciences Centre and Professor of Surgery at the University of Toronto.14

Based on the evidence available, intermittent ADT is gaining momentum as a valid treatment in

patients with locally advanced prostate cancer with or without lymph node involvement and

those experiencing relapse following curative treatment. However, The American Urological

Association does not include IAS in its 2007 treatment guidelines for prostate cancer. 12


Based on available research evidence, Mr. Q is an appropriate candidate for IAS, especially

considering his non-adherence to continuous ADT because of the side effects. Because of the

association between ADT and cardiovascular disease, The American Heart Association

recommended that the treating physician weigh the risks against the benefits of ADT. There is no

recommendation concerning patients who already have cardiovascular disease before starting

ADT.11

Mr. Q did have pre-existing cardiovascular disease before the start of treatment, but he

has an aggressive prostate cancer which will metastasize without treatment. His cardiovascular

disease may be another reason to consider intermittent rather than continuous ADT. After 8

months off treatment, Mr. Q’s PSA is still less than 4. His fatigue has decreased and his exercise

tolerance and libido have improved.

One group of patients who stands to benefit from IAD is those who are not adhering to treatment

with continuous ADT because of unacceptable side effects, like Mr. Q. Because the evidence is

not strong enough at this point to make a clear recommendation, it should be used selectively and

not as a standard treatment approach. Logically, you would expect side effects to decrease when

there is no exposure to the agent, but the cost of this in terms of long-term survival has not been

well-established by the current research. There is more research being conducted on innovative

approaches to ADT that would preserve quality of life without adversely affecting survival.


References

1. Abrahamsson, P. “Potential benefits of intermittent androgen suppression therapy in the

treatment of prostate cancer: a systematic review of the literature.” European Urology 57

(2010):49-59.

2. American Cancer Society. “Cancer Facts & Figures 2011.” (2011) Atlanta: American

Cancer Society.

3. Bruchovsky, N, Klotz, L, Crook, J, et al. “Quality of life, morbidity, and mortality results

of a prospective phase II study of intermittent androgren suppression for men with

evidence of prostate-specific antigen relapse after radiation therapy for locally advanced

prostate cancer.” Clinical Genitourinary Cancer. March (2008):46-52.

4. D’Amico AV, Denham, JW, Crook, J, et al. “Influence of androgen suppression therapy

for prostate cancer on the frequency and timing of fatal myocardial infarctions.” Journal

of Clinical Oncology 25 (2007):2420-2425.

5. Hiroyoshi S, Kamiya N, Imamoto T, et al. “Current topics and perspectives relating to

hormone therapy for prostate cancer.” International Journal of Clinical Oncology.

13(2008):401-410.

6. “Hormone (androgen deprivation) therapy.”

http://ww.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-

hormone-therapy. n. pag. Web 1 July 2011

7. Jefferies, ER, Thurairaja, R, Persad, RA, et al. “Don’t think twice! The cardiovascular

effects of androgen deprivation therapy.” BJU Int. 107 (2011):1023-1028.

8. Keating NL, O’Malley, AJ, Smith, MR. “Diabetes and cardiovascular disease during

androgen deprivation therapy for prostate cancer.” Journal of Clinical Oncology 24

(2006):4485-4456.

9. Kim, HS and Freedland, SJ. “Androgen deprivation therapy in prostate cancer:

anticipated side-effects and their management.” Current Opinions in Supportive

Palliative Care 4(2010):147-152.

10. Klotz LH, Herr HW, Morse MJ, et al. “Intermittent endocrine therapy for advanced

prostate cancer.” Cancer (1986):8,2546-2550.

11. Laino, Charlene. “Prostate cancer: documented now that use of intermittent androgen

suppression does not compromise survival.” Oncology Times. 33(8): 21-22 Web 1 June


2011.

http://journals.lww.com/oncology-imes/Fulltext/2011/04250/Prostate_

Cancer__Documented_Now_that_Use_of.3.aspx

12. Langley, R, Price, Pollock, P and Abel PD. “Osteoporosis in patients with prostate cancer

on long-term androgen deprivation therapy: An increasing but under-recognized

problem.” BJU Int. Letters. 106(2010):726-727.

13. Saigal CS, Gore, JL, Krupski, TL, et al. “Androgen deprivation therapy increases

cardiovascular morbidity in men with prostate cancer.” Cancer 110 (2007):1493-1500.

14. Sharifi N, Gulley JL, and Dahut W L. “An update on androgen deprivation therapy for

prostate cancer. Endocrine-Related Cancer.” 17(2010):305-315.

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