intermittent androgen deprivation therapy for treatment of
TRANSCRIPT
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
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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
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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
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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.
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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
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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
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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
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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
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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.
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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
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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.