Prostate Cancer 1

Front 1

Summarize in a historical context the hormonal treatments used for advanced prostate cancer.

Back 1

*Surgical Castration – first utilized clinically in the late 1930’s and found to be effective in reducing symptoms from metastatic prostate cancer.

*Estrogens (especially DES) – first used clinically in the early 1950’s; estrodiol is 1000 times more potent at suppressing LH and FSH compared to testosterone; DES has shown equivalence to surgical castration in terms of treating advanced CaP.

*LHRH agonists – developed in 1970’s; inhibit LH and FSH secretion by disrupting the phasic pituitary stimulation, however they do produce an initial surge in LH and testosterone

*LHRH antagonists – developed in the 80’s, these compounds suppress LH secretion by directly blocking pituitary stimulation and do not produce and initial LH/Testosterone surge

*Anitandrogens – newest class of agents; block the androgen receptor peripherally and centrally; classified as either steroidal or nonsteroidal

*Abiraterone

*MDV3100

Front 2

Where is the androgen receptor located cellularly? What is its mechanism of action?

Back 2

*Located in the cytoplasm but translocates to the nucleus after binding with androgen.

*There the complex acts as a transcription factor turning on specific genes

Front 3

What different forms of androgens exist and what are their sources?

Back 3

*Testosterone – the major form of circulating androgen; the testes produce 90%.

*Dihydrotestosterone (DHT) – formed in cells containing 5α-reductase (mainly the prostate) from testosterone; more potent activator of the androgen receptor than testosterone

*Androstenedione and Dehydroepiandrosterone – adrenal androgens produced in response to ACTH; relatively weak compared to T and DHT.

Front 4

What is considered “castrate level” of circulating testosterone? How quickly is testosterone reduced after orchiectomy?

Back 4

Less than 50 ng/dl.

*Testosterone levels are diminished by 90% within 24 hours after orchiectomy.

Front 5

What is the main difference between the steroidal (cyproterone acetate trade name Androcur) and nonsteroidal (flutamide (trade name eulexin), bicalutamide (trade name Casodex), and nilutamide (trade name Nilandron)) antiandrogens in terms of clinical usefulness?

Back 5

By blocking testosterone feedback centrally, the nonsteroidal antiandrogens actually increase testosterone levels in otherwise hormonally intact men. Therefore, they theoretically preserve libido, although long-term preservation is only 20% (not much different than castration). Their main drawback involves the increased peripheral aromatization of testosterone to estradiol causing gynecomastia and liver toxicity in some (requires monitoring).

*Steroidal antiandrogens lower testosterone by 70 to 80%; consequently side effects are the result the induced hypogonadal state including loss of libido, ED, and lassitude. Severe cardiovascular toxicity can occur in 10% of people.

Front 6

What is the antiandrogen withdrawal phenomenon?

Back 6

The observation that between 15% and 30% of patients will experience PSA reductions of as much as 50% after the withdrawal of an antiandrogen agent for a median duration of 3.5 to 5 months. Thought to be due to a mutation in the androgen receptor that occurs over time and causes the antiandrogen to actually activate the receptor. There are no studies that show an increase in overall survival

Front 7

Have any of the nonsteroidal antiandrogens proven to be as efficacious as castration or DES when used as monotherapy?

Back 7

Yes, bicalutamide (Casodex) at 150mg/day does appear to be as efficacious as medical or surgical castration. Also, quality of life is improved with Casodex

Front 8

What can be done to prevent the LH/Testosterone flare associated with the initiation of LHRH agonists such as Lupron?

Back 8

Coadminister an antiandrogen such as Casodex. The antiandrogen should be started either one week prior to or concurrent with the initiation of the LHRH agonist. The antiandrogen may be discontinued after 3-4 weeks.

Front 9

What advantages do LHRH antagonists offer (degarelix) compared to agonists? What is their main drawback?

Back 9

They do not stimulate a LH/Testosterone flare and therefore they do not require coadministration of an antiandrogen. Also, they reduce FSH levels more than agonists do and therefore may be useful in otherwise androgen refractory cases.

*Severe allergic reactions can occur, along with significant histamine-mediated side effects.

Front 10

How does ketoconazole decrease testosterone? How long do its effects last? How is it used in the treatment of prostate cancer?

Back 10

An orally active, broad-spectrum azole antifungal agent, ketoconazole interferes with two cytochrome P-450–dependent pathways: inhibition of 14-methylation in the conversion of lanosterol to cholesterol and blockade of 17,20-desmolase, affecting the conversion of C21 to C19 steroids.

The effects were rapid, with testosterone levels dropping to the castrate level within 4 hours of administration in some cases ( Trachtenberg et al, 1983 ); the effects were also immediately reversible, indicating that dosing must be continuous to maintain low testosterone levels (400 mg every 8 hours).

Although it is effective in rapidly bringing testosterone levels into the castrate range, with continuous treatment with ketoconazole in the otherwise hormonally intact individual (no other surgical or chemical ADT), testosterone levels begin to rise and can reach low-normal ranges within 5 months of therapy.

Must also monitor liver functions as it has been shown to cause hepatotoxicity and should probably not be used in patients with pre-existing liver dysfunction. The dose is higher than that seen with the typical dosing for Ketoconazole which is 200 to 400mg a day, for the androgen suppression we are using 400mg every 8 hours.

Front 11

What factors influence the durability of response to ADT before hormone-refractory disease sets in?

Back 11

The magnitude and rapidity of the initial response to ADT as determined by PSA has been shown to predict durability of treatment response. Patients with an 80% drop of PSA within one month of initiation of ADT had significantly longer disease-free progression rate.

Front 12

What are the side effects of ketoconazole?

Back 12

In addition to gynecomastia (caused by alterations in testosterone-to-estradiol ratios [ Pont et al, 1985 ]),

ketoconazole is associated with lethargy, weakness, hepatic dysfunction, visual disturbance, and nausea. The GI side effects are the most common. As far as hepatic dysfunction you should be very careful or not use this medicine in someone with pre-existing liver disease. The most common side effect in regards to the liver is elevated liver enzymes, but can be associated with hepatitis or severe liver dysfunction.

Front 13

What medicine is ketoconazole usually given with?

Back 13

Because of the adrenal suppression, ketoconazole which is dosed for causing a man to by castrate at 400mg three times daily, is usually given with hydrocortisone (20 mg, twice per day).

Front 14

What are some of the general complications associated with androgen deprivation therapy?

Back 14

Osteoporosis- estimated that 4 years of ADT will place the average man in the osteopenia range

*Hot flashes- affects 50 to 80%, treatment with megase 20mg bid, low dose DES or transdermal estradiol (treatment reserved for those who find these symptoms bothersome)

*Loss of Libido and ED- up to 20% of men can retain some sexual function, but only 5% maintaining good libido

*Decreased cognitive function
Changes in body habitus- increased fat/muscle mass ratio

*Gynecomastia- particularly with DES and the antiandrogens; can treat with prophylactic RT

*Anemianormochromic /normocytic, this is common (90% of men have decrease in Hgb by 10%), a very small subset are symptomatic (13%)

Front 15

Does ADT show a benefit when used in combination with either radical prostatectomy or EBRT?

Back 15

The addition of ADT to patients undergoing EBRT clearly improves outcomes over EBRT alone particularly in locally advanced or high-risk cases. ADT does not appear to improve outcomes in patients undergoing radical prostatectomy, although in non-randomized studies positive surgical margins are much lower. No significant difference in PSA progression between the groups.

Front 16

What does combined androgen blockade (CAB) refer to and does it have an impact compared to standard ADT?

Back 16

CAB attempts to eliminate all sources of endogenous androgen (both testicular and adrenal) by adding an antiandrogen such as Casodex to some form of surgical or medical castration.

*While this has been controversial, the best data suggest no statistically significant improvement in disease progression, disease-specific survival, or overall survival in CAB vs. traditional ADT.

Front 17

For the following clinical scenarios, state whether early (at the first sign of primary prostate cancer failure) or delayed (objective evidence of distant metastatic disease) initiation of ADT has been shown to be better: a) localized disease, b) regional lymph node positive disease, c) locally advanced, metastatic disease without symptoms.

Back 17

Localized disease: ADT not indicated at all as it has been shown to actually increase overall mortality.

*N+, M0 disease: if no primary treatment, no advantage to early ADT; in N+ disease with radical prostatectomy, early ADT offers a survival advantage.

*Locally advanced, metastatic disease without symptoms: early ADT offers improved disease-specific survival but not overall survival compared with late ADT.

Front 18

Does ADT as treatment for prostate cancer make economic sense compared to orchiectomy?

Back 18

No. It’s not even close. LHRH agonists (Lupron) on average cost 10-13 times what a bilateral orchiectomy costs for no proven survival benefit. CAB is 17.3-21 time more expensive than orchiectomy.

Front 19

Has intermittent ADT therapy proven to lengthen the time to the development of androgen-refractory disease?

Back 19

No, not yet. Campbells says that adequate studies still pending, but I recall a recent journal club article on the subject that found no difference in survival, but with improved sexual symptoms and obviously less economic impact. Does anyone still have the pdf?

Front 20

Where does the data come from that there is no benefit in overal survival for men with metastatic prostate cancer to get early hormone treatment or simply nothing?

Back 20

Huggins and Hodges [26] are credited with first exploiting the dependence
of prostate cancer on testosterone through studies of orchiectomy and estrogen
in patients who had metastatic disease 45 years after it had been reported
that symptomatic BPH could be successfully treated with
orchiectomy [27]. Much of our understanding and teaching of the use of
hormonal manipulations for the treatment of advanced prostate cancer
came from the Veterans Administration Cooperative Urological Research
Group’s randomized studies performed from 1960 to 1975 [28]. The largest
of these studies, VACURG I, randomized 1105 men who had locally advanced
or metastatic disease to placebo, orchiectomy, 5 mg diethylstilbestrol
(DES), and orchiectomy plus DES. Patients in the placebo arm were crossed
over to hormonal therapy when progression was detected. This study demonstrated
equal survival for placebo and orchiectomy, with reduced survival
for those treated with DES due to significant cardiovascular toxicities [28].
These findings have been the bedrock supporting the widely held view that
hormonal therapy does not enhance survival. Furthermore, with equal survival
in patients receiving immediate therapy and those in the placebo arm
who later crossed over to therapy with disease progression, the concept that
earlier intervention holds no benefits was born.

Endocrinology & Metabolism Clinics of North America 07

Front 21

What are the two most popular GnRH agonists in the United States?

Back 21

*The most popular method of androgen ablation in the United States is
the use of gonadotropin-releasing hormone (GnRH) agonists leuprolide acetate
(Lupron) or goserelin acetate (Zoladex).

Front 22

What are the commonly used nonsteroidal antiandrogens and which is used most frequently?

Back 22

*Although GnRH agonists and orchiectomy result in castrate levels of testosterone,
detectable levels of androgen produced by the adrenal glands
remain that could support survival of androgen-sensitive cells under conditions
of androgen ablation. The commonly used nonsteroidal antiandrogens
are flutamide (Eulexin), nilutamide (Nilandron), and bicalutamide (Casodex).
Each has unique side effects that have limited their use for flutamide
(diarrhea) and nilutamide (ocular effects). Bicalutamide is a once-a-day
drug with an acceptable side-effect profile. Most commonly, an antiandrogen
is used to cover the surge of testosterone induced during the first 2 weeks
of therapy. This is especially important for men who have symptomatic
locally advanced or metastatic cancers who could experience symptoms
without antiandrogen blockade.

Front 23

What is FIRMAGON?

Back 23

Also known as Degarelix.
F - forget about the LH surge
I - injectibel
R - rapid reduction in T
M - equals 3 which studies showed was the day it got to castrate levels
A - an arm and a leg
G - GnRH receptor antagonist in pituitary
O - oh my God its hot - hot flashes
N - nippy....pt's would get chills during first injections.

Front 24

What are the buzzword side effects of Nilutamide and Flutamide?

Back 24

*These are androgen receptor blockers that work both peripherally and centrally thus preventing feedback inhibition thus the main thing you get is the gynecomastia and nipple tenderness seen in >50% of men.

Also with Nilutamide there is the night vision issue.

Flutamide - flush the toilet or diarrhea issue.

Front 25

What did the Keating study in '06 show in association with GnRH therapy and associated cardiovascular complications?

Back 25

Yes, Keating et al '06 found that GnRH therapy had a 44% increased risk of incident DM, 11% increased risk of MI, 15% increased risk of CAD, and 16% increased risk in sudden cardiac death.

Also Tsai found in '07 when doing research on the CAPSURE database that there was a 2.6 times increased risk in cardiovascluar death in men on ADT after prostatectomy.

Front 26

What was the D'Amico group finding in relation to GnRH therapy and cardiovascular disease?

Back 26

*That was the finding stating that there was a shorter time to fatal MI in men on GnRH therapy as opposed to men not on GnRH therapy, the overall rate was not higher.

Front 27

What did the JAMA study published in 2011 of the meta-analysis of randomized studies find in relation to associaton between ADT and cardiovascular complications?

Back 27

*It did not find an increased risk of cardiovascular complications in men on ADT versus men not on ADT. It was a meta-analysis of 8 or so randomized trials of non-favorable prostate cancer and immediate ADT versus no ADT. These were not metastatic patients. Then looked at the rate of cardiac events post-treatment.

Limitations: the study did not know baseline cardiac risk factors for patients and only looked at total events and not time of event and so the finding by D'Amico's group that time to cardiac event was sooner in ADT patients could still be true.

*The author's final conclusion was that ADT is safe for most patients with unfavorable risk prostate cancer and for patients with cardiac co-morbidiites like previous MI or CHF that there should be caution.