Tx of Prostate Cancer

Question 1

Is prostate cancer typically hormonally responsive?

Answer 1

Yes! Just like breast, endometrial, and adrenocortical carcinomas. Thus, drug therapy is tailored around blocking hormone sensitivity

Question 2

What is the first line treatment for prostate cancer?

Answer 2

combined androgen blockade- medical or surgical castration plus a pure anti-androgen. Other non-drug approaches include watchful waiting and external beam irradiation of the prostate, as well as implanted I125 titanium coated seeds used to treat early stage disease (a technique called brachytherapy)

Question 3

Like other hormonally responsive tumors, a prostatic tumor can evolve into an androgen-insensitive growth pattern. How?

Answer 3

Usually there are changes in AR amplication, by point mutation and changed in co-regulatory proteins. Such effects result in a ‘super-AR’ that can respond to lower conc. of androgens or the ability to function in a ligand-independent manner

Question 4

How does GnRH agonism down-regulate hormonally responsive tumor growth?

Answer 4

Normally, GnRH release is pulsatile so the continuous administration of GnRH can down-regulate pituitary receptors and ultimately decrease FSH and LH production. Note that there is an initial transient disease flare that is best managed by co-administration of an androgen receptor blocking drug

Question 5

What are some GnRH analogs?

Answer 5

Goserelin, Histrelin, Leuprolife, and Triptorelin (continuous administration results in chemical castration in about 2-4 weeks).Given SC mostly

Question 6

What are the common AEs of GnRH analogs?

Answer 6

symptoms that would be expected of a castration including hot flashes, decreased libido, ED, osteoporosis (no estrogen), and gynecomastiaCategory X preg

Question 7

What is a GnRH receptor antagonist? Onset? AEs?

Answer 7

Degarelix (Firmagon). This drug is given SC and because it inhibits GnRH receptors directly, produces a much quicker onset than GnRH analogs and avoids the initial hormone flare associated with analogsAEs are similar to GnRH analogs

Question 8

What is Estramustine (Emcyt)?

Answer 8

A PO drug that is a conjugated drug with an alkylating moiety attached to its estradiol structure. By targeting the estramustine binding protein on prostate tumors, it delivers the alkylator which functions as a microtubule inhibitor

Question 9

AEs of Estramustine?

Answer 9

GI disturbancesgynecomastia, mastalgia, and impotence due to elevated levels of estradiol(similar to estrogen therapy)-depressed testosterone levels via nega. HP feedback-elevated LFTs and hyperbilirubinemia

Question 10

What are some other effects of having elevated estrogen levels with prolonged estramustine therapy?

Answer 10

edema, thromboembolismMI, stroke and PE

Question 11

What are some androgen receptor blockers?

Answer 11

Flutamide, Nilutamide, Bicaulatamide, and EnzalutamideNOTE: Spironolactine also inhibits androgen receptors and can be used to treathirsutism in women

Question 12

Describe the androgren receptor blockers

Answer 12

These are PO non-steroidal blockers which diminish androgen-driven tumor proliferation

Question 13

What are the AEs of the ARBs?

Answer 13

Common AEs of lack of estrogen including hot flashes, decreased libidio, ED, etc.

Question 14

What are the other uses of Flutamide?

Answer 14

tx of hirsutism or polycystic ovary syndrome

Question 15

What is Sipuleucel-T?

Answer 15

This drug is essentially immunotherapy customized to individual pts. by taking APCs and processing them to seek out prostatic tumor cells by stimulating a T-cell response against prostatic acid phosphatase

Question 16

What are the AEs ofSipuleucel-T?

Answer 16

Mild infusion rxns; fever/chillds, and dyspneaparesthesias, citrate toxicity and fatigue

Question 17

What does the enzyme 17a- hydroxylase do?

Answer 17

it mediates conversion of pregnenolone to progesterone and subsequently to androgens. Thus androgens levels are reduced and prostatic tumors lose their proliferative signal.

Question 18

What is the difference between the effects of ketoconazole and 17a-hydroxylase inhibitors on adrenal hormone production?

Answer 18

Keto produces a hypo cortisol AND aldosterone state, while 17a inhibitors tend to produce a hyper-aldosterone state

Question 19

What is Abiraterone?

Answer 19

A CYP17 inhibitor (remember these produce a hyperaldosterone state- treat with a corticosteroid (prednisone) to reduce ACTH stimulation)

Question 20

What are the AEs ofAbiraterone?

Answer 20

elevated LFTsCat X drug- thus women should not handle the drug and condoms should be used for sex during pregnancy b/c of the ability of the drug to pass via the semen is unknown

Question 21

How could prostate tumors be resistant to hormone targeting?

Answer 21

AR overexpression or mutations that promote ligand independenceincreased androgen production and reduction in tumor suppressors

Question 22

How would the use of estrogens such as estradiol, DES, and ethinylestradiol be used to reduce testosterone levels?

Answer 22

They would feedback on the HP axis. These drugs are very protective to bone health BUT CV AEs have led to a reduction in use of these drugs in prostate cancer tx (but there has been some renewed interest in transdermal estrogen which has less CV effects than oral estrogen)

Question 23

Note that the use of 5a-reductase inhibitors is still controversial in prostate cancer treatment/prevention

Question 24

What are the conventional chemo drugs used in prostatic cancer tx?

Answer 24

Docetaxel and carbazitaxel for metastatic prostatic cnacer (both use premedication with corticosteroids and anti-H1/H2 histamine blockers to preemptt edema and injection rxns produced with these surfactant-containing drug preps)Mitoxantrone (+ prednisone) for palliation of severe pain for advanced hormone-refractory disease

Question 25

T or F. Unlike other taxanes, Cabazitaxe is a poor substrate for the multidrug resistance P-glycoprotein efflux pump and may be useful for trating multi-drug resistant tumors

Answer 25

T. In addition, cabazitaxel penetrates the BBB, where Pgp efflxu pumps may serve as barriers