Hormonal Antineoplastics

Question 1

What are the two general kinds of cancers that rely on steroids for growth?

Answer 1

androgen-sensitive prostate cancers

estrogen-sensitive breast cancers

Question 2

What are the two GENERAL strategies for hormonal antineoplastics in these cancers?

Answer 2

1. decrease the steroid concentration

2. decrease the steroid action

Question 3

What are the three strategies to reduce steroid concentration?

Answer 3

1. inhibit LH and FSH secretion with either GnRH agonists or antagonists
2. Block androgen biosynthesis with 5alpha reductase inhibitors of 12 alpha hydrosylase inhibitors
3. Aromatase inhibitors

Question 4

What are the two GnRH analogues used to inhibit LH and FSH secretion?

Answer 4

Goserelin and leuprolide

Question 5

In the short term, what do these GnRH agonists cause?

Answer 5

increase in testosterone or estrogen

leads to a flare response which includes increase cancer growth and increase in bone pain if there are mets

Question 6

In the long term, what do these GnRH agonists cause?

Answer 6

eventually, they lead to downregulation of the GnRH receptors, so you get decreased GnRH response and decreased testosterone/estrogen production

Question 7

How does the response to GnRH antagonists differ from that?

Answer 7

The antagonists work right away and you don’t have that flare response

but they’re waaaay more expensive - is it worth it?

Question 8

About how long does it take for Goserelin and Leuprolide to work?

Answer 8

about 7-10 days to get past the flare response

given in depot form

Question 9

What do we use Goserelin an dleuprolide for?

Answer 9

1. advanced prostate CA

2. premenopausal women with ER+ breast cancer

Question 10

We already talked about the flare response as a toxicity. What are some others?

Answer 10

pain at injection site

hot flashes and other decreased hormone effects

Question 11

What is the GnRH antagonist we know?

Answer 11

Degarelix

Question 12

What are the side effects of Degarelix?

Answer 12

generally well tolerated - some injection site reaction only

Question 13

What are the two 5alpha-reductase inhibitors?

Answer 13

dutasteride

finasteride

Question 14

What is the mechanism of action for dutasteride and finasteride?

Answer 14

they block 5alpha-reductase, so you don’t get conversion of testosterone to DHT (which produces better tumor growth than testosterone)

Question 15

What are the main uses for finasteride and dutasteride?

Answer 15

BPH and male pattern baldness

but also off label for prevention of prostate cancer in men with high PSA values

Question 16

What are the side effects of finasteride and dutasteride?

Answer 16

impotence!
but a less degree of bone density loss compared to other meds and less muscle wasting

can have a high degree of teratogenicity if a pregnant woman handles the capsule

Question 17

What is the 17alpha-hydroxylase inhibitor?

Answer 17

abiraterone acetate

Question 18

How does abiraterone acetate work?

Answer 18

It blocks an earlier stage of androgen synthesis

but doesn’t interfere with conversion of pregnenolone, so you don’t get low cortisol side effects

Question 19

What do we use abiraterone acetate for?

Answer 19

metastatic prostate cancer resistant to other androgen-blocking regimens

Question 20

What are the two classes of aromatase inhibitors? Which class is reversible?

Answer 20

Steroid analogues (of androstenedione)
non-steroidals (reversible)

Question 21

What is the example of the steroid aromatase?

Answer 21

exemastane

Question 22

What are the three nonsteroidal aromatases?

Answer 22

anastrozole
letrozole
aminoglutethimide

Question 23

Why is aminoglutethimide 3rd line after anastrozole and letrozole?

Answer 23

it also blocks the conversion of cholesterol to pregnenolone, so you have decreased adrenal glucocorticoids, mineralocorticoids and sex hormones, so tons of side effects

Question 24

What do the aromatase inhibitors block?

Answer 24

the conversion of testosterone and androstenedione to estradiol and estrone

Question 25

What do we use the aromatase inhibitors for?

Answer 25

1st line for ER+ breast cancer in postmenopausal women

Question 26

Why only postmenopausal women?

Answer 26

Because in postmenopausal women, the estrogen is almost completely produced in the periphery, hence, a GnRH antagonist or agonist won't do them any good - you need to block the production in the periphery, which means you need to block aromatase

Question 27

What are the toxicities for aminoglutethamide?

Answer 27

fever, nausea, rash, HA | ADRENAL INSUFFICIENCY with decreased mineralocorticoids and corticosteroids

Question 28

What can you treat that adrenal isnufficiency with? Does it do any good?

Answer 28

hydrocortisone helps until you get an increased ACTH repsonse (due to lack of cortisol) that can eventually overcome the block, producing an increase in cortisol and BONE MARROW SUPPRESSION (bad for a cancer patient)

Question 29

What are the side effects of anastrozole, letrozole and exemestane?

Answer 29

nausea, HA, hot flashes, decreased bone denseity, increased appetite, POLYARTHRALGIA

Question 30

What are the three anti-androgens we learned?

Answer 30

bicalutamide flutamide nilutamide

Question 31

Why do you have an increase in testosterone production when you're on the anti-androgens?

Answer 31

they block testosterone signalling, so you don't get that negative feedback on the LH and FSH production hence, you have increased LH and FSH, which will signal the leydig cells to mae more testosterone however, this doesn't really matter because you have the testosterone receptors blocked

Question 32

Why are the anti-androgens not given alone or for very long?

Answer 32

side effects

Question 33

So what are the anti-androgens primarily used for?

Answer 33

principally to block the flare response to the GnRH analogs during the first 7-10 days of treatment

Question 34

What is this combo of GnRH analog and anti-androgen called?

Answer 34

complete androgen blockade

Question 35

What are the toxicities for the anti-androgens?

Answer 35

diarrhea, nausea, vomiting, decreased lipido, hot flashes, decreased liver function (hepatotoxicity) extremely rare cases of methemoglobinemia

Question 36

What are the two types of anti-estrogens?

Answer 36

the SERMs and the SERDs

Question 37

What are the three SERMs?

Answer 37

raloxifene tamoxifen toremifene

Question 38

What is the one SERD?

Answer 38

fulvestrant

Question 39

Where is Tamoxifen an estrogen antaonist and agonist?

Answer 39

antagonist in the breast (good) agonist in the bone (good - antiresorptive) and uterus (bad for endometrial cancer risk)

Question 40

Where is Toremifene an agonist and antagonist?

Answer 40

antagonist in the breast (good) unknown in uterus no effect in bone

Question 41

Where is Raloxifene an antogonist and agonist?

Answer 41

antagonist in breast (good) Antagonist in uterus (good) Agonist in bone (good

Question 42

Where is Fuvlestrant an agonist and antagonist?

Answer 42

trick question - it's an antagonist everywhere, hence the SERD

Question 43

Why don't we use tamoxifen after 5 yeasr?

Answer 43

there just isn't an additional effect after 5 years

Question 44

How is tamoxifen given?

Answer 44

orally takes 4-6 weeks to reach Css

Question 45

How is Fulvestrant given?

Answer 45

IM in monthly intervals only takes 7 days to effect

Question 46

Why are there more drug-drug interactions with fulvestrant?

Answer 46

it's metabolized by Cyp 3A4

Question 47

What are the SERMs and SERDs used for?

Answer 47

mainstay for ER+ breast cancers in post-menopausal women

Question 48

Why not premenopausal women?

Answer 48

Can't use in premenopausal women because of the strength of their feedback loop

Question 49

What are the side effects of the SERMs/SERDs in general?

Answer 49

signs of decreased estrogen, so hot flashes, nausea, vomiting

Question 50

What is the extra side effect for Tamoxifen?

Answer 50

increased risk for emodmetrial cancer

Question 51

What are the extra side effects for Fulvestrant?

Answer 51

GI effects HA back pain injeciton site reaction

Question 52

Post-surgical adjuvant chemo is typical for breast cancer. What are the general regimens that are standard of care?

Answer 52

5FU, Doxorubicin and cyclophosphamide until the patient reaches her doxorubicin life-time dose, after which you switch to methotrexate