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ER Week 6 > Hormonal Antineoplastics > Flashcards

Hormonal Antineoplastics Flashcards

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1
Q

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

A

androgen-sensitive prostate cancers

estrogen-sensitive breast cancers

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2
Q

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

A
  1. decrease the steroid concentration

2. decrease the steroid action

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3
Q

What are the three strategies to reduce steroid concentration?

A
  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
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4
Q

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

A

Goserelin and leuprolide

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5
Q

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

A

increase in testosterone or estrogen

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

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6
Q

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

A

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

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7
Q

How does the response to GnRH antagonists differ from that?

A

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

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

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8
Q

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

A

about 7-10 days to get past the flare response

given in depot form

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9
Q

What do we use Goserelin an dleuprolide for?

A
  1. advanced prostate CA

2. premenopausal women with ER+ breast cancer

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10
Q

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

A

pain at injection site

hot flashes and other decreased hormone effects

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11
Q

What is the GnRH antagonist we know?

A

Degarelix

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12
Q

What are the side effects of Degarelix?

A

generally well tolerated - some injection site reaction only

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13
Q

What are the two 5alpha-reductase inhibitors?

A

dutasteride

finasteride

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14
Q

What is the mechanism of action for dutasteride and finasteride?

A

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

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15
Q

What are the main uses for finasteride and dutasteride?

A

BPH and male pattern baldness

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

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16
Q

What are the side effects of finasteride and dutasteride?

A

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

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17
Q

What is the 17alpha-hydroxylase inhibitor?

A

abiraterone acetate

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18
Q

How does abiraterone acetate work?

A

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

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19
Q

What do we use abiraterone acetate for?

A

metastatic prostate cancer resistant to other androgen-blocking regimens

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20
Q

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

A 
Steroid analogues (of androstenedione)
non-steroidals (reversible)
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21
Q

What is the example of the steroid aromatase?

A

exemastane

22
Q

What are the three nonsteroidal aromatases?

A

anastrozole
letrozole
aminoglutethimide

23
Q

Why is aminoglutethimide 3rd line after anastrozole and letrozole?

A

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

24
Q

What do the aromatase inhibitors block?

A

the conversion of testosterone and androstenedione to estradiol and estrone

25
Q

What do we use the aromatase inhibitors for?

A

1st line for ER+ breast cancer in postmenopausal women

26
Q

Why only postmenopausal women?

A

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

27
Q

What are the toxicities for aminoglutethamide?

A

fever, nausea, rash, HA

ADRENAL INSUFFICIENCY with decreased mineralocorticoids and corticosteroids

28
Q

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

A

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)

29
Q

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

A

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

30
Q

What are the three anti-androgens we learned?

A

bicalutamide
flutamide
nilutamide

31
Q

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

A

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

32
Q

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

A

side effects

33
Q

So what are the anti-androgens primarily used for?

A

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

34
Q

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

A

complete androgen blockade

35
Q

What are the toxicities for the anti-androgens?

A

diarrhea, nausea, vomiting, decreased lipido, hot flashes, decreased liver function (hepatotoxicity)

extremely rare cases of methemoglobinemia

36
Q

What are the two types of anti-estrogens?

A

the SERMs and the SERDs

37
Q

What are the three SERMs?

A

raloxifene
tamoxifen
toremifene

38
Q

What is the one SERD?

A

fulvestrant

39
Q

Where is Tamoxifen an estrogen antaonist and agonist?

A

antagonist in the breast (good)

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

40
Q

Where is Toremifene an agonist and antagonist?

A

antagonist in the breast (good)

unknown in uterus

no effect in bone

41
Q

Where is Raloxifene an antogonist and agonist?

A

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

42
Q

Where is Fuvlestrant an agonist and antagonist?

A

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

43
Q

Why don’t we use tamoxifen after 5 yeasr?

A

there just isn’t an additional effect after 5 years

44
Q

How is tamoxifen given?

A

orally

takes 4-6 weeks to reach Css

45
Q

How is Fulvestrant given?

A

IM in monthly intervals

only takes 7 days to effect

46
Q

Why are there more drug-drug interactions with fulvestrant?

A

it’s metabolized by Cyp 3A4

47
Q

What are the SERMs and SERDs used for?

A

mainstay for ER+ breast cancers in post-menopausal women

48
Q

Why not premenopausal women?

A

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

49
Q

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

A

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

50
Q

What is the extra side effect for Tamoxifen?

A

increased risk for emodmetrial cancer

51
Q

What are the extra side effects for Fulvestrant?

A

GI effects
HA
back pain
injeciton site reaction

52
Q

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

A

5FU, Doxorubicin and cyclophosphamide

until the patient reaches her doxorubicin life-time dose, after which you switch to methotrexate

ER Week 6 (7 decks)

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