Prostate carcinoma- hormonal therapy 2

Hormonal Therapy in
Prostate Cancer
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

MODERATORS:
Professors:
Prof. Dr. G. Sivasankar, M.S., M.Ch.,
Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
Dr. J. Sivabalan, M.S., M.Ch.,
Dr. R. Bhargavi, M.S., M.Ch.,
Dr. S. Raju, M.S., M.Ch.,
Dr. K. Muthurathinam, M.S., M.Ch.,
Dr. D. Tamilselvan, M.S., M.Ch.,
Dr. K. Senthilkumar, M.S., M.Ch.
DEPT OF UROLOGY,GRH ANDKMC,CHENNAI. 2

HISTORY
In 1786, when Hunter described seasonal variation in prostate size among animals.
As early as 1893, White proposed castration to treat urinary obstruction disorders
based upon his research on aging dogs.
3
DEPT OF UROLOGY,GRH ANDKMC,CHENNAI.

CHARLES HUGGINS – NOBEL PRIZE 1966
“significant improvement often occurs
in the clinical condition of patients with
far advanced cancer of the prostate
after they have been subjected to
castration. Conversely, the symptoms
are aggravated when androgens are
injected” (1941)
4

MOLECULAR BIOLOGY OF THE ANDROGEN AXIS
The AR is a member of the nuclear receptor superfamily, which includes
receptors for the sex steroids (androgen, estrogen, progestin), adrenal steroids
(mineralocorticoids, glucocorticoids), thyroid hormones, vitamin D, and retinoids.
These receptors act as ligand inducible transcription factors
contain three key functional domains: ligand-binding (LBD), DNA-binding, and
transactivation.
5

Membrane-permeable steroid ligands diffuse into the cell,
 where they engage the LBD and activate the DNA-binding domains;
the transactivation domain binds and recruits other gene transcriptional partners
 thus regulate gene expression, either by repression or activation
The AR gene is located on the X chromosome, meaning only one copy is inherited in
XY males.
6

7

THERAPEUTIC APPROACHES
1. Ablation of androgen sources
2. Anti androgens
3. Inhibition of LHRH or LH
4. Inhibition of androgen synthesis
8

9

ANDROGEN SIGNALING PATHWAY
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Intermediate:
• T2b-T2c or
• Gleason score 7 or
• PSA 10-20 ng/mL
High:
• T3a or
• Gleason
score 8-10 or
• PSA >20 ng/mL
neoadjuvant 2 month
concurrent
+/- adjuvant 2 month
- neoadjuvant 2 month
concurrent
adjuvant 24-36 months
Very High:
• T3b-T4
•Primary
Gleason pattern
5
INDICATIONS & DURATION
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Metastatic
ADT is the gold standardfor
patients Who present with
metastasis at presentation.
12

ABLATION OF ANDROGEN SOURCES
1. Bilateral orchidectomy (Total or subcapsular)
2. Bilateral adrenalectomy (Historical and Obsolete)
13

BILATERAL ORCHIDECTOMY
Quickly reduces circulating testosterone levels to less than 50
ng/dL (Castrate range).
Classical castrate range – 50 ng/mL, now 15ng/mL
Within 24 hours of surgical castration, testosterone levels are
reduced by greater than 90%.
14

ANTI ANDROGENS
Steroidal:
1. Cyproterone acetate
Non steroidal:
1. Flutamide
2. Bicalutamide
3. Nilutamide
4. Enzalutamide
5. Apalutamide
15

CYPROTERONE ACETATE
Classical steroidal anti-androgen with direct AR blocking effects.
Rapidly lowers testosterone levels to 70-80%
Acts through progestational central inhibition.
Dose 100 mg twice or thrice daily.
Side effects:
Loss of libido,
Erectile dysfunction,
Lassitude.
16

CYPROTERONE ACETATE
Cardiovascular complications in 10% of patients.
Gynaecomastia in < 20% of patients.
Used for the treatment of Hot flashes. Dose 50-100 mg/day.
17

NON STEROIDAL ANTIANDROGENS
Block testosterone feedback centrally.
Cause LH and testosterone levels to increase.
Testosterone levels reach 1.5 times the normal levels.
Potency can be preserved. (< 20%)
Peripheral aromatization to estradiol.
Gynaecomastia and mastodynia.
Liver toxicity requires periodic LFT monitoring
18

FLUTAMIDE
First ‘Pure’ anti androgen.
Half life 6 hrs.
Dose 250 mg twice or thrice a day.
Gastrointestinal toxicity – Diarrhea is a common complication.
19

BICALUTAMIDE
Half life 6 days
Dose 150 mg once daily
Equivalent efficacy to surgical or medical castration.
Side effects: Gynaecomastia, mastalgia.
20

NILUTAMIDE
Half life 56 hours.
Elimination via Cytochrome P450 system.
Dose 300 mg daily for 1 month followed by 150 mg daily.
Adverse effects: Delayed adaptation to darkness (25%), Interstitial
pneumonitis (1%) progressing to pulmonary fibrosis.
21

ENZALUTAMIDE
AR antagonist inhibiting nuclear translocation and DNA binding.
Effective in castration resistant prostate cancer.
Side effects: Fatigue, diarrhea and hot flashes. Seizures (1%)
Indicated in patients with mCRPC.
Efficacy equal to Abiraterone.
Dose: 160 mg/day. (1 tab – 40 mg)
22

ENZALUTAMIDE
23

APALUTAMIDE
Oral, nonsteroidal antiandrogen
Blocks the action of testosterone by binding to the ligand-binding
domain of the AR receptor.
Used for the treatment of non-metastatic CRPC.
Adverse reactions: Fatigue, hypertension, rash, and diarrhea.
Dose: 240 mg/ day. ( 1 tab- 60 mg)
24

LHRH AGONISTS
Leuprolide
Goserelin
Triptorelin
Histrelin
25

LEUPROLIDE ACETATE
Commonly used LHRH agonist
Available as depot preparation for subcutaneous and im injections.
Lupron depot : Available with 1-,3-,4- and 6th monthly depot
preparations with 7.5 mg, 22.5 mg, 30 mg and 45 mg for im
injections.
Eligard: Same dosage available for SC injections.
Leuprolide acetate 1 mg/0.2 mL/day SC
26

MECHANISM OF ACTION
Exploits sensitization of LHRH receptors in ant pituitary following
chronic exposure to LHRH.
After initial flare up, down-regulation of LHRH receptor occurs.
LH and testosterone production shut down.
27

FLARE UP PHENOMENON
Testosterone surge or Flare up phenomenon associated with upto
10 fold increase in LH. (within 2-3 days)
May last for 10-20 days.
Co administration of an anti-androgen functionally blocks the
increased levels of testosterone.
Anti-androgen administration required for 3-4 weeks.
28

LHRH ANTAGONISTS
Cetrorelix
Abarelix
Degarelix
Relugolix
29

LHRH ANTAGONISTS
Competitively bind to LHRH receptors in the pituitary, reducing LH
concentrations by 84 % with in 24 hours.
Castration level = 2-3 days
No LH and testosterone flare.
No need for antiandrogen coadministration.
30

ABARELIX
Severe allergic reactions even after previous uneventful treatment.
Patient should be monitored for 30 minutes after administration.
Voluntarily withdrawn in 2005.
31

DEGARELIX
No systemic allergic reactions.
1-month SC dose, requiring two initial injections (2 × 3 mL for 240
mg) followed by monthly doses of 4 mL (80 mg).
32

INHIBITION OF ANDROGEN SYNTHESIS
1. Aminoglutethimide
2. Ketoconazole
3. Abiraterone
33

AMINOGLUTETHIMIDE
Inhibits conversion of cholesterol to pregnenolone.
Blocks production of aldosterone and cortisol also. Hence should be
replaced.
Side effects: Anorexia, nausea, skin rash, lethargy, vertigo,
hypothyroidism and nystagmus.
Dose: 1000 mg/day and Hydrocortisone acetate (40 mg/day).
34

KETOCONAZOLE
Interferes with two cytochrome P450 dependent pathways.
Blocks conversion of C21 to C19 steroids.
Effect is rapid. Testosterone level drops to castrate levels in 4 hours
in some cases.
Effect is immediately reversible.
Dose: 400 mg 8 hrly. Usually with hydrocortisone 20 mg bd.
35

KETOCONAZOLE
With continuous use, testosterone levels begins to rise and can
reach low normal ranges with in 5 months of therapy.
Used currently for castration resistant prostate cancer.
Side effects:
• Gynaecomastia,
• lethargy, weakness,
• hepatic dysfunction, visual disturbance and nausea.
36

ABIRATERONE
Selective irreversible inhibitor of Cytochrome P17.
Inhibits 17α hydroxylase and C17-20 lyase.
Increase synthesis of aldosterone and its precursors.
Suppress cortisol and increase ACTH secretion.
Testosterone levels < 1 ng/mL.
Side effects:
•Hypokalemia, hypertension, fluid overload.
Dose: 1000 mg/day ( 1 tab – 250mg/500mg)
37

ABIRATERONE
Co administration of prednisolone supresses ACTH.
Can be used in Metastatic castration resistant prostate cancer.
38

ABIRATERONE
39

40

DRUGS IN DEVELOPMENT
Darolutamide
Relugolix
Orteronel (TAK-700)
ARN-509
41

DAROLUTAMIDE
Oral, nonsteroidal antiandrogen
Similar mode of action to enzalutamide and
apalutamide.
42

ARN-509
Novel antiandrogen similar to enzalutamide
Pure antagonist of AR while also inhibiting AR nuclear translocation
and DNA binding.
Does not cross blood brain barrier. So no seizures.
43

RELUGOLIX
• Oral, GnRH antagonist in phase 3 development.
• Reduced mean serum testosterone levels within 6 h of dosing.
• However, a food effect reduced exposure by 50%
44

ORTERONEL (TAK-700)
Mechanism of action similar to abiraterone.
CYPP17 inhibitor with potentially greater 17,20 lyase selectivity.
Impairs androgen synthesis preferentially over corticosteroid
synthesis.
45

TESTOSTERONE TESTING
Testosterone levels should be measured regularly to ensure its
suppression is being maintained to target.
EAU guidelines recommendation: Test 3 months after the first dose
of ADT and repeated every 3−6 months thereafter.
46

ADT AND PSA RESPONSE
In men with newly diagnosed metastatic prostate cancer started on
ADT, the absolute PSA level after 7 months of ADT was a strong,
independent predictor of survival.
47

ADVERSE EFFECTS
1. Osteoporosis
2. Hot flashes
3. Sexual dysfunction
4. Cognitive decline
5. Changes in body habitus
6. Diabetes and metabolic syndrome
7. Cardiovascular morbidity
8. Gynaecomastia and anemia
48

OSTEOPOROSIS
BMD criteria for osteopenia or osteoporosis-
•More than 2.5 standard deviations below an age specific reference mean –
Prior to the initiation of ADT.
After 5 yrs of ADT, fracture incidence 19.4 %.
Over 15 years incidence 40%.
4 years of ADT will place the average man in osteopenia range.
49

OSTEOPOROSIS
Treatment begins with recognition.
BMD of the hip for all men anticipated on long term ADT.
Smoking cessation, weight bearing exercise, Vitamin D and calcium
supplementation.
Bisphosphonate pamidronate can be used for prevention as
demonstrated in some studies.
Bisphosphonates to be used when evidence of osteopenia or
osteoporosis emerge.
50

OSTEOPOROSIS
Transdermal estradiol increases BMD in men with prostate cancer.
51

HOT FLASHES
Uncomfortable flushes of heat similar to that experienced by women
during menopause.
Warmth in the upper torso and head followed by objective
perspiration.
Experienced by 50-80% of patients.
Mechanism: Increase in hypothalamic adrenergic concentrations and
alternations in endorphins and CGRP acting on thermo-regulating
center in hypothalamus.
52

HOT FLASHES
Treatment reserved for bothersome patients.
Megestrol acetate 20 mg bd can be used. Dose can be reduced to
5 mg bd.
Cyproterone acetate 50 mg/day titrated to 300 mg/day.
DES and transdermal estradiol- Most effective.
Clonidine – Centrally acting α agonist decreases vascular
reactivity.
53

HOT FLASHES
Venlafaxime 12.5 mg bd can be used.
Gabapentin decreased hot flashes to a moderate degree in some
studies.
54

SEXUAL DYSFUNCTION
20% men on ADT have some sexual activity.
10-17% of men can have some erection adequate for intercourse.
Libido is highly compromised. Only 5% of men maintain high level
of sexual interest.
Loss of penile volume and penile length, loss of nocturnal penile
tumescence and loss of testicular volume noted.
55

SEXUAL DYSFUNCTION
Treatment of libido is difficult.
PDE 5 inhibitors or intracavernosal injections of alprostadil can
be used for erectile dysfunction.
56

COGNITIVE FUNCTION
Hypogonadal state is associated with declines in cognitive
functioning.
Short course of ADT is associated with increased depression and
anxiety scores.
Major depressive disorder in 12.8% of men with ADT.
Testosterone supplementation improves verbal fluency.
57

BODY HABITUS
Loss of muscle mass and increase in percent fat body mass is
common.
More pronounced with initiation of ADT.
Weight gain due to increase in body fat mass. (1.8-3.8% increase
in one year)
Regular vigorous exercise may help to limit accumulation of fat.
58

DIABETES AND METABOLIC SYNDROME
Present in 50% of men undergoing long term ADT.
Unlike visceral fat accumulation in classical metabolic syndrome, fat
accumulates in subcutaneous regions.
HDL level is increased.
Insulin sensitivity decreased.
59

CARDIOVASCULAR MORBIDITY AND MORTALITY
Effect more in low risk prostate cancer patients on ADT.
At 1 year of ADT, 20% higher risk of cardiovascular morbidity
compared to normal men.
60

GYNAECOMASTIA
Peripheral conversion of testosterone to estradiol induces
gynaecomastia and mastodynia.
Bicalutamide: 66.3% Gynaecomastia, 72.7% Mastodynia.
Prophylactic radiation therapy (10 Gy) can be used to prevent or
reduce painful gynaecomastia.
Liposuction and subcutaneous mastectomy can be used for
established gynaecomastia.
Tamoxifen can be used for mastodynia.
61

ANAEMIA
Normochromic, normocytic anaemia
Decline in hemoglobin begin within 1 month of ADT initiation. It
continues for 24 months.
Secondary to lack of testosterone stimulation of erythroid
precursors and decrease in erythropoietin production.
Recombinant erythropoietin can be used.
After stopping ADT, anaemia reversal may take upto 1 year.
62

Thank you...
63

Prostate carcinoma- hormonal therapy 2

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