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ADT - Coggle Diagram
ADT
Mechanism
Surgical ADT (Orchiectomy)
Castration level = 6 hr after Sx
12 hr T < 20
Median T level = 15
Subcapasular orchiectomy
Cosmetic & psychogenic
Same cancer response
Lower risk
Cardeac event
Peripheral arterial disease
Skeletal Fx
VTE
DM
AR antagonism
1st generation
Steroid
No longer used
Non-steroid
Overview
Block AR activity
Monotherapy > Increase LH&T levels
SE
Gynecomastia/mastodynia
GI toxicity
Liver toxicity
Interstitial pneumonitits
Clinical use
Combined Androgen blockage with LHRH agonists
Drug
Flutamide
250 mg TID **
HL 6 hr
Bicalutamide
50-150 mg OD
HL 6 day
2nd generation
NonSteroid
Overview
Mechanism
Block AR
Inhibit Nuclear translocation
Prevent DNA binding
More potent than 1st gen
Enzalutamide
Landmark trials
AFFIRM
PREVIAL
TERRAIN
PROSPER
Indication
CRPC (M0/M1) regardless of previous CMT
SE
Fatique
Brease enlargement
Diarrhea
Hot flashes
Seizure
Apalutamide
Landmark trial
SPARTAN : m0CRPC
Improved metastasis free survival
Indications
m0CRPC
SE
Rash
Fall/Fx
Hypothyroidism
Antiandrogen withdrawal syndrome
withdrawal of antiandrogen from CAB
Decline in PSA
No effect to overall survival
Inhibit LH/LHRH release
LHRH agonists
Mechanism
Down regulation of LHRH Receptors
at anterior pitui gland
after chronic exposure to LHRH
Drug
Leuprolide
Enantone IM q 3 mo
Eligard
Triptorelin
Dipherelin IM q 3 mo
Survival = orchiectomy
** LH&T flare phenomenom
Metastasis iin spine and Wt-bearing regions
CAB
Before LHRH agonist 1 wk > continue 21-28 day
LHRH antagonists
Mechanism
Blind LHRH R. in pitui gland
T decline = Orchiectomy
No LH/T flare
Drug
Degarelix (Firmagon)
BCR, PFR, OS more favorable than LHRH agonist
Inhibit androgen synthesis
Ketoconazole
P450 inhibitor
Block 17,20-desmolase
Limit conversion C21>C19
Loss of adrenal steroid synthesis&T synthesis by Leydig cell
Catrate level within 4 h
400 mg q 8 hr
Indication
Failed 1st line ADT > Palliative tx
Hydrocortisone (5-20 mg twice per day)
Abiraterone
CYP17 inhibitor
Inhibit 17a-hydroxylase& C17,20-lyase > inhibit cortisol&androgen production
ACTH rise > increase aldosterone
Toxicity
Aldosteronism
HypoK
HT
Fluid overload
Prednisolone 5 mg OD/BID
Suppress ACTH > lower aldosterone excess
Hepatotoxicity
Landmark trials
COU-AA-301 : mCRPC post-doxetaxel
COU-AA-302 : mCRPC pre-doxetaxel
LATITUDE : mCRPC
Source of androgen
Testes
T
DHT : 13xT
5AR
Adrenal gland
DHEA (weak)
Androstenedione
Prostate cancer cell
Autocrine
Biology
AR
Ligand-inducible
ADT > Block AR activity
Reduce androgen
Reduce conversion to DHT
Block AR binding
Non AR
Resistance mechanism >> MASS
Mutation
Alter ligand specificity
Amplification
Overexpression to androgen
Splice variants
Androgen-receptor splice variant 7(AR-V7)
Steroidogenesis
Other Receptor > Drive AR pathway
Complication
Osteoporosis
Screening
BMD of hip
Tx
Calcium supplement
1000-1200 mg/day
Vit D3
400-1000 IU/day
Wt-bearing excercise
Smoking cessation
Prevention
Zolidronic avid 4-5 mg iv annually
Increase bone density in men w/o metastasis
Decrease skeletal event
Fx
spinal cord compression
need for sx
Consult dentist
Osteonecrosis of Jaw
Hot flushes
50-80% M/C*
Tx
Progesterone
Megestrol acetate 20 mg bid
Cyproterone acetate
50-300 mg/day
Estrogen
Low dose DES
Transdermal extradiol
SSRI : Venlafaxine
Gabapentin 900 mg
ED/Loss of libido
Tx
PDE5I
ICI
Vacuum
Prosthesis
Cognitive function
Change in body habitus
Increase appetite
Loss muscle mass > decrease indurance
Increase fat > wt gain
increase insulin level
DM/ metabolic syndrome
Increase insulin resistance 50%
Cardiovascular event
1 yr >> increase risk 20%
Increase risk CAD, MI, cardiac arrest
Gynecomastia/mastodynia
M/C antiandrogen
Tx
Prophylactic RT
Selective estrogen receptor modulator (SERM)
Tamoxifen 20 mg/day
Anemia
NCNC anemia
onset 6 mo
reversible