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Hemat/Onc EXAM 3
Hemat/Onc EXAM 3 - Prostate Cancer
32
Pharmacology
Graduate
02/08/2012

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Term
signs and symptoms of prostate cancer
Definition
early prostate cancer has no symptoms

advanced cancer:

weak or interrupted urine flow

problems with urination, frequency, hesitation, blood in the urine

impotence

weight loss

anemia

metastatic cancer:

spread to the bones, especially hips, spine, ribs, or other areas

can cause significant pain
Term
prostate cancer risk factors
Definition
age

race:
AA > Caucasian > Asian

family history

occupation

diet

obesity
Term
prostate cancer screening
Definition
controversial

starting at age 50 with men at normal risk

even earlier for men at high risk

high false positives: may identify tumors that will not threaten the health of the patient

digital rectal exam

prostate specific antigen

transrectal ultrasound
follow up to DRE and PSA
Term
DRE
Definition
irregular or firm areas
hard, knobby vs. smooth and rubbery for BPH

cons:
low sensitivity
observer bias

pros:
cancer found usually > 85% of the time
prostate cancer usually develops in a palpable area via rectal exam

inexpensive exam

relatively invasive when compared to other procedures
Term
PSA
Definition
physiologic role: liquefying the seminal fluid

stimulates growth in the prostate

normal 0-3 ng/mL
wide range, dependent on many factors

men > 50 should consider DRE/PSA screening
if PSA > 0.6 ng/mL annual screening recommended

also used in monitoring patients with prostate cancer

predictor of response to therapy

only moderately associated with survival

beneficial in diagnosis

cut off point varies depending on what source is used; sensitivity/specificity problems

fairly cheap test, non-invasive, and is quick

cons:
PSA is not cancer specific!
level may be misinterpreted
Term
transrectal ultrasonography (TRUS)
Definition
used for imaging

helps guide needle biopsy of the prostate

not specific enough for diagnostic purposes

hypoechoic areas are commonly associated with cancers
Term
prevention of prostate cancer
Definition
NOT vitamin E

selenium

diet high in lycopene

weight loss

finasteride vs. dutasteride
Term
SELECT Trial
Definition
selenium and vitamin E taken separately or together

original study showed no benefit form the use of either product alone or in combination

new findings may put a patient at an INCREASED RISK OF CANCER
Term
5 alpha reductase inhibitor
Definition
finasteride, dutasteride

blocks the action of the 5 alpha reductase enzymes
this is crucial for the conversion of testosterone into dihydrotestosterone (DHT)

ADRs:
common - decreased libido, impotence, depression
rare - breast tenderness, allergic reactions

use as prophylaxis:

24.8% reduction in prostate cancer but the men who got prostate cancer with this prophylaxis had extremely aggressive cancer
DO NOT RECOMMEND FOR CANCER PROPHYLAXIS
Term
prostate cancer diagnosis
Definition
physical exam

PSA: cancer marker, but also used in monitoring response

TRUS

transrectal biopsy or transurethral resection of the prostate (TURP)

requires 2 biopsies to confirm diagnosis

bone scan: mets to bone most common; also to the liver and lung
Term
prostate cancer staging
Definition
Gleason grade: 2-10 based on growth and differentiation (8-10 = very fast growth)
Term
treatment: localized disease (stage I and II)
Definition
multiple factors must be weighted: Gleason score and patient characteristics, not all patients require treatment

treatment options (or in combination):
watchful waiting
radical prostatectomy
radiation therapy
androgen ablation
Term
watchful waiting
Definition
most appropriate for elderly patients with a low stage/grade

regular physical evaluations and labs

advantages: avoids unnecessary treatments, risks, and morbidity to the patient

disadvantages: you may be wrong with life expectancy, later course of disease may not respond as well
Term
radical prostectomy
Definition
curative therapy for early stage disease

high risk of complications:
therefore, many choose to postpone therapy
impotence (reduced with nerve sparing surgery)
incontinence
bladder complications
mortality (very low risk)
Term
radiation therapy
Definition
types:
external beam radiation
internal beam radiation (brachytherapy)

options for patients that have low risks of recurrence or cannot tolerate surgery

still significant risks: impotence, bladder/rectal complications

ADRs:
impotence
bladder and bowel complications
incontinence
acute cystitis
Term
external beam radiation
Definition
outside the body focused radiation
Term
brachytherapy (internal beam)
Definition
permanent implantation of radioactive beads

best for patients who have a low risk for recurrent cancer
Term
adrogen deprivation
Definition
types:
orchiectomy
LHRH agonists

use:
not able to have surgery or radiation
surgery or radiation therapy failure
(+) radiation therapy as initial treatment
metastatic disease
Term
orchiectomy
Definition
removal of the testes

pros: rapidly reduces circulating androgens

preferred initial treatment in patients with spinal cord suppression or urethral obstruction
Term
androgen ablation: LHRH agonists
Definition
LHRH: leuprolide, gosrelin, triptoerelin

given with or without antiandrogen therapy or is an alternative to orchiectomy

reversible treatment

goal testosterone level < 20 ng/dL after 1 month

all 3 appear to be relatively equally effective to each other and similar to orchiectomy

leuprolide:
SQ q3-12 months
IM q1-4 months
implant q12 months

implant can be removed if the ADRs are not tolerable

ADRs:
disease flare
injection site reaction
hot flashes
impotence
decreased libido

goserelin:
implant q1-3 months

triptorelin:
IM q1-3 months
Term
antiandrogen therapy
Definition
non-steroidal anti-androgen

mechanism of action: inhibits androgen uptake and binding in target tissues

flutamide, bicalutamide, nilutamide

similar efficacy between the agents

used alone or in combination with LHRH agonists (combined androgen blockade (CAB))

combination therapy especially for advanced prostate cancer
can decrease tumor flare

pure antiandrogens bind to the androgen receptor in the prostate and the hypothalamus
eliminates the negative feedback loop of testosterone on the release of LH
leads to a dramatic increase in testosterone and estrogen levels
therefore it is best used in combination with either and LHRH or orchiectomy

treatment will block the effects of rising testosterone levels, but the effect of rising estrogen levels will remain unopposed
lead to feminizing effects
most notably gynecomastia

objective response: decrease in bone pain, decrease in prostate size, decrease in PSA levels

ADRs:
diarrhea and hematuria
gynecomastia
hot flashes
LIVER FUNCTION TEST ABNORMALITIES; LFTs will rise in more than 50% of patients
Term
combined androgen blockade (CAB)
Definition
majority of patients respond to LHRH agonists or orchiectomy

however, many patients will relapse

goal is to interfere with multiple hormonal pathways to completely eliminate androgen action

antiandrogens used in combination with LHRH agonist or surgical castration can help decrease elevation of estrogen and testosterone levels

interferes with multiple pathways

both testosterone and estrogen are essential for normal bone metabolism
reducing the anabolic bone effects of both androgens will increase bone loss and promote osteoporosis
Term
treatment of locally advanced prostate cancer: stage C (III)
Definition
watchful waiting

adrogen ablation for 2-3 years

radiation with or without androgen ablation

CAB often used for 2-3 months before radiation, then continued for 6 months after

radical prostatectomy with or without androgen ablation
Term
treatment of metastatic disease: stage D (IV)
Definition
androgen ablation
antiandrogen before LHRH agonist

slight survival benefit with CAB

palliative radiation therapy
Term
morbidity with treatment
Definition
urinary problems
prostatectomy > radiotherapy

erectile dysfunction
prostatectomy > radiotherapy > hormonal

bowel dysfunction
radiotherapy > prostatectomy

bone loss
andorgen deprivation therapy
Term
hormone refractory tumors
Definition
failed 2 hormonal therapies

continued tumor growth despite testosterone levels < 50 ng/mL

patients may have lost response to traditional anti hormonal therapy

chemotherapy and immunotherapy:
sipuleucel-T
docetaxel
cabazitaxel
abiraterone
Term
sipuleucel-T
Definition
immunotherapy: for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer

cancer vaccine: dendritic cell based vaccine targeting tumor antigens

administration: 3 dose cycles separated by 2 weeks; premedicate patients with diphenhydramine and APAP

con: cost - extremely expensive (~$90,000)

cell collection center - leukapheresis to collect patient APCs
Provenge manufacturing center - APCs exposed to prostate cancer antigen
infusion center - patient administered activated APCs

ADRs:
infusion reactions most commone
back pain
nausea
joint aches
fatigue
Term
chemotherapy
Definition
for cancer which has spread beyond the prostate; failed hormone therapy

use: shrink tumor, slow tumor growth, reduce pain

options: docetaxel, cabizataxel
Term
chemotherapy - docetaxel
Definition
MOA: binds to microtubules reversibly, stabilizing microtubules and prevents polymerization

docetaxel + prednisone

ADRs:
alopecia
bone marrow suppression
neutropenia
thrombocytopenia
N/V/D
infusion site reactions
Term
abiraterone
Definition
indication: castrate resistant prostate cancer

MOA:
is an androgen biosynthesis inhibitor that directly affects the androgen biosynthesis pathway
inhibits CYP17 (17 alpha-hydroxylase)
androgen biosynthesis is inhibited at 3 sources of testosterone production: testes, adrenal glands, and prostate tumor tissue

abiraterone + prednisone

TAKE ON AN EMPTY STOMACH

ARDs:
toxicity when taken with food
joint swelling
hypokalemia
edema
muscle discomfort
hot flushes

serious ADRs:
mineralocorticoid excess
cardiac adverse reactions
liver toxicity
Term
chemotherapy - cabazitaxel
Definition
taxane antineoplastic

promotes microtubule formation and prevents disassembly, leading to a frozen microtubule state

another option other than docetaxel

potential benefits over docetaxel:
poor binding to Pgp
can transport across the BBB

cabazitaxel + prednisone

ADRs:
hematologic, primarily neutroopenia
diarrhea
fatigue, N/V, hematuria
infusion reactions

BBW for neutropenic death

docetaxel DOES NOT cause neutropenia <- IMPORTANT DISTINCTION BETWEEN THE 2 DRUGS
Term
treatment of bone metastasis
Definition
bisphosphonates: pamidronate, zoledronic acid

helps decrease fractures and relieve bone pain in patients who have advanced cancer

inhibits tumor induced osteoclast mediated bone resorption

ADRs: abdominal pain, nausea, diarrhea, flu like symptoms

denosumab: monoclonal antibody

MOA:
pre-osteoclasts express a receptor on their surfaces called RANK
RANK is activated by RANKL, which is produced by osteoblasts
denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL

ADRs: constipation, urinary and respiratory tract infections, joint pain
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