Prostate Flashcards
epidemiology -3
most common cancer in US
2nd leading cause of cancer death
african am»_space;caucasian both incidence and death
etiology -2
increased exposure to testosterone
genetic (45% of dz if age <55)
risk factors -3
age (median 67),
race (more in blacks, less in asians),
family history
pathophysiology of sx -3
urethra passes through prostrate
THUS sx when hypertrophy
inc freq, inability to start/stop, dyuria, hematuria, nocturia, incomplete emptying, dribbling
Screening -2
- DRE (25-50% of masses are cancer), PPV 26-35%
- PSA, specific to prostate, not to cancer, PPV 40-49%
- TRUS (transrectal u/s) indicated after abnormal PSA or DRE
PSA concepts -6
> 4.0 abnormal.
between 4-10 could be BPH or CA.
free PSA >25% likely BPH, no bx
free PSA between 15-25%, consider bx
PSA velocity 0.35 per year higher RR death
PSA density: PSA/prostate volume by TRUS
Factors affecting PSA -5
finasteride, dutasteride (50% dec),
saw palmetto (unpredictable),
androgen receptor blockers (variable, usually inc),
ejaculation (inc),
bx OR DRE (inc)
Screening recommendations -3
DO GUIDELINES AGREE?
US PSTF lack of evidence that PSA saves lives -> unnecessary testing and tx
European Randomized Study of Prostate CA 20% red in death
US PLCO study no survival advantage
Screening Guidelines -5
ACS start annual PSA when age 50,
NCCN, AUA start when 40, if 75y
Prevention - prostate CA prevention trial (PCPT) -6
NOTE: dutasteride no diff in gleason 7-10 CA
finasteride vs placebo for 7 yrs;
30% reduction;
nonsig 14% inc in high-grade (gleason 7-10)->thus no FDA approval;
ASCO/AUA guideline consider for asymptomatic with PSA <3.0,
if taking for BPH discuss benefits/risks,
NOTE prevelance dec but morbidity/mortality NOT assessed
Prevention - selenium - SELECT trial
4 arms: selenium, vit e, selenium + vit e, placebo
no sig benefit
Prevention - vitamin e - SELECT trial
nonsig (p=0.6) inc risk of prostate CA,
other trials show varying doses of vit e but high dose may be worse
Signs and Symptoms -6
asymptomatic early;
advanced -
alterations in micturition,
impotence,
lower extremity edema,
anemia,
wt loss
Natural hx -3
indolent early,
spreads via local extension (lymphatics, lymph nodes, hematogenously),
met to bone (80%), liver, lung
Diagnosis -8
PE, PSA, TRUS, serum chem, bone scan, CT/MRI, Bx via TURP, 99% adenocarcinoma
Staging -3
Gleason 1-5 two sections added,
higher the score greater probability of extracapsular spread;
T1: clinically undectable tumor (either palpation or imaging)
T2: confined within prostate
T3: extends through prostate capsule
T4: invades bladder, levator muscles, pelvic wall
NOTE: N1: mets in regional lymph node
Treatment - localized disease - general concepts
depend primarily on stage and grade but also on pt’s age, health, and preferences
Treatment - localized disease - active surveillance
inc anxiety
Treatment - localized disease - XRT -3
equivalent to surgery in outcomes
complications (impotence (30%), rectal/bladder sx).
choice external beam or brachytherapy (not choice for high risk, large or sx dz)
Treatment - localized disease - radical prostatectomy (RP) + pelvic lymph node dissection (PLND) tox. -4
complications (early mortality (0.3%),
bladder contacture (1-22%),
incontinence,
impotence (nerve sparing available)
Treatment - localized disease - ADT -3
LHRH agonist +/- antiandrogen or orchiectomy,
goal serum testosterone <20ng/dl 1 mo after initiation of tx; &&&
ADT/XRT 62% vs 57% 10 yr OS vs XRT alone.
Treatment - localized disease - dutasteride
in active surveillance pts, 38% vs 48% with placebo CA progression at 3 ys
short term vs long term ADT
4-6 months versus 2-3 years
androgen deprivation therapy -2
serum testosterone levels <50 ng/ml.
medical castration or surgical castration are equivalent.
Management of localized dz with low recurrence risk - NCCN -2
· T1-T2a
· Gleason score <10 ng/mL
2 RT or brachy
10yr: #1 AS (· PSA at least as often as every 6 mo · DRE at least as often as every 12 mo · Repeat prostate biopsy as often as every 12 mo)
Adverse features: positive margins, seminal vesicle invasion, extracapsular extension, or detectable PSA
Management of localized dz with intermediate recurrence risk - NCCN -2
· T2b-T2c or
· Gleason score 7 or
· PSA 10-20 ng/mL
2 RP+/-PLND (IF: Lymph node metastasis: Observation or ADT or ADT + RT (category 2B), IF: Adverse features: RT or Observation)
10yr: #1 RT+/- short-term ADT, +/-brachytherapy or
Adverse features: positive margins, seminal vesicle invasion, extracapsular extension, or detectable PSA
Management of localized dz with high recurrence risk - NCCN -2
· T3a or
·Gleason score 8-10 or
· PSA >20 ng/mL
1 RT+ long-term ADT (cat 1)
Management of locally advanced (T3b-T4) OR localized dz with very high (not based on GS) recurrence risk - NCCN. -4pts
T3b-T4
Gleason or PSA does not matter
1 RT+ long-term ADT (cat 1)
Management of N1 metastatic - NCCN
ADT or RT+ long-term ADT
Management of metastatic other than N1 - NCCN
ADT
Treatment - locally advance disease - XRT +/- neoadj/ adj /concurrent adt
std tx.
improved OS, dz specific survival, and disease free survival.
ADT drug choice does not change outcome.
Treatment - locally advance disease - RP
+/- neoadj/ adj /concurrent adt have shown no sig OS ->NOT recommended in combo with RP in this setting
Treatment - metastatic disease - general concepts
need to distinguish PSA recurrence vs overt mets.
If PSA recurrence may start ADT if: PSA >50, rapid PSA velocity, long life expectancy–consider toxicity of ADT in pt.
goal of ADT: palliation via elimination or inhibition of testosterone
Treatment - metastatic disease -orchiectomy -4
previous gold std (95% of testosterone pdt in testes),
s/e:
impotence,
hot flashes;
long term more likely to develop DM but NOT coronary heart dz, MI or sudden cardiac death like with LHRH a
Treatment - metastatic disease -LHRH agonists acute s/e -6
tumor flare,
gynecomastia,
hot flashes,
ED,
edema,
inj site rxn
Treatment - metastatic disease -LHRH agonists long term s/e -6
osteoporosis,
clinical fx,
obesity,
insulin resistance,
alteration in lipids,
inc risk of diabetes and CV events
hormonal regulation of prostate -4
hypothalamus->LHRH-> pituitary->
[[LH, FSH-> testes OR LH, FSH, PROL, GH->prostate cell OR ACH->adrenal gland]] ->
[[testes->T OR adrenal gland->A]] ->
T and A converted to DHT in prostate cell
LHRH agonist administration. -4
leuprolide depot (Lupron, Eligard) IM,
goserelin (Zoladex) SQ;
equal eff;
decision made on cost and MD/pt dosing schedule preference
LHRH agonist tumor flare -4
initial induction of LH, FSH,
inc bone pain or inc urinary sx,
resolves in 2 weeks;
antiandrogen should precede LHRH a and be continued in combo for at least 7 days in those with overt met dz
Intermittent androgen suppression
Con’t until s &&&
Delayed versus immediate androgen suppression -4
2007 ASCO Guidelines – 3 different risk groups
- Asym, PSA recurrence - no data
- Progressive dz on watchful waiting - consider immediate though no OS benefit
- Node (+) pts - consider immediate
Treatment - metastatic disease -second line hormonal. -6
1 Anti androgen withdrawal (moa unknown, Time of response depends on half-life differences, 6-8 wks for flutamide).
2 Corticosteroids (Suppress ACTH and subsequent A, pred 5-10qd).
3 aminoglutethimde.
4 ketoconazole (inh A synthesis, recommend corticosteroid replacement with hydrocortisone 20am,10pm)
5 megace
6 degarelix gnrh antagonist
CAB
Modest benefit, mixed studies, some consider as std
Intermittent androgen suppression
Con’t until s &&&
Delayed versus immediate androgen suppression
2007 ASCO Guidelines – 3 different risk groups
- Asym, PSA recurrence - no data
- Progressive dz on watchful waiting - consider immediate though no OS benefit
- Node (+) pts - consider immediate
Treatment - metastatic disease -second line hormonal -6
1 Anti androgen withdrawal (moa unknown, Time of response depends on half-life differences, 6-8 wks for flutamide).
2 Corticosteroids (Suppress ACTH and subsequent A, pred 5-10qd).
3 aminoglutethimde.
4 ketoconazole (inh A synthesis, recommend corticosteroid replacement with hydrocortisone 20am,10pm)
5 megace
6 degarelix gnrh antagonist
Degarelix -6
Gnrh antagonist, 2nd line.
Major advantage speed in dropping testosterone levels. 7 days or less vs 28 days.
Can be considered 1st line when tumor flare a concern.
SQ inj.
Has not been studied with CAB.
S/e: inj site rxn, elevated lft’s (10%)
Treatment - metastatic disease -antiandrogens -4
monotherapy with antiandrogens less effective the LHRH a,
all equally similar efficacy in combo with LHRH a,
more diarrhea with flutamide which is tid,
less tox with bicalutamide which is daily
metatstatic castration resistant prostate CA - definition
serum T < 20 and disease progression
metatstatic castration resistant prostate CA - clinical benefit response. CBR -3
- bone only dz difficult to assess by traditional response criteria
- PSA decline only surrogate
- analgesic consumption, pain scale rating, QOL
metatstatic castration resistant prostate CA - docetaxel 75mg/m2 q3wk + pred 5mg bid - first line -3
1st study to show OS inc. FDA approved. median survival 18.9mo.
s/e: neutropenia 32%, FN 2.7%.
studies combining with bev or lenalid do NOT improve OS, worse TOX
metatstatic castration resistant prostate CA - mitoxantrone 12mg/m2 + pred 5mg bid - typically second line
CBR 29% vs 12% with pred alone.
Response duration 43 vs 18 weeks.
No OS difference.
metatstatic castration resistant prostate CA - estramustine. -4
synthetic fusion of nitrogen mustard to estradiol.
combined with vinblastine, etop, doce, and pac.
with doce+dex inc median OS over mitox+pred but higher tox (NF, n/v, cardio events).
meta-analysis shows inc OS but also inc thromboembolic events.
metatstatic castration resistant prostate CA - abiaterone dose and MOA. -3
empty stomach 1000mg daily+pred 5mg bid.
blocks P450 CYP17, critical enzyme of T biosynthesis.
pred blocks activation of cortisol deficit induced neg feedback mechanism.
metatstatic castration resistant prostate CA - abiaterone - first line. -3
median PFS 16.5 vs 8.83 mo with placebo.
improved OS (# not yet known).
inc time to chemo, need for opioids, PSA progression, and decline in PS
metatstatic castration resistant prostate CA - immunotherapy - sipuleucel-T - dose and MOA -2
give q2wks x3 doses.
theraupeutic vax consisting of autologous peripheral blood mononuclear cells obtained through leukophoresis activated with PAP-GM-CSF.
metatstatic castration resistant prostate CA - immunotherapy - sipuleucel-T - trial -5
IMPACT trial. median OS 25.8 vs 21.7mo with placebo (p=0.03).
consider for:
1. no or minimal sx
- good PS
- > 6mo life expectancy
- no visceral dz
metatstatic castration resistant prostate CA - second line. -7
abiaterone,
cabazitaxel,
mitoxantrone+pred,
doce rechallenge,
salvage chemo,
sipuleucel-T,
clinical trial
metatstatic castration resistant prostate CA - immunotherapy - abiaterone - second line outcome and ae -8
previous doce. median OS 14.8 vs 10.9 mo. improved time to PSA RR, PSA progression time, PFS.
s/e:
mineralocorticoid-related a/e of fluid retention,
HTN
hypokalemia
muscle discomfort,
hot flash,
diarrhea,
UTI
metatstatic castration resistant prostate CA - enzalutamide - dose and MOA -3
160mg daily.
blocks androgen binding and translocation of A receptor into the nucleus and attachment to DNA.
higher potency for A receptor than traditional antiandrogens.
metatstatic castration resistant prostate CA - enzalutamide
pg 818
Degarelix -6
Gnrh antagonist, 2nd line.
Major advantage speed in dropping testosterone levels.
7 days or less vs 28 days.
Can be considered 1st line when tumor flare a concern.
SQ inj.
Has not been studied with CAB.
S/e: inj site rxn, elevated lft’s (10%)
What defines recurrence risk?
tumor size, gleason score, PSA
