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What populations are at an increased risk of prostate cancer?

First degree relative (particularly diagnosed at a younger age or multiple relatives), AA race, age >65yo

What are the most to least common site of mets for CaP?

Pelvic lymph nodes (hypogastric and obturator), bone, lung, liver

What is the most common histologic type of CaP?

Adenocarcinoma (>95%)

What is the most common non-adeno type of CaP?

Urothelial carcinoma, then ductal adenocarcinoma, mucinous adenocarcinoma, neuroendocrine (small-cell) tumors, signet-ring tumors

What cells does prostatic adenocarcinoma originate from?

Epithelial cells
Stains positive for prostatic acid phosphatase (PAP) and PSA

What do prostate adenocarcinoma cells NEVER have histologically?

A basal cell layer.

What do basal cells stain positive for?

High molecular weight keratin (HMWK) and negative for PSA and PAP. So cancer cells are neg for HMWK and pos for PAP and PSA

What zone is the most common location for prostate cancer?

Peripheral zone

Where is capsular penetration most common?

Near the NVB

What percentage of men with ASAP on prostate biopsy will develop prostate cancer?

40-60% therefore these men should undergo repeat prostate biopsy within 3 months with increased sampling from atypical region.

What % of men with HG PIN after a 10-12 core biopsy develop prostate cancer?

10-20%

Describe the inclusion criteria of the PCPT

18,000 men, age >=55, nl DRE, PSA <=3.0 randomized to placebo for finasteride 5mg daily and followed for 7 yrs

What were the results of PCPT?

Finasteride decreased the risk of developing prostate cancer by 25%. There is uncertainty surrounding its effect on high grade cancer. Likely detection bias

Describe inclusion criteria for REDUCE

8,000 men, age >50, neg PBx, prostate vol <80cc, and PSA 2.5-10 randomized to placebo or dutasteride 0.5mg daily and followed for 4 yrs

What were the results of REDUCE?

Dutasteride decreased the risk of Gl 5-6 prostate cancer by 27% but did not reduce Gl 7-10. Did not increase risk of high grade. Did reduce HG PIN and ASAP.

What were the results of REDEEM?

Reduced risk of progression for AS on Dutasteride

What substances should not be recommended for patients with CaP?

Vit E, selenium, and Vit C

Describe the PLCO trial?

76,693 US men, age 55-74 randomized to annual PSA/DRE or "usual care" (could include screening). After 7-10yrs detection was higher in screened group but risk of death from CaP was similar. The problem was contamination in control group

Describe ERSPC trial?

182,000 european men, age 50-74 randomized to routine PSA screening (q4yrs) or none. After 9 yrs screening reduced risk of death by 20%. 1410 men would have to screened and 48 men treated to prevent 1 death

CaP is found in what % of men with abnormal DRE?

30%

What are the age adjusted PSA norms?

W AA Asian
40-49 0-2.5 0-2.0 0-2.0
50-59 0-3.5 0-4.0 0-3.0
60-69 0-4.5 0-4.5 0-4.0
70-79 0-6.5 0-5.5 0-5.0

What is abnormal PSA velocity if PSA <4?

>0.35 ng/ml/yr

What is abnormal PSA velocity if PSA >4?

>0.75 ng/ml/yr

What PSA density suggests CaP?

>=0.15

What is % free PSA valid to use?

When PSA is 4-10ng/ml

What is an alternate regimen for abx prophylaxis during PBx other than fluroquinolone?

Aminoglycoside with metronidazole or with clinda

What is prostate innervation?

Sympathetics and parasympathetics from inf hypogastric plexus

Why do apical biospies hurt?

Above dentate line (anatomic division of anus and rectum) innervated by inf hypogastric plexus. Below innervated by inf rectal nerve and these aren't anesthetized in usual block

When cancer is missed on prostate biopsy where is it usually hiding?

Anterior-apical PZ
Midline PZ
Anterior TZ

Men considering salvage cryo should undergo sampling of what?

SV's
Cancer in SV occurs in 42% of men who recur after radiation

What should repeat biopsies consist of?

12 cores plus lateral peripheral zones and apical ant prostate. +/- TZ

Who should get a bone scan in w/u of CaP?

PSA>20, Gl 8/>, cT3-4, elevated alk phos, elevated serum Ca.
Similar criteria for CT pelvis

What is cT1b CaP?

More than 5% of histologically incidental cancer on resected prostate

In the TNM staging system how are positive surgical margins described?

R1

What factors increase risk of death from CaP?

PSA velocity >2.0 ng/ml/year
High PSA at diagnosis
Biospy Gl 8-10
Palpable nodes

What is low risk CaP?

PSA <10
Gl <=6
cT1 or T2a

What is intermediate risk CaP?

PSA 10-20
Gl 7
cT2b or T2c

What is high risk CaP?

PSA >20
Gl 8-10
cT3

What is PCA-3?

Voided urine test based on reverse transciptase-polymerase chain reaction assay for prostate-specific gene (DD3)

What is EPCA-2?

Blood based test which detects nuclear matrix protein linked to prostate cancer. More sensitive and specific for CaP even if normal PSA and BPH. Predicted ECE as well

What is the treatment of choice for men with CaP <50yo?

RP based on a retrospective report by Pokala and Menon 2009

What are treatment option for men >50yo with low risk prostate cancer?

RP, XRT, permanent brachy and cryo appear to have similar cure rates

Name three trials looking at AS?

PIVOT, ProTeCT, and START

What is the ASTRO definition of PSA failure after XRT?

3 consecutive rises in PSA above post-tx nadir. Now outdated? More recently use an absolute PSA rise of 2ng/ml above the post-treatment nadir PSA level

Regarding CaP the beneficial effects of soy protein are thought to arise from?

Isoflavones

Regarding CaP the beneficial effects of green tea are thought to arise from?

Polyphenols

How does cryotherapy work?

It freezes which creates a region of coagulative necrosis. It achieves cell kill by cell rupture (during freezing), apoptosis (6-12 hrs p freeze), and ischemia (24-48 hrs p freeze)

In what direction is the prostate frozen during cryosurgery?

Anterior to posterior

To ensure cell death how do urologists freeze the prostate?

At a temp of -40C with 2 freeze-thaw cycles

What is the patient population for cryo?

Stage T1-2 N0 M0, impotent, relatively small prostate, no previous TURP

Where does the NVB course and what is it composed of?

Posterior-lateral to prostate and is composed of cavernous blood vessels and nerves

What does BN preservation do?

Allows continence to return sooner and results in lower rate of BNC. Does NOT improve final degree of continence

What area should be avoided during PLND for CaP?

Anterior and lateral to prostate as this increases risk of lymphedema

What medication can be used as a sclerosing agent if lymphocele occurs?

Doxycycline

What % of men with + surgical margins recur?

50%

What is the most common site of positive margin?

Apex for RRP and anterior for perineal

What increased risk is associated with ECE?

14 fold higher risk of dying from prostate cancer than men with cancer confined to the prostate

What is SV invasion associated with?

Higher risk of recurrence, mets, and death

What did the "Messing Trial" show?

Immediate androgen dep improves survival in men who did undergo RP and who have micromets to PLN

Should men with poor pathologic features undergo adjuvant or salvage XRT?

Still unknown which is better. But if the path is really bad consider whole pelvis rads and ADT

What percentage of men progress on AS and require definitive treatment?

25-30%

Outcomes of RRP are better at centers that perform how many per year?

40 or more

Most urologists wait until a PSA of what post-prostatectomy to say its a meaningful rise?

>0.4ng/ml

After recurrence men with a PSA doubling time of less than what may be more likely to die of CaP?

15 months

What is the XRT dose for low risk prostate cancer?

Prostate +/- SV 70-79Gy with no ADT

What is the XRT dose for intermediate risk CaP?

Prostate + SV +/- PLN at 75-80Gy with optional 4-6mo ADT (LHRH agonist +/- antiandrogen)

What is the XRT dose for high risk CaP?

Prostate + SV + PNL at 75-80Gy with 2-3 yrs ADT (LHRH agonist +/- antiandrogen)

What is high dose rate brachy?

Delivered using Ir-192, over 1-2 days several sessions are conducted. Usually combined with 4-5 weeks of XRT

What is the half life, time to deliver 90% of radiation, and dose for elements used for brachy?

1/2 life 90% Dose
I-125 60d 204d 145Gy
Pd-103 17d 58d 125Gy
Cs-131 9.7d 33d 115Gy

Who is brachy avoided in?

Intermediate or high risk patients, gland >60gm, previous TURP, and significant voiding symptoms

What is PSA bounce?

Temporary rise in PSA in 20-30% of men not receiving ADT that occurs 1-3 years after radiation and lasts 6-18 months

How does EBRT work?

Utilizes high-energy photons to destroy cancer by damaging cellular DNA

What dose of radiation is now administered with 3D conformational EBRT?

>75Gy

What is IMRT?

It is photon based. It is quickly becoming the standard of care. Give doses between 81-86.4Gy

What is sterotactic body radiotherapy (SBRT)?

Employs high-dose (700cGy) for several fractions delivered with linear accelerator or cyberknife

What must be done before administering curative salvage therapy for radiation failure?

Document local recurrence with a prostate biopsy

From the time of PSA recurrence after prostatectomy what is the median time to detectable mets? Median time to death?

8 years
13 years

What is the XRT dose for salvage radiation after prostatectomy?

At least 64Gy

What must be done before administering salvage therapy for cryotherapy failure?

Local recurrence must be confirmed with biospy

T/F LHRH agonists and bilateral orchiectomy are equally as effective?

True

What PSA at 7-8 months post-castration is associated with a higher risk of death from CaP?

PSA >0.2ng/dl
Also a PSA DT of <3 months

When does prostate cancer typically stop responding to castration?

Usually after 2-3 years but can range from months to 15 years

Should ADT be stopped when a man becomes "hormone refractory"?

No

What is the algorithm for BCR after ADT?

Obtain a serum T. If <50 they are castrate. If taking an antiandrogen stop it (antiandrogen withdrawal) and recheck PSA. If not taking antiandrogen start one and recheck PSA. If T is >50 then either incomplete orchiectomy or non-compliance/error with LHRH agonist

What are second line therapies for mCaP?

Change to different antiandrogen
Ketoconazole and steroids
Aminoglutethimide and sterioid
Diethylstilbestrol
Docetaxol

Who should IV bisphosphonates be started on with CaP?

Hormone refractory with bone mets should receive IV bisphosphonates. Zometa 4mg IV q3wks for 20 cycles

What should be done for acute spinal compression from mets?

IV steroids (dex 100 IV bolus then 25mg PO QID)
Ketoconazole 400mg PO q8h
GnRH antagonists (Degarelix)
Diethylstilbestrol 1g IV q24hr
MRI spine
Surgery or rads

What is the MOA of GnRH antagonists?

Reversibly binds to GnRH receptor in the pituitary gland and suppresses secretion of LH, FSH, and T
Castrate level in 3 days
Ex: degarelix

What is the MOA of antiandrogens?

Block binding of DHT to androgen receptor blocking the translocation of DHT-androgen receptor complex into the nuclei of cells

What should be considered if a patient is going to have prolonged monotherapy with antiandrogen?

Breast radiation prophylactically prior to initiation of med because of high risk of gynacomastia

What does CAB imply and how is it administered?

Elimination of testicular androgen and blockade of adrenal androgen generally with LHRH analog and antiandrogen agent

What is the MOA of abiraterone or Zytiga?

Inhibits CYP17A1 and enzyme expressed in testicular, adrenal, and prostate tissue. It is an adrenal androgen synthesis inhibitor

What is the MOA of Provenge?

It is sipuleucel-T immunotherapy vaccination. It is an autologus dendritic cell therapy vaccine that utilizes a PAP-GMCSF fusion protein to stimulate immune cells

Who is it approved for?

Men with presymptomatic metastatic castrate resistent prostate cancer.
Survival advantage of 4.1-5 months over sham

Who is not eligible for Provenge?

Men that require narcotics, visceral mets, and life expectancy <6 months

What is MDV3100?

An experimental androgen receptor antagonist with a higher binding affinity for AR than biclutamide

What agents are under Phase III trials in post docetaxel castrate resistant setting?

Cabazitaxel - antimicrotubule agent
Ipilimumab - CTLA-4 blocker combined with XRT
MDV3100 - novel antiandrogen
Abiraterone - adrenal/autocrine androgen synthesis inhibitor
Sunitinib - Oral VEGF/PDGF inhibitor

T/F docetaxel has been shown to have advantage over mitoxantrone?

True

What is the toxicity of mitoxantrone?

Cardiac - should get pretreatment and serial EF measurements during treatment

What are the toxicities of docetaxel?

Myelosuppression and peripheral neuropathy

What are the toxicities of bisphosphonates?

Renal failure and osteonecrosis of the jaw

What is Denosumab

A RANKL anagonist which has shown improvment in prevention of skeletal related events in men with met castration resistant CaP compared to Zoledronic acid. Side effect is osteonecrosis of the jaw

What is the treatment regimen for radiation therapy to palliate bone mets?

30Gy over 10 treatments. Single dose palliative radiation may also be equally as good.

What is the radiation regimen for more extensive disease?

Wide field radiation or administration of radioactive bone-seeking isotopes like stontium-89 Cl or samarium 153 lexidronam

What are sources of androgens in men?

Testis - 90-95%
Adrenal glands - <5%

What does prolactin do to testosterone?

Decreases it by inhibiting GnRH secretion from hypothalamus.
It may stimulate prostate cancer by directly stimulating prostate tissue

What conditions cause increase prolactin?

Prolactinoma, hypothyroidism, stress, CRF, antipsychotic drugs

Castrate levels of T occur how soon after b/l orchiectomy?

2-12 hrs

What is the MOA of estrogen in ADT?

Inhibits hypothalamic-pituitary axis - decreases LH and therefore T. This increases prolactin
Castrate levels in 10-14 days
Ex: diethylstilbestrol, premarin, estradiol

What is the big side effect of estrogen therapy?

Emboli

What is the MOA of progestins?

Inhibits hypothalamic-pituitary axis - decreases LH and therefore T. This DOES NOT increases prolactin
Ex: Megace

What is the MOA of LHRH agonists?

Stimulation of LHRH receptors that causes an initial flare then suppresses secretion
Castrate levels in 30 days
Ex: leuprolide, histrelin, goserelin, and triptorelin

What is the MOA of Ketoconazole in ADT?

Reduces gonadal and adrenal synthesis by inhibiting cytochrome P-450
Castrate levels in 8hrs
Administer with steroid b/c lowers glucocorticoid as well

What is the toxicity of Ketoconazole?

Hepatotoxicity, dose limiter is N/V

What ist he MOA of aminoglutethimide in ADT?

Blocks the transformation of cholesterol to pregnenolone by inhibiting cytochrome P-450. Blocks glucocorticoid and mineralocorticoid as well as sex steroids. Must supplement the first two to avoid Addisonian crisis

What are the side effects of antiandrogens?

Hepatotoxicity, gynecomastia, N/V
Nilutamide has visual disturbances

When does the flare phenomenon peak and how long does it last?

3-4 days, 7 days

What can be done to prevent flare phenomenon?

Usa a GnRH antagonist or orchiectomy instead
Use ketoconazole before LHRH agonist
Antiandrogen (4 1/2 livees) b/f LHRH agonist
Flutamide >32 hrs before
Nilutamide >8 days before
Bicalutamide >24 days before

What is antiandrogen withdrawl?

Decline in PSA (usually by 50%) after stopping antiandrogen. Occurs in 30% of patients and lasts 3-6 months
Flutamide decline begins within few days
Bicalutamide begins 4-8 weeks

What agents cause hot flashes?

LHRH agonists, GnRH antagonists, bilateral orch, and nonsteroidal antiandrogens

What prevents hot flashes?

Progesterone, estrogen, clonidine, venlafaxine, Vit E, gabapentin, and acupuncture

What are the risks of long-term ADT?

Adverse lipids, insulin resistance, DM, CAD, anemia, ostoporosis, peridontal disease, sexual dysfuntion, infertility, fatigue, hot flashes, cognitive deficits

What pathologic changes are seen in the prostate after ADT?

atrophy of gland, decreased gland density, increased fibromuscular stoma, apoptosis, nuclear pyknosis.
Necrosis is rarely seen

What is PSA?

Serum protease human kallikrein gene on Ch 19
Cleaves spermatogelin
Half life of 3.4 days

T/F there is evidence that enemas reduce risk of infection after PBx

False

T/F a PSA velocity >2 years prior to dx portends a worse outcome?

True

Describe the scores for a bone scan?

Z score: compares to age matched population
T score: compares to 25 yr old

What is the MOA of docetaxol?

Interferes with microtubules

What is the survival benefit of docetaxol over mitozantrone + prednisone?

2 months

What is mitoxantrone?

Interferes with DNA synthesis and repair
Improves pain but not survival

What is the treatment of neuroendocrine tumor of the prostate?

Cisplatin and etoposide

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