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PHRM 864 > Lecture 12 - Prostate Cancer > Flashcards

Lecture 12 - Prostate Cancer Flashcards

1
Q

Prostate cancer is the most common cancer in

A

men
2nd most common cause of cancer related death in men
1 in 8 men will be diagnosed with prostate cancer

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2
Q

Etiology/pathogenesis

A

hormonal: testosterone is a growth signal to the prostate, most risk factors associated with prostate cancer are related to increased exposure to testosterone
androgen receptor: alterations in androgen receptor

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3
Q

Risk factors

A

increased age, more common in african-americans, family history, diet (high fat intake), vitamin E, selenium, soy, and lycopenes may protect, textile or industrial workers, long-term vasectomy

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4
Q

Pathophysiology

A

urethra passes through the prostate and prostatic hypertrophy may compress the urethra - increased frequency, inability ot start and stop uring flow, dysuria, hematuria, nocturia, incomplete bladder emptying and dribbling

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5
Q

Signs and symptoms

A

asymptomatic with early disease - can tell from elevated PSA levels
advanced disease: alterations in urinary habits, impotence, lower extremity edema, weight loss, anemia

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6
Q

Diagnosis

A

physical exam, PSA level, transrectal ultrasound, serum chemistries, bone scane, CT/MRI is suspect metastatic disease
biopsy of prostate
histology: adenocarcinoma

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7
Q

Pathology

A

grading: gleason score (2-10)
scores assigned to primary and secondary growth patterns and then added together
scores of 2-4 are slow growing, well differentiated; scores of 8-10 are aggressive, poorly differentiated
higher the score, higher the risk of extracapsular spread

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8
Q

Prostate specific antigen

A

liquefies seminal secretions and increases with disorders of prostate
normal range is 0-4 ng/mL; >4 ng/mL requires evaluation; >10 ng/mL highly suspicious for malignancy
PSA velocity: >0.75 ng/mL rise per year suspicious for malignancy

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9
Q

Treatment overview

A

options: localized therapy, metastatic disease - m0HSPC, m0CRPC, m1HSPC, m1CRPC
m1 = metastatic
m0 = non-metastatic (PSA only)
HSPC = hormone sensitive prostate cancer
CRPC = castrate resistant prostate cancer

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10
Q

Treatment: localized - obervation

A

observation: monitor course of disease with expectation to deliver palliative therapy for development of sx or a change in exam or PSA that suggests sx are imminent
PSA + DRE every 6 mo
advantage: avoids immediate morbidity associated with tx
disadvantage: risk fo disease complications such as urinary retention or fractures

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11
Q

Treatment: localized - active surveillance

A

based on premise that prostate cancer is a benign and indolent disease
active monitoring of disease, if cancer noted to progress, will initiate potentially curative therapy
monitor PSA, DRE, and sx; treatment initiated with rising PSA or development of sx
advantages: 2/3 of pts will avoid therapy, avoid possible SEs, QOL less affected
disadvantages: 1/3 of pts may require tx, periodic f/u and test/biopsies may be necessary

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12
Q

Treatment: localized - radiation therapy

A

external beam vs brachytherapy
reasonable alternative to pts not eligible for surgery
complications: bladder and/or rectal sx, ED, radiation proctitis
give adjuvant ADT if intermediate or poor risk

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13
Q

Locally advanced/high risk

A

androgen deprivation therapy (ADT) in combo with external beam radiation therapy (EBRT) improved overall survival
start ADT prior to radiation and then continue ADT during radiation and for 1-3 years after

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14
Q

Treatment: localized - radical prostatectomy + PLND

A

definitive curative therapy; survival with surgery ~85% at 10 years
complications: early mortality, bladder contracture, incontinence, impotence
follow with ADT therapy

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15
Q

Androgen deprivation therapy

A

goal is to induce castrate levels of testosterone: goal level = <50 ng/dL after 1 month of therapy
surgically: orchiectomy; medically: LHRH agonists
ADT: LHRH agonist +/- anti-androgen or orchiectomy
antiandrogens: blocks androgen receptors and inhibits androgen uptake and binding in target tissues - bicalutamide, nilutamide, flutamide, abiraterone, enzalutamide

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16
Q

LHRH agonists

A

reversible and is as effective as orchiectomy
leuoprolide, goserelin, triptorelin, histerelin
LHRH antagonist - oral: relugolix - has less CV events (if pt has extensive cardiac history use this!)

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17
Q

LHRH agonsit toxicities

A

acute: tumor flare, gynecomastia, hot flashes, ED, edema
long-term: osteoporosis, fracture, obesity, insuling resistance, changes in lipids, increased risk of diabetes and CV events

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18
Q

Anti-androgens

A

flutamide
bicalutamide
nilutamide
these help prevent tumor flare
use these in combo with LHRH in metastatic setting

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19
Q

Metastatic prostate cancer

A

goals of therapy - palliation of disease
suppress testosterone production (<50 ng/dL)
need to determine whether this is a PSA recurrence or overt metastatic disease

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20
Q

Metastatic disease: m0HSPC

A

if only PSA recurrence, may delay start of ADT
if pt experiences a rapid PSA velocity or short PSA doubling time (< 6 mo) and has long-life expectancy: consider ADT
orchiectomy (removal of testes) - immediate drop in testosterone levels; SE = impotence and hot flashes

21
Q

Metastatic: LHRH agonists

A

risk of disease flare in 1st weeks of therapy due to initial release of testosterone - add anti-androgen to prevent disease flare
sx of flare = bone pain or increased urinary sx

22
Q

Intermittent ADT: m0HSPC

A

can start on LHRH agonist alone or with oral ADT
when PSA level has returned to pre-specified baseline, androgen suppression is d/c’d
PSA is monitored while pt off therapy and then androgen ablation therapy is restarted at pre-defined PSA
men with biochemical failure only can consider intermittent therapy
advantages: decreased cost and SEs (less CV evetns and fractures)

23
Q

m0CRPC

A

is PSA still increasing and not responding to ADT and no distant metastasis found on scane, consider m0CRPC
1. continue ADT (usually LHRH agonist)
2. add on one of the following: enzalutamide, apalutamide, darolutamide
abiraterone not indicated in M0 setting!

24
Q

Enzalutamide

A

blocks androgen binding and translocation of androgen receptor
avoid CYP2C8 inhibitors
decreases serum conc of warfarin; caution use in pts with seizure history (lowers seizure threshold)
toxicities: fatigue, seizures, falls, weakness, diarrhea, hot flashes, musculoskeletal pain, HA, HTN

25
Q

Apalutamide

A

non-steroidal androgen receptor inhibitor
decreased proliferation of tumor cells and increased apoptosis
drug interactions with CYP3A4 and CYP2C8
use caution in pts with h/o seizures, QT prolongation, falls, and thyroid dysfunction
toxicities: HTN, fatigue, falls, rash, diarrhea, anemia, endocrinopathies (increase in cholesterol, glucose, tyriglycerides, TSH), seizures

26
Q

Darolutamide

A

structurally unique androgen receptor antagonist
2 active diastereomers - offers less toxicities
drug interaction: CYP3A4
toxicities: fatigue, back pain/arthralgias, rash, diarrhea, HTN, anemia, nausea
key AEs known to be increased with AR inhibitors were LESS with darolutamide - less fractures, falls, seizures, weight loss

27
Q

m1HSPC

A

pt now has visceral metastases
hormone sensitive disease; determine therapy based on volume of disease - low or high volume
tumor testing for MSI-H or dMMR, germline testing for gene mutations

28
Q

Low volume m1HSPC

A
  1. ADT: LHRH agonists or LHRH antagonists
  2. continue ADT and add any of the following: abiraterone + prednisone, enzalutamide, apalutamide
29
Q

Abiraterone acetate

A

selectively and irreversibly inhibits CYP17, an enzyme required for androgen synthesis, inhibits formation of testosterone precursors
MUST be given with prednisone to prevent adrenal insufficiency
major substrate for CYP3A4
common toxicities: HTN, edema, increase triglyerides and LFTs, hypokalemia, afib, muscle aches, diarrhea, hot flashes, fatigue, liver toxicities

30
Q

High volume m1HSPC

A

could do any of the previously mentioned therapies:
ADT
ADT + abiraterone + prednisone
ADT + enzalutamide
ADT + apalutamide
now chemo becomes an option

31
Q

High volume disease

A

visceral metastasis
4 or more bone metastases
at least one metastasis beyond pelvis vertebral column

32
Q

m1HSPC = chemo + ADT

A

docetaxel + ADT for 1st line tx
more neutropenic fevers, fatigue, diarrhea, stomatitis, neuropathy

33
Q

Newer data for high volume

A

use all for high-volume, castrate sensitive, metastatic disease
ADT + docetaxel + abiraterone
ADT + docetaxel + darolutamide

34
Q

Metastatic castrate recurrent prostate cancer (CRPC)

A

all pts will become hormone refractory; median survival of 6 mo; PSA decreases used as surrogate marker of response
continue ADT and maintain castrate testosterone concentrations

35
Q

m1CRPC

A

in addition to continuing ADT therapy, the pts could do any of the following: sipuleucel-T, docetaxel, cabazitaxel, radium-223 for bone metastases, abiraterone + prednisone, enzalutamide, genomic testing: BRCA (olaparib), dMMR/MSI-H (pembrolizumab)

36
Q

Cabazitaxel - 2nd line therapy

A

taxan derivative (microtubule inhibitor) - binds to tubulin promoting assembly into microtubules
poor affinity for MDR proteins, therefore conferring activity in resistant tumors
toxicities: more severe neutropenia, diarrhea, febrile neutropenia

37
Q

Metastatic disease treatment oral therapies

A

docetaxel + prednisone
cabazitaxel + prednisone
mitoxantrone + prednisone

38
Q

Bone metastases

A

radium 223 dichloride: alpha particle-emitting isotope - emits high energy, short-range alpha particles targeting bone metastases; forms complexes with bone mineral in areas with increased turnover leading to DNA strand breaks and an antitumor effect on bone mets
approved for CRPC, symptomatic bone metastases and no known visceral metastatic disease
toxicities: anemia, neutropenia, thrombocytopenia; do not give concurrently with chemo!

39
Q

cancers that express dMMR/MSI-H

A

pembrolizumab

40
Q

Theranostic radiopharmaceuticals

A

the combo of using one radioactive drug to identify and a second radioactive drug to deliver therapy to targeted tissue
biodistribution and uptake of diagnostic agent identified location and extent of disease; therapeutic agent binds to same receptors but delivers toxic dose of radiation directly to cell; unbound drug eliminated to minimize radiation damage to non-essential tissues in body

41
Q

Example of theranostic radiopharmaceutical

A

Lu-177 PSMA (pluvicto) - beta emitting therapeutic
SEs: myelosuppression, renal toxicity, dry mouth, GI toxicity

42
Q

Prostate cancer screening

A

digital rectal exam (DRE)
prostate specific antigen (PSA)

43
Q

Digital rectal exam

A

normla prostate has consistency of tip of nose, prostate cancer has consistency like chin; presence of lumps, hardness, inability to move prostate

44
Q

Prostate specific antigen

A

liquefied seminal secretions and increses with disorders of prostate
>4 ng/mL requires evaluation
< 10 ng/mL highly suspicious for malignancy
PSA velocity > 0.75 ng/mL rise per year suspicious for malignancy

45
Q

Transrectal ultrasonography (TRUS)

A

indicated after abnormal PSA or DRE

46
Q

ACS screening guidelines

A

start at age >/= 50 yrs
annual screening: PSA level >/= 2.5 ng/mL
every 2 years: PSA < 2.5 ng/mL

47
Q

High risk pts

A

discussion take place starting at age 45
african american men and men who have 1st degree relative diagnosed with prostate cancer at early age

48
Q

Prostate cancer prevention

A

finasteride: decreased rate of acute urinary retention, need for surgery of BPH, progression of BPH, and prostate cancer prevalence
pts that developed prostate cancer had disease with an increased gleason score; shrunk prostate enough to get better biopsies

PHRM 864 (20 decks)

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