Lecture 12 - Prostate Cancer Flashcards
Prostate cancer is the most common cancer in
men
2nd most common cause of cancer related death in men
1 in 8 men will be diagnosed with prostate cancer
Etiology/pathogenesis
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
Risk factors
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
Pathophysiology
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
Signs and symptoms
asymptomatic with early disease - can tell from elevated PSA levels
advanced disease: alterations in urinary habits, impotence, lower extremity edema, weight loss, anemia
Diagnosis
physical exam, PSA level, transrectal ultrasound, serum chemistries, bone scane, CT/MRI is suspect metastatic disease
biopsy of prostate
histology: adenocarcinoma
Pathology
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
Prostate specific antigen
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
Treatment overview
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
Treatment: localized - obervation
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
Treatment: localized - active surveillance
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
Treatment: localized - radiation therapy
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
Locally advanced/high risk
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
Treatment: localized - radical prostatectomy + PLND
definitive curative therapy; survival with surgery ~85% at 10 years
complications: early mortality, bladder contracture, incontinence, impotence
follow with ADT therapy
Androgen deprivation therapy
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
LHRH agonists
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!)
LHRH agonsit toxicities
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
Anti-androgens
flutamide
bicalutamide
nilutamide
these help prevent tumor flare
use these in combo with LHRH in metastatic setting
Metastatic prostate cancer
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
Metastatic disease: m0HSPC
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
Metastatic: LHRH agonists
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
Intermittent ADT: m0HSPC
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)
m0CRPC
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!
Enzalutamide
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
Apalutamide
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
Darolutamide
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
m1HSPC
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
Low volume m1HSPC
- ADT: LHRH agonists or LHRH antagonists
- continue ADT and add any of the following: abiraterone + prednisone, enzalutamide, apalutamide
Abiraterone acetate
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
High volume m1HSPC
could do any of the previously mentioned therapies:
ADT
ADT + abiraterone + prednisone
ADT + enzalutamide
ADT + apalutamide
now chemo becomes an option
High volume disease
visceral metastasis
4 or more bone metastases
at least one metastasis beyond pelvis vertebral column
m1HSPC = chemo + ADT
docetaxel + ADT for 1st line tx
more neutropenic fevers, fatigue, diarrhea, stomatitis, neuropathy
Newer data for high volume
use all for high-volume, castrate sensitive, metastatic disease
ADT + docetaxel + abiraterone
ADT + docetaxel + darolutamide
Metastatic castrate recurrent prostate cancer (CRPC)
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
m1CRPC
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)
Cabazitaxel - 2nd line therapy
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
Metastatic disease treatment oral therapies
docetaxel + prednisone
cabazitaxel + prednisone
mitoxantrone + prednisone
Bone metastases
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!
cancers that express dMMR/MSI-H
pembrolizumab
Theranostic radiopharmaceuticals
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
Example of theranostic radiopharmaceutical
Lu-177 PSMA (pluvicto) - beta emitting therapeutic
SEs: myelosuppression, renal toxicity, dry mouth, GI toxicity
Prostate cancer screening
digital rectal exam (DRE)
prostate specific antigen (PSA)
Digital rectal exam
normla prostate has consistency of tip of nose, prostate cancer has consistency like chin; presence of lumps, hardness, inability to move prostate
Prostate specific antigen
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
Transrectal ultrasonography (TRUS)
indicated after abnormal PSA or DRE
ACS screening guidelines
start at age >/= 50 yrs
annual screening: PSA level >/= 2.5 ng/mL
every 2 years: PSA < 2.5 ng/mL
High risk pts
discussion take place starting at age 45
african american men and men who have 1st degree relative diagnosed with prostate cancer at early age
Prostate cancer prevention
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
