PEARLS ON PROSTATE DISEASE
| PROSTATE-SPECIFIC ANTIGEN ELEVATION FOLLOWING RADICAL PROSTATECTOMY: WHEN AND WHAT
TO DO —Charles B. Brendler, MD, Professor and Chief, Section of Urology, Pritzker School of Medicine, University of
Chicago
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| Prostate-specific antigen (PSA) nadir: primary radical prostatectomy—may be effective in men with PSA nadir from >0.1
ng/mL to <0.2 ng/mL; will fail in men with PSA nadir >0.2 ng/mL, or PSA >0.4 ng/mL on single evaluation; manifestations
of metastatic disease—inability to achieve PSA nadir <0.2 ng/mL; rapid increase in PSA following prostatectomy; point—
attempts at subsequent local therapy probably ineffective if patient does not achieve postoperative PSA nadir of 0.2 ng/mL
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| PSA assessment: ultrasensitive PSA—facilitates early detection of recurrence; may replace standard PSA evaluation; risk
for failure increases if patient cannot achieve PSA nadir <0.01 ng/mL; standard PSA—0.1 ng/mL cut point; risk for subsequent
increase in PSA among men with PSA nadir of 0.1 ng/ml is 36% at 1 yr and 67% at 3 yr; men with PSA nadir of
0.3 ng/mL have failure rate of 86% at 1 yr
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| Radical prostatectomy: failure rate disappointing, ie, 15% to 20% of patients fail after 5 yr; classification of risk—low
(PSA <10 ng/mL; low-volume disease; low Gleason score); intermediate (intermediate PSA; higher disease stage and
Gleason score); high (PSA >20 ng/mL; ≥T2c disease; Gleason score ≥8); PSA velocity—preoperative risk factor; men
with increase in PSA >2 ng/mL during year before diagnosis had markedly increased risk for postoperative failure and
cancer-related mortality
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 | Postoperative risk factors: pathologic stage; disease extending beyond prostatic capsule; Gleason score; surgical margin
status; extraprostatic extension; seminal vesicle invasion—≤30% of men with vesicle invasion cured with radical prostatectomy;
significant number of patients with vesicle invasion remain disease-free following surgery, ie, finding
stresses need to remove seminal vesicles in people with large-volume disease; pelvic lymph node metastases—
extended lymph node dissection may provide cure
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| Prognostic analysis: prognosis classified by increasing pathologic parameters of adversity; biochemical survival at 10
yr—95% in men with organ-confined disease or extraprostatic extension, Gleason score of 6, and margin-negative
disease; 13% in men with positive nodes
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| Important postoperative factors: points—likelihood of biochemical disease-free survival 95% at 15 yr among men with
excellent parameters; men in poor-risk group fail, regardless of duration of follow-up; PSA doubling time—key prognostic
factor; patients with long doubling times (ie, >10 mo) have better chance of extended survival and responding
well to localized adjuvant therapy; time to failure—efficacy of subsequent adjuvant therapy determined by length of
time patient can maintain undetectable PSA level following primary therapy; patients who never achieve postoperative
PSA nadir following surgery have metastatic disease and less likely to respond to local adjuvant therapy
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| Detection of residual disease: most tests do not detect residual disease early enough to permit effective local adjuvant therapy,
eg, to be effective, radiation therapy should be administered before PSA level reaches 1.0 ng/mL; ultrasensitive
PSA—detects recurrent disease 10 mo earlier than conventional PSA evaluation; combined with PSA doubling time to
distinguish between benign and malignant disease; digital rectal examination (DRE)—not helpful; abnormal DRE preceded
by detectable PSA; has difficulty distinguishing fibrosis from recurrent cancer; 71% of patients with abnormal
DRE have positive biopsy; transrectal ultrasonography (TRUS) biopsy evaluation of prostatic fossa—sensitivity low
when PSA <1.0 ng/mL; biopsy of vesicourethral anastomosis (VUA) useless when TRUS negative and PSA >2.0 ng/mL,
ie, these patients usually have metastatic disease; should include 6 biopsies of VUA plus biopsies of other TRUS-detected
abnormalities; should be combined with color flow Doppler evaluation; endorectal coil magnetic resonance imaging
(MRI)—most sensitive radiographic test for detecting locally recurrent prostate cancer at low PSA; bone scan and
computed tomography (CT)—lack sensitivity; of little value at low PSA; prostascint scan—less effective than expected;
cannot predict biochemical control after salvage radiation therapy; positron emission tomography (PET)—lacks
sensitivity; 4% of patients with PSA <3 ng/mL have positive scans; reverse transcriptase polymerase chain reaction (RT-
PCR)—overly sensitive in predicting metastatic disease; accuracy unproven
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| Natural history of disease following PCA elevation: can reassure concerned patient, ie, once PSA level detectable, patient
receiving hormonal therapy alone has median survival of 13 yr; patients who fail late do better than patients who fail
early, ie, individuals with detectable PSA on first postoperative PSA evaluation have worst outcome; metastasis—
develops ≈5 yr after failed prostatectomy; patients can survive additional 5 yr after development of metastases
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| Options following failure of radical prostatectomy
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| Adjuvant external beam radiotherapy: early administration can salvage many properly selected patients; best candidates include
men with—poor Gleason scores; prolonged biochemical disease-free survival; prolonged PSA doubling times;
positive surgical margins, ie, disease most likely contained within prostatic fossa; negative seminal vesicles (men with positive
vesicles often have occult metastatic disease); point—adjuvant radiation more effective than salvage radiotherapy;
people with positive margins and no detectable PSA—should not be irradiated; may not have residual disease, ie, ≤50%
of men with low-grade disease and positive margins will not fail following radical prostatectomy; wait until patient develops
biochemical failure before administering radiation; tips on timing—ultrasensitive PSA evaluation may facilitate
early initiation of therapy; PSA doubling time helps distinguish between benign and malignant disease; wait 3 mo after
surgery to permit healing of VUA; efficacy in properly selected patients—biochemical cure rate with conformal external
beam radiation therapy (XRT) 45% to 50% at 4 yr
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| Adjuvant hormonal therapy: concerns—early hormonal therapy not recommended in men with node-positive disease; continuous
androgen blockade associated with many side effects; many men cured by radical prostatectomy receive unnecessary hormonal
therapy; early adjuvant hormonal therapy following radical prostatectomy—eliminates PSA as marker for local
recurrence and ability to administer potentially curative, rather than palliative, therapy; delays disease recurrence; does not affect
disease-specific or overall survival, ie, data suggest approach may improve survival in men with aggressive tumors but
does not affect clinical metastases; bottom line—potential benefit of early hormonal therapy must be weighed against side effects
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| METASTATIC PROSTATE CANCER: STRATEGIES FOR HORMONAL THERAPY —Julie A. Kish, MD, Professor
of Medicine, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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| Standard options for achieving androgen deprivation: orchiectomy—viable option when patient sexually inactive;
compliance friendly; relatively inexpensive; irreversible; psychologic side effects; leuteinizing hormone–releasing hormone
(LHRH) agonists—reversible; work via negative feedback; can produce flare reaction; available options include
leuprolide (Eligard, Lupron) and goserelin (Zoladex); LHRH antagonist, ie, abarelix (Plenaxis)—avoids flare reaction;
diethylstilbestrol (DES)—least expensive agent for achieving androgen deprivation; difficult to obtain; many complications;
nonsteroidal antiandrogens, ie, androgen receptor blockers—bicalutamide (Casodex; standard drug; expensive);
flutamide (Eulexin; less expensive; taken tid; causes diarrhea); nilutamide (Nilandron; causes night vision problems)
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| Complete androgen blockade vs castration monotherapy in men with metastatic disease: early data differ concerning
efficacy of androgen blockade (ie, combination of LHRH agonist and antiandrogen) vs castration; problem may be related
to—incomplete androgen blockade; influence of flare phenomenon on results; unidentified LHRH agonist activity;
value of administering LHRH agonist and antiandrogen up front—meta-analysis shows approach does not make much
difference in overall progression-free survival; finding facilitates use of more sequential therapy
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| Continuous vs intermittent androgen ablation in men with metastatic disease: side effects of continuous androgen
deprivation—loss of libido and potency; fatigue and asthenia in young men; weight gain; muscle atrophy; osteopenia
and osteoporosis; depression; loss of cognitive function in younger men with biochemical recurrence; anemia; hot
flushes; gynecomastia; decrease in high-density lipoprotein (HDL); liver enzyme abnormalities; patients must—
understand long-term consequences of continuous hormonal therapy; implement preventive measures while on therapy,
eg, exercise, monitoring diet
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| Intermittent therapy: advantages—decreased side effects and cost; prolongation of hormone-sensitive state; approach—
requires hormonal therapy be stopped once appropriate PSA level achieved; therapy resumed once testosterone and
PSA begin to increase; limited data show—most patients remain off of hormonal therapy for 6 to 10 mo and respond
well when therapy resumed; intermittent approach superior to continuous therapy; point—trial under way
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| Second-line hormonal therapy: considered when patient has rising PSA with metastatic disease or after monotherapy for
PSA-rising disease; antiandrogen withdrawal—first step in men receiving antiandrogen, ie, 15% to 30% of men who respond
to hormonal therapy respond to antiandrogen withdrawal alone; response lasts 3.5 to 6 mo, but postpones chemotherapy;
addition of antiandrogen—indicated in men receiving LHRH agonist who experience increased PSA with
metastatic disease; limited data on efficacy; well tolerated; approach to second-line therapy—withdraw antiandrogen;
following withdrawal of long-acting bicalutamide, allow 6 to 8 wk before initial PSA evaluation, ie, PSA level will drop
≤4 wk after withdrawal of flutamide; inhibition of adrenal androgens—effective; estrogens difficult to obtain
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| Second antiandrogen: option when patient on LHRH agonist—fails addition of bicalutamide; does not have overwhelming
disease (ie, no drastic change on radiographic imaging), lymphatic disease, or obstruction; flutamide therapy—
usually administered; requires patient be informed of side effects; dosing starts low and increases slowly; bicalutamide
can be given to men with PSA-rising disease—protocol requires 150 mg/day dosing; use not approved by Food and Drug
Administration (FDA); expensive
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| Antiandrogen monotherapy: inferior to maximal androgen blockade for distant disease; combined with LHRH agonist to
manage metastatic disease; results comparable to combination therapy when used to manage nonmetastatic disease; bicalutamide
alone—reduces side effects in men with biochemical recurrence and no obvious disease; permits flexibility
of response if initial monotherapy fails
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| Inhibition of adrenal androgen levels
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| Combination of ketoconazole with hydrocortisone: works better than combination of aminoglutethimide and hydrocortisone;
ketoconazole—taken in acid gastric environment, ie, patient should not be taking H2 blockers; side effects include
malaise and influenza-like symptoms; to avoid problems, increase dose gradually; hydrocortisone—started immediately
to prevent adrenal insufficiency
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| Hormone-refractory/androgen-independent cases: serum testosterone—used to monitor efficacy of LHRH agonist therapy;
should be 20 ng/dL; point—when LHRH agonist therapy fails to achieve castrate levels of serum testosterone, consider
orchiectomy; LHRH agonist therapy in patients with hormone-refractory disease—maintained even when patient
receives chemotherapy, ie, bicalutamide and ketoconazole therapy can be stopped; data show—continued suppression
associated with 2- to 6-mo survival advantage; recurrent prostate cancer tissue contains androgen receptors
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| Biochemical recurrence in hormonal therapy: nontraditional options—antiandrogen monotherapy (spares potency;
fewer side effects; survival benefit with PSA recurrence unproven); combination of 5-α-reductase inhibitors and antiandrogen
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| Additional aspects: hormonal therapy with surgery (no role for neoadjuvant therapy); rising PSA after radical
prostatectomy—median duration of response to androgen deprivation 10 yr; median survival after PSA begins to rise
during androgen deprivation ≈25 mo; point—in some men, prostate cancer has become chronic disease where duration
of survival increases and side effects must be dealt with
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| Androgen suppression with external irradiation: provides better overall survival than irradiation alone; patients with
high-risk disease—have Gleason score ≥7, PSA between 10 ng/mL and 40 ng/mL; have 12% to 30% cancer-specific
mortality rate; achieved better survival rate with combination of hormonal therapy and irradiation than with irradiation
alone; androgen suppression for 6 mo minimizes—osteopenia; cognitive impairment; anemia; hot flushes; muscle
wasting; impaired libido; impotence
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| Clinical trials: key concern; prostate cancer lags behind breast cancer in terms of participation; factors that may contribute
to problem—greater awareness of breast cancer; younger population developing breast cancer; treatment biases of physicians
who manage prostate cancer
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| BIPOLAR SALINE TRANSURETHRAL RESECTION OF THE PROSTATE —Richard A. Santucci, MD, Assistant Professor,
Wayne State University School of Medicine, Detroit, and Chief of Urology, Detroit Receiving Hospital
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| Gyrus bipolar PlasmaKinetic system: uses saline irrigation; should eliminate transurethral resection of prostate (TURP)
syndrome; provides better hemostasis while retaining basic TURP operation; study data show TURP performed using
Gyrus device—reduces duration of postoperative catheterization and hospitalization; produces lower complication rates;
achieves durable postoperative results
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| Additional points: new software resolved problems encountered with earlier Gyrus design; “sled-like” attachment facilitates
surgery on patients who take warfarin (Coumadin); PlasmaKinetic system can also perform—open and laparoscopic
bipolar cautery; bladder tumor surgery
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Educational Objectives
| The goal of this program is to educate the listener about current techniques for managing prostate disease. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Identify patients at risk of developing elevated prostate-specific antigen (PSA) levels following radical prostatectomy.
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| 2. Assess the relative clinical merits of various options used to manage patients who develop elevated PSA levels following
radical prostatectomy.
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| 3. Describe various forms of hormonal therapy used to manage metastatic prostate cancer.
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| 4. Discuss key issues surrounding the use of hormonal therapy in patients who have metastatic prostate cancer.
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| 5. Evaluate the clinical benefits of using the Gyrus PlasmaKinetic system and saline irrigation to perform transurethral
resection of the prostate (TURP).
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Discussed on This Program
Abarelix [Plenaxis]
Aminoglutethimide [Cytadren] 3/16/06
Bicalutamide [Casodex]
Diethylstilbestrol diphosphate (DES) [Stilphostrol]
Flutamide [Eulexin]
Goserelin acetate [Zoladex]
Hydrocortisone (cortisol) [several trade names and preparations]
Ketoconazole [Nizoral, Nizoral Cream Shampoo]
Leuprolide acetate [Eligard, Lupron (several trade names and preparations)]
Nilutamide [Nilandron]
Paclitaxel [Onxol, Paxene, Taxol, Abraxane]
Warfarin sodium [Coumadin]
Suggested Reading
D’Amico AV et al: Predicting prostate specific antigen outcome preoperatively in the prostate specific antigen era. J Urol
166:2185, 2001; D’Amico AV et al: Preoperative PSA velocity and the risk of death from prostate cancer after radical
prostatectomy. N Engl J Med 351:125, 2004; De Sio M et al: Gyrus bipolar versus standard monopolar transurethral resection
of the prostate: a randomized prospective trial. Urology 67:69, 2006; Kish JA et al: The treatment challenge of hormone-refractory
prostate cancer. Cancer Control 8:487, 2001; Messing EM et al: Immediate hormonal therapy compared
with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N
Engl J Med 341:1781, 1999; Moul JW et al: Early versus delayed hormonal therapy for prostate specific antigen only recurrence
of prostate cancer after radical prostatectomy. J Urol 171:1141, 2004; Petrylak DP: Future directions in the treatment
of androgen-independent prostate cancer. Urology 65:8, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty
reported nothing to disclose.
Drs. Brendler and Kish gave their scientific presentations at the 15th Annual Advances in Urology, presented March 30 to
April 2, 2005, in Key West, Florida by the University of South Florida College of Medicine and the H. Lee Moffitt Cancer
Center and Research Institute; Dr. Santucci gave his scientific presentation at the 7th Great Lakes Urology Seminar, presented
March 11 to 12, 2005, in Troy, Michigan, by Imedex. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
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