CURRENT CONCEPTS IN PROSTATE DISEASE MANAGEMENT
| HERBS FOR THE PROSTATE: IS MOTHER NATURE SELLING SNAKE OIL ? J. Curtis Nickel, MD, Professor
and Canada Research Chair in Clinical Urology, Department of Urology, Queens University Faculty of Medicine;
Kingston General Hospital, Kingston, ON
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| Nontraditional complementary herbal therapy for prostate gland: billion dollar market in North America;
for benign prostatic hyperplasia (BPH)—sales of herbal remedies exceed combined sales of α-blockers and 5α-reductase
inhibitors; use of less expensive herbal preparations rivals use of leuteinizing hormone–releasing hormone
(LHRH) analogue therapy; physicians—often less informed than patients about herbal alternatives; require better
grasp of subject to advise patients; must determine whether herbal therapy actually beneficial; popularity of herbal
therapy based on—belief that natural therapies do not have side effects, advertising testimonials that validate benefits
of natural therapy, and low cost (due to absence of large profit margins); ease of purchasing over-the-counter
preparations; options include extracts of—saw palmetto berry (American dwarf palm or Serenoa repens); inner
bark of African plum tree (Pygeum africanum); rye pollen (Secale cereale; used for BPH and prostatitis); pumpkin
seeds (Cucurbita pepo); South African star grass roots (Hipoxis rooperi); stinging nettle (Urtica dioica); purple
coneflower (Echinacea purpurea; used to manage colds and prostate problems)
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| Extracted compounds: combinations of poorly characterized compounds including phytosterols, terpenoids, and
plant alcohols; vary in composition according to method used to obtain extract from leaf, berry, or root, eg, distillation,
or benzene or alcohol extraction; effort to analyze efficacy of extracted compounds hindered by—lack of information
about ingredients contained in various preparations; lack of standardized dosing (prevents accurate
comparison of specific preparations); common use of combinations; lack of stability studies, eg, active ingredients
can lose potency rapidly; experimental data based on supraphysiologic doses; poorly designed clinical trials; marketing
of herbal products based on—anecdotal experience of “experts”; testimonials of “patients”; history; packaging;
promotion of natural ingredients and nonpharmaceutical compounds
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| Saw palmetto berry extract: believed by proponents to possess characteristics beneficial for managing prostate
disease, including—inhibition of 5α-reductase, aromatase, and growth-factor activity; α-blockade; antiandrogenic,
antiestrogenic, antiedematous, and anti-inflammatory activity; ability to protect detrusor function, scavenge
free radicals, and reduce urethral resistance and levels of sex hormone–binding globulin; best studied phytotherapeutic
agent—compound standardized; active ingredients identifiable and comparable; Permixon—produced by
one company; most popular natural product in Europe for treating BPH; use of benzene extraction (carcinogenic) in
production process prevents distribution of agent in North America; saw palmetto—believed to be noncompetitive
inhibitor of types 1 and 2 isoforms of 5α-reductase; reduced intraprostatic levels of dihydrotestosterone (DHT)
when administered in supraphysiologic doses to animals; in test-tube studies, demonstrated ability to inhibit prostate
epithelial cell proliferation induced by fibroblast growth factor (FGF) and epidermal growth factor (EGF); exerts
anti-inflammatory effect in men with BPH by inhibiting synthesis of prostaglandins and leukotrienes
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| Clinical efficacy of saw palmetto berry extract: findings variable; some data suggest no clinically or statistically
significant effect on urodynamics
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 | Placebo-controlled studies in men with BPH: when compared to placebo group, men receiving extract during—1-
mo study had 32% decrease in nocturia, no difference in urinary frequency, and statistically significant improvement
in urine flow rate (both groups had similar numbers of patients who felt clinically better); 6-mo study had
statistically significant decline in international prostate symptom score (IPSS) findings, statistically insignificant
increase in quality of life, no change in sexual function, and slightly poorer urine flow rates
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| Permixon vs finasteride (Proscar): data from 6-mo trial suggest saw palmetto berry extract and Proscar demonstrate
similar efficacy; data from Proscar Long-Term Efficacy and Safety Study (PLESS) and Medical Therapy of Prostatic
Symptoms (MTOP) evaluation show that Proscar—increased prostate volume; produced no change in
prostate-specific antigen (PSA) level; produced greater changes in postvoid residual
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| α-blocker data show: combination of tamsulosin and saw palmetto berry extract no more effective than tamsulosin
alone; although tamsulosin and Permixon demonstrated equal efficacy, Permixon caused fewer ejaculation disturbances
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| Meta-analysis of placebo-controlled studies lasting several weeks to several years: no statistically significant differences
in overall efficacy between placebo and Permixon; when compared to placebo group, men taking
Permixon—achieved ≈1 mL/sec higher maximum urine flow rate (Qmax ); on average, spent one third less time
getting up at night to urinate (approaches statistical significance)
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| Observations: physician must tell patients that herbal therapy lasting 6 to 12 mo—is safe, but does not sufficiently
ameliorate BPH symptoms; provides poor return on investment; long-term analysis of herbal therapy—
benefits of herbal therapy may accrue over long term; 1-yr placebo-controlled trial of men with BPH randomized
to 160 mg of saw palmetto showed similar levels of improvement (compared to baseline) in both groups; new 5-
year dosing study will evaluate higher doses of saw palmetto
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| PROSTATE CANCER IN 40-YEAR-OLDS —Fray F. Marshall, MD, Professor and Chair, Department of Urology,
Emory University School of Medicine, Atlanta, GA
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| Prostate cancer in United States: ≈230,000 new cases diagnosed yearly; ≈27,000 cancer-related deaths in 2006;
men face 1 in 6 lifetime risk of developing disease; ≈25% of men with prostate cancer have known family history
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| Retrospective study of men <49 yr of age who underwent radical prostatectomy: designed to—
determine significance of family history of prostate cancer in men <49 yr of age; validate hypothesis that incidence
of family history of disease among patients <49 yr of age higher than previously reported; analysis of
study population showed—one third of patients <45 yr of age; incidence of positive family history 44% (dramatically
higher incidence than observed previously); T1c disease predominated; favorable positive margin rate;
study subjects—predominantly white; obtained on referral basis; insured
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| Observations: rate of prostate cancer among this age group higher than expected (10%); analysis of study subjects
showed—77% had first-degree relative with prostate cancer; 87% had significant disease; relative risk for prostate
cancer in man with family members diagnosed at any age—3.4 times greater if 1 sibling has disease (less
risk if father has disease); 5 times greater if 2 first-degree relatives have disease (debate exists as to whether this
high-risk family history alone should be used as basis for performing biopsy); additional aspect—risk of developing
disease greater if first-degree relative diagnosed at <65 yr of age
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| Conclusions: men <49 yr of age—can present with significant prostate cancer; with positive family history of
prostate cancer require PSA screening; radical prostatectomy viable alternative because younger patients—
generally healthier; typically have organ-confined disease; fare less well (long-term) with radiation therapy or
watchful waiting
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| CRYOTHERAPY FOR PROSTATE CANCER: EXPANDING INDICATIONS —Peter T. Nieh, MD, Assistant
Professor of Urology, Emory University School of Medicine, Atlanta, GA
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| Cryotherapy: speaker transitioned from skeptic to advocate; standard indications—primary T1-T3 disease; salvage
procedure after external beam radiotherapy, brachytherapy, or combination therapy; traditional indications
for salvage therapy—≤T2b disease; Gleason score ≤8; PSA <8 ng/mL; cryotherapy kills cells by—direct damage
from freeze-thaw cycle (intraoperatively); coagulative necrosis occurring days after treatment; apoptosis or gene-
regulated cell death
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| Standard approach performed until mid-1990s: used liquid nitrogen, large probes, and free-hand placement;
problems—difficulty controlling freeze rate and contour of ice ball; lack of temperature probes to facilitate procedure;
variable availability of urethral warming devices (situation complicated effort to preserve urethral mucosa);
tissue damage in patients who fail x-ray therapy (eg, lack of intensity-modulated radiation therapy [IMRT] and
conformal beam therapy produced wide target areas and indiscriminate radiation scatter)
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| Current third-generation cryotherapy: replaced nitrogen with argon; uses—small probes to contour gland;
brachytherapy template to expedite precise placement of cryoprobes; temperature probes routinely; urethral
warmer; double freeze-thaw approach—current standard; achieves better PSA nadirs; decreases positive biopsy
rates; recommendations—place suprapubic tube (cryotherapy produces marked amount of edema; patients probably
will not initiate voiding for ≈5 days after procedure); use ice rods to treat glands ≥40 cm3 ; with proper technique,
surgeon can—get exactly to rectourethralis; achieve well-defined margins (temperature probes limit
tissue damage); produce defect surrounded by rind (small bridge of urethral tissue goes through doughnut of necrosed
tissue); maintain well-epithelialized bladder neck; caveat—delayed tissue sloughing remains concern;
“cotton candy-like” material—can develop even though bulk of prostatic urethra well epithelialized; resilient,
adherent, and difficult to deal with; risk for incontinence precludes electrocautery; usual options include cold
loop excision, manual debridement of channel, and more prolonged suprapubic tube drainage
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| New cryotherapy approach: reduced incidence (<5%) of tissue sloughing, stress and urge incontinence, and urinary
retention; associated with rectal discomfort in some patients after salvage; no fistulas or infections detected;
erectile dysfunction (ED)—incidence high; many patients recover with time; other patients respond to oral or injected
agents; PSA nadir—81% of patients achieve 0.4-ng/mL nadir at 3 mo; little separation between high-risk
and low-risk groups at 12 mo
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| Salvage cryotherapy: biopsy-proven local recurrence—identifies appropriate candidates; biochemical disease-
free survival less likely in men with positive seminal vesicle involvement; clinician must determine whether to
use Prostascint scan or laparoscopic node dissection to confirm organ-confined disease
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| Pointers: use temperature probe to ensure external sphincter remains >15°; be careful around rectal wall—during
primary cryotherapy, ice ball should go 3 to 4 mm into anterior rectal wall (lethal zone ≈5 mm); use caution in
men who have undergone irradiation; indications for biopsy—>2 ng/mL increase in PSA above nadir occurring
≈6 mo after salvage cryotherapy; palpable disease recurrence; observation—PSA nadir better indicator of biochemical
and biopsy-proven treatment failure than pretreatment PSA level; meta-analysis of reasonably-sized
salvage cryotherapy data shows current approach—reduced rates of incontinence and obstruction; eliminated
rectal injuries and problems related to urethral sloughing; associated with reasonable biochemical recurrence
rate; patients who will do well include those who have—not received hormonal therapy; PSA <10 ng/mL and
Gleason score ≤8; pre-irradiation clinical stage T1 or T2 disease; factors predicting salvage failure—PSA >10
ng/mL; PSA doubling time <16 mo before salvage procedure
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| Nontraditional indications: minimal prostate disease—in patients with favorable disease factors, focal treatment
of minimal disease avoids widespread impact of radiation therapy and radical prostatectomy; retreatment with
nerve-sparing procedure remains option should problems occur after cryotherapy; large-volume prostate—
cryotherapy performed in patients with prostates <100 g can achieve satisfactory PSA levels and fewer voiding
symptoms; patients requesting radiation after failed medical therapy—in noncryotherapy environment, patients
wait 1 to 2 mo after surgery before undergoing radiotherapy; with cryotherapy, PSA levels decline and patient can
void within 2 to 3 wk following procedure; cryotherapy also can—help patients with high-risk disease who are
candidates for palliative therapy; be used to treat obese patients
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| Focal cryotherapy: not necessarily curative; viable means of improving quality of life, as long as patients accept
need for rebiopsy (data suggest targeting index cancer eliminates clinically significant disease in ≈80% of patients,
while minimizing incontinence and ED); option for patients with low-risk disease (60%-70% of patients in low-
risk group do not progress over time; 35% of these men have unifocal and unilateral disease); can be repeated multiple
times with minimal risk for injury; points—place probes unilaterally; to preserve neurovascular bundle, use
helium rather than argon to warm area while rest of tissue frozen; perform postoperative PSA evaluation every 3 to
6 mo, and biopsy evaluation at 6 mo after procedure and at 1, 2, and 5 yr (or whenever patient demonstrates 3 increases
in PSA); procedure achieves—disease-free survival 93%; high negative-biopsy rate; rate of potency preservation
≈90%
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| High-risk populations: patients of concern—have double-digit PSA levels and Gleason scores >8; can achieve
reasonable results from cryotherapy; ploidy—considered determining factor in treatment outcome; data show no
difference between diploid and aneuploid tumors for biochemical disease-free survival
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| Developments to improve results: salvage radiation therapy—remains option; imaging has increased efficacy;
combination of low-dose chemotherapy and cryotherapy in animal models—seems to produce synergistic effect;
may improve cancer cell kill rate by activating different parts of apoptotic cascade; has improved kill rate among cells
located along periphery of cryotherapy treatment zone; immunotherapy effect—cryotherapy may enhance efficiency
of immune response by releasing large amount of antigen from tumor
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| Fundamentals of cryotherapy: can be tailored to manage high-risk or low-risk disease; equals efficacy of radiation
therapy while achieving more rapid PSA nadir; helps relieve many lower urinary tract symptoms; allows clinician
to retreat patients with recurrent disease; point—due to developments in technology and technique,
complication rate now <5% in primary treatment and salvage populations
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Suggested Reading
Avins AL, Bent S: Saw palmetto and lower urinary tract symptoms: what is the latest evidence? Curr Urol Rep
7:260, 2006; Bemis DL et al: The use of herbal and over-the-counter dietary supplements for the prevention of
prostate cancer. Curr Urol Rep 7:166, 2006; Hotston MR et al: Young men with prostate cancer: are they different
and how should they be managed? BJU Int 99:5, 2007; Katz AE, Rewcastle JC: The current and potential role of
cryoablation as a primary therapy for localized prostate cancer. Curr Oncol Rep 5:231, 2003; Mouraviev V et al:
Salvage prostate cryoablation after primary interstitial brachytherapy failure: a feasible approach. Prostate Cancer
Prostatic Dis 9:99, 2006; Mouraviev V, Polascik TJ: Update on cryotherapy for prostate cancer 2006. Curr Opin
Urol 16:152, 2006; Perez-Castro E et al: International consultation on BPH sponsored by WHO. Report of the
sub-group on other non-medical treatment. Arch Esp Urol 45:723, 1992; Schleich S et al: Extracts from Pygeum africanum
and other ethnobotanical species with antiandrogenic activity. Planta Med 72:807, 2006; Ulbricht C et al:
Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration. J Soc Integr Oncol
4:170, 2006; Vestal JC: Critical review of the efficacy and safety of cryotherapy of the prostate. Curr Urol Rep
6:190, 2005.
Educational Objectives
| The goal of this program is to assess current trends in the management of prostate disease in order to maximize clinical
benefits to patients. After hearing and assimilating this program, the participant will be better able to:
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| 1. Discuss the importance of nontraditional complementary herbal therapies for prostate disease.
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| 2. Summarize current data on the clinical efficacy of saw palmetto (Serenoa repens) berry extract in the management
of benign prostatic hyperplasia.
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| 3. Determine the role of radical prostatectomy in managing prostate cancer in men in their 40s.
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| 4. Employ current techniques for performing cryotherapy for prostate cancer.
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| 5. Analyze current indications for performing cryotherapy in patients with prostate cancer.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Nickel is affiliated
with Boston Scientific, Boehringer Ingelheim, Farr Laboratories, GlaxoSmithKline Canada, Merck Frosst Canada,
Ortho-McNeil Pharmaceutical Inc, Plethora, Sanofi Aventis, and Threshold Pharmaceuticals.
Acknowledgements
Drs. Marshall and Nieh presented their scientific lectures at Advances in Urology 2006, held on December 1-2, 2006,
in Atlanta, GA, and sponsored by Emory University School of Medicine; Dr. Nickel gave his scientific lecture at
Current Concepts in Men’s Health 2006, presented August 11-12, 2006, in Bolton Landing, NY, and sponsored by
Albany Medical College, Albany, NY, and the Urological Institute of Northeastern New York. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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