PERILS OF THE PROSTATE
| BENIGN PROSTATIC HYPERPLASIA (BPH)—Christopher J. Kane, MD, Associate Professor and Vice Chair, Department
of Urology, University of California, San Francisco, School of Medicine
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| Introduction: BPH histologic diagnosis referring to stromal and epithelial cell hyperplasia; ≈50% of 60-yr-old men and
≈90% of 80-yr-old men have microscopic BPH; presence of lower urinary tract symptoms (LUTS) not nearly as prevalent,
as many men with histologic BPH asymptomatic; some men with LUTS do not have histologic BPH; moderate-to-
severe LUTS occurs in ≈50% of men with microscopic BPH; comment—American Urologic Association (AUA) panel
has recommended that term “LUTS suggestive of BPH” replace “BPH” and “prostatism”
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| Evaluation: history—ask about LUTS, previous surgery, conditions associated with polyuria or bladder dysfunction (eg,
diabetes, stroke, spine problems); voiding diary useful; utilize standarized questionnaires to help assess patient (AUA
Symptom Score and International Prostate Symptom Score [IPSS] available from AUA Web site)
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 | Physical examination: includes digital rectal examination (DRE), focused neurologic examination, mental status examination,
evaluation of ambulatory status, lower extremity neuromuscular function, and sphincter tone
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| Laboratory work-up: urinalysis; screen for bladder cancer (carcinoma in situ can mimic LUTS due to BPH); test for urinary
tract infection (UTI), microscopic hematuria (causes include urethral strictures and distal ureteral or bladder
stones); prostate-specific antigen (PSA; offer to patient with LUTS and ≥10 yr life expectancy); cytology (screening
test for bladder cancer; not done if no microhematuria); serum creatinine no longer recommended because renal insufficiency
usually not related to BPH
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| Symptom evaluation: speaker prefers 7-question AUA Symptom Score; maximum score 35; score ≥20 severe LUTS
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| Optional tests: flow rate and postvoid residual (usually reserved for someone with history of urinary retention); cystoscopy
(usually not done unless microscopic hematuria present or if surgery being considered); complex urodynamics
(generally reserved for patients who fail therapy and those suspected of having non-BPH cause of LUTS)
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| Indications for urologic referral: presence of urinary retention, complications of BPH, gross hematuria, bladder stones,
recurrent UTIs, or renal insufficiency
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| Approach to patients: reassurance sometimes adequate for patients with mild symptoms; optional tests sometimes required for
those with severe symptoms; most patients treated medically
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| Complementary medicine: saw palmetto no more effective than placebo (in large randomized study) for treating BPH;
advice—do not discourage use of saw palmetto, but do not recommend to new patients with LUTS
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| α1 -blockers: widely used in treating BPH; phenoxybenzamine (Dibenzyline)—used now only to treat pheochromocytoma;
prazosin (Minipress)—selective short-acting agent; has worse side-effect profile than other α-blockers; long-
acting selective agents—terazosin (Hytrin), doxazosin (Cardura), and alfuzosin (Uroxatral) most commonly used
agents; terazosin—titrated from 1 mg to 2 mg to 5 mg (normally 1 wk at each dose); usual maintenance dose 5 mg or 10
mg daily; doxazosin—usually titrated from 2 mg to 4 mg to 8 mg; usual maintenance dose 8 mg; side effects and efficacy
dose-related; alfuzosin—given once daily at 10 mg; no titration required; tamsulosin (Flomax)—only superselective
α1a -blocker; has slightly more favorable side-effect profile, but also more likely to cause retrograde ejaculation;
given 30 min after same meal every day
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| 5-α-reductase inhibitors: finasteride (Proscar)—lowers serum and intraprostatic dihydrotestosterone (DHT); increases
testosterone slightly; in Prostate Cancer Prevention Trial (PCPT), associated with ≈25% reduction in prostate cancer in men
taking it for 4 yr; useful for treating LUTS; dutasteride (Avodart) –blocks both type 1 and type 2 5-α-reductase; has
longer half-life; essentially equal to finasteride in efficacy
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| Medical Therapy of Prostatic Symptoms (MTOPS) trial: >3000 men over 4.5 yr randomized to doxazosin, finasteride,
combination therapy, or placebo; primary end point increase in symptom score or any adverse event, eg, acute urinary
retention, recurrent infection, incontinence, renal insufficiency; those in doxazosin and finasteride arms did about
equally well, but those in combination therapy group overall did better than those given either drug alone; most improvement
in AUA symptom score seen with doxazosin; incidence of invasive therapy lowest with finasteride; decrease in urinary
retention greater among those receiving finasteride and combination therapy
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| Therapeutic recommendations: α-blocker usual first-line drug for patients with LUTS; finasteride or dutasteride preferred
for patients with very large prostates; comments—improvement usually immediate for patients on α-blockers, whereas ≈6
mo required for improvement for those on 5-α-reductase inhibitors; combination therapy generally reserved for patients
with very large prostates
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| BPH complications: refer patient for interventional therapy
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| Prostate-specific antigen: quite sensitive, but not very specific for diagnosing prostate cancer; men in their 50s with PSA
>4 ng/mL have 30% chance of having prostate cancer on biopsy, whereas those in their 60s with PSA >4 ng/mL have
40% chance, and those in their 70s have 60% chance; comments—many men have low-grade prostate cancer that may
not require intervention; risk for high-grade cancer 18% in men in their 50s with PSA >4 ng/mL
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| PCPT: all subjects had end-of-study biopsy; chance of positive biopsy with PSA 3 to 4 ng/mL, 27%; in those with PSA 1
to 2 ng/mL, 17%; and in those with PSA 0 to 1 ng/mL, 8%
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| Observations: lifetime risk of developing prostate cancer 16% to 17%; lifetime risk of dying of prostate cancer ≈3%; prostate
cancers diagnosed at earlier stages because of PSA screening, but unknown whether mortality changing; newly diagnosed
metastatic disease now found in <1% of prostate cancer patients (before PSA screening, it accounted for ≈15% of
cases)
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| Tools for risk assessment: Kattan nomogram—available at www.nomograms.org; predicts likely 5-yr outcomes with
various therapies; Cancer of the Prostate Risk Assessment (CAPRA) system—uses scoring systems to predict biochemical
recurrence after radical prostatectomy; involves PSA, Gleason score, T-staging, percentage of positive biopsies, and patient’s
age
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| Pretreatment PSA velocity: rate of PSA increase during year immediately preceding diagnosis of prostate cancer; strong
predictor of outcome after surgery and radiation therapy; velocity ≥2 ng/mL per year strongly associated with poor outcome;
abnormal PSA velocity now considered ≥0.5 ng/mL per year
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| Factors involved in risk stratification: PSA; clinical stage; Gleason grade; number and extent of positive biopsies (biopsy
information more important than clinical staging for predicting outcome) PSA kinetics
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| Robotic radical prostatectomy: instruments placed into patient via ports; surgeon then operates by manipulating instruments
from remote console; currently accounts for ≈40% of radical prostatectomies; patient typically in hospital 1 day;
blood transfusion rate low; comments—patients can return to work within 2 wk; equivalent to traditional radical prostatectomy
in cancer control and recovery of continence and sexual function
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| Docetaxel (Taxotere): chemotherapeutic agent; improved survival (2 trials) for patients with metastatic prostate cancer refractory
to hormone therapy
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| Immune therapy: not approved by Food and Drug Administration (FDA); phase 3 trials show promise
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| QUESTIONS AND ANSWERS —Dr. Kane
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| Minimizing nighttime symptoms in men on α-blockers: give terazosin bid (1 dose in evening); once-daily dosing adequate
for doxazosin and tamsulosin because of long half-life
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| Generic vs tradename α-reductase inhibitors and α-blockers: generic agents equally effective; speaker likes Flomax
for frail elderly men and those with urinary retention because therapeutic levels achieved quickly; some individuals respond
better to particular agent, so if one α-blocker does not work, try another
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| PSA velocity changes after surgery: concern if velocity >0.5 ng/mL per year; other factors to consider include patient’s
age, ethnicity, and family history
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| Genetics of virulence: gene studies under way to subcategorize high-risk groups of men with prostate cancer
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| Dietary changes: subtle evidence suggests very low-fat diet may reduce risk of developing prostate cancer and its recurrence
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| Incontinence and sexual dysfunction rates after robotic radical prostatectomy: significant incontinence at 1 yr in
2% to 4% of men <70 yr of age and in 8% to 12% of those 70 to 75 yr of age; high prevalence of sexual dysfunction immediately
after surgery, but, by 6 mo, 50% of men can achieve partial erections, often with help of anti-impotence agents
(eg, sildenafil [Viagra]); at 1 yr, 70% of men can achieve erections adequate for intercourse, but erection quality usually
worse than before surgery; only 30% have normal erections after surgery
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| ADDITIONAL THOUGHTS ON PROSTATE CANCER AND BPH—Mark S. Litwin, MD, MPH, Professor of Urology
and Health Services, the David Geffen School of Medicine at the University of California, Los Angeles
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| Prostate cancer: 200,000 to 250,000 new cases yearly; mortality fairly flat, but slight decline seen in past 2 to 3 yr; epidemiologic
risk factors include advanced age (most important), race (prevalence highest among blacks and lowest among
Asians), and family history (men with first-degree relatives with prostate cancer have ≈2-fold increased risk; small subset
of men have highly transmissible rare form of prostate cancer); high-fat diet may increase risk (data soft)
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| Screening: no evidence it decreases population mortality; unknown whether treatment makes enough difference for
enough men to make screening worthwhile, so not recommended by most professional groups; those in favor recommend
screening men >50 yr of age with life expectancy ≥10 yr; begin earlier (40-45 yr of age) in blacks and men with
affected first-degree relatives; PSA “pretty accurate” screening test, but not perfect (more sensitive than specific at 4
ng/dL cutoff); issue of whether to refer for biopsy if PSA positive; PCPT concluded finasteride can help prevent prostate
cancer and that significant risk for prostate cancer exists in men with normal PSAs
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| PSA velocity: PSA increase of 0.75 ng/dL over 1 yr or 1.5 ng/dL over 2 yr more ominous than absolute PSA level; Boston
study concluded that PSA velocity predictive of diagnosis and of prognosis after therapy; those with rapidly rising PSAs
more likely to die; age-specific reference ranges for PSA—PSA 6 ng/dL acceptable for man in 70s; free PSA—lower
percentage of free PSA, more likely patient has cancer; suspect cancer if free PSA ratio <20%
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| PCPT: finasteride decreased incidence of prostate cancer by ≈33%; however, initial finding was that those who developed
cancer while on finasteride more likely to have higher grade tumors; histologic artifact now corrected; can now
tell patients finasteride does decrease prostate cancer risk
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| Diagnosis of prostate cancer: using transrectal ultrasonography, probe with 12 needle cores inserted into rectum and samples
taken from prostate (can still miss tumor); staging indicated once tumor detected; TNM system staging—most tumors
currently detected at T1c stage (nonpalpable, elevated PSA); T2 tumors palpable; Gleason sum—determined by
evaluating histologic patterns and adding them; first number of sum most prevalent histology, second less prevalent (eg, 4
plus 3 worse than 3 plus 4)
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| Factors contributing to poor prognosis: Gleason sum ≥7; high PSA (if PSA >10 ng/dL get bone scan to check for metastatic
disease; if PSA >20 ng/dL, do magnetic resonance imaging [MRI] or computed tomography [CT] of pelvis to
check for lymph node involvement)
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| Management of early-stage prostate cancer: radical prostatectomy—refer patient to experienced urologic surgeon;
pelvic irradiation—external beam radiation or brachytherapy; brachytherapy involves implantation of radioactive seeds
into prostate; risks include urinary problems and sexual and bowel dysfunction (for patients with Gleason score ≤7, long-
term outcomes equivalent for surgery or irradiation); watchful waiting—viable option for older patients and those with
low Gleason scores or low life expectancy
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| Management of advanced prostate cancer: androgen ablation—involves giving leuteinizing hormone-releasing hormone
(LHRH) antagonists or agonists, oral testosterone, or both; castration—controversial; expectant management—
option for older men with limited life expectancy; monitor for bone problems, ie, fractures; chemotherapy—option for
refractory cases
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| Follow-up: PSA “close to perfect” follow-up tool; management of recurrence—consider watchful waiting, depending on
clinical status of patient; if recurrence after surgery, can irradiate bed of prostate; if recurrence after radiation therapy, consider
pros-tatectomy (fraught with complications); consider cryotherapy in postirradiation patient; androgen ablation fallback
therapy
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| Benign prostatic hyperplasia: prevalence of histologic BPH increases with age; hyperplasia of glandular epithelium
causes large bulky prostate; hyperplasia of fibrous stroma causes “tight” but not necessarily larger prostate; obstructive
symptoms tend to resolve quickly with treatment; irritative symptoms caused by increased work of muscles to expel
urine and take longer to resolve; nocturia probably most bothersome symptom; physician should determine how much
of patient’s complaints due to dysfunction and how much due to bother or distress caused by dysfunction; acute urinary
retention more likely in patients with severe symptoms (often requires transurethral resection of prostate [TURP] or at
least medical therapy)
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| Reducing nocturia: tell hypertensive patients not to take diuretics in afternoon or evening and/or try to switch them to another
antihypertensive agent; ask patients to elevate legs during evening hours
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| Urethral strictures: cause same obstructive symptoms as BPH; causes include previous gonococcal urethritis, instrumentation
with Foley catheter, and bypass surgery
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| Points: unenlarged prostate gland does not rule out significant BPH; uroflow optimal diagnostic study; postvoid residual
urine useful test; PSA not part of BPH work-up
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| Management of BPH: expectant—good option if patient can tolerate bother; includes evening fluid restriction; α-blockers
and 5-α-reductase inhibitors—mainstay of treatment; surgery—TURP works well for relieving obstructive symptoms;
simple open prostatectomy reserved for patients with very large prostates
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Suggested Reading
Azzouz H, de la Rosette JJ: Radical prostatectomy for high-risk prostate cancer. Can J Urol 12(Suppl 2):33, 2005;
Dvorkin L, Song KY: Herbs for benign prostatic hyperplasia. Ann Pharmacother 36:1443, 2002; El-Hakim A et al:
Robotic prostatectomy: a pooled analysis of published literature. Expert Rev Anticancer Ther 6:11, 2006; Freedland
SJ et al: Delay of radical prostatectomy and risk of biochemical progression in men with low risk prostate cancer. J
Urol 175:1298, 2006; Freedland SJ et al: Preoperative model for predicting prostate specific antigen recurrence after
radical prostatectomy, using percent of biopsy tissue with cancer, biopsy Gleason grade, and serum prostate specific
antigen. J Urol 171:2215, 2004; Guay DR: Extended-release alfuzosin hydrochloride: a new α-adrenergic
receptor antagonist for symptomatic benign prostatic hyperplasia. Am J Geriatr Pharmacother 2:14, 2004; Hittelman
AB et al: Update of staging and risk assessment for prostate cancer patients. Curr Opin Urol 14:163, 2004;
Holmberg L et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.
N Engl J Med 347:781, 2002; Kane CJ et al: Changing nature of high-risk patients undergoing radical prostatectomy.
J Urol 177:113, 2007; Kane CJ et al: Obesity and prostate cancer clinical risk factors at presentation: data
from CaPSURE. J Urol 173:732, 2005; Kattan MW et al: Postoperative nomogram for disease recurrence after radical
prostatectomy for prostate cancer. J Clin Oncology 17:14989, 1999; Krupski TL et al: Patterns of care for men
with prostate cancer after failure of primary treatment. Cancer 15:258, 2006; Litwin MS, Miller DC: Treating older
men with prostate cancer: survival (or selection) of the fittest: JAMA 296:2733, 2006; Lowe FC: Role of the newer
α-adrenergic-receptor antagonists in the treatment of benign prostatic hyperplasia-related lower urinary tract symptoms.
Clin Ther 26:1701, 2004; McConnell DJ et al: The long-term effect of doxazosin, finasteride, and combination
therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349:2287, 1003; Miner M et
al: Treatment of lower urinary tract symptoms in benign prostatic hyperplasia and its impact on sexual dysfunction.
Clin Ther 28:13, 2006; Naderi N et al: Real life practice in the management of benign prostatic hyperplasia. Curr
Opin Urol 14:41, 2004; Sharifi N et al: Androgen deprivation therapy for prostate cancer. JAMA 294:238, 2005;
Sonn GA et al: Impact of diet on prostate cancer: a review. Prostate Cancer Prostatic Dis 8:304, 2005; Steineck G
et al: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 347:790, 2002; Teillac P et al:
The role of luteinizing hormone-releasing hormone therapy in locally advanced prostate cancer and biochemical
failure: considerations for optimal use. Clin Ther 27:273, 2005.
Educational Objectives
| The goal of this program is to improve management of patients with lower urinary tract symptoms (LUTS), benign
prostatic hyperplasia (BPH), and prostate cancer. After hearing and assimilating this program, the clinician will be
better able to:
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| Clinically evaluate patients suspected of having BPH.
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| Medically treat BPH with α-blockers and 5-α-reductase inhibitors.
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| Decide when to refer BPH patients for surgery.
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| Screen patients for prostate cancer and perform a diagnostic work-up on those with a positive prostate-specific
antigen (PSA) test.
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| Assess benefits and problems associated with various management stategies for early-stage and late-stage
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. Litwin has received
funding for scientific trials from TAP Pharmaceuticals, Amgen, and Sanofi-Aventis. Dr. Kane has financial relationships
with TAP Pharmaceuticals and Boehringer Ingelheim.
Acknowledgements
Dr. Litwin was recorded June 6, 2006, at the annual Family Practice Refresher Course, sponsored by the David Geffen
School of Medicine at the University of California, Los Angeles, and held in Beverly Hills, CA. Dr. Kane spoke
October 27, 2006, at Primary Care Medicine: Principles and Practice, sponsored by the University of California,
San Francisco, School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for making
this program possible.
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