Problems in Urology

From the University of Michigan Medical School’s Update in Urologic Health

Educational Objectives

The goal of this program is to improve prostate-specific antigen (PSA) screening practices and the clinical manage­ment of benign prostatic hyperplasia (BPH) and erectile dysfunction. After hearing and assimilating this program, the clinician will be better able to:

1.   Identify men most likely to benefit from regular PSA screening.

2.   Implement active surveillance protocols in patients with low-risk disease.

3.   Prevent the progression of urinary symptoms in patients with BPH.

4.   Discuss the role of 5-a reductase inhibitors in the prevention of prostate cancer.

5.   Evaluate and treat patients presenting with erectile dysfunction.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee 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. The following has been disclosed: Dr. Wei is a proctor for Amer­ican Medical Systems, serves on the advisory board of Envisioneering Inc., and receives research grants from sanofi-aven­tis. Drs. Montgomery and Hollingsworth and the planning committee reported nothing to disclose. In his lecture, Dr. Wei presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Drs. Montgomery, Wei, and Hollingsworth were recorded at Updates in Urological Health, held November 21, 2009, in Dearborn, MI, and sponsored by the University of Michigan Medical School. The Audio-Digest Foundation thanks the speakers and the University of Michigan Medical School for their cooperation in the production of this program.

PSA Screening: Indications and Controversies

Jeffrey S. Montgomery, MD, Assistant Professor, Department of Urology, Division of Urologic Oncology, Uni­versity of Michigan Medical School, Ann Arbor

Screening: prostate-specific antigen (PSA) testing  —  simple blood test; Medicare reimburses cost at $25 per test; higher false positive rates  —  lower PSA thresholds increase detection; advocates accept increases in negative biop­sies and morbidity associated with treatment for insignificant disease; higher false negative rates  —  raising PSA threshold prevents overtreatment; advocates argue lower detection rates justified by reduced costs and reduced morbidity associated with treatment; early detection may not change outcomes

Studies: Prostate, Lung, Colorectal, and Ovarian cancer Screening (PLCOS) trial (interim analysis)  —  38,000 men randomized to annual screening or usual care; compliance rate for annual PSA test, 85%; compliance rate for an­nual digital rectal examination (DRE), 86%; significant number of men in usual care arm also received annual PSAs and DREs; 7- to 10-yr follow-up; higher number of prostate cancers diagnosed in screening population; how­ever, death rate also higher, compared to usual care; criticism of study  —  high rate of screening in control group (di­lutes results); 7 to 10 yr possibly insufficient to identify true mortality benefit (prostate cancer often shows protracted course of 15 to 25 yr); absolute PSA of 4.0 ng/mL labeled positive (possibly inferior to kinetic PSA mea­surements and associated with underdiagnosis); 18% fewer high-risk prostate cancers diagnosed in screening group; speaker argues chance for earlier diagnosis of low- or intermediate-risk disease constitutes significant find­ing; European Randomized Screening for Prostate Cancer (ERSPC) study (2009)  —  participants randomized to screening group or control group; included 7 countries; 83,000 patients in screening group (»100,000 in control group); PSA obtained every 4 yr (average) in screening cohort (not typical in United States); after median follow-up of 9 yr, prostate cancer diagnosed in >8% of screened group and »5% of control group; rate of dying from pros­tate cancer decreased 20% in screened group; according to results, screening of >1400 men and treatment of »50 incidences required to prevent 1 prostate cancer death (cost-benefit ratio questionable); criticisms of study  —  utilized stagnant absolute value of PSA (3.0 ng/mL labeled positive); biopsy of 6 cores used almost universally (extended 10-18 core biopsies associated with £20% increase in diagnosis); greater diagnosis of localized prostate cancer shown in screened group (speaker cites as significant benefit); issues with PSA testing  —  poor sensitivity (35%-70%, depending on study); marginal specificity (60%-90%); historically, PSA level of 4.0 ng/mL absolute in­dication for biopsy; kinetics (eg, PSA density, PSA velocity, percent-free PSA) increasingly utilized to assess risks; other factors affecting PSA  —infection; inflammation; instrumentation (eg, catheterization may elevate PSA to ex­treme levels); urinary retention; recent ejaculation; vigorous prostate massage (standard DRE does not affect PSA); advanced age; benign enlargement

Prostate cancer diagnosis: American Urological Association’s (AUA) best practice statement on PSA (2009)  —baseline PSA should be obtained at 40 yr of age (high-grade, lethal cancers often occur at 40-60 yr of age); no sin­gle PSA threshold should prompt biopsy; PSA and DRE results, age, family history (incidence in first-degree rela­tives doubles risk), ethnicity (rates elevated among black men), previous biopsy history, comorbidities (eg, serious heart or lung disease), percent free PSA, PSA velocity, and PSA density should receive consideration before rec­ommending biopsy; National Comprehensive Cancer Network (NCCN) guidelines (2006)  —  similar to AUA guide­lines; patients with PSA >0.6 ng/mL may warrant annual screening with PSA and DRE; yearly screening recommended for blacks and patients with family history; patients with PSA <0.6 ng/mL rescreened after 5 yr; in absence of risk factors, begin yearly screening at 50 yr of age; patients with PSA level of <2.5 ng/mL or low PSA velocity receive continued follow-up with annual DRE and PSA test; patients with PSA level ³2.6 ng/mL or high PSA velocity should discuss risks (eg, infection, blood in urine or ejaculate) and benefits associated with biopsy; tolerance of prostate biopsies improved by delivery of local anesthetic to surrounding nerve bundles

Treatment options: watchful waiting  —  recommended for older patients with significant comorbidities; morbidity likely from other causes; cryotherapy  —  freezing of prostate; although protocols for selective cryotherapy exist, en­tire gland typically frozen (due to collateral nerve damage, only 20% of patients retain erectile function); open prostatectomy  —  less common with advent of robotic surgery; still recommended for some high-risk patients

University of Michigan’s active surveillance protocol: traditionally, patients with low-risk disease (ie, Gleason score of 6 and 2 positive biopsy cores) received recommendations for surgery or irradiation; active surveillance  —  increasingly recommended for low-risk patients; recommended for men <70 yr of age with Gleason score £6, or men >70 yr of age with Gleason score £3+4 (not recommended with Gleason score of 4 as dominant pattern); pa­tients eligible if one-third (or fewer) of biopsy cores found positive, or <50% of any 1 core involved; all men with PSA £10 ng/mL or clinical stage £T2b (unilateral disease) eligible; follow-up  —  patients <70 yr of age undergo confirmatory saturation biopsy (transrectal or transperineal, with 40-60 samples to confirm absence of widespread disease; typically well-tolerated due to general anesthesia); biopsies with 12 cores taken annually; saturation biopsy repeated at 5 yr; men >70 yr of age also receive saturation biopsy at entry, but only undergo 12-core biopsy every 2 to 3 yr; PSA, percent-free PSA, and physical examination repeated every 6 mo; moving to active treatment  —  indicated with increase in Gleason score, widespread disease, involvement in more of single biopsy core, higher PSA doubling time, or higher PSA velocity, or patient choice; rely on clinical judgment (ie, DRE findings prompt­ing greater concern may justify treatment)

Cessation of PSA screening: remains controversial; majority of experts recommend cessation between 70 and 85 yr of age; screening must be considered in context (speaker recommends only for patients with 10-15-yr life expec­tancy); cutoff depends on patient’s general condition and comorbidities; speaker recommends annual DRE for pa­tients past PSA cutoff age (potentially identifies extensive or aggressive late-onset cancers capable of metastasizing to bone and causing highly morbid fractures)

Medical Management of
Benign Prostatic Hyperplasia (BPH)

John Thomas Wei, MD, Professor of Urology, Associate Chairman for Research, Department of Urology, Uni­versity of Michigan Medical School, Ann Arbor

Differences in practice: BPH registry study  —  included 6900 men with BPH and urinary symptoms; 75% of patients managed by primary care provider received treatment with a-blockers (compared to 58% for group managed by urologists); on average, urologists 2.5 times more likely to provide prescriptions for patients presenting with lower urinary tract symptoms, 2 times more likely to recommend combination therapy (a-blocker plus 5-a reductase in­hibitor), and 1.5 times more likely to prescribe anticholinergic or antimuscarinic medication

Combination therapy: Medical Therapy Of Prostatic Symptoms (MTOPS) study and combination of dutasteride (Avodart) and Tamsulosin (combAT) trial  —  generally included men >50 yr of age with PSA <10 ng/mL, prostate size >30 g, minimal voided volumes, and AUA symptom scores >12 points, ie, at least moderate urinary symptoms; MTOPS  —  3000 men randomized to placebo, monotherapy (doxazosin or finas-teride), or combination therapy (doxazosin plus finasteride); progression of urinary symptoms (defined as 4-point increase in AUA symptom score) considered end point; change in symptoms (eg, documented urinary tract infection, new-onset urinary incontinence, acute urinary retention, surgery for lower urinary tract symptoms) considered progression; placebo group showed highest incidence of progression; monotherapy achieved middle-range results; combination therapy group showed lowest rate of progression (highly statistically significant); benefits of combination therapy occur after »1 yr; pa­tients with elevated residual urine receiving combination therapy show lower incidence of acute urinary retention and lower risk for prostate surgery for BPH; 1 incidence of progression prevented for every 8 patients treated with combination therapy (among populations with large prostates or high PSA levels, 1 progression prevented per 4 pa­tients treated); combAT  —  similar to MTOPS, but used newer generation of 5-a reductase inhibitors and a-blockers (dutasteride instead of finasteride, tamsulosin instead of doxazosin); patients randomized to dutasteride alone, tam­sulosin alone, or com-bination therapy (no placebo group); 12% of patients on combination therapy showed pro­gression (compared to 17% for dutasteride group and 20% for tamsulosin group; statistically significant result); patients on tamsulosin at risk for urinary retention and prostate surgery (not seen in patients receiving 5-a reductase inhibitor or combination therapy)

Reducing therapy: Symptom Management After Reducing Therapy (SMART-1) trial  —  patients received both dutas­teride and tamsulosin for 24 wk, then randomized to discontinue 1 drug; at 36 wk, 14% of men who discontinued tamsulosin during final 12 wk reported worsening of symptoms

Progression: data from MTOPS placebo group  —  larger total prostate volume, higher PSA level, low urinary flow rate, evidence of blockage on urodynamics, and difficulty emptying bladder associated with elevated risk for pro­gression

Overactive bladder: significant number of men with prostate disease present with comorbid bladder problems (eg, overactive or decompensated bladder; less frequently linked to medical issues [eg, stroke, spinal cord injury]); men with overactive bladder may not respond to treatments targeted at prostate; antimuscarinics  —  traditionally avoided due to risk of inducing urinary retention (emerging data show risk low); Kaplan study  —  600 men randomized to tolterodine, tamsulosin, combination therapy (tolterodine plus tamsulosin), or placebo; data derived from voiding diaries; all medications decreased incidence of urinary incontinence; combination therapy showed significantly greater reduction in urinary urgency and frequency; monotherapy not always superior to placebo; combination ther­apy reduced urinary urgency and frequency episodes by approximately one-third; insignificant differences in AUA symptom scores (scoring may be insufficiently sensitive to urgency and frequency symptoms; excessive reliance on symptom scores may lead to undertreatment of overactive bladder); botulinum toxin type A (BOTOX)  —  experimental procedure delivers 100 units or 300 units to prostate transrectally via ultrasound-guided needle; AUA data showed no significant side effects, and average AUA symptom score improvement of 7 points (clinically sig­nificant); second study showed similar results (average postvoid residual decreased from 200 mL to 75 mL)

Prevention of prostate cancer : shown with both finasteride and dutasteride (use in prevention remains off-label); Prostate Cancer Prevention Trial (PCPT)  —  7-yr trial including >18,000 men; found 25% overall reduction in risk for prostate cancer in men receiving 5-a reductase inhibitors (12-14 men treated per 1 incidence prevented); initial paper showed possible increase in high-grade cancers associated with finasteride (attributed to detection errors after continued analysis); REduction by DUtasteride of prostate Cancer Events (REDUCE) trial (2009)  —  utilized newer 5-a reductase inhibitor capable of blocking 2 receptor types (finasteride blocks only 1); included men 50 to 75 yr of age with PSA of 2.5 to 10 ng/mL; required negative biopsy 6 mo before enrollment; dutasteride reduced risk for prostate cancer by 23% (independent of age, family history, or prostate volume); greatest reductions in low-grade, indolent cancers with Gleason score of £6 (most prevalent type of prostate cancer); dutasteride does not necessarily prevent aggressive forms of disease

Evaluation and Diagnosis of Erectile Dysfunction

John M. Hollingsworth, MD, MS, Clinical Lecturer, Department of Urology, University of Michigan Medical School, Ann Arbor

Background on erectile dysfunction (ED): advanced age associated with 10-fold increase in relative risk (regardless of patient’s health status); etiology  —  dependent on timing of onset (gradual progressive history indicates organic ED; sudden or complete loss of function indicates social or psychologic causes [in absence of antecedent trauma])

Evaluation: ED may be presenting complaint indicating more serious medical conditions (eg, endothelial dysfunc­tion causing ED may result from cardiovascular disease, metabolic syndrome, or diabetes); PCPT data on ED  —cardiovascular events increased by 40% in patients with ED (compared to participants without ED); physiology of erections  —   blood flows into corpora cavernosa when stimulated by parasympathetic nerves, causing engorgement of sinusoids (compresses emissary veins necessary for drainage of corporal bodies); in men with venogenic ED, apoptosis of smooth muscle present as well as decreased nitric oxide; diagnostic evaluation  —  establish any history of vascular or neurologic trauma (associated with surgery, radiation therapy, or pelvic trauma); review patient’s cur­rent medications (eg, diuretics, antihypertensives, cholesterol-lowering medications, selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants, H₂-receptor antagonists); document sexual history (involving patient’s partner often helpful); differentiate ED from other sexual problems (eg, premature ejaculation); assess total effect on sexual performance; note anxiety issues associated with urologic complaints; standardized questionnaire for as­sessing sexual function recommended; physical examination  —  assess abdomen, penis, testicles, secondary sexual characteristics, and lower extremity pulses; underdeveloped testicles, gynecomastia, and reduced body and facial hair indicate hypogonadism; American College of Physicians (ACP) guidelines for hypogonadism  —  prevalence of low testosterone in patients with ED ranges from 12.5% to 36%; due to inconsistent data, ACP neither recommends nor discourages blood tests for hormones in management of ED; testosterone  — no established threshold level nec­essary for erectile function; low levels warrant repeated measurement (include surveillance of prolactin and lutein­izing hormone); glucose and lipid measurements, complete blood cell count, and renal function testing also recommended; routine vascular assessment not recommended

Suggested Reading

Andriole GL et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360:1310, 2009; Crawford ED et al: Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 175:1422, 2006; Kaplan SA et al: Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 296:2319, 2006; Large MC, Eggener SE: Active surveillance for low-risk localized prostate cancer. Oncology (Williston Park) 23:974, 2009; McConnell JD et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Eng J Med 349:2387, 2003; McVary KT: Clinical Practice. Erectile Dysfunction. N Engl J Med 357:2472, 2007; Qaseem A et al: Hormonal testing and pharmacologic treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians. Ann Intern Med 151:639, 2009; Roehr­born CG et al: The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. J Urol 179:616, 2008; Saigal CS, Joyce G: Economic costs of benign prostatic hy­perplasia in the private sector. J Urol 173:1309; Schröder FH et al: Screening and prostate-cancer mortality in a randomized Euro­pean study. N Engl J Med 360:1320, 2009; Siami P et al: Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement. Contemp Clin Trials 28:770, 2007.