UPDATE ON PROSTATE DISEASE MANAGEMENT
From the University of Texas Southwestern Medical School’s 13th Annual Paul C. Peters Urology Symposium
| MEDICAL THERAPY FOR BENIGN PROSTATIC HYPERPLASIA (BPH) AND LOWER URINARY TRACT SYMPTOMS
(LUTS)—Claus G. Roehrborn, MD, Professor and Chair, Department of Urology, University of Texas Southwestern
Medical Center, Dallas
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| Aging male population and urologic practice
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 | Men ≥65 yr of age in United States: report released by National Institutes of Health (NIH); documents aging of general
population; since 1900, life expectancy from birth and from age 65 yr increased markedly for men and women; treatment
decisions for men with prostate cancer currently based on—≈12-yr life expectancy for men aged 70 yr; ≈10-yr
life expectancy for men aged 72 yr; “baby boomers”—will have significant effect on urologic practice; between 2000
and 2030, population that forms core of urologic patient population expected to double
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| Urology workforce issues: observations—incidence of prostate disease increases with age; because current workforce
remains stable or shrinking, any increase in aging population will increase physician’s workload; eg, between 2000 and
2020, number of men eligible for treatment of benign prostatic hyperplasia (BPH) will increase from 6.5 to 10.3 million;
additional factors adding to workload—increased awareness of prostate diseases among general population; increasing
number of patients seeking care for symptoms related to BPH and lower urinary tract symptoms (LUTS);
bottom line—LUTS and BPH already occupy large portion of physician’s time and make significant contribution to
cost of medical care
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| Benign prostatic hyperplasia: once believed to be strictly glandular process involving androgen-derived prostate
growth or growth factors; current data show many other factors also contribute to BPH and LUTS
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| Inflammation: expressions of cytokines and growth factors in BPH tissue suggest hypoxia and inflammation play role in
disease pathophysiology; data suggest—50% to 75% of tissue specimens obtained from biopsy or transurethral resection
of prostate (TURP) contain some element of chronic inflammation; patients with inflammatory infiltrates in biopsy
tissue specimens more likely to progress to urinary retention and to require surgery; presence of chronic
inflammation should be considered important prognostic indicator in men with BPH and LUTS; in men with BPH,
“straight up” correlation exists between prostate-specific antigen (PSA) level, symptom score, and interleukin-8 (IL-8)
level (correlation less strong in men with chronic pelvic pain syndrome, ie, chronic prostatitis); serum levels of C-reactive
protein tend to be elevated in men with LUTS
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| Olmsted County study evaluating protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in men with BPH:
showed marked correlation between regular use of NSAIDs and severity of LUTS and BPH symptoms; determined
NSAID therapy protective against many outcomes, including prostate growth >30 g, PSA >1.4 ng/mL, need to perform
surgery for BPH, and development of acute urinary retention and maximum urine flow rates <12 mL/sec; provides additional
circumstantial evidence pinpointing pathogenic role of inflammatory infiltrates
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| Sex and the prostate: clinical data show—erectile dysfunction (ED) highly correlated with LUTS symptomatology;
patients receiving phosphodiesterase type 5 (PDE-5) inhibitors for ED noticed improvement in voiding function
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| PDE-5 inhibitors: relax smooth muscle in prostate, prostate capsule, and bladder neck; currently tested as treatment option
for men with BPH and LUTS; tadalafil—compared to placebo, once-daily administration of tadalafil (5 mg for 6
wk and 20 mg for additional 6 wk) improved erectile function (in subset of men with ED), quality-of-life scores, global
assessment scores, and BPH impact index (results comparable to those with α-blocker therapy); peak urinary flow rate
unchanged; sildenafil—men ≥45 yr of age with mild ED and LUTS received 50-mg or 100-mg doses at bedtime or before
sexual activity; improved ED scores, irritative and obstructive symptom scores, and BPH impact index vs placebo;
peak urinary flow rate remained unchanged; combination therapy in men with LUTS and ED—study population randomized
to alfuzosin (Uroxatral; α-blocker) and/or sildenafil for 12 wk; achieved greatest improvement in LUTS
symptom score, urine flow rate, and erectile function, compared to either drug administered alone; larger placebo-controlled
trials necessary
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| Doxazosin extended-release tablets (Cardura XL): slow-release α -blocker; maintains clinical efficacy while reducing
incidence of asthenia, dizziness, dyspnea, and postural hypotension associated with high plasma levels generated
by immediate-release formulations, ie, terazosin and doxazosin
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| Leuteinizing hormone-releasing hormone (LHRH) antagonists: points—LHRH agonists initially increase
testosterone levels (undesirable effect in men with prostate cancer); LHRH antagonists considered positive alternative
until patients receiving abarelix (Plenaxis) developed anaphylaxis (problem believed related to manufacturing process,
not drug itself)
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| Ozarelix: fourth-generation LHRH antagonist in phase 3 trials; does not seem to have same anaphylaxis risk as abarelix;
immediately suppresses testosterone production; renders intermittent therapy more attractive option, ie, lack of flare or
surge effect and slower onset of action has presumably reduced risk for side effects; intermittent ozarelix therapy in
BPH—drug provides dose-dependent suppression of testosterone; compared to placebo, drug achieved marked improvement
in symptom scores, fairly sustained improvement in urine flow rate, slight reduction in prostate size, intermittent
but significant reductions in serum testosterone levels, and no significant impact on erectile function; bottom
line—drug requires further evaluation
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| Current medical therapy: has hit “glass ceiling”; on average, achieves 3- to 6-point improvement in LUTS and BPH
symptom scores and leads to fair and sometimes good responses; cannot achieve good-to-excellent responses in patients
with more severe symptoms; points—combining α-blocker and 5-α-reductase inhibitor has improved outcome for select
patients; new targets and drug classes needed to achieve quantum leap forward in therapy; PDE-5 inhibitors can be used
on daily basis rather than intermittently (ED disappears and LUTS symptoms improve); intermittently administered
LHRH antagonists may provide treatment breakthrough; concept of inflammation must be tested
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| THERAPY FOR HORMONE-REFRACTORY PROSTATE CANCER (HRPC)—Oliver Sartor, MD, Dana-Farber Cancer
Institute, Harvard Medical School, Boston, MA
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| Hormone-refractory prostate cancer: cancer cells—demonstrate considerable heterogeneity; can be androgen-dependent
or androgen-independent; within heterogeneity, increasing tendency toward true androgen dependence over
time
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| Prostate cancer stem cell model: evaluates heterogeneity of cancer cells; “mother ship” cell—constitutes minority of
cells and probably does not express androgen receptor; produces well-differentiated daughter cells that are androgen-
receptor positive and retain some androgen sensitivity; points—diseased tissue considered hormone refractory may
contain androgen-independent stem cells; however, heterogeneous androgen-sensitive population of daughter cells
also can be present; stem cell markers for hormone-refractory disease—located in basal layer of prostate; reflect heterogeneity
of cell population
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| Upregulation of: androgen receptor seen with HRPC—consistent finding; implies significant number of prostate cancer
cells continue to be driven by androgen-dependent stimuli, ie, data suggest some prostate cancer cells may synthesize
their own androgens; 5-α-reductase type I—5.3-fold increase in enzyme occurs in conversion from androstenedione
to testosterone
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| Paradox: in men with HRPC, critical androgen-dependent pathways continue to be expressed, and androgen receptors
and synthetic enzymes upregulated
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| Changes in spectrum of HRPC: associated with changes in natural history of disease, not changes in treatment approach;
requires that urologists change mindset about what constitutes HRPC; in pre-PSA era, disease characterized
by—bony metastases; pain; bulky nodal disease; high PSA levels; today, men presenting with HRPC—typically have
rising PSA level after initial endocrine therapy; rarely have bone and nodal metastases; have low PSA levels, ie, many
men with PSAs of 1 or 2 ng/mL being labeled as having HRPC
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| Change in natural history of disease: 1993 data evaluating progression of prostate cancer in men with predominantly
stage D2 disease—patients died 52 wk after detection of elevated PSA levels, and 41 wk after detection of bone progression;
additional data showed 6-mo interval between detection of progression on PSA evaluation to detection on
bone scan, and 10-mo interval between detection on bone scan and progression to pain; evaluation of 254 men initially
treated with hormonal therapy for N0/M0 or M1b disease—HRPC diagnosed when PSA levels began to increase; duration
of survival (after PSA levels began to increase) 68 mo for men with bone scan-negative disease and 40 mo for
men with bone scan-positive disease
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| Options for managing HRPC: withdrawal or administration of antiandrogens; adrenal suppressants (eg, ketoconazole);
corticosteroids (prednisone and dexamethasone); estrogens (diethylstilbestrol [DES]); external beam irradiation;
intravenous bone-seeking radioisotopes; bisphosphonates; chemotherapy; experimental therapy
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| Withdrawal responses in men with HRPC occur with: antiandrogens (ie, flutamide, bicalutamide, and nilutamide);
megestrol acetate (Megace); DES; estramustine; retinoids; TNP-470
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| Southwestern Oncology Group (SWOG) 9426 trial—multivariate analysis of progression-free survival after antiandrogen
withdrawal; predictors of more favorable outcome—long duration of antiandrogen therapy before development of progression;
early diagnosis; presence of PSA progression alone, rather than progression on bone scan or computed tomography
(CT); additional observations—in some cases, patients do not progress for long time after withdrawal of
antiandrogen therapy
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| Secondary hormonal manipulation: no definitive trial data available on survival benefit; may provide some therapeutic
advantage, eg, ≈40% of men receiving nilutamide experienced ≥50% reduction in PSA; dexamethasone (Decadron)
monotherapy—palliates pain; reduces PSA levels in some patients; well tolerated, even though duration of
therapeutic effect limited; associated with side effects, including steroid myopathy, elevated glucose levels, and low incidence
of steroid psychosis; among men receiving low-dose (3 mg) DES therapy—24% achieved >50% decrease in PSA
levels; median duration of therapeutic response, 3.8 mo; median time to disease progression, 2.9 mo
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| Docetaxel (Taxotere): only drug shown to have survival benefit in HRPC; TAX 327 trial—compared to combination
of mitoxantrone and prednisone, combination therapy using docetaxel and prednisone achieved modest survival benefit
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| Newer therapeutic options under investigation: vaccines—granulocyte-macrophage colony-stimulating factor
(GM-CSF) transduced tumor cells; sipuleucel-T (Provenge); sargramostim (GM-CSF; Leukine); recombinant vaccinia
virus vaccine (PROSTVAC-V); PROSTVAC-VF/TRICOM; Anti-CTLA-4 antibody (MDX010); angiogenesis
inhibitors—thalidomide; bevacizumab (Avastin; active in management of colon, breast, and lung cancer; ongoing trials
in management of prostate cancer); anti-vascular endothelial growth factor (anti-VEGF) receptor targeted drugs; new
chemotherapeutic agents—epothilones and other antitubular agents; satraplatin; additional options—vitamin D receptor
1,25 OH-Vitamin D (DN101); mammalian target of rapamycin (mTOR) inhibitors; integrin targeted therapies; kinase inhibitors
(eg, sorafenib); histone deacetylase inhibitors; endothelin axis-targeting agents; heat shock proteins; prostate
stem cell antigens; sonic hedgehog-cyclopamine; prostate-specific membrane antigen (PSMA); radioactive gastrin-releasing
peptide (GRP) agonists
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| Granulocyte-macrophage colony-stimulating factor: molecule used in studying tumor immunity; animal
study—evaluated antitumor response of various cytokine-transduced tumor cells; GM-CSF produced greatest antitumor response;
series of human studies (designed to take advantage of data derived from animal studies) include—infusing irradiated
prostate cancer cell lines and GM-CSF gene to elicit immune response; using phase 3 trials to evaluate efficacy of
prostate cancer vaccine (GVAX) against combination of docetaxel and prednisone, or efficacy of docetaxel alone vs combination
of docetaxel and GVAX; data show GM-CSF alone can—alter PSA kinetics in men who develop rising PSA levels
after definitive local therapy; decrease PSA doubling times; prospective randomized trial using sipuleucel-T technology—
approach (patients underwent leukophoresis; antigen-presenting cells isolated and exposed to prostatic acid phosphatase
GM-CSF antigen); results (“antigen-loaded” androgen presenting cells that were infused into patient produced some survival
benefit); anti-CTLA-4 antibody ipilimumab (formerly MDX-010) enhancement of T-cell responsiveness—underlying
concept (CTLA-4 molecule produces down-regulation of immune response; addition of anti-CTLA-4 monoclonal antibody
may prolong T-cell activation); current trial investigating effect of GM-CSF transduced and irradiated tumor cells on immune
response caused by anti-CTLA-4 inhibition
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| Platinum compounds: data show—platinum compounds typically nonresistant with taxanes; mechanisms of taxane
and platinum resistance distinct
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| Satraplatin: in small trial, provided progression-free survival advantage; Satraplatin Against Refractory Cancer (SPARC)
trial—evaluated satraplatin as second-line therapeutic agent, ie, >50% of patients had previous therapy with docetaxel;
data suggest satraplatin can improve progression-free survival in men treated with docetaxel
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| Additional areas of investigation: novel tubulin-binding agents (albumin-bound paclitaxel; epothilones; halichondrin
B; vinca alkaloids); histone deacetylase (HDAC) inhibitors; combination of bevacizumab and docetaxel (under investigation
in cancer and leukemia group B [CLGB] trial for managing prostate cancer); radioisotopes—samarium-153
( β-emitting isotope) targets bone in specific way; may be used in combination therapy; docetaxel combined with—DN-
101 (vitamin D3 ) in high doses; atrasentan; bevacizumab; GVAX; Vitaxin; GM-CSF; thalidomide; samarium-153
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| Conclusions: second-line hormonal therapies—available; occasionally effective; relatively nontoxic; antiandrogens—
DES, ketoconazole, and prednisone benefit selected patients with minimal complications; chemotherapy—docetaxel
(established; provides modest survival benefits; failures represent challenge); satraplatin data provocative and require
further investigation; bottom line—new therapeutic options needed for managing refractory disease; currently, novel
agents and treatment combinations provide basis for future advancements in treatment efficacy
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Program of Related Interest
Bennet AL: Phosphodiesterase type 5 (PDE-5) inhibitors in the management of lower urinary tract symptoms (LUTS)
and erectile dysfunction (ED). Audio-Digest Urology 31:01(Jan), 2008.
Suggested Reading
Lee KL, Peehl DM: Molecular and cellular pathogenesis of benign prostatic hyperplasia. J Urol 172:1748, 2004;
Oefelein MG et al: Clinical predictors of androgen-independent prostate cancer and survival in the prostate-specific antigen
era. Urology 60:120, 2002; Penna G et al: Seminal plasma cytokines and chemokines in prostate inflammation: interleukin
8 as a predictive biomarker in chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia.
Eur Urol 51:524, 2007; 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: 2 year results from the CombAT
study. J Urol [Epub ahead of print]; Roehrborn CG et al: The relationship between prostate inflammation and
lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol [Epub ahead of print]; Sartor
O: Chemotherapy in prostate cancer: an update. Clin Genitourin Cancer 5:304, 2007; Sartor O: The continuing
challenge of hormone-refractory prostate cancer. Clin Genitourin Cancer 4:238, 2006; Sartor O, George D: Prostate-
specific antigen endpoints in hormone-refractory prostate cancer. Clin Prostate Cancer 4:5, 2005; Tannock IF et al:
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502, 2004.
Educational Objectives
| The goal of this program is to improve management of benign prostatic hyperplasia (BPH), lower urinary tract symptoms
(LUTS), and hormone-refractory prostate cancer (HRPC). After hearing and assimilating this program, the clinician will be
better able to:
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| 1. Evaluate the effect of a rapidly aging population on urology workforce issues.
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| 2. Determine the role of inflammation in BPH.
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| 3. Assess the role of nonsteroidal anti-inflammatory drugs, phosphodiesterase type 5 inhibitors, α-blockers, and luteinizing
hormone-releasing hormone antagonists in the management of BPH and LUTS.
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| 4. Define changes occurring in the spectrum of HRPC.
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| 5. Review current and future therapeutic options for managing HRPC.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
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. Roehrborn is affiliated
with the American Medical Systems, Inc. (AMS), Cancer and Leukemia Group B (CALGB), GlaxoSmithKline (GSK),
ICOS, National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),
Sanofi-Aventis, Southwestern Oncology Group (SWOG), and Veterans Affairs Cooperative Study (VA COOP); Dr. Sartor is
affiliated with Cytogen, Dendreon, and GPC Biotech. The planning committee reported nothing to disclose.
Acknowledgments
Drs. Roehrborn and Sartor gave their scientific lectures at the 13th Annual Paul C. Peters Urology Symposium presented January
25-27, 2007, in Dallas, TX, by the University of Texas Southwestern Medical School, Dallas. The Audio-Digest Foundation
thanks the speakers and the sponsor for their cooperation in the production of this program.
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