PROSTATE CANCER: QUESTIONS AND ANSWERS
From The Annual University of California, San Francisco, School of Medicine’s Advanced Seminar:
Current Controversies in Urologic Oncology
| CHEMOPREVENTION: WHY NOT NOW ? Phillip L. Ross, MD, Clinical Instructor, Department of Urology, University
of California, San Francisco, School of Medicine, Mount Zion Comprehensive Cancer Center, San Francisco,
CA
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| In United States, cancer data: established stage migration, with most cases presenting with organ-confined disease;
show—lifetime risk for diagnosis 17.3% for whites, 20.6% for blacks; attributed decreased mortality (lifetime
risk for death 2.8% for whites and 4.7% for blacks) to early detection and prostate-specific antigen (PSA)
screening; indicate on average, patients—present with smaller lower grade tumors; have disease detected at earlier
stage
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| Chemoprevention: prostate cancer attractive target, based on—prevalence; treatment-related morbidity; long latency
to clinically evident and important disease; well-defined molecular pathogenesis; goals—prevent prostate
cancer in men likely to develop disease; alter progression risk in men with prostate cancer; eliminate treatment-related
morbidity; take advantage of proven benefits associated with chemoprevention for breast and colon cancer;
minimize side-effect profiles of chemoprotective agents; options—hormonal manipulation; 5-α-reductase inhibition;
targeting inflammatory pathways with cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory
drugs (NSAIDs); antioxidants, eg, selenium, vitamin E; dietary manipulation; data suggest—selenium,
vitamin E, and COX-2 inhibition favorably affect cancer risk; odds ratio 58% for prostate cancer detection in men
with history of NSAID use; inverse association between use of NSAIDs and cancer risk among men with particular
genotype, ie, lymphotoxin-α gene; point—as genetic profiling improves, it may be possible to customize chemoprevention
profiles for various patient groups
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| Finasteride therapy (5-α-reductase inhibition)
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 | Prostate Cancer Prevention Trial (PCPT): inhibition therapy based on absence of benign prostatic hyperplasia
(BPH) and prostate cancer in men with congenital 5-α-reductase deficiency; study subjects—≥55 yr of age; normal
digital rectal examination (DRE) and PSA <3 ng/mL; randomized to 5 mg finasteride vs placebo; additional
aspects—prevalence of biopsy-detected cancer served as primary end point; risk reduction remained across all
groups; at 7 yr, finasteride group had 25% reduction in incidence of prostate cancer; areas of concern—higher
incidence of high grade (HG) tumors and sexual side effects in treatment arm; higher than expected incidence of
prostate cancer in both study groups (problem may be related to overdetection bias); data suggest finasteride—
does not appear to directly induce development of HG tumors; changes hormonal milieu; may (when given long
term) reduce validity of conventional Gleason score; decreases gland size and may influence biopsy outcome
data; as chemopreventive agent, would reduce lifetime risk of developing prostate cancer
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| Factors surrounding use of chemoprevention: key issues—cost; lack of Food and Drug Administration (FDA)
approval for finasteride as chemopreventive agent; before initiating chemoprevention, determine whether
patient—has significant urinary tract symptoms; has gland large enough to consider using 5-α-reductase inhibition
to control lower urinary tract symptoms (LUTS), ie, patient undergoing finasteride therapy will benefit both
from LUTS therapy and chemopreventive effect; will be bothered by potential sexual side effects of finasteride;
takes risk reduction seriously (eg, some men who want chemoprevention refuse to make crucial risk-reducing lifestyle
changes); additional factors—societal vs personal costs (societal factors irrelevant when patient assumes financial
responsibility for chemoprevention); ongoing studies evaluating increase in HG tumors
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| ACTIVE SURVEILLANCE: RATIONAL OR RISKY ? Peter Carroll, MD, Professor and Chair, Department of
Urology, and Ken and Donna Derr-Chevron Distinguished Professor, University of California, San Francisco, School
of Medicine
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| Introduction: overdetection does not necessarily lead to overtreatment, ie, combine aggressive detection with selective
treatment; data show—15% of men with normal PSA levels have prostate cancer; effort to screen younger
men and increase number of biopsy evaluations has detected smaller lower-grade lesions; marked migration to
lower-risk disease over past decade; treatment—substantially reduces risk of dying from prostate cancer; speaker
supports aggressive treatment for men at high risk of developing metastases and progression over next 5 to 10 yr;
at-risk patients defined by—cancer risk, grade, and stage; serum PSA kinetics; tumor volume; point—battle for
prostate cancer will be won and lost in men with higher-risk disease
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| Active surveillance: improves patient evaluation; reduces understaging and undergrading; monitors earlier-stage
disease more closely; treatment initiated at first sign of subclinical progression; treatment administered based on
risk; focused on local therapy, ie, brachytherapy and surgery, not hormonal therapy (HT); currently used in United
States to treat—≈8% of ideal candidates overall (ie, men with low-grade disease and <33% of biopsy cores positive);
≈33% of men >75 yr of age with low-risk disease (although considered ideal candidates for surveillance,
most men in this patient population receive aggressive treatment); point—younger, better-educated, and better-insured
men constitute most actively screened population
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| Active surveillance study: basis for hypothesis—surveillance in low-risk patients feasible and associated with limited
progression risk; progression risk quantifiable and predictors of risk identifiable; criteria for patient
selection—PSA <10 ng/mL; Gleason score <7, with no component 4 or 5; involvement of <33% of all biopsy
cores; involvement of <50% of any single biopsy core; T2a disease or lower; predictive factors—prediagnostic serum
PSA kinetics (strong predictor of eventual need for treatment; patient with increasing serum PSA before diagnosis
considered poor candidate); free PSA fraction and PSA density (PSAD) considered good predictors (men
with free PSA of <10% and PSAD >0.15 more likely to require treatment); patients at relatively low risk of requiring
treatment—mean age 64 yr; median PSA 5.9 ng/mL; median Gleason score on biopsy, ≈6; intervals for repeat
monitoring—3 mo for PSA; 6 mo for ultrasonography (US); 12 to 18 mo for biopsy; disease progression defined
as—change in Gleason score to ≥7; PSA velocity >0.75 ng/mL per year; increase in lesion size based on US
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| Study data show: 42% of patients progressed by one or another criterion; patients meeting all selection criteria less
likely to progress; ≈21% of patients required treatment—in two thirds of cases, treatment initiated in response to
disease progression; in one third of cases, patients did not experience disease progression, but preferred definitive
treatment to continued monitoring; factors predictive of need for treatment—change in PSA; increase in Gleason
score on repeat biopsy (single greatest factor, driving need for treatment); increase in lesion size—suggested by
data to be poor indicator of treatment need; complexity of interpreting serial US data renders conclusion questionable;
point—delaying treatment did not appear to adversely affect survival rates
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| Conclusions: progression rate low in well-selected patients on active surveillance; patients at increased risk have
higher probability of progression and must be treated; in well-defined surveillance populations—delayed intervention
effective; progression risk during initial period of active surveillance limited but not absent; patients who are
risk averse should be treated; point—better phenotypic and molecular markers needed to predict progression
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| ANDROGEN DEPRIVATION AND RADIATION THERAPY: WHEN AND HOW LONG ? Mack Roach III, MD,
Professor and Chair, Department of Radiation Oncology, University of California, San Francisco, School of Medicine
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| Hormonal therapy (androgen deprivation): maximum HT—can reduce radiation dose by 50% in androgen-dependent
tumor models; finding provides rationale for administering combination of hormonal and radiation therapies;
HT—plays no role in managing low-risk disease; can improve local control and affect distant disease in men
at intermediate risk (ie, men with low risk for distant failure)
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| Overview of additional study data: in men with high-risk disease, risk for distant metastases favors long-term HT;
meta-analysis of Radiation Therapy Oncology Group (RTOG) data suggests—for patients at intermediate risk,
short-term HT given before or during radiation therapy achieved best outcome (radiation alone provided inferior
survival rate); for patients at high risk, addition of long-term HT achieved better survival results than short-term
HT or radiation alone; additional data analysis shows that among patients at—intermediate risk, long-term therapy
provides no overall survival benefit and may lead to adverse survival outcome; high risk, improved prostate
cancer-specific mortality rate overrides potentially adverse physiologic effects associated with long-term HT; in
every trial—comparing external beam radiation therapy (EBRT) alone to combination of EBRT and HT, short-
term HT proved beneficial; among high-risk patients, long-term HT proved beneficial when compared to radiation
therapy alone or short-term HT
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| Issues of concern: physician’s judgment determines management of patients located between low- and intermediate-
risk groups and intermediate- and high-risk groups; biochemical control rate varies directly with size of radiation
field, ie, randomized trial data favor whole-pelvis irradiation
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| Management based on patient’s risk of dying from prostate cancer: intermediate risk—generally requires 3 to
6 mo of neoadjuvant HT (NHT) and whole-pelvis irradiation; unfavorable intermediate risk—if >50% of biopsy
positive for T3 (Gleason 7) disease, administer long-term HT; favorable high-risk disease—patients have focal
grade 4+4 disease and no other adverse findings; long-term HT may be inappropriate; combining brachytherapy
with EBRT and short-term HT achieves high local-control rates; unfavorable high-risk disease—patients require
NHT followed by whole-pelvis irradiation and long-term HT; optimal duration of HT unknown; however,
2-yr protocol shortest duration of long-term HT shown to prolong survival
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| CURRENT DEFINITION OF ADVANCED DISEASE: HOW HAS IT CHANGED ? Charles J. Ryan, MD, Assistant
Clinical Professor of Medicine, Division of Hematology/Oncology, University of California, San Francisco,
School of Medicine
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| Impact of PSA studies on natural history of prostate cancer: PSA screening reduced number of men presenting
with advanced disease; PSA evaluation redefined—need for diagnosing prostate cancer up front; concept of advanced
disease; as clinical tool, PSA analysis—marker for relapse after radical prostatectomy or radiation therapy,
ie, PSA kinetics help determine prognosis at relapse; frequently sole indicator for initiating HT; defines androgen-
independent prostate cancer and treatment response
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New Clinical Entities
| Serologic relapse or increasing PSA: PSA doubling time critical factor that appears to correspond to likelihood
of developing metastatic disease and cancer-related death; standard of care remains questionable, ie, HT, peripheral
androgen blockade, and lifestyle modification have modest effect on rate of PSA increase; points—HT increasingly
being used earlier in clinical course; increasing use of adjuvant HT (AHT) alone and in combination
with EBRT affects natural history and how relapse and high-risk disease defined
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| Nonmetastatic androgen-independent prostate cancer (AIPC): some men without evidence of metastases may
experience increase in PSA while on HT; factors driving growth of problem—increased use of AHT (evidence
supporting benefits); PSA monitoring for relapse after curative-intent therapy; therapeutic enthusiasm (ie, one
third of patients with postradical prostatectomy, PSA-documented relapse are treated with HT ≤12 mo after relapse);
PSA monitoring during HT
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| PSA as means of evaluating response of hormone-sensitive disease: Southwest Oncology Group (SWOG) data—
show patients who underwent 6 mo of HT experienced marked reduction in PSA level and prolongation of survival;
suggest PSA (in this context) reasonable marker for prognosis and clinical outcome
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| Current information on nonmetastatic AIPC: issues—no standard of care, ie, role of chemotherapy undefined;
long median time to development of metastases complicates effort to study drugs that may delay metastatic disease;
study randomizing subjects to receive zoledronic acid or placebo—used development of bone metastases
as end point; suggests that men with castrate levels of testosterone, increasing PSA levels, and negative bone
scans may go ≥3 yr before developing metastatic disease; PSA doubling time—of prognostic value; if PSA level
increases slowly, patient more likely to have indolent disease and natural history that can be measured in years; if
PSA doubling rapidly, patient more likely to develop metastases
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| Study program using secondary HT with ketoconazole and cytokine granulocyte macrophage colony-stimulating
factor (GMCSF): subjects stratified by presence or absence of positive bone scan at start of study; showed men
with nonmetastatic disease had significantly longer time to progression, compared to men with metastatic disease;
clinicians currently subdividing hormone-refractory prostate cancer (HRPC)—outcome for men with
nonmetastatic HR disease may be better than for patients with metastatic disease
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| Clinical states model: <2% of patients diagnosed with prostate cancer go untreated or are lost to treatment, then
subsequently present with untreated hormone-sensitive metastases; in more likely scenario, men—placed on HT
for increasing PSA go on to develop nonmetastatic HRPC, and years later develop asymptomatic or another type
of metastatic HRPC; with docetaxel (Taxotere), chemotherapy may define next clinical state of disease
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| Hormone-refractory prostate cancer
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| Asymptomatic HRPC: characterized by metastatic disease on bone scan and increasing PSA; symptom definition
difficult; areas of debate—role of chemotherapy; outcomes comparison with symptomatic patients
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| Symptomatic HRPC: duration of survival 18 to 24 mo; characterized by—metastatic disease; positive bone scan
and computed tomography (CT); outcomes of study trials based on—pain palliation; improved survival; TAX-
327 study—findings led to approval of docetaxel (Taxotere; given every 3 wk) as standard of care for HRPC;
50% of subjects had asymptomatic disease (≈50% of patients required opioid analgesics for pain control); hazard
ratio for survival identical for men with symptomatic and asymptomatic disease
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| Taxane-refractory HRPC: new classification; men receiving chemotherapy live longer but also become refractory
to treatment; data show men who became intolerant or resistant to taxane, had median survival of ≈12 mo after
second- and third-line chemotherapy
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Suggested Readings
Ankerst DP, Thompson IM: New answers from the Prostate Cancer Prevention Trial on the chemoprevention of
prostate cancer. Arch Ital Urol Anrol 78:154, 2006; Cooperberg MR et al: Prostate cancer 2004: insights from nation
disease registries. Oncology 18:1239, 2004; D’Amico AV, Barry MJ: Prostate cancer prevention and finasteride.
J Urol 176:2010, 2006; Greco C et al: Androgen ablation therapy does not increase the risk of late morbidity
following 3D-conformal radiotherapy of organ-confined prostate cancer: the experience of the European Institute of
Oncology. Tumori 90:567, 2004; Klotz L: Active surveillance with selective delayed intervention for favorable risk
prostate cancer. Urol Oncol 24:46, 2006; Moul JW: The evolving definition of advanced prostate cancer. Rev Urol
8:S10, 200.
Cultural and Linguistic Resources
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resources on its website. Please visit this site: www.audiodigest.org/ CLCresources.
Educational Objectives
| The goal of this program is to improve management of prostate cancer. After hearing and assimilating this program,
the clinician will be better able to:
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| 1. Discuss critical issues surrounding the use of chemoprevention.
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| 2. Review current avenues for administering chemopreventive therapy.
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| 3. Evaluate the potential risks and benefits associated with active surveillance.
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| 4. Determine when and how long patients should receive a combination of radiation and hormone therapy.
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| 5. Trace the evolution of the current definition of high-risk 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. Roach is affiliated
with AstraZeneca and TAP Pharmaceutical Products Inc.
Acknowledgements
Drs. Carroll, Roach, Ross, and Ryan gave their scientific lectures at Current Controversies in Urologic Oncology,
presented February 2-3, 2007, in San Francisco, by the University of California, San Francisco, School of Medicine.
The Audio-Digest Foundation thanks the speakers and the University of California, San Francisco, for their cooperation
in the production of this program.
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