PROSTATE CANCER: CURRENT CLINICAL ISSUES
From University of Toronto’s Urology Update: New Ideas, Approaches, and Techniques
| OPTIONS FOR GOOD-RISK LOCALIZED CANCER—Freddie C. Hamdy, MB, MD, Professor and Head of Urology
and Director, Division of Clinical Sciences, University of Sheffield, and Consultant Urological Surgeon, Royal Hallamshire
Hospital, Sheffield, South Yorkshire, United Kingdom
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| Background: concern exists about overdiagnosis and overtreatment; aggressive treatment not shown to improve survival or
quality of life in men with clinically localized prostate cancer; age at diagnosis and grade of cancer affect prognosis; early
detection increases likelihood that patients will receive surgery or hormone therapy; hormone therapy becoming more common,
even among men whose disease may not warrant treatment
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| Prostate cancer mortality: incidence of prostate cancer—introduction of test for prostate-specific antigen (PSA) led to
dramatic increase in incidence in United States; relatively stable incidence in United Kingdom attributed to infrequent
use of test; mortality—decrease seen during 1990s in United States attributed to early detection and treatment; but mortality
rates decreased simultaneously in England and Wales; differences in screening and treatment practices do not appear
to explain differences in rates of mortality; mortality rates likely affected by environmental and hygienic factors not
fully understood
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| Treatment outcomes: choice of treatment does not affect long-term outcome in patients at low risk for progression; prognosis
determined primarily by risk factors, not by specific treatment; Canadian surveillance study followed 299 men with
low-risk prostate cancer (T1b or T2, nonmetastatic disease; PSA <15 ng/mL; Gleason score of 6 or 7); 85% of men survived
8 yr with good measures of quality of life (QOL)
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| Scandinavian Prostatic Cancer Group Study No. 4 (SPCG-4) trial: level-1 randomized trial compared watchful waiting
with surgery; study followed almost 700 men, with median time for follow-up of 6.2 yr; surgery associated with 50% decrease
in disease-specific mortality and reductions in rates of local progression and metastasis, but did not affect overall
mortality; limitations of study—patients predominantly had large T2 tumors, and 10% of patients had positive lymph
nodes (not comparable with current criteria for patient selection); small number of deaths; unreliable criteria for local
progression; men with high-grade disease excluded from study; pathologic staging insufficiently reported; rates of morbidity
associated with surgery higher than those currently reported from high-volume institutions; radiotherapy not evaluated;
conclusions—need to perform 17 radical prostatectomies to prevent 1 death from prostate cancer
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| Prostate Testing for Cancer and Treatment (ProtecT) trial: randomized controlled trial in United Kingdom (currently recruiting
patients); feasibility study—study group included 6000 men, 50 to 69 yr of age; patients with abnormal PSA
levels offered physical examination, transrectal ultrasonography, and biopsy; patients with cancer informed by urologist,
then given informational appointment with urologist or nurse (randomized to determine differences in recruitment); patients
given choice of participating in 3-arm trial (comparing surveillance, surgery, and radiotherapy) or 2-arm trial (comparing
surgery and radiotherapy) to assess willingness to participate in nonintervention arm of study; results from
feasibility study—80% of patients successfully randomized, with 73% agreeing to assignment; patients prefer treatment
in primary care setting over hospital; trained nurses provide excellent counseling; 3-armed study preferred; training and
monitoring of recruiters essential; current trial—recruitment ends in 2006; screening trial incorporated to look at effect
on mortality from prostate cancer at 10 yr
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| WATCHFUL WAITING—Gerald Chodak, MD, Director, Midwest Prostate and Urology Health Center, Chicago
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| Cohort study: study using information from Connecticut database (with up to 15 yr of follow-up) looked at disease-specific
mortality in men who never received local therapy after diagnosis of prostate cancer; men with Gleason scores of 2 to 4
have low rate of mortality from prostate cancer, regardless of age; rate increases slightly with Gleason score of 5 (11% in
oldest age group), but deaths from other causes more common; among men with Gleason score of 6, 18% of patients 50
to 59 yr of age and 28% of patients 70 to 74 yr of age die from prostate cancer within 15 yr (additional 5%-10% have
metastatic disease); watchful waiting not recommended for men with Gleason scores of 7 to 10 because of high mortality
rates; note—avoid pooling data from men with Gleason scores of 5 to 7 because of significant impact of score on outcome;
problems—data collected before introduction of PSA testing; early detection made possible with PSA testing has
decreased average age of diagnosis from 69 to 62 yr of age
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| SPCG-4 trial: randomized trial compared outcomes of men who underwent radical prostatectomy with those assigned to
watchful waiting; average PSA level at entry to study, 13 ng/mL (note, men in United States have average PSA level of 6
ng/mL at time of diagnosis); >74% of patients had T2 disease; results—although rate of cancer mortality at 6 yr decreased
with therapy (8.6% vs 4.9%), overall survival did not change; rate of metastasis decreased significantly with
treatment, which may affect differences in survival over time; note—more men with advanced cancer (Gleason score of
7-10) randomly assigned to watchful waiting, possibly biasing survivorship (ie, increasing mortality rate in that group);
problem—for purpose of data analysis, patients cannot be reassigned to different group; some patients assigned to
watchful waiting later opted for treatment, potentially affecting outcome and clouding results; quality of life—
significantly worse among patients who underwent surgery
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| Practices in United States: practice of early biopsy (at relatively low levels of PSA) and increasing number of biopsy needles
leads to increased detection of small (clinically insignificant) cancers; data from Johns Hopkins University showed
50% of men had small-volume cancers after radical prostatectomy; public perception—once diagnosed with cancer,
most patients want to take action, regardless of risk for progression; informed consent—before performing PSA test,
patient informed of risks, benefits, and uncertainties of diagnosis and treatment; PSA level rises with time in men assigned
to watchful waiting; counseling important; aggressive follow-up recommended
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| Disease progression: Gleason score—presence of pattern 4 cells worsens prognosis (note, some men with Gleason score
of 3+3 have small number of pattern 4 cells); follow-up—periodically follow PSA level and repeat biopsy; counsel patients
when they progress to higher-risk group; practice implications—more data needed on long-term outcome of
watchful waiting, but conservative approach prevents overtreatment in some men; decision to undergo therapy—after
4 yr of watchful waiting, 33% of men decide to undergo therapy (reasons include change in status and anxiety)
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| Slowing progression: data from epidemiologic studies have identified dietary factors that may have impact on progression;
reducing dietary fat, increasing certain fruits and vegetables, and supplementing with vitamin E and selenium reduce risk
for prostate cancer; laboratory studies have shown activity of soy, green tea, and lycopene; herbal supplement (Prostasol)
may impact PSA; slowing natural history could have significant impact on cancer-specific mortality
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| EVOLVING ROLE OF PSA DOUBLING TIME—Laurence Klotz, MD, Professor of Urology, University of Toronto,
Canada
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| PSA kinetics: rate of rise in PSA level has important role in assessing risk in many clinical situations; study—prospective
trial followed low-risk patients undergoing watchful waiting; PSA levels monitored; biopsies and ultrasonography repeated
frequently; patients with evidence of rapid progression in PSA or Gleason score treated; wide variation found in
doubling time of PSA level (mean of 7 yr); some patients had doubling time >100 yr; 42% of patients had doubling time
>10 yr; 20% of patients had doubling time of 3 yr (good cutoff to identify patients with rapid biochemical progression);
similar study in Japan found same overall distribution
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| Biochemical progression: simple arithmetic often sufficient to assess progression; logarithmic regression increases accuracy;
programs to calculate PSA doubling time available for download; rate of rise—benign prostatic hyperplasia
(BPH) contributes to PSA and confounds calculation; subtracting baseline PSA level from subsequent measurements corrects
for effect of BPH and decreases doubling time (median changes from 7 to 4.1 yr); study found 22% of patients had
uncorrected doubling time of 3 yr (ie, rapid progression); corrected doubling time of 1.2 yr captures 22% of patients; using
corrected doubling time, progression category changed from slow to rapid in 10% of patients; PSA velocity and
mortality—velocity (rate of rise) before radical prostatectomy helps segregate men into high- and low-risk groups; significant
increase in mortality seen in men with PSA velocity >2 ng/mL per year; comparison of PSA doubling time and
velocity—for patients with PSA of 6 to 8 ng/mL, doubling time of 3 yr corresponds to absolute rise of 2 ng/mL per year;
doubling time parallels tumor biology and kinetics; PSA velocity avoids issue of baseline PSA from BPH; note—most
patients with rate of rise >2 ng/mL per year or doubling time of 3 yr still curable (10-yr survival rate 85%)
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| Salvage radiation after radical prostatectomy: multicenter retrospective review identified factors that predict response to
salvage irradiation after biochemical failure; 77% of men with PSA doubling time >10 mo, but only 22% of men with doubling
time <10 mo, free of progression at 4 yr; other factors include Gleason score, PSA level before salvage irradiation
(PSA >2 ng/mL eliminates patient as candidate), and surgical margins (negative margins associated with decreased response);
even patients with high Gleason scores may have good chance of responding to salvage irradiation if other factors
favorable
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| Risk for metastasis after prostatectomy: short doubling time increases risk for metastasis, even at relatively low PSA levels;
>10% of patients with PSA <10 ng/mL and doubling time <6 mo have bone metastases
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| Androgen deprivation therapy: men with Gleason scores of 8 or PSA doubling times <1 yr should begin androgen deprivation
therapy early (PSA of 5-10 ng/mL); patients with low Gleason scores and slow doubling time benefit from delayed
therapy; short doubling time associated with failure to respond to second-line hormone therapy and shorter life expectancy
with hormone-refractory disease
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| BISPHOSPHONATES IN PATIENTS TREATED WITH ANDROGEN DEPRIVATION—Dr. Chodak
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| Bone metastases: complications include pain, fractures, spinal cord compression, and hypercalcemia; traditional therapy
includes narcotics, radiopharmaceuticals, and focal irradiation; adverse effects of therapy include nausea, constipation,
lethargy, and suppression of bone marrow; lesions—osteolytic and osteoblastic lesions may occur; normal osteoclasts
provide growth factors that stimulate cancer cells
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| Bisphosphonates: class of drugs that stimulates apoptosis of osteoclasts, thereby inhibiting further destruction of bone; available
agents include alendronate (Fosamax), clodronate, pamidronate, and zoledronic acid
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| Efficacy: clodronate—randomized trial in men with metastatic prostate cancer found no impact on development of bone
lesions; pamidronate—although approved for patients with metastatic breast cancer and multiple myeloma, randomized
trial found no effect on rate of skeletal events in men with prostate cancer; zoledronic acid—most potent bisphosphonate
currently available; approved for patients with metastatic breast cancer, multiple myeloma, and progressive metastatic
prostate cancer (progression after treatment with hormone therapy); adverse effects include renal insufficiency and
hypocalcemia
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| Zoledronic acid (Zometa): randomized controlled trial studied effect in men with bone metastases and 3 increasing PSA
levels; candidates had PSA levels ≥4 ng/mL and low levels of testosterone (castrate); men undergoing chemotherapy excluded;
treatment decreased rate of skeletal events and increased time to first event from 300 days to >500 days; ratio of
telopeptide to creatinine decreased, and serum levels of parathormone increased; but requirements for surgery and radiation,
incidence of spinal cord compression, pain scores, PSA levels, quality of life, and survival unaffected by treatment
(ie, treatment mostly affected incidence of fractures); adverse effects—increase in creatinine level (ameliorated when
duration of infusion increased to 15 min); flu-like syndrome; advantages—short infusion time; recommended use—
offer treatment to qualifying patients at risk for bone fractures
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| Hormone therapy and fractures: most patients begin hormone therapy before developing metastatic disease; increased
risk for osteoporosis exacerbated by weight gain and obesity (also associated with hormone therapy); intermittent hormone
therapy may have role in decreasing risk for fractures; mortality rate associated with hip fractures higher in men
than in women; castration doubles rate of fracture in men
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| Preventing osteoporosis: study found treatment with Zometa every 3 mo in castrated men with nonmetastatic disease increased
bone mineral density in hip and spine; similar study with pamidronate (60 mg every 3 mo) also showed improvements
in bone mineral density; treatment with raloxifene (Evista) associated with improvements in bone mineral density
in men on hormone deprivation therapy; note—increased density of bone may not translate to decreased rate of fractures;
teriparatide (Forteo)—new drug for treating patients with severe osteoporosis (loss of bone mineral density and
history of fractures); trial showed increased thickness in cortical and trabecular bone and increased bone mineral density,
but so far, data show rate of fractures reduced only in women; recommended use limited to 18 mo because of concern
about development of sarcomas (seen with long-term use in mice); supplements—all men on hormone therapy should
take 500 mg calcium and 400 IU vitamin D daily
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Educational Objectives
| The goal of this activity is to provide information about important clinical issues in the management of prostate cancer.
After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Discuss the effect of surgical intervention for prostate cancer on mortality.
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| 2. Identify candidates for watchful waiting.
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| 3. Counsel patients about testing for prostate-specific antigen (PSA).
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| 4. Discuss importance of PSA doubling time and rate of rise for stratifying men with prostate cancer into risk
groups.
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| 5. Discuss the use of bisphosphonates in men undergoing androgen deprivation therapy.
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Discussed on This Program
Alendronate sodium [Fosamax]
Clodronate sodium [Bonefos, Loron] (not available in United States)
Pamidronate disodium [Aredia]
Raloxifene [Evista]
Teriparatide acetate (rDNA origin; parathyroid hormone) [Forteo]
Zoledronic acid [Zometa]
Suggested Reading
D’Amico AV, et al: Identifying patients at risk for significant versus clinically insignificant postoperative prostate-
specific antigen failure. J Clin Oncol 23:4975, 2005; D’Amico AV, et al: Pretreatment PSA velocity and risk of death
from prostate cancer following external beam radiation therapy. JAMA 294:440, 2005; Freedland SJ, et al: Risk of
prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433,
2005; Green JR: Skeletal complications of prostate cancer: pathophysiology and therapeutic potential of bisphosphonates.
Acta Oncol 44:282, 2005; Klotz LH: Active surveillance for good risk prostate cancer: rationale, method, and
results. Can J Urol 12Suppl2:21, 2005; Krege JH, et al: Teriparatide, osteoporosis, calcium, and vitamin D. N Engl J
Med 353:634, 2005; Marantz PR, et al: Radical prostatectomy vs watchful waiting. N Engl J Med 353:1298, 2005;
Patel DA, et al: Preoperative PSA velocity is an independent prognostic factor for relapse after radical prostatectomy.
J Clin Oncol 23:6157, 2005; Pickard AS, et al: Opportunities for disease state management in prostate cancer. Dis
Manag 8:235, 2005; Richie JP: Radical prostatectomy vs watchful waiting in early prostate cancer. BJU Int 96:951,
2005; Saad F: Clinical benefit of zoledronic acid for the prevention of skeletal complications in advanced prostate
cancer. Clin Prostate Cancer 4:31, 2005; Unger HA, et al: Relative importance of PSA in prostate cancer treatment.
Urol Oncol 23:238, 2005; Walsh PC: Radical prostatectomy versus watchful waiting in early prostate cancer. J Urol
174:1291, 2005; Zhou P, et al: Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation
therapy. J Clin Oncol 23:6992, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Chodak is a speaker and consultant for Astra Zeneca.
Drs. Hamdy, Chodak, and Klotz were recorded in Toronto at Urology Update 2004: New Ideas, Approaches, and
Techniques, sponsored by the Faculty of Medicine, University of Toronto, Department of Surgery, Division of Urology,
and held October 29-30, 2004. The Audio-Digest Foundation thanks the speakers and the University of Toronto
for their cooperation in the production of this program.
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