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Diagnosis and Treatment of Diagnosis and Treatment of BPH BPH and Prostate Cancer and Prostate Cancer using using Prostate Specific Prostate Specific Antigen (PSA)Antigen (PSA)
Where have we been in the last 20 Where have we been in the last 20 years?years?
George T. Ho, MDGeorge T. Ho, MD
October 27, 2007October 27, 2007
Discovery of PSADiscovery of PSA
• Hara et al (Japanese J. Legal Hara et al (Japanese J. Legal Medicine, 1971): 1Medicine, 1971): 1stst report of gamma report of gamma seminoprotein from seminal plasma seminoprotein from seminal plasma isolate.isolate.
Discovery of PSADiscovery of PSA
• Li et al (Fertility and Sterility, 1973): Li et al (Fertility and Sterility, 1973): identification of Protein E1 from identification of Protein E1 from seminal plasmaseminal plasma
Discovery of PSADiscovery of PSA
• Sensabaugh et al (J. Forensic Sensabaugh et al (J. Forensic Science, 1978): description of p30 in Science, 1978): description of p30 in seminal plasmaseminal plasma
Discovery of PSADiscovery of PSA
• Wang et al (Invest. Urology, 1979): Wang et al (Invest. Urology, 1979): identified seminal specific protein as identified seminal specific protein as PSA and developed assay for PSAPSA and developed assay for PSA
PSA ResearchPSA Research
• Sensabaugh et al (1985): PSA is not Sensabaugh et al (1985): PSA is not found in the semen of bulls, rams, found in the semen of bulls, rams, bears, and other mammals!bears, and other mammals!
PSA ResearchPSA Research
• Watt et al (PNAS 1988): PSA Watt et al (PNAS 1988): PSA sequence at 237 amino acids at sequence at 237 amino acids at Cetus CorpCetus Corp
PSA hits prime timePSA hits prime time
• Stamey et al (NEJM 1987):Stamey et al (NEJM 1987):
• 11stst clinical evaluation of PSA in men with clinical evaluation of PSA in men with and without Prostate Cancerand without Prostate Cancer
• Levels of serum PSA correlated to Levels of serum PSA correlated to prostate size/volume and stage of prostate size/volume and stage of Prostate CancerProstate Cancer
• Serum PSA increases with sexual activitySerum PSA increases with sexual activity
• Serum PSA increases after DRESerum PSA increases after DRE
Issues surrounding the use of Issues surrounding the use of PSA in Clinical PracticePSA in Clinical Practice
PSA as an earlyDetector of
Prostate Cancer
Mutiple formsOf PSA
Differences in PSABetween BPH and Prostate Cancer
PSA parameters:PSA parameters:
• PSA DensityPSA Density
• PSA VelocityPSA Velocity
• Age Specific PSAAge Specific PSA
• Free/Total PSA (PSAII)Free/Total PSA (PSAII)
PSA Density:PSA Density:
• PSA-D = serum PSA/prostate volumePSA-D = serum PSA/prostate volume
• Normal range < 0.15Normal range < 0.15
PSA Velocity:PSA Velocity:
• PSA-V = Change in PSA over timePSA-V = Change in PSA over time
• Normal Range < 0.75ng/cc/yr.Normal Range < 0.75ng/cc/yr.
Age Specific PSAAge Specific PSA
Age Range:Age Range: PSA range:PSA range:
40-4940-49 <2.5ng/cc<2.5ng/cc
50-5950-59 <3.5ng/cc<3.5ng/cc
60-6960-69 <4.5ng/cc<4.5ng/cc
70-7970-79 <6.5ng/cc<6.5ng/cc
>79>79 ??? Should we be ??? Should we be screeningscreening
Free/Total PSA:Free/Total PSA:
• PSA is present in serum in PSA is present in serum in various molecular forms. various molecular forms. The two major forms The two major forms recognized by commercial recognized by commercial kits are:kits are:
Mol. Mol. WTWT
% Total% Total
PSA-PSA-ACTACT(bound (bound PSA)PSA)
90kDa90kDa 60-90%60-90%
FreeFree
PSAPSA30kDa30kDa 10-40%10-40%
Free/Total PSA:Free/Total PSA:
• Percentage of Free PSA decreases as Total Percentage of Free PSA decreases as Total PSA increases in serum of men with PSA increases in serum of men with prostate cancer (free/total PSA < 25% prostate cancer (free/total PSA < 25% considered “abnormal”)considered “abnormal”)
• Percentage of bound PSA (PSA-ACT) Percentage of bound PSA (PSA-ACT) increases in serum of men with prostate increases in serum of men with prostate cancer and prostatitiscancer and prostatitis
Distribution of Free/Total PSA (PSAII):Distribution of Free/Total PSA (PSAII):
• Based on ROC, the FDA agreed on NR Based on ROC, the FDA agreed on NR of PSAII as >25%of PSAII as >25%
• The AUA however suggests NR of The AUA however suggests NR of PSAII as >20% to decrease number PSAII as >20% to decrease number of unnecessary biopsiesof unnecessary biopsies
Future PSA tests:Future PSA tests:
• B-PSA and C-PSA (Hybritech, La Jolla, B-PSA and C-PSA (Hybritech, La Jolla, CA)CA)
Factors affecting serum PSAFactors affecting serum PSA
• Sex• DRE• UTI• Instrumentation of Lower GU tract • Bicycle riding?• Medications (Proscar and Avodart)
Prostate Cancer ChemopreventionProstate Cancer ChemopreventionTrial (PCPT)Trial (PCPT)
(Thompson, IM , et al. NEJM, 2003: 349:215-224)(Thompson, IM , et al. NEJM, 2003: 349:215-224)
• 25% decrease in incidence of well-moderately diff. prostate cancers in men taking proscar vs. placebo
• Potential increase of poorly differentiated cancers in men taking proscar
• 28% men diagnosed with prostate cancer had normal PSA!
Problems in Early DiagnosisProblems in Early Diagnosis
Does early detection really improve Does early detection really improve survival?survival?
What are the most accurate measures for What are the most accurate measures for early detection?early detection?
How can clinically significant disease be How can clinically significant disease be distinguished?distinguished?
What are the most effective methods of What are the most effective methods of treatment?treatment?
Early Detection Does DecreaseEarly Detection Does DecreaseDeath Rate from Prostate Death Rate from Prostate
CancerCancer Men who have a yearly PSA test are Men who have a yearly PSA test are
nearly three times less likely to die nearly three times less likely to die from prostate cancer than those who from prostate cancer than those who don’t have annual screening (3.6% vs. don’t have annual screening (3.6% vs. 11.3%).11.3%).
Jason Efstathiou, MDJason Efstathiou, MD
Annual Meeting of ASTROAnnual Meeting of ASTRO
Denver, CO 10/20/05Denver, CO 10/20/05
Best Use of PSA
• Following radical prostatectomy (Serum PSA should be nondetectable forever. Any detectable PSA may signal return of disease. No other monitoring modalities are necessary)
Legal Ramifications of PSALegal Ramifications of PSAfor PCP’sfor PCP’s
American Cancer Society recommends American Cancer Society recommends annual DRE and PSA, beginning at age 50 annual DRE and PSA, beginning at age 50 (age 40 in men with family history and in (age 40 in men with family history and in Afro-Americans).Afro-Americans).
Beware of PSA velocity.Beware of PSA velocity. Consider PSA II in young men and those at Consider PSA II in young men and those at
high risk, as well in those men with high risk, as well in those men with enlarged prostates and elevated total enlarged prostates and elevated total PSA’s.PSA’s.
Always perform a DRE. Always perform a DRE.
Use of PSA inUse of PSA inBenign Prostate HyperplasiaBenign Prostate Hyperplasia
PSA increases as size of prostate PSA increases as size of prostate enlargesenlarges
Alpha Blockers are no better than Alpha Blockers are no better than placebo in preventing growth of prostate placebo in preventing growth of prostate (MTOPS, NEJM, December 2003)(MTOPS, NEJM, December 2003)
Alpha Blockers do not alter the natural Alpha Blockers do not alter the natural progression of BPH (ie, rate of urinary progression of BPH (ie, rate of urinary retention or need for surgery)retention or need for surgery)
Stopping the ProgressionStopping the ProgressionOf BPHOf BPH
Use of 5 alpha reductase inhibitors (5 Use of 5 alpha reductase inhibitors (5 ARI)ARI)
Differences in the two available 5 ARIDifferences in the two available 5 ARI
Near Complete DHT Near Complete DHT Suppression Requires Suppression Requires Inhibiting Both 5AR Inhibiting Both 5AR
IsoenzymesIsoenzymesAVODART
AVODART
Finasteride
Prostatevolumereduced
Bartsch G et al. Eur Urol. 2000;37:367380.
DHTTestosterone
Type II 5AR
Type I 5AR
AVODART® (dutasteride) Provides More Complete and Reliable DHT Suppression than Finasteride*
AVODART® (dutasteride) Provides More Complete and Reliable DHT Suppression than Finasteride*
–100
–80
–60
–40
–20
0
0 4 8 12 16 20 24Time (weeks)
Ch
an
ge
in D
HT
fro
m b
asel
ine
(%)
–62%
–93%
Finasteride 5.0 mg (n = 11)
AVODART 0.5 mg (n = 12)
93% vs 62%
DHT
suppression at 24 weeks
Adapted from Clark RV et al. J Clin Endocrinol Metab. 2004;89:21792184. Data on file, GlaxoSmithKline.
*The clinical benefit of more complete and consistent DHT suppression has not been established. DHT suppression may vary. In another study finasteride reduced DHT by approximately 70%.
Standard deviation (variability among patients)
P < 0.001
–30
–20
–10
0
–5.2
–13.8
–19.9–23.6
–26.0 –27.3
Double-blind phase
Open-labelphase
Mea
n c
han
ge
in
pro
sta
te v
olu
me
(%)
1 3 6 12 24 48
Treatment month
Debruyne F et al. Eur Urol. 2004;46:488494.
AVODART® (dutasteride) Rapidly Reduces Prostate Volume as Early as 1 Month
AVODART® (dutasteride) Rapidly Reduces Prostate Volume as Early as 1 Month
–5
–15
–25
510
Mean Prostate Volume Reduction From Baseline to Year 4 (n = 796)
AVODARTAVODART®® (dutasteride) (dutasteride) Significantly Improves Urinary Significantly Improves Urinary
Symptoms Out to 4 YearsSymptoms Out to 4 Years
1 3 6 12 24 48
Time (months)
36
–1.4
–2.7–3.4
–3.8–4.4
–5.6
–6.5
Double-blind phase Open-label phase
–6
–5
–4
–1
0
–2
–3
–7
Mea
n A
UA
-SI
sco
re
chan
ge
fro
m b
asel
ine
4-yearsymptom
improvement(n = 860)
Debruyne F et al. Eur Urol. 2004;46:488494.
AVODARTAVODART®® (dutasteride) (dutasteride) ReducedReduced
the Risk of AUR by 57% at 2 the Risk of AUR by 57% at 2 YearsYears
1.8%*
Out to 4 years, the incidence of AUR was maintained at rates consistent with those during the double-blind phase
*P < 0.001 vs placebo. Results of three combined, double-blind, pivotal studies of 4325 men with BPH. Roehrborn CG et al. Urology. 2002;60:434–441; Data on file, GlaxoSmithKline.
4.2%
0
1
2
3
4
5
Pat
ien
ts (
%)
0 6 12 18 24Month
57%risk
reduction
Placebo
AVODART
AVODART
Out to 4 years, the incidence of BPH-related surgery was maintained at rates consistent with those during the double-blind phase
Pat
ien
ts (
%)
*P < 0.001 vs placebo. Results of three combined, double-blind, pivotal studies of 4325 men with BPH. Roehrborn CG et al. Urology. 2002;60:434–441; Data on file, GlaxoSmithKline.
48%risk
reduction
Placebo
0
1
2
3
4
5
0 6 12 18 24
Month
2.2%*
4.1%
AVODARTAVODART®® (dutasteride) Reduced (dutasteride) Reduced the Risk the Risk
of BPH-Related Surgery by 48% of BPH-Related Surgery by 48% At 2 YearsAt 2 Years
Questions?Questions?
Feel free to call me at (614) 222-Feel free to call me at (614) 222-33693369
Or email at [email protected] email at [email protected]