Diagnosis and Treatment of BPH and Prostate Cancer

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Diagnosis and Treatment of BPH and Prostate Cancer Powered By Docstoc
					Diagnosis and Treatment of BPH
    and Prostate Cancer using
    Prostate Specific Antigen (PSA)

 Where have we been in the last 20 years?

            George T. Ho, MD
            October 27, 2007
Discovery of PSA

• Hara et al (Japanese J. Legal Medicine,
 1971): 1st report of gamma seminoprotein
 from seminal plasma isolate.
Discovery of PSA

• Li et al (Fertility and Sterility, 1973):
  identification of Protein E1 from seminal
  plasma
Discovery of PSA

• Sensabaugh et al (J. Forensic Science,
 1978): description of p30 in seminal
 plasma
Discovery of PSA

• Wang et al (Invest. Urology, 1979):
 identified seminal specific protein as PSA
 and developed assay for PSA
PSA Research

• Sensabaugh et al (1985): PSA is not
 found in the semen of bulls, rams, bears,
 and other mammals!
PSA Research

• Watt et al (PNAS 1988): PSA sequence at
 237 amino acids at Cetus Corp
PSA hits prime time

• Stamey et al (NEJM 1987):
• 1st clinical evaluation of PSA in men with
  and without Prostate Cancer
• Levels of serum PSA correlated to prostate
  size/volume and stage of Prostate Cancer
• Serum PSA increases with sexual activity
• Serum PSA increases after DRE
Issues surrounding the use of PSA
in Clinical Practice


       Differences in PSA      PSA as an early
       Between BPH and           Detector of
        Prostate Cancer        Prostate Cancer




                     Mutiple forms
                       Of PSA
PSA parameters:

• PSA Density
• PSA Velocity
• Age Specific PSA
• Free/Total PSA (PSAII)
PSA Density:

• PSA-D = serum PSA/prostate volume
• Normal range < 0.15
PSA Velocity:

• PSA-V = Change in PSA over time
• Normal Range < 0.75ng/cc/yr.
Age Specific PSA
  Age Range:       PSA range:
  40-49            <2.5ng/cc

  50-59            <3.5ng/cc

  60-69            <4.5ng/cc

  70-79            <6.5ng/cc

  >79              ??? Should we be
                   screening
Free/Total PSA:
• PSA is present in serum in
  various molecular forms. The
  two major forms recognized by            Mol. WT % Total
  commercial kits are:


                                  PSA-ACT 90kDa    60-90%
                                  (bound
                                  PSA)

                                  Free     30kDa   10-40%
                                  PSA
Free/Total PSA:
• Percentage of Free PSA decreases as Total PSA
    increases in serum of men with prostate cancer
    (free/total PSA < 25% considered “abnormal”)
•   Percentage of bound PSA (PSA-ACT) increases in
    serum of men with prostate cancer and
    prostatitis
Distribution of Free/Total PSA (PSAII):

• Based on ROC, the FDA agreed on NR of
  PSAII as >25%
• The AUA however suggests NR of PSAII as
  >20% to decrease number of unnecessary
  biopsies
Future PSA tests:

• B-PSA and C-PSA (Hybritech, La Jolla, CA)
    Factors affecting serum PSA
•   Sex
•   DRE
•   UTI
•   Instrumentation of Lower GU tract
•   Bicycle riding?
•   Medications (Proscar and Avodart)
Prostate Cancer Chemoprevention
          Trial (PCPT)
       (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 Diagnosis

   Does early detection really improve survival?
   What are the most accurate measures for early
    detection?
   How can clinically significant disease be
    distinguished?
   What are the most effective methods of
    treatment?
     Early Detection Does Decrease
    Death Rate from Prostate Cancer
   Men who have a yearly PSA test are nearly
    three times less likely to die from prostate
    cancer than those who don’t have annual
    screening (3.6% vs. 11.3%).
               Jason Efstathiou, MD
               Annual Meeting of ASTRO
               Denver, 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 PSA
               for PCP’s
   American Cancer Society recommends annual
    DRE and PSA, beginning at age 50 (age 40 in
    men with family history and in Afro-Americans).
   Beware of PSA velocity.
   Consider PSA II in young men and those at high
    risk, as well in those men with enlarged
    prostates and elevated total PSA’s.
   Always perform a DRE.
              Use of PSA in
       Benign Prostate Hyperplasia
   PSA increases as size of prostate enlarges
   Alpha Blockers are no better than placebo
    in preventing growth of prostate (MTOPS,
    NEJM, December 2003)
   Alpha Blockers do not alter the natural
    progression of BPH (ie, rate of urinary
    retention or need for surgery)
        Stopping the Progression
                Of BPH
   Use of 5 alpha reductase inhibitors (5 ARI)
   Differences in the two available 5 ARI
       Near Complete DHT Suppression
        Requires Inhibiting Both 5AR
                Isoenzymes
                                               AVODART
                                                Finasteride
                            Type II 5AR


Testosterone                                             DHT




                            Type I 5AR                         Prostate
                                                AVODART         volume
                                                               reduced
 Bartsch G et al. Eur Urol. 2000;37:367380.
                      AVODART® (dutasteride) Provides More Complete
                       and Reliable DHT Suppression than Finasteride*
                      0
                                                 Finasteride 5.0 mg (n = 11)
                               P < 0.001         AVODART 0.5 mg (n = 12)
                     –20
from baseline (%)




                                                 Standard deviation (variability among patients)
  Change in DHT




                     –40
                                                                                        93% vs 62%

                     –60                                                         –62%      DHT
                                                                                        suppression
                                                                                        at 24 weeks
                     –80
                                                                                 –93%
                    –100
                           0     4         8      12     16                20   24
                                                Time (weeks)
*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%.

Adapted from Clark RV et al. J Clin Endocrinol Metab. 2004;89:21792184.
Data on file, GlaxoSmithKline.
                      AVODART® (dutasteride) Rapidly Reduces
                        Prostate Volume as Early as 1 Month
                       Mean Prostate Volume Reduction From Baseline to Year 4 (n = 796)

                     10                          Double-blind                        Open-label
                      5                             phase                              phase
prostate volume(%)
 Mean change in




                      0
                     –5
                             –5.2
                     –10
                     –15
                                             –13.8
                     –20
                                                           –19.9
                     –25                                            –23.6
                     –30                                                     –26.0     –27.3
                               1                3            6       12       24        48
                                                           Treatment month
            Debruyne F et al. Eur Urol. 2004;46:488494.
              AVODART® (dutasteride) Significantly
              Improves Urinary Symptoms Out to 4
                             Years
                                                              Time (months)
                               1           3           6       12      24        36      48
                        0
change from baseline




                       –1
 Mean AUA-SI score




                                                                                                    4-year
                       –2   –1.4                                                                   symptom
                                                                                                 improvement
                       –3               –2.7                                                       (n = 860)

                       –4                            –3.4
                                                              –3.8
                       –5                                             –4.4
                       –6                                                       –5.6
                       –7                                                               –6.5
                                               Double-blind phase             Open-label phase

               Debruyne F et al. Eur Urol. 2004;46:488494.
                            AVODART® (dutasteride)
                                    Reduced
                          the Risk of AUR by 57% at 2
                                      Years
                 5                                                                     Placebo 4.2%
                 4
Patients (%)




                                                                                                       57%
                 3                                                                                       risk
                                                                                   AVODART 1.8%*      reduction
                 2
                1

                0
                     0                   6                 12                     18            24
                                                          Month
                                   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.
                      AVODART® (dutasteride) Reduced
                                  the Risk
                     of BPH-Related Surgery by 48% At 2
                                    Years
                 5
                                                                                       Placebo   4.1%
                 4
Patients (%)




                                                                                                         48%
                 3                                                                                         risk
                                                                                      AVODART 2.2%*     reduction
                 2

                1

                0
                     0                    6                  12                     18           24
                                                            Month
                     Out to 4 years, the incidence of BPH-related surgery 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.
               Questions?
 Feel free to call me at (614) 222-3369
 Or email at gthomd@yahoo.com