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

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.

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

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  1. 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

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

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

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

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

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

  7. PSA Research • Watt et al (PNAS 1988): PSA sequence at 237 amino acids at Cetus Corp

  8. 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

  9. Issues surrounding the use of PSA in Clinical Practice

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

  11. PSA Density: • PSA-D = serum PSA/prostate volume • Normal range < 0.15

  12. PSA Velocity: • PSA-V = Change in PSA over time • Normal Range < 0.75ng/cc/yr.

  13. Age Specific PSA

  14. Free/Total PSA: • PSA is present in serum in various molecular forms. The two major forms recognized by commercial kits are:

  15. 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

  16. 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

  17. Future PSA tests: • B-PSA and C-PSA (Hybritech, La Jolla, CA)

  18. Factors affecting serum PSA • Sex • DRE • UTI • Instrumentation of Lower GU tract • Bicycle riding? • Medications (Proscar and Avodart)

  19. Prostate Cancer ChemopreventionTrial (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!

  20. 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?

  21. Early Detection Does DecreaseDeath 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

  22. 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)

  23. Legal Ramifications of PSAfor 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.

  24. Use of PSA inBenign 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)

  25. Stopping the ProgressionOf BPH • Use of 5 alpha reductase inhibitors (5 ARI) • Differences in the two available 5 ARI

  26. Near Complete DHT Suppression Requires Inhibiting Both 5AR Isoenzymes AVODART Finasteride Type II 5AR Testosterone DHT Type I 5AR Prostatevolume reduced AVODART Bartsch G et al. EurUrol. 2000;37:367380.

  27. 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 Standard deviation (variability among patients) –40 Change in DHTfrom baseline (%) 93% vs 62% DHT suppression at 24 weeks –60 –62% –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.

  28. 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 phase Open-label phase 5 0 –5 –5.2 Mean change in prostate volume(%) –10 –15 –13.8 –20 –19.9 –25 –23.6 –26.0 –30 –27.3 3 6 12 24 48 1 Treatment month Debruyne F et al. Eur Urol. 2004;46:488494.

  29. AVODART® (dutasteride) Significantly Improves Urinary Symptoms Out to 4 Years Time (months) 48 1 3 6 24 36 12 0 –1 4-year symptom improvement(n = 860) –1.4 –2 Mean AUA-SI score change from baseline –3 –2.7 –3.4 –4 –3.8 –4.4 –5 –5.6 –6 –6.5 –7 Open-label phase Double-blind phase Debruyne F et al. Eur Urol. 2004;46:488494.

  30. 57% riskreduction AVODART® (dutasteride) Reducedthe Risk of AUR by 57% at 2 Years 5 4.2% Placebo 4 3 Patients (%) 1.8%* AVODART 2 1 0 12 6 24 0 18 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.

  31. 48% riskreduction AVODART® (dutasteride) Reduced the Risk of BPH-Related Surgery by 48% At 2 Years 5 4.1% Placebo 4 3 Patients (%) 2.2%* AVODART 2 1 0 12 6 24 0 18 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.

  32. Questions? • Feel free to call me at (614) 222-3369 • Or email at gthomd@yahoo.com

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