1. PSA in 2010 James L. Mohler, MD Chair, NCCN Prostate Cancer Panel Department of Urology Prostate Cancer Research Program Roswell Park Cancer Institute, Buffalo, NY

2. Every 3 Minutes an American is Diagnosed with Prostate Cancer Every 18 Minutes an American Dies of Prostate Cancer

3. The Prostate Cancer Challenge Complex disease Many controversial aspects of management Lack of sound data to support most recommendations Several variables must be considered to tailor prostate cancer therapy to an individual patient Guidelines provide a framework on which to base treatment decisions

4. Prostate Cancer: #1 Incidence (192,280) #2 Deaths (27,360) Cancer Statistics, 2009

5. U.S. Annual Age- Adjusted Incidence Rates 1975 – 2005 Cancer Statistics, 2009

6. U.S. Annual Age-Adjusted Mortality Rates, 1930 – 2005 Cancer Statistics, 2009

7. CaP Screening Recommendations American Urological Association –Annual PSA & DRE -From age 50 until LE <10 yrs -From age 40 if high risk (AA or family history) American Cancer Society (3/3/2010) -Annual PSA ± DRE -From age 50 until LE <10 yrs -From age 45 if high risk (AA or family history) -From age 40 if multiple family members

8. CaP Screening Recommendations American College of Physicians; American Academy of Family Physicians –Counsel men 50 to 65 regarding risk vs. benefit U.S. Preventive Services Task Force –Routine screening not advocated especially >75 NCCN (the best recommendation) –PSA and DRE at 40, if <1, at 45 –PSA and DRE at 45, if <1, at 50 –If high risk because African American, family history or PSA >1, annual PSA and DRE –Routine screening less frequent in older men (65-75) and not advocated especially >75

9. How reliable is PSA ? 70% of men with elevated PSA have negative biopsies PSA can fluctuate by 36% day to day Rate of rise more accurate – PSA Velocity or PSA Doubling Time –Requires 3 PSAs over 18 mo PSAV 0.75 ng/ml or PSADT 3 yrs

10. How Reliable is Prostate Biopsy? Biopsies sample prostate Biopsy detection rate –First: 75% of existing cancers –Second: 91% –Third: 97% –Fourth: 99% Accuracy of Gleason grade compared to RP –30% grade increases –5% grade decreases

11. PSA and Prostate Cancer Screening PSA increases the detection of organ confined CaP Serial PSA screening improves the ability to detect organ confined prostate cancer PSA detects 2x as many cancers as DRE

12. Screening Performance MammographyPSA + Predictive Value7-17%33% Organ Confined50%80% + Lymph Nodes20%2% Latent Cancer8%7%

13. Screening Men with a Family History 2-3 fold increased risk if first-degree relative with CaP (Keetch, J Urol, 1995; Walsh, Cancer, 1997) Younger age at presentation Comparable results with RP (Beva, J Urol, 1998) Begin screening at age 40

14. Prostate Cancer Incidence and Death Rates by Race and Ethnicity, 2001 - 2005 Cancer Statistics, 2009 Caucasian American African American Asian American and Pacific Islander American Indian and Alaska Native Hispanic Latino Incidence156.7248.593.873.3138 Mortality24.659.411.021.120.6

15. Use of PSA for Early Detection is Most Appropriate for: A) African Americans B) Men with CaP in father or brother C) Men with life expectancy 10 yrs D) Men with BRAC1 mutation E) All of the above

16. March 26, 2009 CaP Explosion NEJM 360:1310-19 and 1320-28

18. ERSPC (European) Trial 182,000 men ages 50-74 Statistics on 162,387 men ages 55-69 Mean number of PSA tests 2.1 Median f/u 9 yrs PSA cutoffDesignBiopsyInterval Finland4.0Pop-based10-124 Italy4.0Pop-based6 (transperineal) 4 Netherlands4.0Efficacy64 Belgium4.0 (originally 10) Efficacy64-7 Switzerland3.0Efficacy64 Spain3.0Efficacy64 Sweden3.0Pop-based62

19. European Trial ScreeningControl Incidence8.2%4.8% Prostate cancer deaths214327 Rate ratio for prostate cancer death0.80 (p=0.04) To prevent one death from prostate cancer: 1410 men need screened 48 additional cases of prostate cancer need treated

20. European Trial

22. PLCO (American) Trial 76,693 men ages 55-74 at 10 centers Annual PSA screening for 6 yrs vs. usual care Median f/u 11.5 years

23. American Trial ScreeningControl PSA testing86%40% Incidence7.5%6.1% No. of advanced cases122135 Prostate cancer deaths 7 years5044 10 years (f/u for 67% of subjects)9282 Non-prostate cancer deaths (10 yrs)312225

24. Possible Reasons for a Negative Trial PSA cutoff 4 ng/ml too high Control arm contaminated -38% contamination anticipated -PSA within past year -86% in screened group -40% in control group

25. Possible Reasons for a Negative Trial Widespread PSA testing removed prostate cancer patients from consideration for enrollment Improved treatments for prostate cancer applied to both arms blunted effects of screening Follow-up too short

26. PSA Screening? …our results support the validity of the recent recommendations of the U.S. Preventive Services TaskForce, especially against screening all men over the age of 75 years. NEJM: Authors of PLCO trial The real impact and tragedy of prostate cancer screening is the doubling of the lifetime risk of a diagnosis of prostate cancer with little if any decrease in the risk of dying from this disease, Otis Brawley, Chief Medical Officer, American Cancer Society

27. What does all this mean? PSA was doomed to failure (screened older men and didnt include many African Americans or men with family history of CaP) Over-treatment may blunt benefits of treatment Even with longer followup, the American study is unlikely to be positive. Even if it is, the impact of screening will be so small that it may not be clinically significant. Annual screening may be too frequent In the European study, screening was every 4 yrs In the American study, the majority of subjects in the control arm were screened and the control arm looks rather similar to the q 4 yrs screening arm of the European study

28. What does all this mean? PSA was doomed to failure (screened older men and didnt include many African Americans or men with family history of CaP) Over-treatment may blunt benefits of treatment Even with longer followup, the American study is unlikely to be positive. Even if it is, the impact of screening will be so small that it may not be clinically significant. Annual screening may be too frequent In the European study, screening was every 4 yrs In the American study, the majority of subjects in the control arm were screened and the control arm looks rather similar to the q 4 yrs screening arm of the European study

29. 2010 Guideline Updates 1. Defined new risk category: very low risk CaP 2. Active surveillance only recommendation for men with a. low risk CaP and L Exp < 10 yrs b. very low risk CaP and L Exp < 20 yrs 3. Active surveillance program defined

30. Preoperative Criteria associated with Clinically Insignificant Disease in the Radical Prostatectomy Specimen Gleason Sum <7 PSA <10 No. positive biopsy cores <3 CaP <50% in any biopsy PSAD <0.15 Epstein, JAMA, 1994

31. 2010 NCCN Concerns Approximately 3% of all men will die of prostate cancer (2007) Second leading cause of cancer mortality Mortality from prostate cancer has declined by 31% over past 13 yrs -Screening? -Treatment? Any active treatment will significantly decrease quality of life

32. 2010 Guideline Updates 1.Very low risk CaP Low Risk -T1-T2a -GS 2-6 -PSA<10 Very Low Risk -T1c -GS 2-6 -PSA<10 -<3 cores positive -<50% CaP in any core -PSAD<0.15 Incorporates the strictest Epstein criteria from all definitions for clinically insignificant CaP (Epstein, JAMA, 1994) New nomogram may be better (Chun, Cancer, 2008)

33. 2010 Guideline Updates 2. Active surveillance only recommendation for men with a.Low risk CaP and L Exp < 10 yrs b. Very low risk CaP and L Exp < 20 yrs Concern: problems of over-treatment related to the increased diagnosis of early CaP from PSA testing

34. 2010 Guideline Updates 3. Active surveillance program a.PSA as often as every 6 mo b.DRE as often as every 12 mo c.Prostate biopsy as often as every 12 mo when L Exp > 10 yrs d.Uncertain what the progression criteria should be to warrant treatment