Background:

1. Background: • Based on ACS data, nearly 217,730 men will be diagnosed with CaP in 2010. • Over 32,050 men will die of this disease in 2010. • Over 2 million men are alive today in US with CaP. • The 5-yr survival rate is now almost 100% & 10-yr rate 91%. • The ACS attributes this to “modern detection & treatment” techniques while they have not supported early detection. • Survival rates for A.A.’s are 10-15% lower than those of whites for the most common cancers (other than lung). • The incidence of CaP among A.A. men is 73% higher than for white men. ACS. Cancer.org / June 30, 2010 Lu-Yao et al. The Prostate Patient Outcomes Research Team. JAMA 1993;269:2633-2636

2. The Diagnosis and Prevention of Prostate Cancer:A Challenge for the 21st Century Man Brian A. Stone MD, FACS Baptist Health Systems of Alabama Jasper Urology Associates

3. Prostate Cancer in African American Men Higher incidence of prostate cancer, greater mortality compared with white men • Access to care • Attitudes about care • Distrust of medical institutions • Less likely to be screened • Socioeconomic, educational differences • Knowledge regarding prostate cancer dependent on education and income • Men without health insurance more likely to be diagnosed with advanced stage disease • Relationship between low income and advanced stage at diagnosis • Differences in type and aggressiveness of treatment • Less likely to be treated with aggressive therapy • Genetic differences • More potent androgen receptor for given androgen concentration • Increased androgen receptor expression • Slower testosterone deactivation • Dietary differences? Freedland S, Isaacs W. Prostate. 2005; 62(3):243-252.

4. Prostate Cancer - African Americans • African Americans with advanced prostate cancer exhibited:  Socioeconomic status  Under insured  Incidence early detection • Biologic differences in disease behavior • Earlier age onset • Pathologic, genetic differences (i.e., tumor volume, androgen receptor pathway) • Modifiable factors affecting gene expression (diet, obesity) Hoffman R, et al. J Gen Intern Med. 2003;18:845-853.

5. To Screen or Not to Screen?????? Several studies have attempted to answer the big question. • The Quebec Trial (Labrie et al) – 46,486 men • The Tyrol Study (Tyrol, Austria) – 21,079 men • ERSPC (European Study of Screening for CaP) – 162,243 men • PLCO Cancer Screening Trial – 154,942 men

6. Have They Succeeded???? • Quebec study criticism: Concerns over the study design & absence of men of African descent. • Tyrol study criticism: Follow up period not long enough & absence of men of African descent. • ERSPC study criticism: Follow up period inadequate to assess mortality impact & absence of data on men of African descent. • PLCO study criticism: Follow up period not long enough & absence of data analysis in African American men.

7. Suggestive Benefits of Labrie Data • Unscreened men had 41.6% death rate vs. 13.7% in the screened men. (Yields 3.85 odds ration advantage!) • 6 deaths out of 7233 screened men vs. 69 deaths out of 14419 controls. (82% fewer deaths; even correcting for the 4 vs 7 yr f/u there were 69% fewer deaths!) • Low stage Ca detection is enhanced. • Stage migration is clear. • Metastatic disease at Dx is reduced. • Suggests survival benefits.

8. New Findings of ERSPC • 5990 cancers found in screened men vs 4307 found in controls. • Cumulative CaP incidence is 8.2% vs 4.8%. • 71% more cancers found in screened men! • 72% of screened men had < G6 vs 55% of controls. • 45% of controls had > G7 vs 28% of screened men. • Local disease favored in screened men. • 20% reduction in cancer deaths in screened group vs the controls.

9. Prostate Cancer Screening US Preventive Services Task Force Current evidence is insufficient to assess the balance of benefits and harms of prostate cancer screening in men younger than 75 years USPSTF recommends against screening for prostate cancer in men age 75 years or older A clinician should not order the PSA test without first discussing with the patient the potential but uncertain benefits and known harms of prostate cancer screening and treatment Men should be informed of the gaps in the evidence and should be assisted in considering their personal preferences before deciding whether to be tested US Preventative Services Task Force. Ann Intern Med. 2008;149:185-191.

10. Who in the world should men listen to regarding early detection???? • The US Preventative Services Task Force • American College of Preventive Medicine • The National Comprehensive Cancer Network • American Urological Association • The R. Frank Jones Urological Society • The American Cancer Society

11. AUA PSA Best Practice Statement 2009 • A thoughtful and broad approach to PSA is important • The age for obtaining a baseline PSA has been lowered to 40 years • There is no longer a single threshold PSA value that should prompt prostate biopsy • Decision to biopsy should be based: • Primarily on PSA and DRE results • Also take into account • Free and total PSA • Patient age • PSA velocity • PSA density • Recent studies suggest that prostate screening leads to overdetection and overtreatment of some patients • Men should be informed of the risks and benefits of prostate cancer screening before biopsy • Certain men newly diagnosed with prostate cancer should be informed of the option of active surveillance instead of immediate treatment • Family history • Ethnicity • Prior biopsy history • Comorbidities AUA: American Urological Association Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf. Accessed May 2009.

12. Large Scale 1°Prevention Trials Andriole G. Urology. 2009;73(S5A):36-43. NCT00030901; NCT00106691. Available at: www.clinicaltrials.gov. Accessed June 2009.

13. PCPT Study Design Primary endpoint: prevalence of prostate cancer during 7 years of study Enrollment N = 18,882 men > 55 years, normal DRE, PSA < 3.0 ng/mL Randomization Placebo Finasteride (5 mg daily) Annual DRE, PSA for 7 years End of Study Biopsy End of Study Biopsy Thompson I, et al. N Engl J Med. 2003;349:215-224.

14. PCPT Results • Prostate cancer @ 7 years • Placebo: 24.4% • Finasteride: 18.4% • 24.8% reduction P < 0.001 • Tumors ~ Gleason Score 7–10 • Placebo: 237/1068 tumors (22%) • Finasteride: 280/757 tumors (37%) P < 0.001 • May be due to sampling artifact and not drug-induced high grade disease • Safety • Sexual side effects (gynecomastia, loss of libido, impotence, decreased ejaculate) more common in finasteride-treated patients; urinary symptoms more common in placebo-treated patients Thompson I, et al. N Engl J Med. 2003;349:215-224.

15. Reduction by Dutasteride of Prostate Cancer Events (REDUCE) • 4 year, multicenter, international, randomized, double-blind, placebo-controlled trial • Dual 5-α reductase inhibitor dutasteride (0.5 mg/day) vs placebo • Looking at patients with higher risk for prostate cancer (PSA 2.5-10 ng/mL for men 50-60 years; 3.0-10 ng/mL for men > 60 years) • Single negative biopsy within 6 months of enrollment at baseline • Primary endpoint: biopsy-detectable prostate cancer at 2 and 4 years of treatment Andriole GL. Urology. 2009;73(S5A):36-43.

16. REDUCE Results • Prostate cancer @ 4 years • Placebo: 11.8% • Dutasteride: 9.1% • 23% reduction P < 0.001 • Tumors ~ Gleason Score 7–10 • Placebo: 233/3406 (6.8%) • Dutasteride: 220/3298 (6.7%) P = 0.81 • Safety • Sexual side effects (gynecomastia, loss of libido, erectile dysfunction) more common in dutasteride-treated patients Andriole G, et al. American Urological Association Annual Meeting, Chicago, IL. April 28, 2009. LBA1.

17. The Ideal Candidate for 5-ARI Chemoprevention • Man who is 55 years old or older • Prostate volume > 40 mL • Symptomatic: AUA score > 10 or so • Risk factor for prostate cancer: AA, family history • Elevated PSA with prior negative biopsy • Male pattern baldness • Wants to prevent prostate cancer • Already on Alpha-Blocker Thompson IM, et al. N Engl J Med. 2003;349:215-224. Andriole GL, et al. Urology. 2004;64:537-543.

18. ASCO/AUA - Chemoprevention • Men with a prostate-specific antigen (PSA) score of 3.0 or below who are screened regularly (or plan to get yearly PSA tests) and currently show no signs of prostate cancer are encouraged to talk with their doctor about the risks and benefits of taking a 5-alpha reductase inhibitor (5-ARI) to further prevent their likelihood of getting prostate cancer • Men who are already taking a 5-ARI for other conditions should talk with their doctor about continuing to use this drug for the prevention of prostate cancer Strength of evidence: The systematic review completed for this guideline identified 15 randomized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period-prevalence. Kramer B, et al. J Clin Oncol. 2009;27:1502-1516. ASCO: American Society of Clinical Oncology

19. SELECT Study Design(Selenium and Vitamin E) Pre-Randomization Period Calendar Year 2001 – 2004 (Planned 2001 – 2006) Randomized Vitamin E + Selenium Vitamin E + Placebo Placebo + Selenium Placebo + Placebo Calendar Year 2001 - 2013 Follow - up Prostate cancer, other cancer, death Klein E. Ann NY Acad Sci. 2004;1031:234-241. Selenium: 200 mcg/day; Vitamin E: 400 International Units/day

20. Placebo Vitamin E Selenium Vitamin E + selenium SELECT: Prostate Cancer Incidence Hazard Ratios for Prostate Cancer (compared with placebo) Vitamin E: 1.13 (P = 0.06) Selenium + Vitamin E: 1.05 (P = 0.52) Selenium: 1.04 (P = 0.62) Lippman S, et al. JAMA. 2009;301(1):39-51. Data as of October 23, 2008; median follow-up 5.46 years

21. Pragmatic Approach for Patient Management When to refer to a urologist: • Significant risk based on “risk calculator” • Abnormal PSA velocity (> 0.75 ng/mL/year) • Abnormality detected on DRE • Failure of medical management for BPH • Patients with hematuria (> 3 RBCs/HPF) BPH: benign prostatic hyperplasia; RBCs: red blood cells;HPF: high powered field

22. Take Home Messages – Implications for Patient Care • Age, race/ethnicity, and family history are significant risk factors for prostate cancer • Prostate cancer screening • Clinician and patient dialog regarding DRE, PSA • Thoughtful and broad approach to PSA • Discuss risks and benefits of testing in advance of tests • AUA now recommends a baseline PSA at 40 years of age for healthy, well-informed men who wish to be tested • Chemoprevention • Promising results from PCPT and REDUCE with 5-alpha-reductase inhibitors finasteride, dutasteride; significant reduction in prostate cancer incidence at study endpoints (25 and 23%, respectively) • ASCO/AUA practice guideline • Selenium or vitamin E alone or in combination did not prevent prostate cancer in the SELECT trial