1. Probing Your Prostate Health: What Every Man Should Know Prostate Cancer Douglas S. Scherr, M.D. Clinical Director, Urologic Oncology Weill Medical College of Cornell University

2. What is the Prostate?

3. Problems of the Prostate Prostatitis Benign Prostatic Hyperplasia (BPH) Prostate Cancer Infection Urinary Retention Urinary Bleeding

4. What Causes the Prostate To Grow? Testosterone Dihydrotestosterone (DHT) Testosterone DHT Finasteride (Proscar)

6. Prostate Cancer In 2007, 225,000 new cases of prostate cancer 28,900 men will die from prostate cancer Highest death rates in Caribbean and African American Men 1 in 6 men in the U.S. will development prostate cancer

7. Prostate Cancer in African American Men 275.3 per 100,000 men Incidence in African American men is 60% higher than among white men Between 1992-1999 the death rate from prostate cancer was 2.3 times higher than white men and 3.3 times higher than Hispanic men More men present with metastatic disease in the African American population

8. Prostate Cancer in African American Men 5 year survival rates have improved over the last 3 decades for African American men 40% of prostate cancers occurring in men under age 55 have a hereditary basis Risk of developing prostate cancer doubles for men with a father or brother with prostate cancer

9. Prevalence of Prostate Cancer Decade % Men With PIN Or CaP Sakr et al., J Urol, 150: 379, 1993

11. Myths of Prostate Cancer in Asian Men Asian men do not get prostate cancer Asian men have small prostates that do not cause problems Not important to check PSA levels in Asian Men

12. Prostate Cancer in Asian- American Men Higher % of foreign born Asian Americans are diagnosed with distant disease at presentation (controlled for socioeconomic status and co-morbidities) Distribution of Stage for North American-born Asian Americans is similar to whites and both groups are diagnosed at the same age Foreign-born Asian Americans are diagnosed at older ages Death rates higher for foreign-born Asian Americans but no difference for North American-born Asian Americans Oakley-Girvan et al. Am J Pub Health, Vol 93(10): 1753, 2003

13. Why the Differences? Lack of screening programs in Asia Socioeconomic Status Cultural barriers to medical care Biological Explanation? Birthplace?

14. Policies of Prostate Cancer Screening GroupPolicy StatementRecommendations AUA Screen annually at age 50 Take personal decision after consultation ACS Screen annually at age 50 Provide risk and benefit information AMA Mass screening is premature Allow well informed decision ACP Routine PSA is inappropriate Counsel patient EU Introduction as policy is premature Provide risk and benefit, await randomized trials

15. Evidence for the Effectiveness of Screening PSA screening initiated in 1989 A decrease in prostate cancer mortality has been demonstrated in the U.S. by 4.4%/year from 1994-97 Total decrease in mortality of 17.6%

16. Does Screening for Prostate Cancer Help? Mortality decreased by 27% between 1991-1997 in white men and by 17% in African American men Less men present with advanced disease and thus potential for cure increases

17. Diet and Prostate Cancer Saturated fat intake is associated with prostate cancer High red meat intake may increase risk of prostate cancer High soy intake may have a protective effect Vitamin E, Selenium, Lycopene

18. High Risk Prostate Cancer Single treatments often not effective Surgery does have a role Quality of life can be maintained

19. The Problem Low RiskHigh Risk DAmico AV, et al. JAMA. 1998;280:969-974. RP External Beam Radiation Therapy Implant and Neoadjuvant Hormonal Therapy Implant 100 90 80 70 60 50 40 30 20 10 0 PSA Survival (%) 012345 Time (Years) 164147117835536 109 77 4217 4 2 10 8 5 2 1 0 6 4 3 3 2 1 100 90 80 70 60 50 40 30 20 10 0 PSA Survival (%) 012345 Time (Years) 239158102472611 3092189938120 23143000 19134000

20. Prostate Cancer Risk Stratification Cooperberg et al, J Urol 170: S21-7, 2003.

21. Why is high-risk disease bad? Primary therapy inadequate -positive surgical margins -unrecognized node positive disease Early tumor dissemination

22. Occult Node-Positive Disease Schumacher et al, Eur Urol, 2006 231 patients: PSA < 10, RP + PLND (extended) Positive nodes: 11% overall 25% in men with Gl 7 Distribution: 23% obturator only 31% internal only 73% with some internal involvement

23. Recurrence in NED Patients * p<0.01 Recurrence: PSA 0.4 ng/ml or salvage radiation Rx Recurrence: PSA 0.4 ng/ml or salvage radiation Rx

24. Early tumor dissemination –Circulating tumor cell data Why is high-risk disease bad?

25. Improved Cancer Detection Through Imaging Endorectal MRI/Spectroscopy Potential improvement over ultrasound Biochemical gradients to decipher cancer from benign Possible role in high risk patients

26. Image 8 I 54.44 mm Image 9 I 57.56 mm H H H H H H H H H H H H H H H H H H H H H H H H * * * sc vc vc

28. Treatment Stratifications Allow for improvement in patient understanding More objective in guiding treatment decisions Less physician bias

29. Biopsy Gleason Grade 2+ 2 3+3 3+ 4 2+3 4+ Total Points 0 20 40 60 80100120140160180200 60 Month Rec. Free Prob..96.93.9.85.8.7.6.5.4.3.2.1.05 3+ 2 Clinical Stage T1cT1ab T2aT2cT3a T2b Points 0 10 20 30 40 50 60 70 80 90100 PSA 0.11236891012163045701107 20 4 Preoperative Nomogram for Prostate Cancer Recurrence Instructions for Physician: Locate the patients PSA on the PSA axis. Draw a line straight upwards to the Points axis to determine how many points towards recurrence the patient receives for his PSA. Repeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each time drawing straight upward to the Points axis. Sum the points achieved for each predictor and locate this sum on the Total Points axis. Draw a line straight down to find the patients probability of remaining recurrence free for 60 months assuming he does not die of another cause first. Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy. You can use this only on a man who has already selected radical prostatectomy as treatment for his prostate cancer. Instruction to Patient: Mr. X, if we had 100 men exactly like you, we would expect between and to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare. 1997Michael W. Kattan and Peter T. Scardino Kattan MW et al: JNCI 1998; 90:766-771.

30. Palm Pilot Nomogram Software Includes pretreatment and postoperative predictions. Uses published nomograms in prostate cancer.

31. 10 3, Postoperative Nomogram for Prostate Cancer Recurrence 1998Michael W. Kattan and Peter T. Scardino 1998Michael W. Kattan and Peter T. Scardino

32. PSA Kinetics PSA Velocity (PSAV) in year preceding diagnosis 1 –1095 pts, clinically localized CaP undergoing RP –PSAV > 2 ng/ml/yr predicted disease-free, cancer- specific, and overall survival PSA Doubling Time (PSADT) at recurrence 2 –8,669 pts treated by RP or XRT for localized CaP –PSADT < 3 months associated with cancer-specific mortality (HR 19.6, 12.5-30.9, p<0.001) 1 DAmico, NEJM 351:125, 2004 2 DAmico, JNCI 95:1376, 2003

33. Technical Improvements in Surgery Nerve Grafts Cavernosal nerves necessary for post- operative erectile functions In advanced disease, nerves may need to be resected to obtain a negative margin Sural nerve or genitofemoral nerve serve as sources of nerve grafts in this setting

34. Robotic Prostatectomy

35. Conclusion Prostate Cancer is a common disease Family history is important Screening can lead to earlier diagnosis Treatment strategies have improved and quality of life concerns are addressed

36. Adjuvant Radiation after RP Two completed, randomized studies: SWOG 8794 1 and EORTC 22911 2 Patients with pT3/T4, +/- pos margins Adjuvant RT (prostatic fossa) vs. Observation Primary endpoint – metastasis free survival 1. Thompson, JAMA, 2006 2. Bolla, Lancet, 2005

37. Adjuvant RT vs Observation for pT3+ CaP 1.Bolla, Lancet, 2005 2.Thompson, JAMA, 2006 EORTC 1 SWOG 2 (RT vs. Obs) Number1005473 Median F/U5 yrs10 yrs PSA failure26% vs 44%35% vs. 64% (HR 0.48, 0.37-0.62)(HR 0.43, 0.31-0.58) Metastasis-free survivalNRNS (HR 0.75, 0.55-1.02) Overall survivalNS (HR 1.09, 0.67-1.79)(HR 0.80, 0.58-1.09)

38. Stephenson et al, J Clin Onc, 2007 Progression-Free Probability After Salvage RT 0.5 1.01-1.50 0.51-1.00 > 1.5 Pre-RT PSA

39. Neoadjuvant Therapy in High-risk Localized Prostate Cancer: CALGB 90203 RANDOMIZE Docetaxel 70 mg/m 2 IV day (6 cycles) ADT X 4 months Q 21 days Radical prostatectomy Entry Criteria: cT1-3aNXM0 and nomogram probability of <60% PFS at 5 yrs. N: 750 patients Outcome: 5-yr bPFS (45 mo. to 60 mo.) HR 1.35 Radical prostatectomy

40. Patients post-RP pT3, G7-10, N0 Kattan nomogram Docetaxel (6 cycles) + prednisone Surveillance RANDOMIZE VA Cooperative Studies # 553: Adjuvant Therapy in High Risk Disease Primary endpoint: PSA progression Secondary endpoints: OS, CSS, mets-free survival Docetaxel 75mg/m2 q 3wks x 6 cycles n = 700

41. Gleason 9, PSA 150, any T category Gleason 8, PSA < 20, T2 Gleason 7-8, PSA 20-150, any T category RT + Hormonal therapy (2 yrs) RT + Hormonal therapy (2 yrs) + 6 cycles adjuvant docetaxel ( starting 1 mo after RT) RANDOMIZE RTOG 0521: Adjuvant Docetaxel Docetaxel 75mg/m2 q 3wks x 6 cycles n ~ 600

42. Take Home Points High-risk disease difficult –Inadequate primary therapy, early tumor dissemination, tumor biology Predictive models with improved ability to identify high-risk patients –Biopsy information –Tertiary grade –PSA kinetics –Emerging biomarkers

43. Take Home Points Adjuvant therapy –RT : Efficacy in subset with positive margin, undetectable PSA, low/int Gleason –ADT: in N+ disease –Substantial side effects Future –Neoadjuvant or adjuvant chemo/chemohormonal therapy in high-risk disease –Await RCTs

44. 200 (1%) Clinic al trials 20,000/year High Risk 100,000/year Have surgery ~230,000/year Prostate Cancer in the USA Radical Prostatectomy -M. Eisenberger, JHU