Probing Your Prostate Health: What Every Man Should Know Prostate Cancer

1. Probing Your Prostate Health:  What Every Man Should KnowProstate 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 % Men With PIN Or CaP Decade 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 whitesand 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

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 Risk High Risk 100 100 90 90 80 80 70 70 60 60 PSASurvival(%) PSASurvival(%) 50 50 40 40 30 30 20 164 147 117 83 55 36 109 77 42 17 4 2 10 8 5 2 1 0 6 4 3 3 2 1 20 239 158 102 47 26 11 309 218 99 38 12 0 23 14 3 0 0 0 19 13 4 0 0 0 10 10 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Time (Years) Time (Years) RP External Beam Radiation Therapy Implant and Neoadjuvant Hormonal Therapy Implant D’Amico AV, et al. JAMA. 1998;280:969-974.

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 • 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 Schumacher et al, Eur Urol, 2006

23. Recurrence in NED Patients * p<0.01 • 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 ImagingEndorectal 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 vc sc vc H H H H H H H H

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

29. Preoperative Nomogram for Prostate Cancer Recurrence 0 10 20 30 40 50 60 70 80 90 100 Points PSA 4 20 0.1 1 2 3 6 7 8 9 10 12 16 30 45 70 110 T2a T2c T3a ClinicalStage T1c T1ab T2b  2+3  4+ 3+  2 Biopsy Gleason Grade  2+  2 3+3  3+ 4 Total Points 0 20 40 60 80 100 120 140 160 180 200 60MonthRec. Free Prob. .96 .93 .9 .85 .8 .7 .6 .5 .4 .3 .2 .1 .05 Instructions for Physician: Locate the patient’s 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 patient’s 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 <predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.” • 1997 Michael 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. Postoperative Nomogram for Prostate Cancer Recurrence 10 3, •  1998 Michael W. Kattan and Peter T. Scardino

32. PSA Kinetics PSA Velocity (PSAV) in year preceding diagnosis1 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 recurrence2 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) 1D’Amico, NEJM 351:125, 2004 2D’Amico, JNCI 95:1376, 2003

33. Technical Improvements in SurgeryNerve 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 87941 and EORTC 229112 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 Bolla, Lancet, 2005 Thompson, JAMA, 2006

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

39. Neoadjuvant Therapy in High-risk Localized Prostate Cancer: CALGB 90203 Docetaxel 70 mg/m2 IV day (6 cycles) ADT X 4 months Q 21 days Radical prostatectomy RANDOMIZE 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

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

41. RTOG 0521: Adjuvant Docetaxel • 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) RANDOMIZE • RT + Hormonal therapy (2 yrs) + 6 cycles adjuvant docetaxel (starting 1 mo after RT) 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%) Clinical trials 20,000/year High Risk 100,000/year Have surgery ~230,000/year Prostate Cancer in the USA Radical Prostatectomy -M. Eisenberger, JHU