1. PROSTATE CANCER - 2012 241,740 new cases 29 % of all new male cancer cases 28,170 deaths Lifetime risk of prostate cancer 1:5

2. 2012 Estimates – American Cancer Society INCIDENCE DEATHS

3. PROSTATE CANCER

4. 30% of men > 50 years old have CaP at autopsy Lifetime risk of malignancy in 50y/o - 42% Lifetime risk of CLINICAL CaP - 19 % Risk of dying from CaP - 2.9% UNIQUE DISCREPANCY OF PREVALENCE versus CLINICAL

5. U.S. Preventive Services Task Force (Draft report: 10/11/2011) Recommends against screening for prostate specific antigen Moderate or high certainty that no net benefit or harms outweigh benefits Grade D recommendation – discourage the use of this service- applies to all healthy men.

6. U.S. Preventive Services Task Force (Draft report: 10/11/2011) Relied heavily on meta-analyses combining high and low quality evidence Used overall mortality rather than cancer specific mortality Considered only intention to treat Did not consider risk stratification or longer duration of followup

7. USPSTF on Prostate Ca Screening: FINAL REPORT Class D recommendation: Screening for prostate cancer should be actively discouraged Committee of primary care physicians; headed by pediatrician No Urological or Oncology consultants Same group: No mammograms age 40-50 Promulgated May, 2012

8. Effect of USPSTF Recommendation on Metastatic Prostate Ca SEER data 1983-1995 vs. 2006-2008 Adj. for age, race, geographic variation Computed # of men who presented w/ M1 in SEER 9 registries area in 2008 Expected/observed ratio M1 in 2008 = 3.1 If USPSTF rec. applied to US population = 25,000 vs. 8000 CaP pts. with metastases Scosyrev E…Messing EM. Cancer Online (July 30, 2012)

9. PLCO - CaP Screening Trial 76,693 men Randomized to annual screen vs. usual practice At 7-10 years, death rate low and not different Findings per 10,000 pt. yrs. Screened (38,343 pts.) Control (38,350 pts.) Incidence of CaP 116 (2820 cancers) 95 (2322 cancers) CaP Deaths2.0 (50 deaths)1.7 (44 deaths) Andriole GL et al NEJM 360:1310, 2009.

10. PLCO - CaP Screening Trial Contamination (40-52%) # of patients “pre-screened” Short followup for mortality Wide confidence bars Percent of controls with higher stage/grade Andriole GL et al NEJM 360:1310, 2009.

11. EORTC Randomized CaP Screening Study 162,387 men age 55-69 years Screened every 4 years; cutpoint PSA > 3.0 * 20% reduction in CaP deaths ( p = 0.04) Findings Screened (72, 890 pts) Control (89,353 pts) Incidence CaP 8.2% 4.8% CaP Deaths 214* 326* Schroder FH et al. NEJM 360:1320, 2009.

12. EORTC Randomized CaP Screening Study - Conclusions High rate of overdiagnosis (8.2 vs. 4.8%) PSA screening reduced CaP deaths (p =.04) Death risk difference 0.71/1000 men 1410 men screened/48 Rx to prevent 1 death Benefit of screening: Age 55-69 years 41% reduction in adverse features (p <0.001) Schroder FH et al. NEJM 360:1320, 2009.

13. Göteborg CaP Screening Study Randomized population-based 1:1 (59 y/o) 20,000 men PSA testing every 2 years Median followup 14 years Dx CaP: 12.7% vs 8.2% (p < 0.0001) CaP deaths 0.56 in screened men (p=0.002) 293 screened; 12 dx to prevent 1 CaP death Hugosson J et al. Lancet Oncol 11: 725, 2010.

14. CONCLUSIONS Careful analysis SUPPORTS screening for CaP Problem is overtreatment, not overdiagnosis Better predictors of aggressiveness would limit overtreatment Less morbid therapies would diminish problems with overtreatment Controversies about prostate cancer will persist

16. 12-core Biopsy Technique

17. Gleason Pathologic Grading System Gleason DF. In: Tannenbaum M, ed. Urologic Pathology: The Prostate. Philadelphia, Pa: Lea & Febiger; 1977:171-197. X X

18. Clinical T(umor) Stage T1a/b – Incidental CaP after TURP T1c - Discovered by PSA; no nodule T2a – Prostate nodule < ½ of 1 side T2b – Prostate nodule > ½ of 1 side T2c – Prostate nodules both sides T3a – CaP through capsule 1 or both sides T3b – Seminal vesicle invasion

19. RISK STRATIFICATION Risk Grp. PSA Gleason T-stage Low  10 &  7& T1c/T2a Intermed. 10-20 or 7 or T2b High >20 or 8-10 or T2c /+ or > 2 ng in past year

20. PROSTATE CANCER Mgt : LOCALIZED CaP Active Surveillance Radical Radiation Therapy Radical Prostatectomy Factors: Age and health of patient Extent of disease Morbidity

21. Watchful Waiting - Localized CaP Albertson PC et al. JAMA 293:2095-2101, 2005

22. Active Surveillance - Candidates > age 70-75 (?? Age 65 +) Intercurrent illness or comorbidities Gleason 3 +3 on few biopsies Low stage (T 2 or <) Low PSA with slow rise on serial study Understand need for periodic biopsies

23. Watchful Waiting vs. RRP Bill-Axelson et al NEJM 352:1977, 2005

24. PIVOT TRIAL: Observation vs. Radical Prostatectomy 731 men, randomized, 1994-2002 Mean age 67; Intention to treat analysis Median followup: 10 years All cause MR: 47% vs. 49.9% CaP MR: 5.8% vs. 8.4% (p = 0.09) ↓ all cause MR if PSA >10 and possibly intermediate/high risk CaP Wilt,TJ et al. NEJM 2012; 367:203

25. PIVOT TRIAL: Observation vs. Radical Prostatectomy Original goal 2000 pts Median age older (67 y/o); only 50% T1c VA population with ↑ comorbidities 25% of pts. for RRP did not undergo Rx 10% of pts. for obs. underwent RRP Bone mets in obs. - 10% vs. 4.7% Wilt,TJ et al. NEJM 2012; 367:203

26. Open Radical Prostatectomy 2 ½ hour operation 2 day hospitalization Catheter x 1 week Recovery 3-4 weeks Palpation of prostate http://www.orlive.com/brighamandwomens/videos

27. Robotic Radical Prostatectomy 2-3 hour operation 1 day hospitalization Catheter x 1 week Recovery 2-3 weeks Long learning curve (minimum 300) No palpation of prostate

28. Radical Prostatectomy Advantages Definitive therapy to remove primary tumor Stage dependent Allows for pathological staging Better prognosis determination Nerve sparing Psychological impact Disadvantages Major inpatient surgery – Bleeding during surgery Incontinence Persistent erectile dysfunction Bowel complications Anastomotic stricture Recovery period – loss of human capital Eastham JA, Scardino PT. Campbell’s Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:3080,3091,3126.

29. External Beam Radiation Therapy (EBRT) 3D Conformal Advantages Efficacy equal to prostatectomy at 5 years Outpatient procedure More precise treatment target - less side effects than nonconformal Painless procedure Allows escalation of RT dose to 81 Gy No loss in human capital Disadvantages Acute/chronic bowel complications Incontinence Persistent erectile dysfunction Daily treatments for 7-8 weeks D’Amico, AV, et al. Campbell’s Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:3152. Zelefsky MJ, et al. J Urol. 2001;166:876-881.

30. Intensity Modulated RT (IMRT) Inverse treatment planning Computer controlled RT intensity Mathematical optimization technique utilized Enables further delivery of minimal and maximal dose RT vs 3-D EBRT Less rectal complications than 3-D and conventional EBRT Allows escalation of the RT dose to 86.4 Gy Limited availability D’Amico, AV, et al. Campbell’s Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:3155. Zelefsky MJ, et al. J of Urol. 2001;166:876-881.

31. Brachytherapy Advantages Efficacy approaching that of EBRT or surgery (short term) Procedure completed in one session Outpatient procedure Delivers higher doses radiation over shorter period of time Disadvantages Urinary voiding symptoms Rectal discomfort Edema Persistent erectile dysfunction Migration of seeds Variability of duration of action Epidural or general anesthesia Unknown long-term effectiveness (10-year effectiveness) D’Amico, AV, et al. Campbell’s Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:3158. Grimm PD, et al. Int J Radiat Oncol Biol Phys. 2001;51:31-40. Beyer DC, et al. Radiother Oncol. 2000;57:263-267. Blasko JC, et al. Radiother Oncol. 2000;57;273-278.

32. MGT. of Localized CaP Optimal Rx of local disease controversial Radical prostatectomy is the most proven method for long term survival Quality of life is an important consideration Further improvements in survival depend on development of effective adjuvant Rx