1. Journal Club August 10, 2012 Ryan M. Zitnay MD

2. Case 71 y/o male veteran w PMH CAD s/p MI, HTN, HL, constipation Followed by urology for rising PSA x 4 years – ’08: 3.5 – ’09: No data – ’10: 5.1 – ’11: 9.6 DRE without palpable abnormality US guided biopsy March ’12: + adenoCA – Confined to prostate gland Histologic grade of tumor: Gleason score 6

3. Case No LUTS, bowel or bladder sx Has nocturia 2-3x/night, stable No trouble emptying No hematuria No back/bone pain, no AP Bone scan negative for mets

4. Problem List CAD s/p MI Hypertension Hyperlipidemia Vitamin D deficiency Constipation Osteoarthritis knees b/l PTSD Medications Lisinopril 20mg Qday HCTZ 12.5mg Qday Toprol XL 100mg Qday ASA 81mg Qday Colace 100mg BID Vitamin D 50,000 QOweek Tylenol 1000mg TID

5. What are the possible treatment options for this patient? Surgery – Radical Prostatectomy (RP) Radiation – External Beam Radiation Therapy (EBRT) – Brachytherapy Observation – Active surveillance – “Watchful waiting”

6. Is watchful waiting a viable option for this patient?

7. Background Treatment of early stage prostate cancer is controversial – Especially if asymptomatic detected through PSA Lifetime risk of diagnosis 17% – Risk of dying 3% Suggests that conservative management may be appropriate for some men

8. Background Two prior RCTs looking at RP vs. observation – Conducted before PSA widespread – Iverson et al 1995 No significant difference in overall mortality after 20+ years – Bill-Axelson et al 2011 Absolute differences in all-cause & prostate CA-specific mortality at 15 yrs in favor of surgery – Benefits confined to <65

9. Background During PSA era, observational study – High 10 year survival rates among men treated conservatively Despite excellent, long-term disease specific survival, observation rarely used – Lack of evidence from RCTs for observation vs. potentially curative treatments

10. PIVOT TRIAL

11. Study Design Enrollment: Nov 1994 – January 2002 – Early era of PSA testing Follow-up through January 2010 – F/up for 8-15 yrs or until pt died PSA & additional therapy Q 6 mo QOL score Q 1 yr Bone scans Q 5 yrs 44 VA, 8 NCI sites

12. Inclusion/Exclusion Criteria “Medically fit” for RP Clinically localized prostate CA – Stage T1-2NxM0 Diagnosed within previous 12 mos PSA <50ng/ml Age <75 Bone scan negative for mets Life expectancy of at least 10 yrs from time of randomization

13. Outcomes Primary – All cause mortality Secondary – Prostate cancer-specific mortality Additional – Bone metastasis – 30 day peri-operative harms – Prevalance of urinary incontinence, erectile and bowel dysfunction at 2 yrs

14. Statistical Analysis Intention-to-treat analysis Goal enrollment: 2000 men – Revised to 740 over 7 yr period with 8 yr f/up Proportional-hazards model used to measure outcomes Kaplan-Meier analysis for mortality & bone mets Subgroup Analyses – Age, Gleason score, race, performance status, Charlson comorbiditiy index

15. Results: Table 1

17. Figure 1: Study Enrollment & Treatment

18. Results: All-Cause Mortality By end of study, 48% men had died – RP 47% (171) vs Obs 50% (183) – Hazard ratio = 0.88, P = 0.22 – ARR 2.9% – AR of mortality not significant at any interval & declined over time 4.6 percentage points at 4 yrs  2.9 at 12 yr – Median survival 13.0 yrs RP vs. 12.4 yrs Obs

19. Results: Death from Any Cause

20. Secondary Endpoint: Prostate-Cancer Mortality 7% (52)death attributed to prostate CA or tx – RP 5.8% (21) vs Obs 8.4% (31) – HR 0.63, P=0.09 – ARR 2.6% – Absolute reduction of mortality not significant at any interval

21. Results: Death From Prostate CA

22. Statistically significant difference – RP 5% (17) vs Obs 11% (39) – HR 0.4, P<0.001

23. Subgroup Analyses Figure 3A

24. Surgical Morbidity

25. Discussion RP did not reduce all-cause or prostate- cancer mortality compared with Obs Adds to evidence supporting observation – Especially with low PSA levels & low risk disease

26. Strengths Addressed understudied dilemma in era of PSA testing – Up to 2/3 men now diagnosed have low risk tumors – 90% receiving early intervention Overdiagnosis & overtreatment – RCTs have not addressed this population in past PIVOT: majority nonpalpable (stage T1c), PSA<10 Large # pts >65 yo

27. Limitations Underpowered – 2000 proposed  731 randomized 1/5 participants did not adhere to assigned treatment group – RP 85% definitive therapy; 15% Obs – Obs 20% definitive therapy; 10% RP

28. How would you advise our patient to proceed if he asks your opinion? Has this study changed your thinking on observation as an option?

29. Conclusions Prostate CA is very common in older men – But likely significant overdiagnosis & tx Curative treatment will not save the life of most & has significant associated adverse effects Must find tools to risk stratify who may benefit from more aggressive therapy – ? PSA >10

30. Thank You!