1. Salvage Radical Prostatectomy Salvage Radical Prostatectomy RJ Karnes MD, FACS RJ Karnes MD, FACSVice-Chair Associate Professor and Consultant Dept. of Urology/Urologic Oncology Dept. of Urology/Urologic Oncology Mayo Clinic-Rochester

3. Professor Horst Zincke 1937-2011 "He was a man, take him for all in all, I shall not look upon his like again."

4. Radiation Recurrence? Most radiation failures treated with “palliative” hormonal therapy (HT) Most radiation failures treated with “palliative” hormonal therapy (HT) CAPSURE: 63% treated - recurrent or secondary treatment at mean f/u of 38 months (93% HT) CAPSURE: 63% treated - recurrent or secondary treatment at mean f/u of 38 months (93% HT) Long-term HT not without side effects Long-term HT not without side effects Agarwal, Cancer, 2008 Agarwal, Cancer, 2008 Better definition? Better definition? ASTRO: 2ng/ml >from nadir; predictive of progression not local recurrence ASTRO: 2ng/ml >from nadir; predictive of progression not local recurrence Nadir PSA above 1 or 1.5 ng/ml-probably worrisome? Nadir PSA above 1 or 1.5 ng/ml-probably worrisome?

5. Local Recurrence: Chance for Cure? EORTC Bolla trial= ~20% LR only (EBRT and EBRT + ADT) EORTC Bolla trial= ~20% LR only (EBRT and EBRT + ADT) Lancet Oncology 2010 Lancet Oncology 2010 Even at dosages to 78 Gy almost 1/3 will have a positive biopsy at 2 years Even at dosages to 78 Gy almost 1/3 will have a positive biopsy at 2 years Predictive of progression compared to negative biopsy Predictive of progression compared to negative biopsy Crook J Crook J Late wave of metastasis from local persistence Late wave of metastasis from local persistence Coen et al, Shipley, JCO 2002 Coen et al, Shipley, JCO 2002

6. My workup Radiographic imaging: Radiographic imaging: CT scan CT scan Bone scan Bone scan Endorectal coil MRI (3 Tesla) Endorectal coil MRI (3 Tesla) Investigational:11C-choline PET/CT scan (PPV >95%) Investigational:11C-choline PET/CT scan (PPV >95%)

7. CT Scan

8. MRI-Endorectal coil

10. My workup (after “OK” imaging) Standard 12 core TRUS prostate biopsy including 2 cores of SVs (seminal vesicles) Severe treatment effect= Behave like – Severe treatment effect= Behave like – Wait at least 12-24 months Wait at least 12-24 months Office flexible cystoscopy (anatomy, high risk disease, secondary bladder cancer) Office flexible cystoscopy (anatomy, high risk disease, secondary bladder cancer) Rare-Urodynamic study Rare-Urodynamic study Colonoscopy within 5 years Colonoscopy within 5 years Stoma counseling/marking/enema bowel prep Stoma counseling/marking/enema bowel prep

11. Pattern of Spread: Importance of Seminal Vesicles Sanctuary Sanctuary

12. Brachytherapy Failures Treated by Surgery n=9 Brachytherapy Failures Treated by Surgery n=9 All specimens whole mounted and step- sectioned All specimens whole mounted and step- sectioned Iodine or Palladium seeds collected and counted Iodine or Palladium seeds collected and counted

13. Benign Cancer

14. Base Apex RL 33 Seeds Gleason 4+3 Tx Vol=12.5cc pT3bN0 Rt SVLt SV A P A P PP A P P P A A A P Prostate map created for each specimen Prostate map created for each specimen A P = Anterior = Posterior

15. Results

16. 0 1 2 3 4 5 Count T2aN0T2bN0T3aN0T3bN0T3bN1T4Nx Pathologic Stage Seminal Vesicle Involvement (n=6) Results Importance of Seminal Vesicles!

17. Seed Kill Zone

18. Seed Kill Zone Cancer “Re-Growth”

19. Oncologic Outcomes

20. “Ideal” Surgical Candidate….not unlike radiation naive >10 year life expectancy >10 year life expectancy Coping skills Coping skills PSA < 10 ng/ml PSA < 10 ng/ml Lower Gleason score (non 8-10) Lower Gleason score (non 8-10) cT1-T2 cT1-T2 cN- cN- However I do not rule out others….. However I do not rule out others…..

21. Mayo Clinic Before 2000, Largest series n=108 (106 EBRT), `66-`96 Before 2000, Largest series n=108 (106 EBRT), `66-`96 pT2 39%, pTxN+ 18%, R1 36% pT2 39%, pTxN+ 18%, R1 36% 10 yr BCR(PSA)-free 34% 10 yr BCR(PSA)-free 34% 10 yr Cancer specific survival (CSS) 70% 10 yr Cancer specific survival (CSS) 70% Amling, J Urol 1999 Amling, J Urol 1999 Update to 2000, n=138 (127 EBRT), Median F/U 84 mths. Median age 65 yo Update to 2000, n=138 (127 EBRT), Median F/U 84 mths. Median age 65 yo 10 yr CSS 77% 10 yr CSS 77% Ward, J Urol 2005 Ward, J Urol 2005

22. International Collaboration Salvage Radical Prostatectomy (SRP) Salvage Radical Prostatectomy (SRP)

23. OverallN=392 Interval between XRT and SRP (months) 41 (27, 58) Year of SRP 1985 to 1994 78 (20%) 1995 to 1999 73 (19%) 2000 to 2004 113 (29%) 2005 to 2009 128 (33%) Age at SRP (years) 65 (60, 69) PSA before SRP (ng/ml), n=371 5.0 (2.6, 8.0) Biopsy Gleason before SRP ≤ 6 109 (28%) 7 ≥ 8 77 (20%) Unknown/Not graded 97 (25%) Clinical stage before SRP T1 87 (22%) T2 166 (42%) T3 76 (19%) Unknown 63 (16%) Chade D, Eur Urol, 2011

24. OverallN=392 Pathology Gleason ≤ 6 54 (14%) 7 144 (37%) ≥ 8 99 (25%) Unknown/Not graded 95 (24%) R1/SMS Negative 294 (75%) Positive 96 (24%) Unknown 2 (1%) pT3a/ECE No 208 (53%) Yes 181 (46%) Unknown 3 (1%) pT3b/SVI No 270 (69%) Yes 118 (30%) Unknown 4 (1%) Lymph node status Not done/Negative 336 (86%) Positive 56 (14%)

25. ResultsBCRMetastasisDeath Number of events 1866237 Median follow up for event-free patients 3.64.44.4 5-year event-free probability % 48 (95% CI 42, 53) 82 (95% CI 77, 86) 92 (95% CI 88, 95) 10-year event-free probability % 37 (95% CI 30, 43) 76 (95% CI 69, 81) 83 (95% CI 77, 88)

26. Low risk subgroup: biopsy Gleason score before SRP ≤ 7 and pre-SRP PSA ≤ 4 ng/ml Low risk subgroup: biopsy Gleason score before SRP ≤ 7 and pre-SRP PSA ≤ 4 ng/ml 96 pts (25%) 96 pts (25%) 35 pts BCR, 4 metastases, 1 death from PCa 35 pts BCR, 4 metastases, 1 death from PCa BCR-free probability BCR-free probability 62% (95% CI 49%, 72%) at 5 years 62% (95% CI 49%, 72%) at 5 years 46% (95% CI 31%, 60%) at 10 years. 46% (95% CI 31%, 60%) at 10 years. Results

27. Outcome: biochemical recurrenceOutcome: metastases Hazard Ratio95% CIP ValueHazard Ratio95% CIP Value Preoperative model (n=371) Log PSA before SRP (ng/ml)1.191.02, 1.380.0281.391.07, 1.810.015 Biopsy Gleason before SRP ≤ 6Reference 0.006ReferenceReferenc0.004 71.701.10, 2.642.280.88, 5.95 ≥ 82.201.41, 3.424.741.97, 11.4 Unknown/Not graded1.621.06, 2.472.451.02, 5.86 Clinical stage before SRP T1Reference 0.6ReferenceReferenc0.3 T21.190.78, 1.831.580.60, 4.10 T31.140.70, 1.862.030.74, 5.58 Unknown0.870.49, 1.550.880.23, 3.31 Multivariable Cox proportional hazards regression to evaluate predictors of biochemical recurrence and metastases following salvage prostatectomy.

28. Outcome: biochemical recurrenceOutcome: metastases Hazard Ratio95% CIP ValueHazard Ratio95% CIP Value Postoperative model (n=369) Log PSA before SRP (ng/ml)1.221.05, 1.420.011.571.19, 2.060.001 Pathology Gleason at SRP ≤ 6Reference 0.002Reference 0.001 71.540.92, 2.590.730.28, 1.88 ≥ 82.611.53, 4.442.691.11, 6.49 Unknown/Not graded1.550.90, 2.671.060.41, 2.73 Extracapsular extension1.070.76, 1.490.71.550.85, 2.840.15 Seminal vesical invasion1.290.91, 1.830.151.210.67, 2.170.5 Lymph node involvement0.950.64, 1.400.81.911.07, 3.410.029 Multivariable Cox proportional hazards regression to evaluate predictors of biochemical recurrence and metastases following salvage prostatectomy.

29. Functional Outcomes Urinary Incontinence Urinary Incontinence 0 ppd= 21-90% 0 ppd= 21-90% Artificial Urinary Sphincter @ 6 mths/stabilization Artificial Urinary Sphincter @ 6 mths/stabilization Erectile Function Erectile Function Pre-op EF=9-50% Pre-op EF=9-50% Sufficient for intercourse 0-20% Sufficient for intercourse 0-20% Bladder neck contracture <10-20% Bladder neck contracture <10-20% Rectal injury <10% Rectal injury <10%

30. Pisters, J Urol, 2009 Cryo does not treat LNI and SVI

31. Surgical Technique: RP+EPLND Catheter in for 3 weeks and assess with cystogram Catheter in for 3 weeks and assess with cystogram 5 point anastomosis (2-0 Monocryl) over 20 Fr catheter 5 point anastomosis (2-0 Monocryl) over 20 Fr catheter Prepare perineum for possible Vest sutures Prepare perineum for possible Vest sutures

32. Spermatic Cord Common Iliac Hypogastric (Internal Iliac) HIGH RISK PROSTATE CANCER SURGICAL TECHNIQUE: EXTENDED PELVIC NODE DISSECTION

33. General Approach EBRT only EBRT only Assess tissue/fat plane at bladder neck if developed then approach similar to radiation naïve, i.e. retrograde otherwise antegrade Assess tissue/fat plane at bladder neck if developed then approach similar to radiation naïve, i.e. retrograde otherwise antegrade Brachytherapy or Combined Brachytherapy or Combined Antegrade (take down bladder first) Antegrade (take down bladder first) Non-nerve sparing Non-nerve sparing

34. Wide Local Excision Resection Rt NVB Beyond Prostate Apex Pararectal Fat

35. Wide Local Excision Peri/Pararectal FatRhabdosphincter

36. Wide Local Excision versus Bilateral Nerve Sparing Edge of pelvic fascia lateral to resected NVB Superior pedicle resected to tip of SV Superior pedicle preserved (pelvic plexus) NVB preserved

37. Wide Resection Specimen

38. Wide Local Excision versus Bilateral Nerve Sparing Resected NVB Superior pedicle resected to tip of SV Superior pedicle preserved (pelvic plexus) NVB

39. Conclusions Importance of staging (pT3b and pTxN+) Importance of staging (pT3b and pTxN+) Technically challenging Technically challenging Reasonable morbidity? Reasonable morbidity? Survival outcomes acceptable Survival outcomes acceptable Diagnose earlier? Diagnose earlier? Goal-Cure; Avoid long-term hormonal therapy Goal-Cure; Avoid long-term hormonal therapy