1. Salvage Lymph Node Dissection for Prostate Cancer Nodal Recurrence Detected by 11 C-Choline PET/CT RJ Karnes MD, FACS Vice-Chair Associate Professor and Consultant Dept. of Urology/Urologic Oncology Dept. of Urology/Urologic Oncology Mayo Clinic-Rochester

2. Introduction Approximately a third of radical prostatectomy (RP) patients will have a biochemical recurrence (BCR) BCR can be indicative of a local and/or systemic relapse performs well in men with BCR following primary treatment failure 11 C-Choline PET/CT performs well in men with BCR following primary treatment failure Nodal recurrence

3. Introduction enhances the rate of prostate cancer lesion detection by ~30% over conventional imaging 11 C-Choline PET/CT enhances the rate of prostate cancer lesion detection by ~30% over conventional imaging Mitchell C, et al J Urology, April ’13 FDA NDA 2012 Choline C11- Mayo Clinic

4. ©2011 MFMER | slide-4 Radical prostatectomy (RP) patients with BCR (n=127): Radical prostatectomy (RP) patients with BCR (n=127): Sensitivity: 95% Sensitivity: 95% Specificity: 86% Specificity: 86% PPV: 94% PPV: 94% NPV: 89% NPV: 89% Clinical Usefulness: 36% Clinical Usefulness: 36% PSA cut-off for positive scan: 1.7 ng/ml PSA cut-off for positive scan: 1.7 ng/ml Introduction-Performance Characteristics

5. Percentage with positive scan in relation to PSA value: PSA dependent PSA (ng/ml) 5/16 10/18 11/17 10/14 16/20 26/3025/2929/32

6. ©2011 MFMER | slide-6 Performs well in men with BCR following primary treatment failure (75% +) Performs well in men with BCR following primary treatment failure (75% +) Optimum PSA value for lesion detection is between 1.7 - 2.0 ng/ml Optimum PSA value for lesion detection is between 1.7 - 2.0 ng/ml PSA kinetics did not matter (high rate of ADT/CRPC) PSA kinetics did not matter (high rate of ADT/CRPC) Generally not recommended for PSA <1 Generally not recommended for PSA <1 Over 1/3 of our scans at this level were + Over 1/3 of our scans at this level were + Patient cohort (median PSA 3.2 at scan; others 0.8-2.15 ng/ml) and higher % of adjuvant/salvage therapies Patient cohort (median PSA 3.2 at scan; others 0.8-2.15 ng/ml) and higher % of adjuvant/salvage therapies PET C11 Choline Observations

8. Introduction In the treatment naïve man, surgery alone can be potentially curative in limited nodal (pN+) disease Nodal recurrence tends to have a more favorable prognosis than bone or visceral metastasis The role of salvage lymph node dissection (sLND) is optional - EAU guidelines

9. Introduction Contemporary role of sLND was recently reviewed Delay clinical progression Postpone hormonal therapy (HT) Approximately 1/3 free of further BCR at 5 yrs Abdollah, et al., Eur Uro, 2014

10. Prospective analysis of 72 patients affected by BCR after RP associated with a nodal pathologic [11C]choline PET/CT scan. Patients underwent salvage lymph node dissection Biochemical response (BR) to treatment was defined as PSA <0.2 ng/ml at 40 d after salvage LND. Rigatti P et al, Eur Urol 2011, 60:935-43

11. Kaplan-Meier analysis depicting time to: -Biochemical recurrence-no ADT -Clinical recurrence -Prostate cancer specific survival. PSA<0.2 ng/ml at 40 days after sLND achieved by 56.9% patients PSA<0.2 ng/ml at 40 days after sLND achieved by 56.9% patients PSA is a valid surrogate PSA is a valid surrogate Mean and median follow-up after LND: 39.4 and 39.8 mo, respectively. Mean and median follow-up after LND: 39.4 and 39.8 mo, respectively. 40% n=29

12. Rigatti P et al, Eur Urol 2011, 60:935-43

13. Studies reporting results of salvage LND Study# ptsMean pre-op. PSA # nodes removedPost-op. PSA < 0.2 ng/ml Rinnab et al.152.56NA8% Winter et al.113.02NA40% Martini et al.81.6211.662% Schilling et al10-7NA Tilki et al566.021.3NA Jilg et al4711.123.346% According to the EAU guidelines the role of salvage LND is optional but still experimental, needing to be further tested in prospective clinical trials Mottet et al, Eur Urol, 59:572-83,2011

14. Case

15. Inaugural case of sLND: Choline PET not available

16. Inaugural case sLND: Metastatectomy/organ sparing surgery for radiation failure Biopsy of node+ for prostate ACA Biopsy of node+ for prostate ACA One month shot of leuprolide One month shot of leuprolide Refuses and says “take the node out and nothing else” Refuses and says “take the node out and nothing else” 2 nodes + for 4+4 at PLND in summer 2007 2 nodes + for 4+4 at PLND in summer 2007 PSA stable 0.1 to 0.2 to date and CT - PSA stable 0.1 to 0.2 to date and CT -

17. Case

18. 65 yo GS 7 PSA <10 2006: RP pT2cN0R0 Salvage XRT 0.4 then steady climb PSA 1.7 2008: sLND Currently PSA <0.2 without ADT 1 st EPLND post RP/PLND w PET

19. Case

20. 70 yo G 4+5 XRT decade earlier ADT for 6 months 2008: PSA 8.1 ng/ml Testosterone nl 2008: sLND Hypogastric region No ADT (metabolic syndrome) 2010: PSA <0.1 and CT- 1st EPLND post XRT w PET

21. Case

22. mCRPC might not = unresectable disease? pT3aN0R1-No adjuvant tx pT3aN0R1-No adjuvant tx One year later PSA 0.31 One year later PSA 0.31 Salvage Radiation Salvage Radiation PSA 0.43>3.1>9.8 ng/ml (imaging-) PSA 0.43>3.1>9.8 ng/ml (imaging-) LH-RH agonist started LH-RH agonist started

23. PSA drops to 3.2 ng/ml PSA drops to 3.2 ng/ml Starts rising: Secondary hormonal manipulation Starts rising: Secondary hormonal manipulation Referred to Medical Oncology Referred to Medical Oncology CRPC -PSA 14 ng/ml one year later (post ADT) CRPC -PSA 14 ng/ml one year later (post ADT) PET-CT C11 Choline scan ordered PET-CT C11 Choline scan ordered

25. Medical Oncology refers for LND Path: Right 3/8 Pelvic Nodes (ECE) and rest (0/10) Retroperitoneum : 6/44 Positive (M1a) Complication: Chylous Ascites PSA <0.10 at 18 month mark

26. Case

27. 52 yo s/p dvP for pN+: MRI and PET-CT same 2 years CAB PSA 2.4 PSA 2.4

28. PSA <0.10 @ 12 mths Bilateral EPLND

29. Objective Report the largest series in the U.S. of sLND targeting 11 C Choline PET avid nodes in the setting of BCR

30. Methods Retrospective analysis of a prospectively kept database of bilateral sLNDs using 11 C Choline PET by a single surgeon (RJK) Only previously treated RP+/-LND patients were included and the main surgical intent was sLND Primary endpoints: BCR and systemic progression Evaluation by Kaplan Meier analysis

31. Results 2009-2013; n=52 bilateral sLND for pN+ Included 9 RPLNDs All men had a RP in past (1993-2012) 4 cases pN1 at RP 78% received post-RP therapy (hormonal and/or radiation) Over 50% had pre-sLND “normal” conventional CT and/or MRI scans On PET: 1.8 mean lesions (no preop biopsies)

32. Results Age at sLND Range 47-78; median 60 (IQR 57,68) PSA at sLND Range 0.2-48 ng/ml; median 2.2 (IQR 1.4,3.7) # of lymph nodes removed Range 7-62; median 21.5 (IQR 16,30) # of + lymph nodes Range 1-31; median 3.5 (IQR 1.25,6.5)

33. Post-sLND management (n=52) Adjuvant HT advocated LHRH agonists for >2 + nodes (range 3- 9 months) Median time 5 months Bicalutamide 50 mg qd for 6 weeks for 1-2 + nodes 43/52 Received Adjuvant HT 13 took Bicalutamide for 6 weeks only 9/52 Refused

34. Results Median followup= 622 days; 20 months (IQR 8,33) N=52 24/52 No further therapy 18/52 Continue on HT 10/52 Multimodal treatments

35. Biochemical Recurrence (BCR) – defined as PSA > 0.2 ng/mL after sLND 29/52 – PSA remains undetectable at last follow- up 15/52 – PSA never became undetectable 8/52 – Have suffered BCR after PSA became undetectable following sLND Time to BCR (days) – from date of sLND Range: 102 – 719 Median = 438.5 (q1 186.5, q3 655.5) Results – BCR

36. K-M Survival Analysis BCR TimeSurvival (%) No. At Risk 6 mos.66.930 1 yr.64.018 18 mos. 64.016 2 yrs.45.59 3 yrs.45.54

37. Systemic progression – defined by either positive imaging study or biopsy for metastasis 13/52 have suffered systemic progression Time to Systemic Progression (days) – from date of sLND Range: 92 – 1122 Median = 554 (q1 245, q3 816) 39/52 remain free of systemic progression Results – Systemic Progression

38. K-M Survival Analysis Systemic Progression TimeSurvival (%) No. at Risk 6 mos.96.144 1 yr.88.726 18 mos. 81.223 2 yrs.73.117 3 yrs.46.96

39. LND survival benefit T LND can be estimated using PSA kinetics, by assuming 1. PSA is proportional to tumor volume (TV) 2. PSA & TV grow exponentially Described by doubling time (PSADT) Years after RP PSA- PSA+ PSA (µg/L) TV (cc) C11 T2T2 T1T1 LND PSADT ~ 2.5 mo T LND ~ T 1 + T 2 T 1 ~ 20 mo depends on the PSA reduction @ LND T 2 > 11 mo is the time PSA remains @ PSA+ after LND Can increase w/follow-up T LND ~ 2.6 yr and counting Same PSADT

40. For our cohort (n = 52), we estimate that LND provided a median survival benefit of T LND ~ 1.5 years & counting Patient distribution of outcomes falls off exponentially with T LND Number ≈ exp(- T LND / 1.6 yrs) Determined by median PSADT ~ 0.3 yr Relative to PSADT, LND survival benefit is significant T LND / PSADT ~ 5 ± 4 Survival benefit due to LND (years) Number of patients

41. Discussion Univariate: Nothing significant Heterogenous population Non-randomized Non-randomized No comparable control group No comparable control group

42. Conclusion Valid treatment option PSA as surrogate of tumor volume Most derive some benefit (PSA decreased) Some derive much (PSA <0.2) Deserves further study Imaging: PET-CT vs other Ideal patient not yet defined