1. Lymphadenectomy in the surgical treatment of prostate cancer - does it influence survival? Oliver Hakenberg Urologische Klinik und Poliklinik Universitätsklinikum Rostock

2. Incidence and mortality of prostate cancer in Europe 1998 Davidson & Gabbay, WHO Report 2007

3. Pelvic lymphadenectomy Node-positive prostate cancer is a systemic disease Surgery should be aborted if pelvic lymph nodes are positive

4. trends in risk stratification of surgically treated prostate cancer (CaPSURE) Cooperberg et al, J Urol 2003, 170, S21ff

5. temporal trends in RPE Retrospective study n=37 centres 5291 patients Stage shift PSA-recurrence = 36% Chun & Djavan et al, Eur Urol 2007, 52, 1067-75

6. Lymphadenectomy - pros and cons Pro –A significant percentage of patients will harbour N+ disease –Better staging with LAE –LAE in limited N+ will be curative Con –Overtreatment in most patients –Associated with morbidity –No influence on outcome

7. Incidence of pN+ in RPE npN+ Allaf, 200440002.2% Masterson, 200650383.8% Burckhard, 200246326% Briganti, 200785810.3% Weckermann, 2007105519.6% Burckhardt et al, Eur Urol, 2002 Allaf et al, J Urol 2004 Masterson et al, J Urol 2006 Briganti et al, Urology 2007 Weckermann & Wawroschek et al, J Urol 2007

8. Partin tables for the preoperative prediction of pathologic stage

9. Difference in Gleason Score: original vs. reference pathology

10. Validation of the Partin tables for the prediction of an organ-confined cancer Blute et al. J Urol 164, 2000 Line of equality Predicted % organ confined by Partin tables Mayo % organ confined n=2.295

11. Sentinel nodes and radio-guided surgery npN+Outside standard PLND Jeschke et al, 2005 7112.9%73% Weckermann et al, 2007 105519.6%63% Jeschke et al, J Urol 2005 Weckermann & Wawroschek et al, J Urol 2007

12. Lymphoceles clinical series n Viville 199412888.5% Hautmann 19944180.2% Noldus 199751111% Augustin 20031243 without PLAD with PLAD 0.3% 4.3% Heinzer 19983204.7% Paul 20045719%

13. Lymphoceles by imaging studies 33% with ultrasound 27% with ultrasound 61% with CT scanning Hakenberg et al, Eur Urol 2005 Spring et al, Radiology 1981 Solberg et al, Scand J Urol Nephrol 2003

14. n= 446 consecutive RPEs pelvic U/S and venous duplex sonography on days 0, 8 and 21 146 pelvic lymphoceles (size 1-20 cm) - 32.7% –18.7% day 8, 27.9% day 21 –only 26 with venous thromboses, 13/26 with measurable reduction in venous flow 73 patients with venous thromboses - 16.4% –7.2% day 8, 10.5% day 21. –3 patients with distal thromboses (calf muscles) were diagnosed preoperatively –majority of thromboses was distal and small –DVTs: day 8 n=4, day 21 n=10 –pulmonary emboli: day 8 n=2, day 21 n=2 A reduction in venous flow was seen only in patients with lymphoceles Hakenberg et al, Eur Urol 2005

15. Extent of PLND Limited (standard) = obturator fossa Modified = + internal iliac artery Extended = + common iliac artery

16. Standard PLND underestimates nodal disease n = 100 standard vs n= 103 extended PLND Heidenreich et al, 2002 PLNDstandardextended nodes (mean) 1128 pN+12%26%

17. Standard PLND underestimates nodal disease laparoscopic RPE Stone et al, 1997 Touijer & Guilloneau, 2006 n nodes (mean) pN+ Stone et al, 1997 Modified extended 189 9.3 17.8 7.3% 23.1% Touijer et al, 2006 Limited extended 212 9 14RR 21.2

18. pN+ disease in Berne n= 365-463 consecutive RPE patients, 50.6% pT2 nPSAnodespN+ Bader et al, 200236511.9 (0.4-172) 2124%Internal iliac artery 58% Obturator 34% Exclusively internal iliac 19% Burckhard et al, 2002 46311.02124%PSA < 10: 12% PSA < 20: 17% PSA < 10 and Gleason < 7: 0% PSA < 10 and Gleason < 8: 10% Bader et al, 2003367Follow- up: 45 months (13-141) 19 (22%) DOD Disease-free survival with 1 pN+ 39% with = 2 pN+ 10% with> 2 pN+ 14% Bader et al, J Urol, 2002 Bader et al, J Urol, 2003 Burckhardt et al, Eur Urol, 2002

19. But…contemporaray RPE n= 123 Limited vs extended PLND on either side PSA 7.4 ng/ml, 72% cT1c –Extended: 4 pN+ –Limited: 3 pN+ Clark et al, 2003

20. Extent of PLND and pN+ yield n= 858 PSA 5.8 ng/ml 55% pT1c, 41% pT2 14 nodes (mean) 10.3% pN+ –2-10 nodes: 5.6% pN+ –20-40 nodes: 17.6% pN+ no of nodes examined predicted for pN+: p<0.001 –< 10 nodes examined: 0% probability of pN+ –> 28 nodes: 90% probability of detecting pN+ Briganti et al, Urology 2007

21. Volume of N+ disease and progression nVolume of N+ disease others Cheng et al, 1998 269 RPE patients significantGleason score Cancer volume DNA ploidy Daneshmand et al, 2004 235 pN+ patientssignificant  RR of clinical recurrence compared to N- Golimbu et al, 1987 43 D1 patients with median FU > 5 years significant1 N+ vs > more N+ Cheng et al, Am J Surg Pathol 1998 Daneshmand et al, J Urol 2004 Golimkbu et al, Urology 1987

22. Influence of PLND with limited N+ -disease on PFS Surgeon 1 extended PLND Surgeon 2 limited PLND n21351865 nodes11.68.9p<0.001 pN+3.2%1.1% <15% nodes + 5-yr PSF survival 43%10% Allaf et al, J Urol 2004

23. Influence on survival? nPSA recurrence Bhatta Dhar, 2004 Low risk PCa with PLND without PLND 140 196 14% 12% Berglund, 2007 CaPSURE with PLND without PLND 4963 No significant difference

24. Influence on survival? nnodes Masterson, 20065038mean 9 (3.8% positive) No of nodes removed correlated with bNED in node- negative patients DiMarco, 20057036mean 14 (1987) to 5 (2000) No correlation of no of nodes and PSA-progression

25. Conclusions PLND carries morbidity many positive nodes are outside obturator fossa the more nodes removed the more likely the detection of positive nodes no influence of limited PLND on survival influence of extended PLND on PFS is unclear but likely extent of PLAD should depend on case and case mix low risk PCa (Gleason < 7 and PSA < 10 ng/ml) does not need PLAD