1. Radical Nephrectomy The Role Of Surgery In mRCC Peter Mulders Professor and Chairman Department of Urology University Medical Center Nijmegen The Netherlands

2. Banff, Januari 26-28th 2006 Renal Cell Carcinoma General Aspects RCC accounts for 3% of all adult tumors 100.000 deaths from RCC every year worldwide Most aggressive GU tumor

3. Banff, Januari 26-28th 2006 Renal Cell Carcinoma General Aspects 54 % of cases present with localized disease* 70 % are not cured by surgery alone * SEER data

4. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Surgical Aspects Surgery is the primary curative treatment in RCC Changing techniques: From open radical tumor nephrectomy to laparoscopic partial nephrectomy

5. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Surgical Aspects Robsons radical tumor nephrectomy –No-touch procedure –Total nephrectomy and adrenalectomy –Lymphadenectomy

6. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Surgical Aspects Partial nephrectomy: similar oncological outcome in <4 cm tumors Laparoscopic (partial) nephrectomy feasible

8. Banff, Januari 26-28th 2006 Prospective Randomised Study Open vs Laparoscopic Nephrectomy (n=160) OpenLapP value Conversions00 Surgery time163,5198,5< 0,001 Blood loss240100< 0,001 Warm ischemia time36< 0,001 Complications preoperative6%12%0,49 postoperative6% 1,0

9. Banff, Januari 26-28th 2006 Prospective Randomised Study Open vs Laparoscopic Nephrectomy OpenLapP value Hospital stay430,003 pain (Morphine use:mg)25160,005 Graft survival: 1 year98%100% QoL scoreslowerbetter Returrn to normal activity23 days11 days0,001

10. Banff, Januari 26-28th 2006 Conclusions LIDO-trial Laparoscopic nephrectomy: –Safe and effective –Similar oncological results –Quick recovery –Better QoL –Quicker recovery for initiating systemic therapy

11. Banff, Januari 26-28th 2006 Renal Cell Carcinoma 5 year survival*: –89% for localized disease –61% for locally advanced disease –9% for metastatic disease *SEER data

12. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Risk Factors Conventional risk factors –ECOG Performance Status –Tumor stage –Tumor grade –Microvessel density –Histological subtype –Histological tumor necrosis Molecular markers –Cytogenetics –Proliferation and anti-apoptosis markers –Hypoxia-inducible pathway –Cell adhesion, cell motility and invasion markers

13. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Risk Groups pT3a AuthorN pT2 5y pT2 10y N pT3a 5y pT3a 10y Skinner10265%56%2247%20% Golimbu8388%67%4866%35% McNichols17767%56%5751%28%

14. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Risk Factors Combinations* T Grade PS *Han K J Urol 2003;170:222

15. Banff, Januari 26-28th 2006 Risk Group Assessment in RCC After Nephrectomy Zisman A JCO 2002;20:4559

16. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Risk Factors (Han K J Urol) Low Risk 5y Intermediate Risk 5y High Risk 5y Nijmegen94%65%40% UCL93%78%48% MDA92%73%30%

17. Prognosis And Surgery Of Renal Cell Carcinoma With Extension Into The Caval Wall

18. Banff, Januari 26-28th 2006 cavathrombus Surgery for RCC with Caval Thrombus

19. cavathrombus

20. Banff, Januari 26-28th 2006 Risk Factors Vascular invasion: T3c Vena cava involvement: if completely resected probably no risk factor N=44 –27 T2N0 –69 % 5y (mobile thrombus) –25 % 5y (VC wall involvement) –57 % 5y (VC wall resected) WHO 2002: pT3c: tumor extension into vena cava above the diaphragm is a poor prognostic sign Lam et al J Urol 2005 Hatcher et al J Urol1991

21. Banff, Januari 26-28th 2006 Risk Factors Microscopic Vascular Invasion* Retrospective analysis of 180 patients –129 no vascular invasion 94% NED med FU 160 months –51 microscopic vascular invasion 39% progresion med FU 79 months Van Poppel J Urol 1997;158:45 This observation is not yet confirmed as an independent prognostic factor by others nor in a prospective randomised study

22. Banff, Januari 26-28th 2006 Renal Cell Carcinoma Histological Subtypes (WHO 2004) Clear cell (80%) –Synonym: common or conventional –In 85% of cases associated with mutations in the VHL gene Papillary tumor (10%) Chromophobe tumors (4%) Multilocular cystic clear cell (5%)

23. Banff, Januari 26-28th 2006 RCC Associated Antigen G250/MN/CAIX Present in >85% of all RCC, 99% of the clear-cell subtype No expression in normal kidney Mulders et al, J Urol 2006: Mab G250 has clinical efficacy in mRCC patients

24. Banff, Januari 26-28th 2006 Association of CAIX Staining and Pathologic Predictive Group and Response to IL-2 Therapy With high CA IX Pathological Risk group Non Responders N=34 Responders N=27 All N=66 Good5/ (71)12/17 (71)717/24 (71) Intermediate11/22 (50)9/9 (100)20/31 (65) Poor4/10 (40)0/1 (0)4/11 (36)

25. Banff, Januari 26-28th 2006 Survival Curves for Patients In Good and Poor Predictive Groups.

26. Adjuvant Therapy After Nephrectomy in RCC Randomised studies Aspecific immunotherapy – IFN, IL2, Combination Tumor vaccine – Modified tumor cells – HSP – G250 Mab Angiogenesis inhibitors

27. Banff, Januari 26-28th 2006 RCC Adjuvant Interferon Alfa-NL Overall Survival Messing E et al. JCO 2003;21:1214

28. Banff, Januari 26-28th 2006 RCC Adjuvant High Dose Bolus IL-2* DF survivalOverall survival Clark J et al JCO 2003;21:3133

29. Banff, Januari 26-28th 2006 RCC Adjuvant Autologous Tumour Vaccine* Randomised study N= 558 –553 included –276 vaccine group 177 treated (PT2-3b, N0-3,M0) –277 control group 202 Jocham D et al. Lancet 2004;363:594

30. Banff, Januari 26-28th 2006 RCC Adjuvant Autologous Tumour Vaccine* Well balanced for risk factors (T, Grade, histology, N etc) 5 y PFS 77.4% versus 67.8 % (p=0.0204) –T2: 81.3% versus 74.6% (n=264) (NS) –T3: 67.5% versus 49.7% (n=115) (p=0.039) Median time to progression not reached Overall survival not given Jocham D et al. Lancet 2004;363:594

31. Banff, Januari 26-28th 2006 RCC Adjuvant No standard treatment. The results of several studies are not available yet. Adjuvant treatment should only be given in the frame work of clinical studies

32. Banff, Januari 26-28th 2006 mRCC The Role of Tumor Nephrectomy Two prospective randomised studies performed to address this issue SWOG EORTC

36. Banff, Januari 26-28th 2006 mRCC The Role of Tumor Nephrectomy Flanigan NEJM 2001 SWOG: 246 ptn R Nx+ IFN  2b IFNa2b n120(92)121(83) CR/PR0/3 3.3%1/2 3.6% mOS(m)11 8 (p=0.05) Mickisch Lancet 2001 EORTC; 85 ptn mOS (m) 1811 (p<0.05) Combined analysis J Urol 2004;171(3):1071-6 mOS 13.67.8 m (p<0.05)

37. Banff, Januari 26-28th 2006 Take Home Messages Prognostic factors and risk group formation should be regarded and implemented in treatment decision Surgery is the only chance for cure in localized disease Surgery can be minimal invasive with similar oncological outcome Surgery in combination with Interferon-alpha gives survival benefit BUT

38. What is the exact role of surgery in the era of angiogenesis inhibitors? What is the exact place of angiogenesis inhibitors in patient who undergo surgery?

39. Banff, Januari 26-28th 2006 Unaddressed Questions What is the role of tumor nephrectomy in combination with anti-angiogenesis ? What is the best timing of nephrectomy ? What is the effect on the primary tumor? Will anti-angiogensis treatment in an adjuvant setting give benifit ?