2. Linfoadenectomia e nefrectomia citoriduttiva Vincenzo Ficarra Associate Professor of Urology, University of Udine, Italy Associate Editor BJU International

3. "... to occlude the renal artery at an early stage of the procedure and remove the renal tumor en bloc with the lymphatics" "The para-aortic (left) and para-caval (right) lymph nodes should be removed from the crus of the diaphragm distally to the biforcation of the aorta". Robson CJ J Urol 1963; 89: 37-42 Radical nephrectomy for RCC: the Robson criteria

4. Lymphatic drainage of the Kidney and extended LND dissection

5. Template for extended LND dissection Crispen PL. et al. Eur Urol. 2011; 59: 18-23

6. The available technology is capable of accurately identifying only large lymph node metastasesThe available technology is capable of accurately identifying only large lymph node metastases Patients with (micro)metastases in normal- sized nodes who might benefit from LND cannot be visualized by any of the available imaging techniques (US, CT, MRI)Patients with (micro)metastases in normal- sized nodes who might benefit from LND cannot be visualized by any of the available imaging techniques (US, CT, MRI) Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220 Imaging techniques and nodal metastases staging

7. Hutterer GC. et al. Int J Cancer 2007; 121: 2556-61 Nomogram predicting hilar LNI in RCC (external validation) Accuracy: 78.4%

8. Role of extended LND in cN0 RCC: EORTC trial 30881 Blom JHM et al. Eur Urol. 2009; 55: 28-34 772 cases (T1-3, N0M0) 383 RN + extended LND 389 RN alone 1. Expected 5-year survival rate 70 % 85 %

9. Role of extended LND in cN0 RCC: EORTC trial 30881 Blom JHM et al. Eur Urol. 2009; 55: 28-34

10. EORTC trial 30881: clinical characteristics Blom JHM et al. Eur Urol. 2009; 55: 28-34 * TNM, 1978 *

11. EORTC trial 30881: Pathological characteristics Blom JHM et al. Eur Urol. 2009; 55: 28-34 * TNM, 1978 *

12. Pathological LNI prevalence according to pathological characteristics Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

13. High-risk clear cell RCC for LNI Crispen PL. et al. Eur Urol. 2011; 59: 18-23 pT3-4 tumors Grade 3-4 Sarcomatoid dediff. Size >10 cm Coagulative necrosis

14. Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220 Rational algorithm for RCC patient candidates for LND

15. Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220 Rational algorithm for RCC patient candidates for LND

16. cT2b (>10 cm); N0 cT3-4; N0 cN+ M+

17. Role of extended LND in cN+ RCC

18. Role of extended LND in cN+M0 RCC Pantuck AJ J Urol 2003; 169: 2076-83

19. Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220 Rational algorithm for RCC patient candidates for LND

20. Role of LND in patients with distan metastases: fractional percentage of tumour volume removed Pierorazio PM et al BJU Inter 2007; 100: 755-759

21. Recommendations for lymph node dissection? NCCN, 2013  Lymph node dissection is recommended for patients with palpable or CT detected enlarged lymph nodes and to obtain adequate staging information in those with nodes that appear normal EAU, 2013 Extended lymphadenectomy does not improve survival and can be restricted to staging purposes. NCCN Kidney Cancer Guidelines, Veersion 1.2013 Ljungberg B. et al EAU Guidelines, 2013

22. Role of Nephrectomy in mRCC Curative (Nephrectomy + metastasectomy) Cytoreductive (To resect primary tumor in the prior to the initiation of systemic therapy for unresectable metastases) Palliative (To improve symptoms) - pain related to the kidney mass - intractable hematuria - paraneoplastic syndrome

23. Palliative Nephrectomy in mRCC SATURN database – LUNA fundation (unpublished data) 492/5378 (9.1%) cases surgically treated from 1995-2007

24. Combined analysis (SWOG/EORTC) Flanigan RC et al J Urol 2004; 171: 1071-1076 13.6 months 7.8 months + 5.8 months

25. Cytoreductive nephrectomy significantly improve overall survival in patients with mRCC treated with IFN-alpha independent of patients - performance status - site of metastasis (lung) - presence of measurable disease - (?) single Vs multiple metastases Flanigan RC et al J Urol 2004; 171: 1071-1076 Combined analysis (SWOG/EORTC)

26. Zini L. et al Urology 2009; 73: 342-346 Population-based assessment (SEER - 1988-2004)

27. Guidelines on Renal Cell Carcinoma EAU, 2013ESMO, 2010NCCN, 2013 Palliative or complementary systemic treatments are necessary Recommended for mRCC patients with good PS when combined with IFN-alfa (Grade A) Only limited data are available addressing the value of CN combined with targeting agents Standard of cure in patients receiving cytokines [1, A] Role of CN needs to be re-evaluated in the present era of molecular targeted therapies Curative intent in patients with resectable solitary metastasis Cytoreductive intent in patients with good PS and without brain metastasis Role of CN and patients selection may warrant assessment in the setting of targeted therapies Palliative in symptomatic mRCC

28. Cytoreductive Nephrectomy in the era of Targeted molecular agents

29. A population-based study examining the role of nephrectomy prior to treatment Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89

30. A population-based study examining the role of nephrectomy prior to treatment Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89

31. Sunitinib in patients with or without prior nephrectomy in an expanded-access study Szcylik C. et al Eur Urol (Suppl) 2009; abstract # 248 1.0 0.8 0.6 0.4 0.2 0 0510152025 30 Time (months) OS probability Patients with prior Nx (n=1,020) Median = 19.0 months (95% CI: 18.2−21.4) Patients without prior Nx (n=146) Median = 11.1 months (95% CI: 8.4−15.1) P<0.0001

32. Value of Cytoreductive Nephrectomy for mRCC in the Era of Targeted Therapy Choueiri TK. et al J Urol 2011; 185: 60-66

33. Value of Cytoreductive Nephrectomy for mRCC in the Era of Targeted Therapy You D. et al J Urol 2011; 185: 54-59 CN: 20% sarcomatoid features Non CN: 3% sarcomatoid feature Sarcomatoid feature: HR 2.7 (1.2-6.7)

34. Ideal candidate for cytoreductive nephrectomy Lactate dehydrogenase Albumin level Symptoms (S3) Liver metastasis N+ retroperitoneal N+ supradiaphragmatic ≥ T3 Culp SH et al Cancer 2010; 116: 3378-88 MD Anderson: 470 CN and 88 medical therapy only

35. Temsirolimus as first line therapy in poor-risk mRCC

36. Candidate for cytoreductive nephrectomy Good surgical risk (good performance status) Limited metastatic tumor burden to lung or bone Extensive metastatic disease with systemic therapy planned Symptoms related to the primary tumor NCCN Guidelines, 2013

37. Hopitaux de Paris and Pfizer – www.clinicaltrials.gov www.clinicaltrials.gov Primary endpoint: Overall Survival Secondary endpoints: Objective response, PFS, Safety Eligibility Criteria ECOG PS of 0 or 1 Clear cell histology Resectable primary tumour No prior systemic treatment Adequate organ function Cytoreductive Nephrectomy + Sunitinib Sunitinib alone Randomization (N=576) CARMENA (NCT00930033) Trial Study start data: May 2009 – Estimated Study completition: May 2013

38. Hopitaux de Paris and Pfizer – www.clinicaltrials.gov www.clinicaltrials.gov Primary endpoint: Overall Survival Secondary endpoints: Objective response, PFS, Safety Eligibility Criteria Clear cell histology Resectable primary tumour Asymptomatic primary tumour Measurable disease No prior systemic treatment Adequate organ function Sunitinib (3 course) + Deferred CN Immediate CN + Sunitinib (3 course) Randomization (N= 458) SURTIME (EORTC 30073) Trial Study start data: April 2010 – Estimated Study completition: October 2014

39. Conclusions Nephrectomy is still an important part of the multidisciplinary treatment of RCC Targeted agents represent a substantial improvement but since they are not curative, the cytoreductive paradigm is still relevant Today, the more relevant question should address the timing of and appropriate patient selection for cytoreductive nephrectomy