Linfoadenectomia e nefrectomia citoriduttiva Vincenzo Ficarra Direttore Clinica di Urologia Azienda Ospedaliera Universitaria di Udine

Radical nephrectomy for RCC: the Robson criteria " ... 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

Lymphatic drainage of the Kidney and extended LND dissection

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

Imaging techniques and nodal metastases staging The 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) Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

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

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

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

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

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

Role of extended LND in M0 RCC: SEER database Sun M. et al. BJU Int 2014; 113: 36–42.

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

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

* Capitanio U. et al. BJU Inter. 2014; doi:10.1111/bju.12125

Accuracy 86.9% * Capitanio U. et al. BJU Inter. 2014; doi:10.1111/bju.12125

The use of a threshold of 3% would allow the avoiding of ~50% of the LNDs * Capitanio U. et al. BJU Inter. 2014; doi:10.1111/bju.12125

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

* Bekema HJ et al. Eur Urol. 2013; 64: 799-810

* Bekema HJ et al. Eur Urol. 2013; 64: 799-810

EORTC trial 30881: cT3-4 subanalysis * Blom JHM et al. Eur Urol. 2009; 55: 28-34

Lymph node dissection in locally advanced Renal Cell Carcinoma * Bekema HJ et al. Eur Urol. 2013; 64: 799-810

Lymph node dissection in locally advanced Renal Cell Carcinoma * Bekema HJ et al. Eur Urol. 2013; 64: 799-810

* There is insufficient evidence to draw any conclusions on oncologic outcomes for patients having concomitant LND compared with patients having RN alone for cT3–T4N0M0 RCC The quality of evidence is generally low and the results potentially biased. * Bekema HJ et al. Eur Urol. 2013; 64: 799-810

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

Role of extended LND in cN+ RCC

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

Role of LND in patients with distan metastases: fractional percentage of tumour volume removed However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. Pierorazio PM et al BJU Inter 2007; 100: 755-759

Rational algorithm for RCC patient candidates for LND cT2b (>10 cm); N0 cT3-4; N0 cN+ M+

Russell CM et al. J Urol. 2014; (in press)

Isolated Nodal Recurrences Russell CM et al. J Urol. 2014; (in press)

Isolated Nodal Recurrences Russell CM et al. J Urol. 2014; (in press)

Isolated Nodal Recurrences Russell CM et al. J Urol. 2014; (in press)

Isolated Nodal Recurrences Surgical resection represents the best curative option for patients who present with isolated retroperitoneal lymph node recurrence of RCC Durable postoperative progression-free survival is attainable in many patients regardless of histology or clinical TNM stage Russell CM et al. J Urol. 2014; (in press)

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

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

Combined analysis (SWOG/EORTC) 13.6 months However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. + 5.8 months 7.8 months Flanigan RC et al J Urol 2004; 171: 1071-1076

Combined analysis (SWOG/EORTC) 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 However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. Flanigan RC et al J Urol 2004; 171: 1071-1076

Population-based assessment (SEER - 1988-2004) However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. Zini L. et al Urology 2009; 73: 342-346

Guidelines on Renal Cell Carcinoma EAU, 2013 ESMO, 2010 NCCN, 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 Gli obiettivi del nostro studio sono di… 42

Cytoreductive Nephrectomy in the era of Targeted molecular agents However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death.

A population-based study examining the role of nephrectomy prior to treatment However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89

Value of Cytoreductive Nephrectomy for mRCC in the Era of Targeted Therapy However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. Choueiri TK. et al J Urol 2011; 185: 60-66

Value of Cytoreductive Nephrectomy for mRCC in the Era of Targeted Therapy CN: 20% sarcomatoid features Non CN: 3% sarcomatoid feature Sarcomatoid feature: HR 2.7 (1.2-6.7) However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. You D. et al J Urol 2011; 185: 54-59

Ideal candidate for cytoreductive nephrectomy MD Anderson: 470 CN and 88 medical therapy only Lactate dehydrogenase Albumin level Symptoms (S3) Liver metastasis N+ retroperitoneal N+ supradiaphragmatic ≥ T3 However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. Culp SH et al Cancer 2010; 116: 3378-88

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 However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death. NCCN Guidelines, 2013

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

SURTIME (EORTC 30073) Trial Study start data: April 2010 – Estimated Study completition: October 2014 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 (N= 458) Randomization Immediate CN + Sunitinib (3 course) Primary endpoint: Overall Survival Secondary endpoints: Objective response, PFS, Safety Hopitaux de Paris and Pfizer – www.clinicaltrials.gov

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 However, not only an ideal cancer staging system should aid the clinician in the appropriate selection of therapeutic options but above all, in my opinion, it should stratify the patient’s risk of cancer progression or cancer death.