Linfoadenectomia e nefrectomia citoriduttiva

Vincenzo FicarraAssociate Professor of Urology, University of Udine, Italy

Associate Editor BJU International

" ... to occlude the renal artery at an early stage of " ... to occlude the renal artery at an early stage of the procedure and remove the renal tumor en bloc the procedure and remove the renal tumor en bloc with the lymphatics"with the lymphatics"

"The para-aortic (left) and para-caval (right) lymph "The para-aortic (left) and para-caval (right) lymph nodes should be removed from the crus of the nodes should be removed from the crus of the diaphragm distally to the biforcation of the aorta".diaphragm distally to the biforcation of the aorta".

Robson CJ J Urol 1963; 89: 37-42Robson CJ J Urol 1963; 89: 37-42

Radical nephrectomy for RCC: the Robson criteria

Lymphatic drainage of the Kidney and extended LND dissection

Template for extended LND dissection

Crispen PL. et al. Eur Urol. 2011; 59: 18-23Crispen PL. et al. Eur Urol. 2011; 59: 18-23

• The available technology is capable of The available technology is capable of accurately identifying only large lymph node accurately identifying only large lymph node metastasesmetastases

• Patients with (micro)metastases in normal-Patients with (micro)metastases in normal-sized nodes who might benefit from LND sized nodes who might benefit from LND cannot be visualized by any of the available cannot be visualized by any of the available imaging techniques (US, CT, MRI)imaging techniques (US, CT, MRI)

Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

Imaging techniques and nodal metastases staging

Hutterer GC. et al. Int J Cancer 2007; 121: 2556-61Hutterer GC. et al. Int J Cancer 2007; 121: 2556-61

Nomogram predicting hilar LNI in RCC

(external validation) Accuracy: 78.4%

Role of extended LND in cN0 RCC: EORTC trial 30881

Blom JHM et al. Eur Urol. 2009; 55: 28-34Blom JHM et al. Eur Urol. 2009; 55: 28-34

772 cases(T1-3, N0M0)

383 RN +extended LND

389 RNalone

1. Expected 5-year survival rate

70 %

85 %

Role of extended LND in cN0 RCC: EORTC trial 30881

Blom JHM et al. Eur Urol. 2009; 55: 28-34Blom JHM et al. Eur Urol. 2009; 55: 28-34

EORTC trial 30881: clinical characteristics

Blom JHM et al. Eur Urol. 2009; 55: 28-34Blom JHM et al. Eur Urol. 2009; 55: 28-34

* TNM, 1978

*

EORTC trial 30881: Pathological characteristics

Blom JHM et al. Eur Urol. 2009; 55: 28-34Blom JHM et al. Eur Urol. 2009; 55: 28-34* TNM, 1978

*

Pathological LNI prevalence according to pathological characteristics

Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

High-risk clear cell RCC for LNI

Crispen PL. et al. Eur Urol. 2011; 59: 18-23Crispen PL. et al. Eur Urol. 2011; 59: 18-23

• pT3-4 tumors• Grade 3-4 • Sarcomatoid dediff.• Size >10 cm• Coagulative necrosis

Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

Rational algorithm for RCC patient candidates for LND

Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

Rational algorithm for RCC patient candidates for LND

Rational algorithm for RCC patient candidates for LND

• cT2b (>10 cm); N0

• cT3-4; N0

• cN+

• M+

Role of extended LND in cN+ RCC

Role of extended LND in cN+M0 RCC

Pantuck AJ J Urol 2003; 169: 2076-83Pantuck AJ J Urol 2003; 169: 2076-83

Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220Capitanio U. et al. Eur Urol. 2011; 60: 1212-1220

Rational algorithm for RCC patient candidates for LND

Role of LND in patients with distan metastases: fractional percentage of tumour volume removed

Pierorazio PM et al BJU Inter 2007; 100: 755-759Pierorazio PM et al BJU Inter 2007; 100: 755-759

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 1.2013NCCN Kidney Cancer Guidelines, Veersion 1.2013Ljungberg B. et al EAU Guidelines, 2013Ljungberg B. et al EAU Guidelines, 2013

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

SATURN database – LUNA fundation (unpublished data)

492/5378 (9.1%) cases surgically treated from 1995-2007

Combined analysis (SWOG/EORTC)

Flanigan RC et al J Urol 2004; 171: 1071-1076Flanigan RC et al J Urol 2004; 171: 1071-1076

13.6 months

7.8 months+ 5.8 months

• 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: 1071-1076Flanigan RC et al J Urol 2004; 171: 1071-1076

Combined analysis (SWOG/EORTC)

Zini L. et al Urology 2009; 73: 342-346Zini L. et al Urology 2009; 73: 342-346

Population-based assessment (SEER - 1988-2004)

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

Cytoreductive Nephrectomy in the era of Targeted molecular agents

A population-based study examining the role of nephrectomy prior to treatment

Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89

A population-based study examining the role of nephrectomy prior to treatment

Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89Warren M. et al Can Urol Assoc J 2009; 3 (4): 281-89

Sunitinib in patients with or without prior nephrectomy in an expanded-access study

Szcylik C. et al Eur Urol (Suppl) 2009; abstract # 248Szcylik C. et al Eur Urol (Suppl) 2009; abstract # 248

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 2530 Time (months)

OS

prob

abili

ty

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

Value of Cytoreductive Nephrectomy for mRCC in the Era of Targeted Therapy

Choueiri TK. et al J Urol 2011; 185: 60-66Choueiri TK. et al J Urol 2011; 185: 60-66

Value of Cytoreductive Nephrectomy for mRCC in the Era of Targeted Therapy

You D. et al J Urol 2011; 185: 54-59You D. et al J Urol 2011; 185: 54-59

CN: 20% sarcomatoid featuresNon CN: 3% sarcomatoid feature

Sarcomatoid feature: HR 2.7 (1.2-6.7)

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: 3378-88Culp SH et al Cancer 2010; 116: 3378-88

MD Anderson: 470 CN and 88 medical therapy only

Temsirolimus as first line therapy in poor-risk mRCC

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, 2013NCCN Guidelines, 2013

Hopitaux de Paris and Pfizer – Hopitaux de Paris and Pfizer – 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 Ran

dom

izat

ion

(N=576)

CARMENA (NCT00930033) TrialStudy start data: May 2009 – Estimated Study completition: May 2013

Hopitaux de Paris and Pfizer – Hopitaux de Paris and Pfizer – 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)

Ran

dom

izat

ion

(N= 458)

SURTIME (EORTC 30073) TrialStudy start data: April 2010 – Estimated Study completition: October 2014

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