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Radical Nephrectomy The Role Of Surgery In mRCC Peter Mulders Professor and Chairman Department of Urology University Medical Center Nijmegen The Netherlands Renal Cell Carcinoma General Aspects RCC accounts for 3% of all adult tumors 100.000 deaths from RCC every year worldwide

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Radical Nephrectomy The Role Of Surgery In mRCC

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Radical NephrectomyThe Role Of Surgery In mRCC

PeterMulders

ProfessorandChairmanDepartmentofUrologyUniversityMedicalCenterNijmegen

TheNetherlands


Renal Cell CarcinomaGeneral Aspects

  • RCC accounts for 3% of all adult tumors

  • 100.000 deaths from RCC every year worldwide

  • Most aggressive GU tumor

Banff, Januari 26-28th 2006


Renal Cell CarcinomaGeneral Aspects

  • 54 % of cases present with localized disease*

  • 70 % are not cured by surgery alone

* SEER data

Banff, Januari 26-28th 2006


Renal Cell CarcinomaSurgical Aspects

  • Surgery is the primary curative treatment in RCC

    Changing techniques:

    From open radical tumor nephrectomy

    to laparoscopic partial nephrectomy

Banff, Januari 26-28th 2006


Renal Cell CarcinomaSurgical Aspects

  • Robsons radical tumor nephrectomy

    • No-touch procedure

    • Total nephrectomy and adrenalectomy

    • Lymphadenectomy

Banff, Januari 26-28th 2006


Renal Cell CarcinomaSurgical Aspects

  • Partial nephrectomy: similar oncological outcome in <4 cm tumors

  • Laparoscopic (partial) nephrectomy feasible

Banff, Januari 26-28th 2006


Prospective Randomised Study Open vs Laparoscopic Nephrectomy (n=160)

Banff, Januari 26-28th 2006


Prospective Randomised Study Open vs Laparoscopic Nephrectomy

Banff, Januari 26-28th 2006


Conclusions LIDO-trial

  • Laparoscopicnephrectomy:

    • Safeandeffective

    • Similaroncologicalresults

    • Quickrecovery

    • BetterQoL

    • Quickerrecoveryforinitiatingsystemictherapy

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

Banff, Januari 26-28th 2006


Renal Cell CarcinomaRisk 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

Banff, Januari 26-28th 2006


Renal Cell CarcinomaRisk Groups pT3a

Banff, Januari 26-28th 2006


Renal Cell CarcinomaRisk Factors

  • Combinations*

    • T

    • Grade

    • PS

*Han K J Urol 2003;170:222

Banff, Januari 26-28th 2006


Risk Group Assessment in RCC After NephrectomyZisman A JCO 2002;20:4559

Banff, Januari 26-28th 2006


Renal Cell Carcinoma Risk Factors(Han K J Urol)

Banff, Januari 26-28th 2006


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


Surgery for RCC with Caval Thrombus

cavathrombus

Banff, Januari 26-28th 2006


cavathrombus


Risk FactorsVascular 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

Hatcher et al J Urol1991

Lam et al J Urol 2005

Banff, Januari 26-28th 2006


Risk FactorsMicroscopic 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

This observation is not yet confirmed as an

independent prognostic factor by others nor

in a prospective randomised study

Van Poppel J Urol 1997;158:45

Banff, Januari 26-28th 2006


Renal Cell CarcinomaHistological 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%)

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

Banff, Januari 26-28th 2006


Association of CAIX Staining and Pathologic Predictive Group and Response to IL-2 Therapy

Banff, Januari 26-28th 2006


Survival Curves for Patients In Good and Poor Predictive Groups.

Banff, Januari 26-28th 2006


Adjuvant Therapy After Nephrectomy in RCC

  • Aspecific immunotherapy

    • IFN, IL2, Combination

  • Tumor vaccine

    • Modified tumor cells

    • HSP

    • G250 Mab

  • Angiogenesis inhibitors

Randomised studies


RCC Adjuvant Interferon Alfa-NL Overall Survival

Messing E et al. JCO 2003;21:1214

Banff, Januari 26-28th 2006


RCC Adjuvant High Dose Bolus IL-2*

DF survival

Overall survival

Clark J et al JCO 2003;21:3133

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

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

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

Banff, Januari 26-28th 2006


mRCCThe Role of Tumor Nephrectomy

Two prospective randomised studies performed to address this issue

  • SWOG

  • EORTC

Banff, Januari 26-28th 2006


EORTC


mRCCThe Role of Tumor Nephrectomy

  • FlaniganNEJM2001SWOG:246ptn

    RNx+IFN2bIFNa2b

    n120(92)121(83)

    CR/PR0/33.3%1/23.6%

    mOS(m)118(p=0.05)

  • MickischLancet2001EORTC;85ptn

    mOS(m)1811(p<0.05)

  • CombinedanalysisJUrol2004;171(3):1071-6

    mOS13.67.8m(p<0.05)

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

Banff, Januari 26-28th 2006


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?


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

  • ?

Banff, Januari 26-28th 2006


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