Radical Nephrectomy The Role Of Surgery In mRCC

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Radical NephrectomyThe Role Of Surgery In mRCC

• Peter Mulders
• Professor and Chairman Department of Urology
  University Medical Center Nijmegen
• The Netherlands

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Renal Cell CarcinomaGeneral Aspects

• RCC accounts for 3 of all adult tumors
• 100.000 deaths from RCC every year worldwide
• Most aggressive GU tumor

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Renal Cell CarcinomaGeneral Aspects

• 54 of cases present with localized disease
• 70 are not cured by surgery alone

SEER data
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Renal Cell CarcinomaSurgical Aspects

• Surgery is the primary curative treatment in RCC
• Changing techniques
• From open radical tumor nephrectomy
• to laparoscopic partial nephrectomy

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Renal Cell CarcinomaSurgical Aspects

• Robsons radical tumor nephrectomy
• No-touch procedure
• Total nephrectomy and adrenalectomy
• Lymphadenectomy

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Renal Cell CarcinomaSurgical Aspects

• Partial nephrectomy similar oncological outcome
  in lt4 cm tumors
• Laparoscopic (partial) nephrectomy feasible

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Prospective Randomised Study Open vs Laparoscopic
Nephrectomy (n160)
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Prospective Randomised Study Open vs Laparoscopic
Nephrectomy
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Conclusions LIDO-trial

• Laparoscopic nephrectomy
• Safe and effective
• Similar oncological results
• Quick recovery
• Better QoL
• Quicker recovery for initiating systemic
  therapy

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Renal Cell Carcinoma

• 5 year survival
• 89 for localized disease
• 61 for locally advanced disease
• 9 for metastatic disease

SEER data
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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

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Renal Cell CarcinomaRisk Groups pT3a
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Renal Cell CarcinomaRisk Factors

• Combinations
• T
• Grade
• PS

Han K J Urol 2003170222
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Risk Group Assessment in RCC After
NephrectomyZisman A JCO 2002204559
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Renal Cell Carcinoma Risk Factors(Han K J Urol)
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• Prognosis And Surgery Of Renal Cell Carcinoma
  With Extension Into The Caval Wall

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Surgery for RCC with Caval Thrombus
cavathrombus
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cavathrombus
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Risk FactorsVascular invasion T3c

• Vena cava involvement if completely resected
  probably no risk factor
• N44
• 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
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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 199715845
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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)

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RCC Associated Antigen G250/MN/CAIX

• Present in gt85 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
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Association of CAIX Staining and Pathologic
Predictive Group and Response to IL-2 Therapy
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Survival Curves for Patients In Good and Poor
Predictive Groups.
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Adjuvant Therapy After Nephrectomy in RCC

• Randomised studies

• Aspecific immunotherapy
• IFN, IL2, Combination
• Tumor vaccine
• Modified tumor cells
• HSP
• G250 Mab
• Angiogenesis inhibitors

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RCC Adjuvant Interferon Alfa-NL Overall Survival
Messing E et al. JCO 2003211214
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RCC Adjuvant High Dose Bolus IL-2
DF survival
Overall survival
Clark J et al JCO 2003213133
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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 2004363594
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RCC Adjuvant Autologous Tumour Vaccine

• Well balanced for risk factors (T, Grade,
  histology, N etc)
• 5 y PFS 77.4 versus 67.8 (p0.0204)
• T2 81.3 versus 74.6 (n264) (NS)
• T3 67.5 versus 49.7 (n115) (p0.039)
• Median time to progression not reached
• Overall survival not given

Jocham D et al. Lancet 2004363594
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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

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mRCCThe Role of Tumor Nephrectomy

• Two prospective randomised studies performed to
  address this issue
• SWOG
• EORTC

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EORTC
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mRCCThe Role of Tumor Nephrectomy

• Flanigan NEJM 2001 SWOG 246 ptn
• R Nx IFN?2b IFNa2b
• n 120(92) 121(83)
• CR/PR 0/3 3.3 1/2 3.6
• mOS(m) 11 8 (p0.05)
• Mickisch Lancet 2001 EORTC 85 ptn
• mOS (m) 18 11 (plt0.05)
• Combined analysis J Urol 2004171(3)1071-6
• mOS 13.6 7.8 m (plt0.05)

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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

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• 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?

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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
• ?