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Prognostic factors and predictive models
Vincenzo Ficarra
Associate Professor of Urology, University of Padova, ItalyScientific Director OLV Robotic Surgery Institute, Aalst, Belgium
RCC Prognostic Factors
Kidney Cancer
Localized MetastaticClinicalLaboratory? Bioptical
Surgery
PathologicalMolecular
Cytogenetic
Medical therapies
ClinicalLaboratory
RCC Oncologic Outcomes
Kidney cancerDiagnosis
Localized Local/Distant recurrence
Death
MetastaticDisease
RFS
PFS
OSCSS
PFS
• Postoperative counseling
• Postoperative surveillance protocols
• Definition of selection criteria for ongoing adjuvant trials
Role of Integrated staging systems in non-metastatic RCC
Clinical Prognostic Factors
• Age
• Gender
• Performance Status
• Mode of presentation (Symptoms)
• Clinical tumour size
• Clinical staging (cTNM)
Performance Status ECOG
Karakiewicz P., Ficarra V. et al. Eur J Cancer 2007; 43: 1023-29
Karakiewicz P., Ficarra V. et al. Eur J Cancer 2007; 43: 1023-29
Mode of presentation
Models predicting recurrence after NT:Preoperative parameters
SymptomsClinical size
SymptomsClinical size
GenderClinical sizeSymptoms
Nodes (Imaging)Necrosis (imaging)
Models predicting survival after NT:Preoperative parameters
Accuracy: 84-88% (external)
Karakiewicz P. et al. Eur Urol 2009; 55: 287-295
Preop. Karakiewicz nomogram (3364 pts)Preop. Karakiewicz nomogram (3364 pts)
Gontero P. and SATURN Project members (submitted to BJU Intern)
c index (1 year)87.8 (84.4-91.4)
c index (2 yrs)87 (84.4-89.5)
c index (5 yrs)84 (82.3-87.1)
c index (10 yrs) 85.9 (83.2-88.6)
Models predicting survival after NT:Preoperative parameters
Accuracy: 70-73% (external)
Kutikov A. et al. J Clin Oncol 2009; 28: 311-317
Pathologic Prognostic Factors
• Tumour extension (TNM)
• Tumour size
• Histologic Subtypes
• Grading
• Necrosis
• Sarcomatoid de-differentiation
• Microvascular invasion
T1 T1 7 cm7 cm
T1aT1a 4 cm 4 cm 4 cm 4 cm
T1bT1b > 4 - 7 cm > 4 - 7 cm > 4 - 7 cm > 4 - 7 cm
T2 T2 > 7 cm> 7 cm > 7 cm > 7 cm
T2aT2a > 7 - ≤ 10 cm > 7 - ≤ 10 cm
T2bT2b > 10 cm> 10 cm
TNM, 1997TNM, 1997
Evolution of the TNM staging system for organ-confined RCC
TNM, 2002TNM, 2002 TNM, 2009TNM, 2009
TNM, 2009 Version – Why ?TNM, 2009 Version – Why ?
Frank I et al. J. Urol. 2005; 173: 380-384
544 patients with unilateral, sporadic pT2 RCC treated with radical nephrectomy or nephron sparing surgery between 1970 and 2000
Validation of the 2009 TNM version
Novara G et al. Eur Urol 2010; 58: 588-95
5,339 patients with RCC surgically treated between 1997 and 2007
Waalkes S et al. Eur. Urol. 2011; 59: 258-263
Validation of the 2009 TNM version
T3a Fat and adrenal invasion Fat invasion or V1
T3b V1 – V2 V2
T3c V3 V3
T4 Outside Gerota’s fascia Outside Gerota’s fascia and adrenal invasion
TNM, 2002
Development of the TNM staging system for locally advanced RCC
TNM, 2009
Validation of the 2009 TNM version
Novara G et al. Eur Urol 2010; 58: 588-95
5,339 patients with RCC surgically treated between 1997 and 2007
Redefining pT3 RCC: Fat invasion + Venous involvement
V1
V2
V1+fat inv
V2+fat inv
V1-2+adrenal inv
Redefining pT3 RCC: Fat invasion + Venous involvement
Margulis V. et al. Cancer 2007; 109: 2439-44
Clear Cell
Papillary
Chromophobe
Oncocitoma
clear cell papillary RCC
Tubulocystic RCC Oncocytic papillary RCC
RCC with prominent leiomyomatous proliferation
Prognostic Value of Histologic Subtypes
Capitanio U. et al BJU Inter 2008: 103: 1496-1500
Prognostic Value of Histologic Subtypes
Capitanio U. et al BJU Inter 2008: 103: 1496-1500
Histologic Subtypes and definition of other histologic factors
Clear Cell Papillary Chromophobe
Nuclear grading +++ + -
Nucleolar grading
- ++ -
Coagulative necrosis
+++ + ++
Microvascular invasion
+ ? ?
Sarcomatoide de-diff.
+++ +++ +++
Fuhrman Nuclear GradingGrade 1 Grade 2
Grade 3 Grade 4
Fuhrman nuclear grading14,064 cases (clear cell RCC)
Sun M. et al Eur Urol 2009; 56: 775
Sika D et al Am J Surg Pathol. 2006 Sep;30(9):1091-6.
Nucleolar Grade but not Fuhrman Grade Is applicable to Papillary RCC
Fuhrman nuclear grading in papillary RCC
Nucleolar grading Nuclear grading
Klatte T et al J Urol. 2010; 183: 2143-2147
A novel tumor grading scheme forChromophobe Renal Cell Carcinoma
Paner et al Am J Surg Pathol. 2010; 34: 1233-1240
Prognostic Value of Coagulative necrosis in clear cell
Sengupta S. et al Cancer 2005; 104: 511-520
Prognostic Value of Coagulative necrosis in clear cell
Klatte T. et al J Urol 2009; 181: 1558-64
Prognostic Value of Coagulative necrosis in papillary RCC
Sengupta S. et al Cancer 2005; 104: 511-520
Prognostic Value of Coagulative necrosis in papillary RCC
Klatte T. et al Clin Cancer Res 2009; 15: 1162
Prognostic Value of Coagulative necrosis in chromophobe RCC
Amin MB et al Am J Clin Surg Pathol 2008; 32: 1822-34
Independent predictors of aggressive chromophobe RCC
Prognostic Value of Sarcomatoiddedifferentiation
Prognostic Value of Sarcomatoiddedifferentiation
Cheville JC et al Am J Surg Pathol 2004; 28: 435-441
Models predicting recurrence after NT:Postoperative parameters
Accuracy: 74% (internal) - 61-84% (external)
Kattan M. et al J Urol 2001; 166: 63-67
Models predicting recurrence after NT:Postoperative parameters
Accuracy: 75-81% (external)
Zisman A. et al JCO 2002; 20: 4559-4566Cindolo L., Ficarra V., et al Cancer 2005; 104: 1362-1371
Models predicting recurrence after NT:Postoperative parameters
Accuracy: 82% (internal) – 78-79% (external)
Sorbellini M. et al J Urol 2005; 173: 48-51
Models predicting recurrence after NT:Postoperative parameters
Accuracy: 84% (internal) – 80% (external)
• T stage (TNM, 2002) Score - pT1a 0 - pT1b 2 - pT2 3 - pT3-4 4
• N stage - pNx-pN0 0 - pN1-2 2
• Tumor Size Score - less than 10 cm 0 - 10 or greater 1
• Nuclear Grade - Grade 1-2 0 - Grade 3 1 - Grade 4 3
• Necrosis - absent 0 - present 1
Leibovich B. et al Cancer 2003; 97: 1663-71
Stage, Size, Grade and Necrosis (SSGN) Score e RFS
Leibovich B. et al Cancer 2003; 97: 1663-71
(0-2)
(3-5)
(> 6)
Adjuvant therapy in RCC: planned trials
Trial Sponsor Treatment Primary outcome
Histologic subtypes
Stratification tools
Scheduled conclusion
ARISER Wilex Girentuximab vs Placebo
RFS, OS Clear cell pT, Grading
9/2013
ASSURE NCI/SWOK/ECOG
Sunitinib vsSorafenib vsPlacebo
RFS Clear cell & non-clear cell
pT,Grading
4/2016
S-TRAC Pfizer Sunitinib vsPlacebo
RFS Clear cell & non-clear cell
UISS 1/2012
SORCE9 Medical Research Council (UK)
Sorafenib vsPlacebo
RFS Clear cell & non-clear cell
Leibovich score
8/2012
EVEREST NCI/SWOG Everolimus vsPlacebo
RFS Clear cell & non-clear cell
pTGrading
8/2013
PROTECT GlaxoSmithKline
Pazopanib vsPlacebo
RFS Prominent clear cell
pT, Grading
10/2015
Models predicting survival after NT:Postoperative parameters
N0/M0
N+/M+
Zisman A. et al JCO 2002; 20: 4559-4566
Patard JJ, Ficarra V. et al JCO 2004; 22: 3316-3322
External validation of the UCLA Integrated Staging System
3,199 confined RCC and 1,083 metastatic RCC
C index: 0.765 – 0.863 C index: 0.584 – 0.776
Models predicting survival after NT:Postoperative parameters
Frank I et al 2002; 168: 2395-2400
• T stage (TNM, 1997) Score - pT1 0 - pT2 1 - pT3a-b-c 2 - pT4 0• N stage - pNx-pN0 0 - pN1-2 2• M stage - M0 0 - M1 4
• Tumor Size Score - less than 5 cm 0 - 5 or greater 2
• Nuclear Grade - Grade 1-2 0 - Grade 3 1 - Grade 4 3
• Necrosis - absent 0 - present 2
(SSGN) Score accuracy: 75-88% (external)
Ficarra V., Martignoni G. et al J Urol 2006; 175: 1235-1239Concordance index: 0.88
External validation of the SSIGN Score(slides revision)
Models predicting survival after NT:Postoperative parameters
Karakiewicz P., Ficarra V. et al JCO 2007; 25: 1316-1322
Accuracy: 75-89% (external)
Molecular markers for RCC
Belldegrun As et al Eur Urol Suppl 2007; 6: 477-483
Molecular markers for RCC
Klatte T. et al Cancer Epidemiol Biomarkers 2009; 18: 894-900
concordance index 0.90
Cytogenetic nomogram for clear cell RCC
Klatte T. et al. J Clin Oncol 2009; 27: 746-753
concordance index 0.89
Motzer (MSKCC) criteria
Motzer RJ. et al. J Clin Oncol 2002; 20: 289-296
• Serum calcium >10 mg/dl
• Hemoglobin less than sex-specific limits
• LDH more than 1.5x normal
• Karnofsky performance status
• Interval from initial RCC diagnosis to treatment
Motzer (MSKCC) criteria
Motzer RJ. et al. J Clin Oncol 2002; 20: 289-296
Models predicting survival for RCC before targeted therapy era
Sun M. Ficarra V. et al. Eur Urol 2011; 60: 640-661
Motzer, 2002 Motzer, 2004 Mekhail, 2005 Escudier, 2007 Negrier, 2002
Immun Immun Immun Immun Immun
KPS KPS KPS N° sites M+ N° sites M+
LDH LDH LDH
Hb Hb Hb Hb
Corrected Ca Corrected Ca Corrected Ca Corrected Ca
Diagn-IFN Diagn-IFN Diagn-IFN Diagn-IFN
RT
N+
Hepatic M+ Hepatic M+
Lung M+
Neutrophil count
External validation of Motzer criteria in patients treated with Bevacizumab + IFN
Karakiewicz P. et al. Eur Urol 2011; 60: 48-56
Accuracy: 52-62%
Models predicting prognosis in mRCC treated with targeted therapy
Author Cases Target population Variables Accuracy (%)
Choueiri, 2007
120 NT + VEGF inhibitors
PS, Platelet, Neutrophil, cCa, time diagnosis-
treatment
NR
Motzer, 2008 375 Sunitinib PS, LDH, Hb, cCa, Lung and liver M+, prior NT,
Numb. M+, time diagnosis-treatment
63%(internal)
Heng, 2009
645 VEGF inhibitors PS, Hb, cCa, Neutrophile, Platelet,
time diagnosis-treatment
73%(internal)
Karakiewicz, 2011
628 Bevacizumab + IFN
Age, PS, albumin, alkaline phosphatase,
time diagnosis-treatment
70-75%(internal)
Manola, 2011 3,748 Targeted therapy PS, numb M+, previous IFN/IL, Hb, LDH, WBC,
ALP, cCa
71%(internal)
74%(external)
Ljungberg B. et al Eur Urol 2010; 58: 398-406
ESMO Guidelines on Renal Cell Carcinoma
Escudier B. et al Ann Oncol 2010; 21 (Suppl 5): 137-139
• Predictive models based on traditional clinical or pathological parameters significantly improve the prognostic accuracy
• These models can be used to select patients suitable for adjuvant protocols, plan the more appropriate follow-up, and perform careful patient counselling.
Take home messages
• Motzer criteria were formally validated only in patients treated with bevacizumab + IFN and their accuracy resulted very low
• New predictive models generated in the targeted therapy era must be further evaluated and tested
Take home messages
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