TNM staging system for Renal Cell Carcinoma: current status and future perspectives Vincenzo Ficarra Dipartimento di Scienze Oncologiche e Chirurgiche

TNM staging system for Renal CellTNM staging system for Renal CellCarcinoma: current status and Carcinoma: current status and

future perspectivesfuture perspectives

Vincenzo Ficarra

Dipartimento di Scienze Oncologiche e Chirurgiche Clinica di Urologia - Università degli Studi di Padova

An ideal cancer staging system should effectively: An ideal cancer staging system should effectively:

• comunicate critical tumor characteristics, comunicate critical tumor characteristics,

• aid the clinician in the appropriate selection aid the clinician in the appropriate selection

of therapeutic options, of therapeutic options,

• stratify the patient’s risk of cancer progressionstratify the patient’s risk of cancer progression

or cancer death and or cancer death and

• eventually determine the selection criteria for eventually determine the selection criteria for

clinical trialsclinical trials

Sobin LH: TNM classification of malignant tumours; 2002Sobin LH: TNM classification of malignant tumours; 2002

Staging systems for RCC

• Flocks and Kadesky, 1958 Flocks and Kadesky, 1958

• Robson, 1969 Robson, 1969

• TNM, 1978TNM, 1978

• TNM, 1987TNM, 1987

• TNM, 1997TNM, 1997

• TNM, 2002TNM, 2002

• TNM, ….. ?TNM, ….. ?

Staging systems for RCC

Development of the TNM staging system for localized RCC

Ficarra V.et al. Eur Urol 2004; 46: 559-64

Year Edition T1 T2

1968 UICC (I) Kidney not listed Kidney not listed

1974 UICC (II) Small tumor1 Large tumor2

1987 UICC (IV) ≤ 2.5 cm > 2.5 cm

1988 AJCC (III) ≤ 2.5 cm > 2.5 cm

1997 UICC/AJCC ≤ 7 cm > 7 cm

2002 UICC/AJCC ≤ 4 cm (T1a) > 7 cm

4-7 cm (T1b)

TNM, 2002 Version – Why ?TNM, 2002 Version – Why ?

Hafez KS et al. J. Urol. 1999; 162: 1930-1933

• This update was mainly proposed to help the clinicians to identify patients suitable for a elective partial nephrectomy

Authors Yrs Nephr/NSS 5 yrs (nephrect.) 5 yrs (NSS)

Butler 1995 42/46 97% 100%

Lerner 1996 209/185 89% 89%

Indudhara 1997 71/35 94% 91%

D'Armiento 1997 21/19 96% 96%

Barbalias 1999 48/41 98,4% 97,5%

Belldegrun 1999 125/108 91,2% 98%

Lee 2000 183/79 95% 95%

Ficarra 2001 96/107 97% 100%

Radical nephrectomy Vs partial nephrectomy:Radical nephrectomy Vs partial nephrectomy:comparative, non randomized studiescomparative, non randomized studies

Patients with RCC 4 cm (pT1a)

Multi-Institutional European Validational Multi-Institutional European Validational of the 2002 TNM Staging Systemof the 2002 TNM Staging System

Ficarra V. et al. Cancer 2005; 104: 968-74

0,0 12,0 24,0 36,0 48,0 60,0 72,0 84,0 96,0 108,0 120,0

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,0 pT1apT1b

pT2

pT1a Vs pT1b (p = 0.0001)pT1a Vs pT2 (p < 0.0001)pT1b Vs pT2 (p = 0.0002)

• 2,217 localized RCC

• 10-year CSS (%):

- pT1a: 91%

- pT1b: 83%

- pT2: 75%

BUT … is this the best strategy to subdivide confined RCC ?

Patard JJ, Ficarra V et al. J. Urol 2004; 171: 2181-2185Patard JJ, Ficarra V et al. J. Urol 2004; 171: 2181-2185

Bensalah K. et al. Eur. Urol 2008; 53: 691-693Bensalah K. et al. Eur. Urol 2008; 53: 691-693

Elective Partial Nephrectomy Elective Partial Nephrectomy for pT1b RCCfor pT1b RCC

Anatomic features related toselection of the candidate for NSS

Ficarra V et al. Eur Urol 2008 (in press)

• Peripheral or intraparenchymal location

• Spherical shape

• Adiacent nodular areas

• Tumor deepening into the kidney

• Relathionship with UCS

BUT … is this the best strategy to subdivide confined RCC ?

Ficarra V et al. Eur. Urol 2004; 46: 559-564Ficarra V et al. Eur. Urol 2004; 46: 559-564

• 4.5 cm (Zisman, 2001)

• 5 cm (Gelb, 1993; Targaski, 1994; Igarashi,2001; Lau, 2002; Elmore, 2003; Zucchi, 2003)

• 5.5 cm (Kinouchi, 1999; Ficarra, 2004)

Identification of different risk groups for progression or deathIdentification of different risk groups for progression or death

Proposal for Revision of the TNM1,138 patients with a mean follow-up of 87 months after

partial or radical nephrectomy

5.5 cm

Ficarra V., Patard JJ et al Cancer 2005; 15: 104: 2116-23

Variables Categories Hazard Ratio

95%-C.I. p value

Age (years) < 60 Vs >60 1.950 1.459-2.606 < 0.001

Mode of presentation S1 Vs S2/S3 2.185 1.589-3.005 < 0.001

Nuclear Grade G1 Vs G2 Vs G3 1.587 1.281-1.967 < 0.001

Pathological size <5.5 Vs >5.5 cm 1.893 1.392-2.575 < 0.001

Proposal for Revision of the TNM Staging System for Renal Cell Carcinoma

Ficarra V. et al Cancer 2005; 15: 104: 2116-23

Prognostic Stratification of Localized Renal Prognostic Stratification of Localized Renal Cell Carcinoma by Tumor SizeCell Carcinoma by Tumor Size

Bedke J. et al J Urol 2008; 180: 62-67

464 patients with a mean follow-up of 60 months after radical or partial nephrectomy

Prognostic Stratification of Localized Renal Prognostic Stratification of Localized Renal Cell Carcinoma by Tumor SizeCell Carcinoma by Tumor Size

Bedke J. et al J Urol 2008; 180: 62-67

5.5 cm

7 cm

Proposal for Revision of the TNM

• Ficarra et al, 2005• Multicenter study (7 Centres)• 1984 - 2001• Retrospective• 1,138 cases - 873 RN - 265 NSS• Median tumor size: 5 cm• IQR tumor size: 3-7 cm• Median FU: 87 mo• (IQR FU: 68-130 mo)• Martingale residuals: 5.5 cm• Cut-off: 5.5 cm

• Bedke et al, 2008• Single Center study• 1990 - 2006• (?) Prospective• 464 cases - 398 RN - 66 NSS• Median tumor size: ?• IQR tumor size: ?• Median FU: 60 mo• (range FU: 1-180 mo)• Martingale residuals: 5.5 cm• Cut-off: 7 cm

Klatte T., Patard JJ, Ficarra V., et al J Urol 2007; 178: 35-40

Prognostic Impact of Tumor Size on pT2

706 patients with pT2 RCC surgically treated at 9 International academic centers

Tumor Size Improves the Accuracy of TNMTumor Size Improves the Accuracy of TNMPredictions in patients with Renal CancerPredictions in patients with Renal Cancer

Karakiewicz PI, Ficarra V. Patard JJ et al Eur Urol 2006; 50: 521-529

• Identification of an ideal breakpoint representsIdentification of an ideal breakpoint represents a complex process, wich is affected by differencesa complex process, wich is affected by differences in patient characteristicsin patient characteristics

• Spectrum bias and associated floor and ceilingSpectrum bias and associated floor and ceiling effects may be circumvented, if variables areeffects may be circumvented, if variables are used without being catagorizedused without being catagorized

Tumor Size Improves the Accuracy of TNMTumor Size Improves the Accuracy of TNMPredictions in patients with Renal CancerPredictions in patients with Renal Cancer

Karakiewicz PI, Ficarra V. Patard JJ et al Eur Urol 2006; 50: 521-529

AJCC/UICC stage groupings cannot Incorparate countinuosly coded variables

Karakiewicz PI, Ficarra V. Patard JJ et al JCO 2007; 25: 1316-1322

T3a Fat and adrenal inv. Fat and adrenal invasion

T3b Renal vein (V1) V1 – V2

T3c IVC below diaphr (V2) V3

T4 Outside Gerota’s fascia

T4a Outside Gerota’s fasciaT4b IVC above diaphr (V3).

TNM, 1987 TNM, 1997 TNM, 2002

Development of the TNM staging system for locally advanced RCC

Ficarra V., et al. J Urol 2007; 178: 418-424

0 24 48 72 96 120

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,0 1,969 locally advanced (pT3-4) RCC

pT3a

pT3b

pT3c

pT4p value < 0.0001

• pT3a: Fat and/or adrenal invasion

• pT3b: renal vein or IVC below diaphr.

• pT3c: IVC above diaphr.

• pT4: beyond Gerota

Multi-Institutional European Validational of the 2002 TNM Staging System

60%

46%

12%

New staging system for pT3-4 RCC: a multicentric european study

0 24 48 72 96 120

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,01,117 pT3a RCC

Perirenal fat

Adrenal only

p value = 0.0002



0 24 48 72 96 120

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,0 705 pT3b RCC

V1

V2

V2+fat

V1-2+adrenal

V1+fat

p value< 0.0001


Reclassification of patients with pT3 and pT4RCC improves prognostic accuracy

Thompson RH et al. Cancer 2005; 104: 53-60

Stage Features

Mayo's pT3a Renal vein thrombosis only

Mayo's pT3b Perirenal fat invasion only

Mayo's pT3c Renal vein thrombosis AND perirenal fat invasion

IVC thrombosis below diaphragm alone

Mayo's pT3d IVC thrombosis below diaphragm AND perirenal fat invasion

IVC thrombosis above diaphragm alone

Mayo's pT4 Adrenal or Gerota's fascia invasion

Reclassification of patients with pT3 and pT4RCC improves prognostic accuracy

Thompson RH et al. Cancer 2005; 104: 53-60

Proposal for reclassification of the TNM In patients with pT3-4 RCC

Ficarra V et al. Eur Urol 2007; 51: 722-731

pT3a new

pT3b new

pT4 new

pT3a = perirenal fat invasion or renal vein involvement (V1) or IVC below diaphragm (V2)

pT3b: V1 or V2 plus concomitant perirenal fat invasion

pT4: adrenal gland or Gerota fascia invasion or IVC above diaphragm (V3)

p < 0.001

Redefining pT3 Renal Cell Carcinoma In the modern Era

Margulis V. et al. Cancer 2007; 109: 2439-44


Local extension Cases 5-year CSS Median Surv Interq range

V1 276 62,2% 117 60-173

Fat invasion 1071 60,9% 98 72-123

V2 60 55,7% 67 42-91

Adrenal invas 46 38% 24 12-36

V1 + fat inv 252 37,6% 24 17-30

V2 + fat inv 72 23,8% 24 16-30

V1-2 + adrenal 45 15,9% 11 10-14

V3 27 10,5% 12 3-20

Gerota inv 120 12% 12 9-14

New staging system for pT3-4 RCC: New staging system for pT3-4 RCC: a multicentric european studya multicentric european study



0 24 48 72 96 120

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,0

pT3a (new)

pT3b (new)

pT4 (new)

p value< 0.0001

0 24 48 72 96 120

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,01,969 pT3-4 RCC 1,248 pT3-4 N0M0 RCC

pT3a (new)

pT3b (new)

pT4 (new)

p value< 0.0001



Variables Categories HR 95%-C.I. p value

Symptoms S1 Vs S2/S3 1.403 1.162-1.693 0.001

Tumour size (cm) < 8 Vs > 8 1.319 1.135-1.532 0.001

Histotype Heidelberg 1.067 0.961-1.185 0.001

Nuclear Grade G1-2 Vs G3 Vs G4 1.209 1.147-1.274 0.001

pN pN0 Vs pN+ 1.827 1.605-2.087 0.001

Metastases M0 Vs M+ 2.717 2.329-3.168 0.001

New classification pT3a Vs pT3b Vs pT4 1.628 1.475-1.797 0.001


Renal sinus involvement in RCC

Bonsib SM et al. Am J Surg Pathol 2000; 24: 451-458


Thompson RH et al. J Urol 2005; 174: 1218-1221


Margulis V et al. J Urol 2007; 178: 1878-1882

365 patiens with pT3a RCC

Renal sinus involvement in pT3a

Prognostic relevance of tumour size in T3aPrognostic relevance of tumour size in T3a

Lam JS., Ficarra V, Patard JJ et al. Eur Urol 2007; 52: 155-162

623 patients with pT3a Renal Cell Carcinoma

Lam JS., Ficarra V, Patard JJ et al. Eur Urol 2007; 52: 155-162

N0-2 / M0-1 N0 / M0

Prognostic relevance of tumour size in T3aPrognostic relevance of tumour size in T3a

• Urinary collecting system (UCS) involvement is not included in the current TNM staging system.

• The UCS invasion in high stage tumours did not support a significantly worse prognosis, whereas in low stage tumours this prognostic factor can influence negatively the cancer specific survival rate

• However, in published series the UCS invasion did not result an independent prognostic factor

• At this time, this pathologic finding should not be considered in the new TNM staging system.

Urinary collecting system invasion

Proposal of an improved prognostic Classification for pT3

Terrone C. et al. J Urol 2008; 180: 72-78

Stage Features

Low risk group Perirenal fat invasion alone

Sinus fat invasion alone

Intermediate risk group Venous involvement alone OR

in association with sinus fat invasion

High risk group perirenal fat and venous invasion

perirenal and sinus fat invasion

adrenal gland invasion

Proposal of an improved prognostic Classification for pT3

Terrone C. et al. J Urol 2008; 180: 72-78



0 24 48 72 96 120

Follow-up (months)

0,0

0,2

0,4

0,6

0,8

1,0

pT3a (new)

pT3b (new)

pT4 (new)

p value< 0.0001

1,969 pT3-4 RCC

645 (524)

241 (223)

159 (156)

A new staging system for locally A new staging system for locally advanced (T3-4) RCCadvanced (T3-4) RCC

A new staging system for locally A new staging system for locally advanced (T3-4) RCCadvanced (T3-4) RCC

Ficarra V et al. Eur Urol 2007; 51: 722-729

Tumour Nodes and Metastases (TNM) Staging System

Tumour Nodes and Metastases (TNM) Staging System

Nx Regional Lymph nodes Nx Regional Lymph nodes idem idem idem idem cannot be assessedcannot be assessed

N1 Metastasis in 1 Lymph N1 Metastasis in 1 Lymph Metastasis to Metastasis to Metastasis to Metastasis to node node 2 cm 2 cm a single node a single node a single node a single node

N2 Metastasis in 1 Lymph N2 Metastasis in 1 Lymph Metastasis in > Metastasis in > Metastasis in > Metastasis in > node > 2 cm but < 5 cm 1 Lymph node 1 Lymph nodenode > 2 cm but < 5 cm 1 Lymph node 1 Lymph node

N3 Metastasis in 1 Lymph N3 Metastasis in 1 Lymph node > 5 cmnode > 5 cm

TNM, 1987TNM, 1987 TNM, 1997TNM, 1997 TNM, 2002TNM, 2002

Reassessing the current TNM Lymph Node Staging for RCC

Terrone C et al. Eur Urol 2006; 49: 324-331


Terrone C et al. Eur Urol 2006; 49: 324-331


Dimashkieh HH et al. J Urol 2006; 176: 1978-1983

Synchronous Distant Metastasis in patients with RCC

Cancer-specific survival according to TNM Staging System

Karakiewicz P., Ficarra V. et al. Eur Urol 2007; 51: 1616-24

39%30%

27%

(4.3%)

15%

8%

Other Independent Prognostic FactorsOther Independent Prognostic Factors

• Age at diagnosis, mode of presentation, performance status ECOG

• Pathological tumour size, Nuclear grading, Tumour necrosis, Sarcomatoid differentiation

• (?) Tumour histological type

• Molecular and genetic variables

Integrated prognostic systems

Authors Centre Setting Endpoint Histotype Variables

Kattan, 2001 MSKCC N0M0 DFS All Clin / Pathol

Leibovich, 2003 Mayo Clin N0M0 DFS Clear Pathol

Sorbellini, 2005 MSKCC NOMO DFS Clear Clin / Pathol

Zisman, 2002 UCLA All OS/CSS All Clin/Pathol

Frank, 2002 Mayo Clinc All CSS Clear Pathol

Karakiewicz, 2007 Multicenter All CSS All Clin/Pathol

Motzer, 2002 MSKCC M+ OS All Clinical

Leibovich, 2005 Mayo Clinic M+ CSS Clear Clin /Pathol

• In real clinical practice, the mathematical models are today less used than the TNM especially for their

- higher complexity

- presence of more than one system

- heterogeneity of the variables included

Mathematical models to predict survival

Ficarra V. et al. Lancet Oncol 2007; 8: 554- 558

Adjuvant therapy in RCC: planned trials

Protocol Sponsor Treatments Histologic Histotypes Stratification tool

Included Excluded

ASSURE ECOG Sunitinib Clear Bellini TNM

Sorafenib Non Clear Medullary Grading

Placebo

STAR Pfizer Sunitinib Clear Bellini UISS

Placebo Non Clear Unclassified

>50% Sarcom.

SORCE MRC Sorafenib Clear Leibovich score

Placebo Non Clear

• The TNM system is a dynamic staging method which evolves and changes according to evidence coming for clinical data

• Confined RCC should be classified according to the new breakpoint of 5.5 cm and the different mode of presentation

• The correct classification of locally advanced RCC requires a better clustering of the various anatomical features characterizing the local extension of the primary tumour

Conclusions

• According to the results of the multivariate analyses, outcome predictive models including several clinical and pathological variables should be considered the best prognostic tools

• All the available nomograms and algorithms include older versions of the TNM staging system

• The integrated systems are today less used than the TNM classification

ConclusionsConclusions

Documents

TNM staging system for Renal Cell Carcinoma: current status and future perspectives Vincenzo Ficarra Dipartimento di Scienze Oncologiche e Chirurgiche