1. TNM staging system for Renal Cell Carcinoma: current status and future perspectives Vincenzo Ficarra Dipartimento di Scienze Oncologiche e Chirurgiche Clinica di Urologia - Università degli Studi di Padova

2. An ideal cancer staging system should effectively: comunicate critical tumor characteristics,comunicate critical tumor characteristics, aid the clinician in the appropriate selectionaid 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 foreventually determine the selection criteria for clinical trials clinical trials Sobin LH: TNM classification of malignant tumours; 2002 Staging systems for RCC

3. Flocks and Kadesky, 1958 Flocks and Kadesky, 1958 Robson, 1969 Robson, 1969 TNM, 1978 TNM, 1978 TNM, 1987 TNM, 1987 TNM, 1997 TNM, 1997 TNM, 2002 TNM, 2002 TNM, ….. ? TNM, ….. ? Staging systems for RCC

4. Development of the TNM staging system for localized RCC Ficarra V.et al. Eur Urol 2004; 46: 559-64 YearEditionT1T2 1968UICC (I)Kidney not listed 1974UICC (II)Small tumor 1 Large tumor 2 1987UICC (IV)≤ 2.5 cm> 2.5 cm 1988AJCC (III)≤ 2.5 cm> 2.5 cm 1997UICC/AJCC≤ 7 cm> 7 cm 2002UICC/AJCC≤ 4 cm (T1a)> 7 cm 4-7 cm (T1b)

5. 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

6. Radical nephrectomy Vs partial nephrectomy: comparative, non randomized studies Patients with RCC  4 cm (pT1a)

7. Multi-Institutional European Validational of the 2002 TNM Staging System Ficarra V. et al. Cancer 2005; 104: 968-74 pT1a pT1b 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%

8. BUT … is this the best strategy to subdivide confined RCC ? Patard JJ, Ficarra V et al. J. Urol 2004; 171: 2181-2185

9. Bensalah K. et al. Eur. Urol 2008; 53: 691-693 Elective Partial Nephrectomy for pT1b RCC

10. Anatomic features related to selection 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

11. BUT … is this the best strategy to subdivide confined RCC ? Ficarra 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 death

12. Proposal for Revision of the TNM 1,138 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

13. Proposal for Revision of the TNM Staging System for Renal Cell Carcinoma Ficarra V. et al Cancer 2005; 15: 104: 2116-23

14. Prognostic Stratification of Localized Renal Cell 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

15. Prognostic Stratification of Localized Renal Cell Carcinoma by Tumor Size Bedke J. et al J Urol 2008; 180: 62-67 5.5 cm 7 cm

16. 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

17. 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

18. Tumor Size Improves the Accuracy of TNM Predictions 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 differences a complex process, wich is affected by differences in patient characteristics in patient characteristics Spectrum bias and associated floor and ceilingSpectrum bias and associated floor and ceiling effects may be circumvented, if variables are effects may be circumvented, if variables are used without being catagorized used without being catagorized

19. Tumor Size Improves the Accuracy of TNM Predictions in patients with Renal Cancer Karakiewicz PI, Ficarra V. Patard JJ et al Eur Urol 2006; 50: 521-529

20. AJCC/UICC stage groupings cannot Incorparate countinuosly coded variables Karakiewicz PI, Ficarra V. Patard JJ et al JCO 2007; 25: 1316-1322

21. 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 fascia T4b IVC above diaphr (V3). TNM, 1987 TNM, 1997TNM, 2002 Development of the TNM staging system for locally advanced RCC

22. Ficarra V., et al. J Urol 2007; 178: 418-424 1,969 locally advanced (pT3-4) RCC pT3a pT3b pT3c pT4 p 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%

23. New staging system for pT3-4 RCC: a multicentric european study 1,117 pT3a RCC Perirenal fat Adrenal only p value = 0.0002 Ficarra V., et al. J Urol 2007; 178: 418-424

24. New staging system for pT3-4 RCC: a multicentric european study 705 pT3b RCC V1 V2 V2+fat V1-2+adrenal V1+fat p value< 0.0001 Ficarra V., et al. J Urol 2007; 178: 418-424

25. Reclassification of patients with pT3 and pT4 RCC improves prognostic accuracy Thompson RH et al. Cancer 2005; 104: 53-60

26. Reclassification of patients with pT3 and pT4 RCC improves prognostic accuracy Thompson RH et al. Cancer 2005; 104: 53-60

27. 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

28. Redefining pT3 Renal Cell Carcinoma In the modern Era Margulis V. et al. Cancer 2007; 109: 2439-44

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

30. New staging system for pT3-4 RCC: a multicentric european study Ficarra V., et al. J Urol 2007; 178: 418-424

31. New staging system for pT3-4 RCC: a multicentric european study pT3a (new) pT3b (new) pT4 (new) p value< 0.0001 1,969 pT3-4 RCC 1,248 pT3-4 N0M0 RCC pT3a (new) pT3b (new) pT4 (new) p value< 0.0001 Ficarra V., et al. J Urol 2007; 178: 418-424

32. New staging system for pT3-4 RCC: a multicentric european study Ficarra V., et al. J Urol 2007; 178: 418-424

33. Renal sinus involvement in RCC Bonsib SM et al. Am J Surg Pathol 2000; 24: 451-458

34. Renal sinus involvement in RCC Thompson RH et al. J Urol 2005; 174: 1218-1221

35. Renal sinus involvement in RCC Margulis V et al. J Urol 2007; 178: 1878-1882 365 patiens with pT3a RCC

36. Renal sinus involvement in pT3a

37. Prognostic 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

38. 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 T3a

39. 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

40. Proposal of an improved prognostic Classification for pT3 Terrone C. et al. J Urol 2008; 180: 72-78

41. Proposal of an improved prognostic Classification for pT3 Terrone C. et al. J Urol 2008; 180: 72-78

42. New staging system for pT3-4 RCC: a multicentric european study Ficarra V., et al. J Urol 2007; 178: 418-424 pT3a (new) pT3b (new) pT4 (new) p value< 0.0001 1,969 pT3-4 RCC 645 (524) 241 (223) 159 (156)

43. A new staging system for locally advanced (T3-4) RCC Ficarra V et al. Eur Urol 2007; 51: 722-729

44. Tumour Nodes and Metastases (TNM) Staging System Nx Regional Lymph nodes idem idem cannot be assessed cannot be assessed N1 Metastasis in 1 Lymph Metastasis to Metastasis to node  2 cm a single node a single node node  2 cm a single node a single node N2 Metastasis in 1 Lymph Metastasis in > Metastasis in > node > 2 cm but 2 cm but < 5 cm 1 Lymph node 1 Lymph node N3 Metastasis in 1 Lymph node > 5 cm node > 5 cm TNM, 1987 TNM, 1997 TNM, 2002

45. Reassessing the current TNM Lymph Node Staging for RCC Terrone C et al. Eur Urol 2006; 49: 324-331

46. Reassessing the current TNM Lymph Node Staging for RCC Terrone C et al. Eur Urol 2006; 49: 324-331

47. Reassessing the current TNM Lymph Node Staging for RCC Dimashkieh HH et al. J Urol 2006; 176: 1978-1983

48. Synchronous Distant Metastasis in patients with RCC

49. 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%

50. Other 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

51. Integrated prognostic systems

52. 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

53. Adjuvant therapy in RCC: planned trials

54. 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

55. 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 Conclusions