3. Adjuvant therapy: – Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Neo-adjuvant therapy: – Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given NCI Dictionary of Cancer Terms

5. Presentation at diagnosis 1 : – 45% with localized disease – 25% with locally advanced disease – 20–30% metastatic disease 33% of patients treated for localized disease will develop metastatic disease 2 1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90.

6. Closed adjuvant trialsNAuthor (year)Outcome of the study RT vs. observation72Kjaer (1987)negative MPA vs. observation136Pizzocaro (1987)negative Aut. tumor vaccine + BCG vs. observation43Adler (1987)negative Aut. tumor vaccine ± BCG vs. observation120Galligioni (1996)negative UFT vs. observation71Naito (1997)negative IFN-  vs. observation 247Pizzocaro (2001)negative IFN-  NL vs. observation 283Messing (2003)negative HD IL-2 vs. observation69Clark (2003)negative Autologous tumor vaccine vs. observation553Jocham (2004)positive in terms of PFS (p=0.02) s.c. IL-2 + IFN-  + 5-FU vs. observation 203Atzpodien (2005)negative s.c. IL-2 + IFN-  vs. observation 310Passalacqua (2007)negative Aut. tumour-derived HSP-96-peptide complex vs. observation 918Wood C (2008)negative Thalidomide vs. observation46*Margulis (2009)negative *trial stopped due to inefficacy s.c. IL-2 + IFN-  + 5-FU vs. observation 550Aitchinson (2012)negative Girentuximab (anti-CAIX MoAb) vs. observation 856Belldegrun (2013)negative

7. Closed adjuvant trialsNAuthor (year)Outcome of the study RT vs. observation72Kjaer (1987)negative MPA vs. observation136Pizzocaro (1987)negative Aut. tumor vaccine + BCG vs. observation43Adler (1987)negative Aut. tumor vaccine ± BCG vs. observation120Galligioni (1996)negative UFT vs. observation71Naito (1997)negative IFN-  vs. observation 247Pizzocaro (2001)negative IFN-  NL vs. observation 283Messing (2003)negative HD IL-2 vs. observation69Clark (2003)negative Autologous tumor vaccine vs. observation553Jocham (2004)positive in terms of PFS (p=0.02) s.c. IL-2 + IFN-  + 5-FU vs. observation 203Atzpodien (2005)negative s.c. IL-2 + IFN-  vs. observation 310Passalacqua (2007)negative Aut. tumour-derived HSP-96-peptide complex vs. observation 918Wood C (2008)negative Thalidomide vs. observation46*Margulis (2009)negative *trial stopped due to inefficacy s.c. IL-2 + IFN-  + 5-FU vs. observation 550Aitchinson (2012)negative Girentuximab (anti-CAIX MoAb) vs. observation 856Belldegrun (2013)negative

8. Massari F, et al. Clin Genitourin Cancer 2013 (E-pub ahead of print)

9. Ongoing adjuvant trials SORCE (MRC/EORTC) Sorafenib 1 year (+ 2 years placebo) vs. Sorafenib 3 years vs. placebo 3 years 1656Leibovich score of 3 to 8. Primary end-point: DFS Closed at enrolment; no data available yet ASSURE (ECOG) Sunitinib 1 year vs. Sorafenib 1 year vs. placebo 1 year 1923T3b-4 N0, T1-4 N+, or T1-4 with positive margins or vascular invasion) Primary end-point: DFS Closed at enrolment; no data available yet S-TRAC (Pfizer) Sunitinib 1 year vs. placebo 1 year 856High risk according to UISS. Primary end-point: DFS Closed at enrolment; no data available yet EVEREST (SWOG) Everolimus vs. placebo (days 1-42; treatment repeats every 6 weeks for 9 courses) 1218Pathologically intermediate high-risk or very high-risk. Primary end-point: DFS Not yet enrolling (US only) VEG113387 PROTECT study (GSK) Pazopanib 1 year vs. placebo 1 year 1500Intermediate and high risk. Primary end-point: DFS Closed at enrolment; no data available yet NCT01599754 (SFJ Pharmaceuticals) Axitinib 3 yeas vs. placebo 3 years 592pT2 or higher, pNx pN0 or pN1, M0, Fuhrman G3-4 and ECOG PS 0-1 Primary end-point: DFS Enrolling (Japan only)

10. To date, no treatment emerged as a standard of care in this setting Presently, patients should be thus offered just obser- vation Enrollment into well-desigend and adequately con- ducted RCTs is mandatory

12. ProCons Litmus test for patients who will do wellTherapy may impact wound healing and recovery Potential for higher incidence of wound complications Incorporates cytoreductive surgery to examine tissue before and after therapy for endpoint targets Local tumor progression in non- responders increases complexity of the surgery More “ectomies”= Worse outcome May see responses in the primary tumor not seen before Timing is everything Why interrupt a therapeutic response? Who wants to operate on therapy refractory disease? Eliminates unnecessary and morbid surgery in patients who don’t respond

13. Escudier B, et al. ECCO 13 – the European Cancer Conference, Paris, October 30-November 3, 2005; abs.794. Sorafenib treatment

14. Shuch B, et al. BJU Int 2008;102:692-696 Level II thrombus Level I thrombus Sunitinib treatment (4 cycles)

15. Jonasch E, et al. J Clin Oncol 2009;27:4076-81 Baseline 8 Weeks of therapy Bevacizumab treatment

16. Van der Veldt AAM, et al. Clin Cancer Res 2008;14:2431-6; Thomas AA, et al. J Urol 2009;181:518-23; Jonasch E, et al. J Clin Oncol 2009;27:4076-81 Primary Tumor Regression n=45 (%) >20% growth 1 (2) 10-20% growth 2 (4) 0-10% growth19 (42) 1-10% shrinkage13 (29) 11-20% shrinkage 7 (16) 20-30% shrinkage 3 (7)

17. CG Wood, personal communication

18. Pre-Surgical Therapy Immediate Surgery Totalp Overall 25 (43.1)28 (28.7)54 (33.5)0.048 Peri-operative Death 1 (1.7)2 (2.0)3 (1.9)0.91 Readmission to Hospital 6 (10.3)11 (11.0)17 (10.8)0.90 Bleeding 1 (1.7)2 (2.0)3 (1.9)0.91 Thromboembolic 5 (8.6)5 (5.0)10 (6.3)0.36 Cardiac 1 (1.7)3 (3.0)4 (2.5)0.63 Gastrointestinal 5 (8.6)9 (8.9)14 (8.8)0.95 Infection 4 (6.9)6 (5.9)10 (6.3)0.81 Superficial Wound Healing 12 (20.7)2 (2.0)14 (8.8)<0.001 Fascial dehiscence 2 (3.5)0 (0.0)2 (1.3)0.06 Chylous Ascites 2 (3.5)6 (5.9)8 (5.0)0.49

19. CG Wood, personal communication Univariate analysisOdds Ratio95 % CIP Overall Complications 1.981.00, 3.890.049* Peri-operative Death 0.870.08, 9.790.91 Readmission to Hospital 0.930.33, 2.670.90 Bleeding 0.870.08, 9.790.91 Thromboembolic 1.810.50, 6.540.37 Cardiac 0.570.06, 5.640.63 Gastrointestinal 0.960.31, 3.030.95 Infection 1.170.32, 4.340.81 Superficial Wound Healing 12.912.78, 60.060.001* Chylous Ascites0.570.11, 2.900.49

20. CG Wood, personal communication *Adjusted for: – Pre-operative albumin – Smoking status (never, current, former) – Pre-operative hemoglobin – Laparoscopic vs open surgery – ECOG performance status – Body mass index – Age Odds Ratio*95% CIp-value Superficial Wound Healing 19.72.13, 181.88<0.01

21. Withheld treatment for at least 2 or 3 half-lives before and after surgery Maximum response Days after wounding (log scale) I. inflammation II. cell proliferation and matrix deposition III. matrix remodelling ● Bleeding ● Coagulation ● Platelet activation ● Complement activation ● Granulocytes ● Phagocytosis ● Fibroplasia ● Angiogenesis ● Re-epithelization ● Extracelluar matrix sythesis ● Collagens ● Fibronectin ● Proteoglicans ● Macrophages ● Cytokines Stages of wound healing Extracellular matrix synthesis, degradation and remodelling  Tensile strength  Cellularity  Vascularity Consider drug half-life Temsirolimus: 17 hrs Sorafenib: 24-48 hrs Sunitinib: 60-110 hrs Bevacizumab: 14-21 days Pazopanib: 30.9 hrs

22. CG Wood, personal communication Present, initial, body of evidence would suggest that significant primary tumor downstaging will not be realized with the current generation of targeted therapy agents

23. c.porta@smatteo.pv.it