1. Adjuvant therapies for RCC Dr. Camillo Porta S.C. di Oncologia Medica I.R.C.C.S. Policlinico San Matteo, Pavia

2. Back to the basics: terminology Adjuvant therapy: – additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back NCI Dictionary of Cancer Terms

3. The natural history of RCC Presentation at diagnosis1: – 45% with localized disease – 25% with locally advanced disease – 20–30% metastatic disease 33% of patients treated for localized disease will develop metastatic disease2 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.

4. Completed RCTs of adjuvant Tx 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. observation247Pizzocaro (2001)negative IFN-  NL vs. observation283Messing (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. observation203Atzpodien (2005)negative s.c. IL-2 + IFN-  vs. observation310Passalacqua (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. observation550Aitchinson (2012)negative Girentuximab (anti-CAIX MoAb) vs. observation 856Belldegrun (2013)negative

5. Completed RCTs of adjuvant Tx 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. observation247Pizzocaro (2001)negative IFN-  NL vs. observation283Messing (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. observation203Atzpodien (2005)negative s.c. IL-2 + IFN-  vs. observation310Passalacqua (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. observation550Aitchinson (2012)negative Girentuximab (anti-CAIX MoAb) vs. observation 856Belldegrun (2013)negative

6. Meta-analysis of RCTs of adjuvant Tx Massari F, et al. Clin Genitourin Cancer 2013 (E-pub ahead of print)

7. Ongoing RCTs of targeted agents as adjuvant Tx 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)

8. What theoretically hampers the adjuvant use of antiangiogenics?

9. Adjuvant Tx for RCC: conclusions 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

10. Thank You for Your kind attention!!! c.porta@smatteo.pv.it