1. “INTEGRAZIONE TRA TERAPIA CHIRURGICA E TERAPIA MEDICA” Camillo Porta, MD Medical Oncology I.R.C.C.S. San Matteo University Hospital Foundation, Pavia

2. SURGERY AND MEDICINE

3. 5568 new cases/year in Italy2639 new cases/year in Italy RCC: DISEASE BURDEN IN ITALY FemmineMaschi

4. Men: 2052 deaths/year in Italy Women: 1133 deaths/year in Italy RCC: DISEASE BURDEN IN ITALY

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

6. THE ROLE OF SURGERY IN mRCC: THE QUESTIONS ARE … Has metastasectomy a role in mRCC di per se ? Is there any difference according to specific metastatic sites? What really changes in the era of molecularly targeted agents? Surgery of primary tumor in mRCC: a unique – and unusual – opportunity

7. SURGERY OF PRIMARY mRCC: A UNIQUE – AND UNUSUAL – OPPORTUNITY

8. EORTC 30947SWOG 8949 Flanigan R, et al. NEJM 2001;345:1655-1659Mickisch G, et al. Lancet 2001:358:966-970 CYTOREDUCTIVE NEPHRECTOMY IN THE METASTATIC SETTING Anything new in the era of molecularly-targeted agents?

9. HAS METASTASECTOMY A ROLE IN mRCC, DI PER SE ?

10. 1° RECURRENCE :141 PTS  CURATIVE METASTASECTOMY Solitary M1 RESECTION AND SURVIVAL

11. Alt AL, et al. ASCO GU 2010  887 pts treated with nephrectomy for RCC from 1976-2006 with multiple metastases; 125 of these underwent resection of metastases IMPACT OF R0 STATUS ON CSS AFTER METASTASECTOMY

12. IS THERE ANY DIFFERENCE ACCORDING TO SPECIFIC METASTATIC SITES?

13. ● Conclusions: … patients with multiple metastases of RCC can achieve durable survival with complete resection of all metastatic lesions, especially patients with lung only metastases and those with asynchronous metastases Asynchronous HIGHEST BENEFIT IN LUNG AND SYNCHRONOUS METS Alt AL, et al. ASCO GU 2010

14. % pts HEPATIC METASTASES FROM RCC Selected patients with hepatic mets from RCC benefit from hepatic resection Selected patients with hepatic mets from RCC benefit from hepatic resection

15. WHAT REALLY CHANGES IN THE ERA OF MOLECULARLY TARGETED AGENTS?

16. ANTIANGIOGENETIC AGENTS AND WOUND HEALING Withholding Tx for at least 2 or 3 half-lives before and after surgery may prevent AEs on microvasculature and tissue integrity Maximum response 0.10.3131030100300 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 ● Proteoglucans ● 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 Potential risk Rebound phenomenon due to early regrowth of tumor vascularization after TKI discontinuation

17. ANOTHER ISSUE: TIMING OF SURGERY No more than 3-4 cycles of treatment before surgery

18. SURGERY OF METASTATIC SITES AND PALLIATION … Altough the absolute curative impact of metastasectomy remains uncertain, operative intervention can provide effective palliation for symptomatic metastatic disease to sites such as bone, brain and adrenal glands …

19. WHAT WOULD WE NEED … … Ultimately, a prospective and randomized clinical trial comparing metastasectomy to best standard systemic therapy could more clearly define the effectiveness of metastasectomy in the face of various selection factors …

20. SURGERY AND THE GUIDELINES

21. THANK YOU FOR YOUR KIND ATTENTION!!! T T c.porta@smatteo.pv.it