1. Neo-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 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

3. Neo-adjuvant Tx: pros and cons 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

4. Are we able to achieve tumor shrinkage? Escudier B, et al. ECCO 13 – the European Cancer Conference, Paris, October 30-November 3, 2005; abs.794. Sorafenib treatment

5. Shuch B, et al. BJU Int 2008;102:692-696 Level II thrombus Level I thrombus Sunitinib treatment (4 cycles) Are we able to achieve tumor shrinkage?

6. Jonasch E, et al. J Clin Oncol 2009;27:4076-81 Baseline 8 Weeks of therapy Bevacizumab treatment Are we able to achieve tumor shrinkage?

7. The issue is: how much tumor shrinkage are we really able to achieve? 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)

8. CG Wood, personal communication Are there risks with such an approach?

9. Are there risks with such an approach? CG Wood, personal communication 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

10. 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 Ascites 0.570.11, 2.900.49 Are there risks with such an approach?

11. 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 Are there risks with such an approach?

12. How to deal with these issues? 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

13. Conclusions 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

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