Adjuvant therapy: Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back

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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

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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 cancerstatistics fact sheet:cancerof the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:

6 Closed adjuvant trials N Author (year) Outcome of the study RT vs. observation 72 Kjaer (1987) negative MPA vs. observation 136 Pizzocaro (1987) negative Aut. tumor vaccine + BCG vs. observation 43 Adler (1987) negative Aut. tumor vaccine ± BCG vs. observation 120 Galligioni (1996) negative UFT vs. observation 71 Naito (1997) negative IFN α vs. observation 247 Pizzocaro (2001) negative IFN α NL vs. observation 283 Messing (2003) negative HD IL 2 vs. observation 69 Clark (2003) negative Autologous tumor vaccine vs. observation 553 Jocham (2004) positive in terms of PFS (p=0.02) s.c. IL 2 + IFN α + 5 FU vs. observation 203 Atzpodien (2005) negative s.c. IL 2 + IFN α vs. observation 310 Passalacqua (2007) negative Aut. tumour derived HSP 96 peptide complex 918 Wood C (2008) negative vs. observation Thalidomide vs. observation 46* Margulis (2009) negative *trial stopped due to inefficacy s.c.il 2 + IFN α + 5 FU vs. observation 550 Aitchinson (2012) negative Girentuximab (anti CAIX MoAb) vs. observation 856 Belldegrun (2013) negative

7 Closed adjuvant trials N Author (year) Outcome of the study RT vs. observation 72 Kjaer (1987) negative MPA vs. observation 136 Pizzocaro (1987) negative Aut. tumor vaccine + BCG vs. observation 43 Adler (1987) negative Aut. tumor vaccine ± BCG vs. observation 120 Galligioni (1996) negative UFT vs. observation 71 Naito (1997) negative IFN α vs. observation 247 Pizzocaro (2001) negative IFN α NL vs. observation 283 Messing (2003) negative HD IL 2 vs. observation 69 Clark (2003) negative Autologous tumor vaccine vs. observation 553 Jocham (2004) positive in terms of PFS (p=0.02) s.c. IL 2 + IFN α + 5 FU vs. observation 203 Atzpodien (2005) negative s.c. IL 2 + IFN α vs. observation 310 Passalacqua (2007) negative Aut. tumour derived HSP 96 peptide complex 918 Wood C (2008) negative vs. observation Thalidomide vs. observation 46* Margulis (2009) negative *trial stopped due to inefficacy s.c.il 2 + IFN α + 5 FU vs. observation 550 Aitchinson (2012) negative Girentuximab (anti CAIX MoAb) vs. observation 856 Belldegrun (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 1656 Leibovich score of 3 to 8. Primary end point: DFS Closed at enrolment; no data available yet ASSURE (ECOG) (COG) 1923 T3b 4 N0, T1 4 N+, or T1 4 Closed at enrolment; Sunitinib 1 year vs. Sorafenib 1 year vs. placebo 1 year with positive margins or vascular invasion) Primary end point: DFS no data available yet S TRAC (Pfizer) Sunitinib 1 year vs. placebo 1 year EVEREST (SWOG) Everolimus vs. placebo (days 1 42; treatment repeats every 6 weeks for 9 courses) VEG PROTECT study (GSK) Pazopanib 1 year vs. placebo 1 year 856 High risk according to UISS. Primary end point: DFS 1218 Pathologically intermediate high risk or very high risk. Primary end point: DFS 1500 Intermediate and high risk. Primary end point: DFS Closed at enrolment; no data available yet Not yet enrolling (US only) Closed at enrolment; no data available yet NCT (SFJ Pharmaceuticals) Axitinib 3 yeas vs. placebo 3 years 592 pt2 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 observation Enrollment into well desigend and adequately con ducted RCTs is mandatory

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

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

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

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

16 Primary Tumor Regression n=45 (%) >20% growth 1 (2) 10 20% growth 2 (4) 0 10% growth 19 (42) 1 10% shrinkage 13 (29) 11 20% shrinkage 7 (16) 20 30% shrinkage 3 (7) 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:

17 CG Wood, personal communication

18 Pre Surgical Therapy Immediate Surgery Total Overall 25 (43.1) 28 (28.7) 54 (33.5) 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 p CG Wood, personal communication

19 Univariate analysis Odds Ratio 95 % CI P Overall Complications , * Peri operative Death , Readmission to Hospital , Bleeding , Thromboembolic , Cardiac , Gastrointestinal , Infection , Superficial i lwound dhealing , * Chylous Ascites , CG Wood, personal communication

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

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

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

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