Integration of Surgery And Systemic Therapy In The Treatment of

Transcription

1 Integration of Surgery And Systemic Therapy In The Treatment of Advanced Renal Cell Carcinoma Christopher G. Wood, M. D., FACS Professor and Deputy Chairman Douglas E. Johnson, M. D. Professorship In Urology Department of Urology The University of Texas MD Anderson Cancer Center

2 Therapy of Renal Cell Carcinoma Prior to 2006 Stage I-III: nephrectomy Stage IV: nephrectomy + systemic therapy Common therapies Single-agent and combination regimens containing cytokines (eg, IFN-α, IL-2) and chemotherapeutics Surgery Radiation in selected cases IFN, interferon; IL, interleukin. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Available at: physician_gls/pdf/kidney.pdf. Yang et al. N Engl J Med. 2003;349: Ratain et al. J Clin Oncol. 2006;24: Motzer et al. J Clin Oncol. 2006;24: Motzer et al. JAMA. 2006;295: Motzer et al. N Engl J Med. 2007;356:

3 Treatment options for RCC have been revolutionized in a short period of time FDA approvals High dose interleukin-2 Sunitinib (Jan 2006) 2 Sorafenib (Dec 2005) 1 Temsirolimus (May 2007) 3 Pazopanib (Oct 2009) 6 Bevacizumab + IFN-α (Jul 2009) 5 Everolimus (Mar 2009) 4 Axitinib (Jan 2012) US FDA. Sorafenib US FDA. Sunitinib malate US FDA. Temsirolimus US FDA. Everolimus US FDA. Bevacizumab US FDA. Pazopanib US FDA. Axitinib

4 RCC Treatment Algorithm: 2014 * Regimen Setting Therapy Options Treatment Naïve Patient MSK Risk : Good or Intermediate MSK Risk : Poor Sunitinib Bevacizumab ± IFNα Pazopanib Temsirolimus Sunitinib HD IL-2? Sorafenib?Sorafenib Treatment Refractory Patient ( 2 d i ) Ctki Cytokine Refractory ( 2 nd Line) Refractory to VEGF/VEGFR or mtor Inhibitors Sorafenib Pazopanib Axitinib Everolimus Axitinib Sunitinib?Sequential TKI s or VEGFInhibitor *Adapted from M Atkins, ASCO 2006 Non clear cell: Temsirolimus

5 Mechanisms of Therapeutic Effect and Angiogenic Escape Rini, B Clin Cancer Res, 2010

6 What is the proper integration of surgery and systemic therapy in the setting of advanced disease?

7 62 y/o WM with hematuria PMH: DM, Htn PSH: Appy, Knee surgery SH: Denies Tobacco/ETOH use PE: unremarkable PS = 1 CT abdomen Locally advanced right renal mass CT chest Bilateral pulmonary nodules

8 62 y/o WM with hematuria

9 62 y/o WM with hematuria

10 62 y/o WM with hematuria Hb 9.8 LDH 1000 All other labs WNL Bone scan/mri brain negative for mets

11 62 y/o WM with hematuria Patient undergoes cytoreductive nephrectomy T3aN0M1 Clear cell RCC, FG 4 Follow-up scans at 6 weeks show modest progression of pulmonary metastases Started on Sunitinib 4 weeks/2 weeks 50 mg Required dose reduction at 6 months to 37.5 mg due to toxicity

12 62 y/o WM with hematuria Disease progression at 14 months out from surgery Changed to everolimus Currently stable disease 2 years out from surgery

13 73 y/o WF presents with fatigue and anemia PS = 1 PMH: Htn, Hypothyroidism, MVP, CKD (egfr 36) CT chest: Bilateral pulmonary nodules Labs: Hb 9.5 (after transfusion), LDH 868, all other labs WNL Brain MRI and Bone Scan negative

14 73 y/o WF presents with fatigue and anemia

15 73 y/o WF presents with fatigue and anemia

16 73 y/o WF presents with fatigue and anemia Undergoes right radical nephrectomy with RPLND. Mass noted in right fallopian tube (metastatic renal cell carcinoma) T3aN1M1 ccrcc with 30 40% sarcomatoid and rhabdoid features, FG 4 3/10 LN s positive All surgical margins negative

17 73 y/o WF presents with fatigue and anemia Returns 1 month later, PS = 4 Admitted through the emergency center for failure to thrive Hb 8.2, LDH 1094, Ca , egfr 33

18 73 y/o WF presents with fatigue and anemia

19 73 y/o WF presents with fatigue and anemia

20 73 y/o WF presents with fatigue and anemia Patient never received therapy due to poor performance status Died of disease 45 days after surgery

21 Is there still a role for cytoreductive surgery in the setting of metastatic disease?

22 100 Metastatic RCC Nephrectomy & Immunotherapy UCLA % Surv vival P<0.05 IMT NX Nx + IMT Months J UROL 166: 1611, 2001

23 Effect of Nephrectomy on Survival in Metastatic RCC Radical Nephrectomy + IFN- Patients with metastatic t ti RCC with PS 0-1 (SWOG, N=241) (EORTC, N=83) (SWOG, N=120) (EORTC, N=42) IFN- (SWOG, N=121) (EORTC, N=43) IFN = interferon Flanigan RC et al. N Eng J Med. 2001;345:1655. Mickisch GH et al. Lancet. 2001;358:966.

24 Role of Cytoreductive Nephrectomy in the Setting of Metastatic Disease: EORTC Time to Progression Overall Survival IFN + Nx 5 CR, 3 PR (19%) IFN 1CR, 4 PR (12%) Mickisch G et al. Lancet, 2001

25 Role of Cytoreductive Nephrectomy in the Setting of Metastatic Disease: SWOG 8949 IFN+Nx3PR(3%) Nx IFN 1 CR, 2 PR (4%) Flanigan R et al., NEJM, 2001

26 2001 SWOG vs. UCLA 100 Retrospective. 80 P<0.05 Surviv val Pantuck et al; NEJM, 2001 Nx + IL-2 Nx + IFN IFN Months

27 RCC Treatment Algorithm: 2014 * Regimen Setting Therapy Options Treatment Naïve Patient MSK Risk : Good or Intermediate MSK Risk : Poor Sunitinib Bevacizumab ± IFNα Pazopanib Temsirolimus Sunitinib HD IL-2? Sorafenib?Sorafenib Treatment Refractory Patient ( 2 d i ) Ctki Cytokine Refractory ( 2 nd Line) Refractory to VEGF/VEGFR or mtor Inhibitors Sorafenib Pazopanib Axitinib Everolimus Axitinib Sunitinib?Sequential TKI s or VEGFInhibitor *Adapted from M Atkins, ASCO 2006 Non clear cell: Temsirolimus

28 Cytoreductive Nephrectomy Utilization Tsao CK et. al., Clinical GU Cancer, 2011

29 How Does It Work? Reduction in major portion of tumor burden Immunologic: Surgery induces exposure of new tumor antigens or removal of immunologic i sink Altering the metabolic milieu: Relative renal insufficiency induces metabolic acidosis which is somehow anti-tumoral Endocrine/Paracrine: Removal of secreted factor that promotes progression/metastasis

30 Arguments Against Cytoreductive Nephrectomy Surgical morbidity/mortality significant Only proven benefit in combination with IFN (an inferior therapy) Spend majority of time left on this earth recovering from surgery Significant disease progression or morbidity during post-operative operative recovery period may preclude systemic therapy Newer therapies may result in primary tumor regression

31 Phase 3 Randomized Study Comparing Nephrectomy plus Sunitinib versus Sunitinib without Nephrectomy in 1st line Metastatic RCC Randomization N = 576 Nephrectomy Sunitinib 50 mg 4/2 Sunitinib 50 mg 4/2 - Primary Objective: - To show thatt Sunitinib ib alone is not inferior i to Nephrectomy plus Sunitinib (non inferiority study) in terms of Overall Survival (OS) - Hypothesis: - Median OS expected in the nephrectomy plus Sunitinib = 24 months - Sunitinib alone will be considered as a clinically valid option if median OS > 19,9 months CARMENA Study Pr Arnaud Mejean (CCAFU Necker Hospital Paris, France) Pr Alain Ravaud (GETUG Saint-André Hospital Bordeaux, France)

32 Sunitinib in Patient With or Without Prior Nephrectomy in an Expanded Access Trial of mrcc: Response Response, n (%) Patients with prior Patients without Nx (n=3014*) prior Nx (N=192)* Objective response rate Complete response 538 (18) 31 (1) 17 (9) 0 Partial response 507 (17) 17 (9) Stable disease >3 months 1764 (59) 118 (61) Clinical benefit 2302 (76) 135 (70) Nx=nephrectomy *Only patients with evaluable efficacy data included Clinical benefit=orr + SD 3 months Szczylik et al. ASCO Abstract 5124

33 Sunitinib in Patients With or Without Prior Nephrectomy in an Expanded Access Trial of mrcc: PFS (No Prior Cytokine Treatment) PFS proba ability Patients with prior nephrectomy (n=1020) Median = 12.0 mo (95% CI, ) Patients without prior nephrectomy (n=146) Median = 6.5 mo (95% CI, ) P= Months mrcc = metastatic renal cell carcinoma; PFS = progression free survival Szczylik et al. ASCO, Abstract 5124.

34 Sunitinib in Patients With or Without Prior Nephrectomy in an Expanded Access Trial of mrcc: OS (No Prior Cytokine Treatment) lity OS probabi Patients with prior nephrectomy (n=1020) Median = 19.0 mo (95% CI, ) Patients without prior nephrectomy (n=146) Median = 11.1 mo (95% CI, ) P< OS = overall survival Months Szczylik et al. ASCO, Abstract 5124.

35 Cytoreductive Nephrectomy In The Era of Targeted Therapy: What do we do until the prospective trials are completed? Yes= 201 No = 113 KPS 80 KPS < 80 Choueiri, T et al., J Urol, 2011

36 Cytoreductive Nephrectomy In The Era of Targeted Therapy (SEER ) Culp and Wood, Submitted

37 Cytoreductive Surgery For Metastatic Renal Cell Carcinoma: It s Not For Everyone! Patient Selection Is CRITICAL!!!!!

38 Cytoreductive Nephrectomy: Tufts University 28 highly selected patients (61 pts. deferred) >75% debulking, absence of CNS, Liver, Bone mets, PS 0-1, clear cell histology 93% received systemic therapy Response rate 39%» 18% CR» 21% PR Median survival: 20.5 months Systemic therapy: IL-2 J Urol, 1997

39 Identifying Patients who will Not Benefit from Cytoreductive Nephrectomy: MDACC 566 pts undergoing CN between 1991 and pts undergoing g medical therapy only Compared survival between groups and identified when survival diverged between surgical and non-surgical groups Identified pre-operative variables that differed between surgical groups based on follow-up Pre-operative Risk Factors based on significance in multivariate analysis Culp et al., Cancer, 2010

40 Surgery vs. No Surgery Overall Survival Overall Survival Basedon Follow up of 8.5 months Culp et al., Cancer, 2010

41 Pre-operative Risk Factors Serum albumin < lower limit of normal Serum LDH > upper limit of normal Liver metastasis Symptoms at presentation due to metastasis Retroperitoneal lymph node involvement Supra-diaphragmatic lymph node involvement Clinical T stage 3 or 4 Culp et al., Cancer, 2010

42 Pre-operative Assessment HR (95% CI) P Median Survival (mos) Medical Therapy Only CN - # of risk factors Referent (0.15, 0.30) < (0.25, 0.57) < (0.34, 0.57) < (0.48, 0.84) ( (0.54, 109) 1.09) (0.88, 2.80) (0.24, 4.00) Culp et al., Cancer, 2010

43 Pre-operative Assessment HR (95% CI) P Median Survival (mos) Medical Therapy Only CN - # of risk factors Referent (0.15, 0.30) < (0.25, 0.57) < (0.34, 0.57) < (0.48, 0.84) ( (0.54, 109) 1.09) (0.88, 2.80) (0.24, 4.00) Culp et al., Cancer, 2010

44 Pre-operative Assessment Culp et al., Cancer, 2010

45 Cytoreductive Nephrectomy In The Era of Targeted Therapy (SEER ) Predictive Clinical Factors 1. Size > 7 cm 2. ct3 or ct4 Stage 3. High grade (3 or 4) 4. Clinically + LN s 5. Sarcomatoid Histology Culp and Wood, Submitted

46 Canwedobetter? Is the relevant question whether or not surgery should be incorporated into the management of locally advanced/metastatic renal cell carcinoma?

47 Neoadjuvant (Pre-surgical) Therapy for Renal Cell Carcinoma Potential Benefits Primary tumor downstaging/sizing Decrease surgical morbidity Increase utilization of nephron sparing Make the unresectable become resectable Improve prognosis Eliminate/Downsize metastatic tumor burden Operate on responding patients (litmus test) Potential Risks May increase surgical morbidity Disease may progress (locally or metastatic) on therapy Therapy may alter biology of metastatic disease adversely VEGF rebound may actually cause rapid disease progression

48 Bevacizumab Presurgical Trial Metastatic disease, no prior nephrectomy or therapy Bevacizumab 10 mg/kg IV Q14 days Opened 4/05 Accrual to date: 50 Response Or Stable Progressive, Good PS Progressive, Poor PS 50 patients Clear Cell Histology Nephrectomy, Continue Bevacizumab Nephrectomy, New Chemo New Chemo, or Best Supportive Care Jonasch E et al., JCO, 2009

49 Sunitinib Presurgical Trial Metastatic disease, no prior nephrectomy or therapy Sunitinib 50mg Stable/Respond: Nephrectomy Mid By mouth 2 nd Continue Course 2 Courses Sunitinib June patients Clear Cell Histology

50 Rules of the Game in RCC Surgical Therapy Advances Neoadjuvant Therapy Advances 1. Oncologic equipoise 1. Safety (Lack of disease 2. Nephron sparing progression/increased surgical morbidity) 3. Minimally invasive 2. Improved patient t outcomes (DFS/CSS) 3. Primary tumor downstaging/downsizing

51 Is Neoadjuvant Therapy Safe?

52 Pre-Surgical Therapy: Is it safe? Retrospective review Synchronous M1 disease. Stratified by timing of initiation of targeted systemic therapies. Pre-operative systemic targeted therapy was administered to 70 patients (Pre-surgical). Immediate CN was performed in 103 patients, (Immediate). Complications occurring within 12 months of CN were assessed. Chapin et al. Eur Urol, 2011

53 Complications from cytoreductive nephrectomy by timing of nephrectomy. No. (%) Event All Patients Immediate CN Pre-surgical (n=173) (n=103) Therapy (n=73) p-value Any Complication (by patient) 99 (57.2) 53 (53.4) 39 (55.7) Clavien > 3 (by event) 69 (29.7) 32 (30.2.) 37 (29.4) Complication > 90 days (by event) 24 (10.3) 4 (3.8) 20 (15.9) >1 Complications (by event) 62 (62.6) 27 (50.9) 35 (76.1) Wound Complications+ 27 (15.6) 8 (7.8) 19 (27.1) <0.001 Superficial Wound Dehiscence 23 (13.3) 6 (5.8) 17 (24.3) <0.001 Wound Infection 12 (6.9) 3 (2.9) 9 (12.9) Fascial Dehiscence 2 (1.2) 0 (0) 2 (2.9) Incisional Hernia 3 (1.7) 0 (0) 3 (4.3) DVT 7 (4) 2 (1.9) 5 (7.1) PE 13 (7.5) 6 (5.8) 7(10) Wound Complications = Superficial wound dehiscence, wound infection and fascial dehiscence Chapin et al. Eur Urol, 2011

54 Predictors of Wound Complications After Cytoreductive Nephrectomy Characteristic Univariable Multivariate Odds Ratio (95% CI) p-value Odds Ratio (95% CI) p-value Pre-surgical Targeted Therapy* 4.42 ( ) < ( ) BMI 30* 2.46 ( ) ( ) Diabetic* 1.35 ( ) ( ) Smoker* 1.03 ( ) ( ) Duration of surgery* (per minute increase) 100( ( ) 0) ( ( ) 00) Clinical N1 or N2* 1.84 ( ) ( ) * included in multivariate analysis Chapin et al. Eur Urol, 2011

55 Predictors of Overall Post-operative Complications After Cytoreductive Nephrectomy Analysis of Preoperative and Post-operative Characteristics by risk of overall complications for all patients undergoing cytoreductive ti nephrectomy. Univariable Multivariate Characteristic Odds Ratio (95% CI) p-value Odds Ratio (95% CI) p-value ECOG 2* 9.1 ( ) ( ) Clinical N1 or N2* 2.5 ( ) ( ) Clinical T3 or T4* 20(1138) 2.0 ( ) ( ( ) Pre-surgical Targeted Therapy* 1.8 ( ) ( ) BMI ( ) * included in multivariate analysis Chapin et al. Eur Urol, 2011

56 Predictors of Overall Complications in Patients Receiving Pre-Surgical Targeted Therapy Characteristic i Univariable Multivariate Odds Ratio (95% CI) p-value Odds Ratio (95% CI) p-value Decline in Serum Albumin* 4.3 ( ) ( ) BMI 30* 38( ( ) (0689) 2.35 ( ) Clinical T3 or T4* 2.7 ( ) ( ) ECOG 2* 3.5 ( ) ( ) Charlson ( ) Received bevacizumab 1.4 ( ) * included in multivariate analysis Chapin et al. Eur Urol, 2011

57 Predictors of Overall Survival Characteristic Univariable Multivariate Odds Ratio (95% CI) p-value Odds Ratio (95% CI) p-value Pre-surgical Targeted Therapy* 0.96 ( ) ( ) T-Stage 3 or 4* 1.97 ( ) < ( ) Pathologic Node Positive* 2.53( ) < ( ) 26) < Sarcomatoid Histology* 2.53 ( ) < ( ) Post-operative Complication* 2.23( ) < ( ) ECOG>1 (at presentation) * included in multivariate analysis Chapin et al. Eur Urol, 2011

58 Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis John M.L. Ebos1, 2, Christina R. Lee1, William Cruz-Munoz1, Georg A. Bjarnason3, James G. Christensen4 and Robert S. Kerbel1, 2,, 1Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada 2Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada 3Sunnybrook Odette Cancer Centre, Toronto, ON M5G 2M9, Canada 4Pfizer Global Research and Development, La Jolla Labs, La Jolla, CA 92121, USA

59 Neoadjuvant Therapy: Axitinib 81 y/o WM s/p 12 weeks Axitinib Bilateral T1b Gr 2

60 What about primary tumor downstaging/sizing?

61 Results of Therapy with Primary Tumor in Place Institution Number of patients Response Rate Response in Primary Tumor Median Survival (mos) NCI 51 6% 0% 13 Netherlands Cancer Institute % 0% 3

62 Presurgical targeted therapy 63 yo male treated with sunitinib prior to nephrectomy

63 Are These Anecdotes Or Can We Rely On These Agents To Reliably Downstage Tumors?

64 Response of Primary Tumor Sunitinib 17 Evaluable Patients 4PR 12 SD 1 PD Response Rate in Primary Tumor: 23% Mean Volume Reduction: 31% Van der Veldt et al., CCR, 2008

65 Response of Primary Tumor Sunitinib Thomas AA et al., J Urol 2009

66 Pre-Surgical Bevacizumab Therapy Primary Tumor Regression N=45 (%) >20% growth 1 (2) 10-20% %g growth 2 (4) 0-10% growth 19 (42) 1-10% shrinkage 13 (29) 11-20% shrinkage 7 (16) 20-30% shrinkage 3 (7) Jonasch E et al., JCO, 2009

67 Pre-surgical Sorafenib *4 patients downstaged from T2 to T1 *2 patients with RV thrombus on imaging were neg. on path *Median tumor shrinkage 96% 9.6% Cowey et al., JCO, 2010

68 Patient characteristics 168 patients Tumor size e96c 9.6 cm ( ) Age 59.1 ( ) Follow- up 11.6 months ( ) ECOG PS (73.2) 2 29 (16.1) 3 16 (9.5) Abel at al., Eur Urol, 2011

69 Clinical rationale for treatment with primary tumor in situ Widespread metastatic disease 52 (30.1) Enrolled in clinical trial 46 (27.4) Brain metastasis, sarcomatoid or non-clear histology in biopsy 30 (17.9) Doctor/ patient preference 17 (10.1) Poor PS/ comorbidities 16 (9.5) Unresectable primary 7 (4.2) Abel at al., Eur Urol, 2011

70 Types of targeted therapy RESULTS N % sunitinib bevicizumab bevicizumab/ erlotinib sorafenib temsirolimus bevicizumab/ chemo erlotinib pazopanib Sunitinib Bevacizumab + Erlotinib Temsirolimus Erlotinib Bevacizumab Sorafenib Bevacizumab + Chemo Pazopanib Total Abel at al., Eur Urol, 2011

71 Maximum overall response in primary tumor Median -7.1% Abel at al., Eur Urol, 2011

72 Impact of Pre-Surgical Targeted Therapy On Venous Tumor Thrombus Delacroix S et al., ASCO GU 2011

73 Clinically meaningful changes occurred in 25% of patients (12/48) table 3 Stable Disease in 75% 36/48 Progression occurred in 14.5% (7/48) Regression in 10.4% (5/48). No Cases of Pulmonary Embolism Delacroix S et al., ASCO GU 2011

74 Initial body of evidence would suggest that significant primary tumor downstaging will not be realized with the current generation of targeted therapy agents. The jury is still out with regards to the newer generation of agents in the pp pipeline.

75 Presurgical/Neoadjuvant Therapy 1. Is it safe? 2. Does it reliably downsize/downstage tumors? 3. Is this treatment paradigm an advancement in the care of patients?

76 Presurgical Bevacizumab Therapy 50 patients were enrolled in the trial 42 patients underwent nephrectomy 6 patients had disease progression and went on to salvage systemic therapy rather than nephrectomy Med PFS 11 mos; Overall Survival 25.4 mos Jonasch et al, J Clin Oncol

77 Is an Early Minor (>=10%) Primary Tumor Response Associated with Overall Survival? OBJECTIVE: to evaluate whether an early minor PT response was associated with improved overall survival in patients undergoing treatment with sunitinib Abel et al., Eur Urol, 2011

78 Maximum rate of decrease is early in therapy Pe ercent Respons se Days of Treatment Abel et al., Eur Urol, 2011

79 Early response associated with higher maximum primary tumor response Patients with Multiple Imaging Points 10% response in 1 st <10% response in 1 st 60 days 60 days (N=18) (N=43) Maximum response (range) % -7.2 % (-53.4, -14.3) (-33.8, 9.8) Time to maximum response (days) (range) 175 (54, 839) 154 (37, 531) Abel EJ, Culp SH et al. Eur Urol. 2011

80 Study Population 75 patients treated with sunitinib for metastatic RCC with primary tumor in place Median follow-up of 15 mos (IQR: 7.5, 30.2) Median treatment time of 160 days (IQR: 83, 260) Abel et al., Eur Urol, 2011

81 Significant predictors of overall survival from univariable analysis HR 95% CI PT response (decrease in diameter) <10% Referent. 10% and > 60 days , % and 60 days , 0.82 Venous thrombus , 1.73 Radiographic retroperitoneal lymphadenopathy , 3.59 Local symptoms at presentation , 3.77 ECOG performance status >= , 4.00 Liver metastases , 4.08 Multiple bone metastases , 4.29 Lactate dehydrogenase > ULN , 4.26 Absolute lymphocyte count < LLN , 5.14 Number of metastatic sites > , 5.18 Abel et al., Eur Urol, 2011

82 Independent predictors of overall survival on multivariable analysis HR 95% CI 10% PT response se in 60 days* , 08, 0.89 Renal vein or IVC thrombus , 1.63 Multiple bone metastases , 4.21 Lactate dehydrogenase > ULN , 4.63 Local symptoms at presentation , 5.84 Number of metastatic sites > , 6.52 Abel et al., Eur Urol, 2011

83 In targeted therapy: PT response better than established prognostic criteria at estimating overall survival Abel EJ and Culp SH, European Urology December 2011

84 Phase II Presurgical Sunitinib: Response in Primary Tumor Predicts Survival 2 cycles of Sunitinib N = 22 Bex A, et al., Urology 2011

85 Cytoreductive Nephrectomy For Metastatic Renal Cell Carcinoma in The Era of Targeted Therapy: Not a question of if but when?

86 Timing Of Cytoreductive Nephrectomy In Metastatic Renal Cell Carcinoma Untreated Metastatic Renal Cell Carcinoma With Primary Tumor In Place (PS 0-1, Surgical Candidate) Non Clear Cell Histology; Sarcomatoid Managed By Standard of Care or Other Clinical Protocol Biopsy To Establish Clear Cell Histology; Lack of Sarcomatoid Cytoreductive ti Sunitinib ib Nephrectomy 4/2 Sunitinib 4/2 X 2 cycles Primary: PFS Secondary: OS, Response Rate, Surgical morbidity/mortality Cytoreductive Nephrectomy A. Bex, EORTC

87 Integration Of Targeted Therapy With Surgery In RCC Targeted therapy has dramatically improved the outcomes for patients with metastatic RCC Efficacy in the adjuvant and neoadjuvant setting is still under investigation Without complete responses, surgery remains integral part of multi-disciplinary approach in metastatic disease Control of primary tumor Metastasectomy Reliable complete responses with any agent will force re-examination of current paradigm Presurgical approach may have merit but needs further study and validation Not clear when it is most appropriate to integrate surgery