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Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma Fabio Calabrò Department of Medical Oncology San Camillo-Forlanini Hospital Highlights in the.

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Presentation on theme: "Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma Fabio Calabrò Department of Medical Oncology San Camillo-Forlanini Hospital Highlights in the."— Presentation transcript:

1 Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma Fabio Calabrò Department of Medical Oncology San Camillo-Forlanini Hospital Highlights in the management of Kidney Cancer Rome, November 7-8, 2008

2 New Approaches to Renal Cell Carcinoma Adjuvant therapy Cytoreductive surgery (upfront nephrectomy) Neoadjuvant therapy

3 New Approaches to Renal Cell Carcinoma Adjuvant therapy Citoreductive suregry (upfront nephrectomy) Neoadjuvant therapy

4 Adjuvant treatment for RCC TreatmentNAuthorOutcome RT vs Obs72KjaerOs 50 v 62% NS MPA vs Obs136PizzocaroRelapse 33 v 33% NS Tumor + BCG v Obs43 120 Adler Galligioni DFS NS DFS 63 vs 72% IFN vs Obs283MessingOS 5.1 vs 7.4 yrs NS HD-IL-2 vs Obs69ClarkRelapse 76 v 65% NS Aut Tum Vacc vs Obs553JochamPFS 77 v 68% (p=0.02) IL-2 + IFN v Obs303PassalacquaRFS OS NS HSPPC-96 vs Obs818WoodRFS NS IL-2 + IFN + 5FU vs Obs309AitchisonDFS OS (preliminary) NS

5 Adjuvant Trials in RCC in the TKI’s Era Rationale Poor prognosis for selected groups after nephrectomy No proven adjuvant treatment Efficacy of TKI’s in advanced disease TKI’s are suitable for prolonged use

6 Adjuvant Therapy in the TKI’s Era Essentials Effective therapy Feasible therapy Selection of patients

7 UCLA Prognostic Groups T stage 1234 Grade1-23-41>1 PS0≥1Any 0≥1 RiskLowIntermediateHigh Zisman A. J Clin Oncol 23:4559 2002

8 Prognostic Models CenterHistologySurgeryClinical Variables Path Variables RecurrAccuracyExt Validation MSKCCPapillary Chromo Partial Radical Disease related Histo, Size, pT Local distant 0.74No MSKCCccRCCPartial Radical Disease related Size, pT, G,V.I., necrosis Local Distant 0.82Yes Mayo Clinic CcRCCRadicalpT, N, size G,necrosi s, histo Distant0.82No UCLAAll RCCPartial Radical ECOG PSTNM Grade Local Distant NANo Crispen PL, Cancer 113:450, 2008

9 Adjuvant Therapy in RCC Prognostic Molecular Markers Cell proliferation / cell cycle regulation Ki67, p53, p27 Cell adhesion EpCAM, VACM Apoptosis Survivin, Smac/DIABLO Degradation of the extracellular matrix MMP-2, MMP-9, uPA Hypoxia inducible factors CA IX, HIF-1 

10 Molecular Markers Prognostic Model Kim HL Clin Cancer Res 10:5464, 2004

11 Adjuvant Trials for RCC TreatmentNSponsorOutcome G250Ab v Placebo856WilexRecruiting Sunitinib vs Placebo Sorefenib vs Placebo 1332ECOGRecruiting Sorafenib vs Placebo Sorafenib 1yr vs 3 yr 1656MRC/EORTCRecruiting Sunitinib vs Placebo228EAU/PfizerRecruiting

12 ECOG 2805 (ASSURE) Adjuvant Sorafenib Sunitinib Unfavorable REnal Cell Carcinoma Group A Sunitinib 50mg (4 capsules) orally q.d. 4 weeks followed by rest 2 weeks for nine cycles † Group B Sorafenib 400mg (2 tablets) orally b.i.d. 6 weeks for nine cycles † * Accrual goal = 1,332; † one cycle = 6 weeks Stratification Tumour–node–metastases  Intermediate or high risk  Very high risk Histological sub-type  Clear cell  Non-clear cell (except collecting duct or medullary) ECOG PS  0  1 Surgery  Laparoscopic  Open Group C Placebo Primary objective: disease-free survival randomizationrandomization

13 S-TRAC High risk pts T3 N0-x M0 Fuhrman’s grade >2 PS >1 OR T4 N0-X Fuhrman’s grade any PS any OR Any T, N1-2 Fuhrman’s grade any PS any RANDOMIZATIONRANDOMIZATION Sunitinib 50 mg/die (4w/2w) for 1 year Placebo for 1 year

14 SORCE A phase III, randomised, double-blind controlled study comparing SO rafenib with placebo in patients with R esected primary renal CE ll carcinoma at high or intermediate risk of relapse Patients with resected RCC at high or intermediate risk of relapse RANDOMISATIONRANDOMISATION Sorafenib (400mg b.i.d.) 3 years Sorafenib (400mg b.i.d.) 1year Placebo 2 years Placebo 3 years

15 Adjuvant Therapy in RCC The Ideal Trial Innovative trial design Translational component Health economic component Validation of prognostic models

16 Adjuvant therapy in RCC Conclusions Currently, there is NO evidence that targeted therapy will be active as adjuvant treatment Immunotherapy and vaccine have limited activity TKI’s are under evaluation

17 New Approaches to Renal Cell Carcinoma Adjuvant therapy Cytoreductive surgery (upfront nephrectomy) Neoadjuvant therapy

18 Cytoreductive surgery Advantages Decrease of tumor burden and metastatic cells Removal of a potential source of angiogenic growth factors Enhance response to therapy Elimination of a source of symptoms Spontaneous regression of metastases (?)

19 Cytoreductive surgery Disdvantages Growth of metastatic disease in the recovery period Morbidity and mortality associated with any major operation Potential for rapid progression despite surgery

20 Cytoreductive surgery Phase III Trials Inclusion Criteria ECOG PS 0-1 Clear cell histology No prior treatment Primary tumor amenable for surgery Lack of CNS, liver or extensive bone metastases

21 Cytoreductive Surgery SWOG 8949 n=246 Median survival Nephrectomy + IFN11.1 months IFN alone 8.1 months P=0.05 Flanigan RC, NEJM 345:1655, 2001

22 SWOG Trial Median Survival StratifiedSubgroupIFN aloneNephr + IFNP All Patients8.111.70.012 Performance status 011.717.40.08 14.86.9 Type of metastases Lung only10.314.30.008 Other6.310.2 Flanigan RC, NEJM 345:1655, 2001

23 Cytoreductive Surgery EORTC Trial n=85 Time to progressionOverall survival Mickisch, Lancet 358:966, 2001

24 Cytoreductive Surgery Combined Analysis GroupYearNMedian Survival Nephrectomy + IFN MS IFN p SWOG2001246119<0.05 EORTC2001851811< 0.05 Flanigan (combined) 200433113.67.8< 0.05 31% decrease in risk of death with nephrectomy Flanigan RC J Urol 171:1071, 2004

25 Cytoreductive Surgery Combined Analysis GroupRR % Nephrectomy + IFN RR % IFN Unable to receive post- surgery IFN Operative mortality SWOG3.63.3NR1 (0.8%) EORTC1912NR1 (2.4 %) Flanigan (combined) 6.95.75.6%2 (1.4%) Flanigan RC J Urol 171:1071, 2004

26 Cytoreductive surgery Summary Robust data 2 phase III randomized trials 40-50% survival advantage Safe Did not delay systemic therapy No increase in perioperative mortality Prognostic Factors (retrospective data) No hepatic or brain metastases No collecting duct or sarcomatoid Good PS (0-1) Resectability

27 RCC in 2008 Sunitinib improves PFS in first-line RCC: 11 vs 5 months; p< 0.001; HR: 0.42) Sorafenib improves PFS in second-line RCC: 5.5 vs 2.8 months; p< 0.01; HR: 0.44) Temsirolimus improves OS in poor risk metastatic kidney cancer (10.9 vs 7.3 months; p< 0.008; HR:0.73) Everolimus (RAD 001) improves PFS in second line (4 vs 1.9 months; p< 0.0001; HR:0.30) Bevacizumb + IFN improves PFS in first line (10.2 vs 5.4 months; p< 0.0001; HR:0.63) Motzer, NEJM 2007, 356: 115-24 Escudier, NEJM 2007, 356: 125-34 Hudes, NEJM 2007, 356: 2271-81, Motzer, Lancet 2008, Jul 22 epub

28 Nephrectomy and targeted therapy Bevacizumab AuthorLinePhaseDrugsNNephr % ORRPFSOS Bukowski1IIBev Bev/Erlotinib 53 51 100 13 14 8.5 9.9 NR Yang2IIBev HD Bev LD Placebo 39 37 40 90 89 95 10 0 4.8 3.0 2.5 NS Avoren1IIIBev + IFN IFN 327 322 100 30.6 12.4 10.2 5.4 +

29 Nephrectomy and targeted therapy Sorafenib AuthorLinePhaseDrugsNNephr % ORRPFSOS Szczylik1IISorafenib IFN 97 92 98 95 5959 5.7 5.6 NA TARGET2IIISorafenib Placebo 451 452 94 93 10 2 5.5 2.8 17.8 14.3

30 Nephrectomy and targeted therapy Sunitinib AuthorLinePhaseDrugsNNephr % ORRPFSOS Motzer1IIISunitinib IFN 375 91 89 31 6 11 5 NR Motzer2IISunitinib106100348.3NR

31 Nephrectomy and targeted therapy Sunitinib RRPFS months Median OS Prior nephrectomy 18%1219 No prior nephrectomy 9%6.511.1 Szczylik C. Proc ASCO 2008 abstr. # 5124

32 Nephrectomy and targeted therapy Sunitinib Szczylik C. Proc ASCO 2008 abstr. # 5124

33 Nephrectomy and targeted therapy Temsirolimus AuthorLinePhaseDrugsNNephr % ORRPFSOS ARCC1IIITemsirolimus Tem + IFN IFN 209 210 207 66 67 8.6 8.1 4.8 3.8 3.7 1.9 10.9 8.4 7.3

34 RAND Appropriateness Panel Good surgical risk, –symptoms related to the primary, –limited metastatic tumor burden to the lung or bone Good surgical risk and planned immunotherapy –If limited metastatic burden or asymptomatic primary –Extensive metastatic burden if primary symptomatic Nephrectomy inappropriate Nephrectomy appropriate Poor surgical risk No primary tumor related symptoms Extensive metastatic burden Poor surgical risk and planned targeted therapy No symptoms Limited metastatic burden Halbert J Cancer 107: 2375, 2006

35 RAND Appropriateness Panel Surgical risk SymptomsNephrectomy Immunotherapy Nephrectomy Targeted Therapy Metastatic burden LimitedExtensiveLimitedExtensive Good YesApprop ApproprUncertain NoApproprUncertain Poor YesUncertain NoUncertainInappropr Halbert J Cancer 107: 2375, 2006

36 RAND Appropriateness Panel Surgical risk SymptomsNephrectomy Immunotherapy Nephrectomy Targeted Therapy Metastatic burden LimitedExtensiveLimitedExtensive Good YesApprop ApproprUncertain NoApproprUncertain Poor YesUncertain NoUncertainInappropr Halbert J Cancer 107: 2375, 2006

37 Cytoreductive surgery Conclusions Survival advantage Safe and effective in selected patients Newer therapies may alter the appropriateness of any given option Well designed trials are clearly needed

38 New Approaches to Renal Cell Carcinoma Adjuvant therapy Cytoreductive surgery (upfront nephrectomy) Neoadjuvant therapy

39 Neoadjuvant Approach Rationale Success of neoadjuvant therapies in other cancers Assurance that patients will receive systemic treatment Potential for more rapid determination of response Response as a selection tool Ability to analyze post-treatment tissue

40 Neoadjuvant Approach Advantages Select for surgery responding patients Downstaging Eliminates morbidity and mortality in those that would’n benefit anyway Screen for patients with borderline PS Harvest of treated tissue for mechanistic studies

41 Neoadjuvant Approach Disdvantages May add morbidity/mortality to surgery May decondition good surgial candidates No proven benefit Unclear timing of surgery

42 Neoadjuvant Approach AgentORRTumor shrinkage rate Sunitinib40-45%~70-75% Bevacizumab + IFN 10-15% 25-30% ~70-75% Sorafenib2-10%~70-75% Temsirolimus9%~35%

43 Neoadjuvant Approach Bevacizumab Four cycles of Bevacizumab in previously untreated patient

44 Neoadjuvant Approach Sorafenib 4 weeks of Sorafenib in previously untreated patient Baseline: 9.5 cm Week 4: 7.9 cm

45 Neoadjuvant Approach Surgical issues Therapy may impact on wound healing, recovery Higher incidence of wound complications Local tumor progression increase complexity of surgery Timing When to operate responders Risk of progression and death in non responders

46 Surgical morbidity associated with Targeted Therapies before Cytoreductive Nephrectomy Odds ratioP value All complications0.5600.145 Re-exploration1.1000.993 Readmission1.0000.997 Thromboembolic1.2000.990 Cardiovascular1.1150.607 Pulmonary0.7650.447 Gastrointestinal1.1541.000 Infectious1.0090.995 Incision related0.9950.880 Margulis V. J Urol 180:94, 2008

47 Neoadjuvant Bevacizumab N=50 Metastatic Clear Cell No prior therapy Bevacizumab 10 mg/Kg Q 14 days (+Erlotinib 150 mg daily for 8 weeks) Response Or stable Progressive Good PS Progressive Poor PS Nephrectomy Continue Bevacizumab Nephrectomy New therapy BSC Nephrectomy performed during week 2 or 3 of cycle 2 Erlotinib discontinued after 25 patients

48 Neoadjuvant Approach Presurgical Bevacizumab (phase II) N= 46 RR= 10% Clinical benefit= 69.6% Median PFS= 6 months No major perioperative complications Jonash E. PROC ASCO 2008 abstr # 5104

49 Pre and Post Surgical Sunitinib MD Anderson n=50 N=50 Metastatic Clear Cell No prior therapy Sunitinib 50 mg/die 4wk/2wk Progressive Poor PS Stable Response Progressive Good PS Nephrectomy Continue Sunitinib Nephrectomy New treatment BSC

50 Neoadjuvant Approach 2 key questions Do patients who receive targeted therapy need a nephrectomy? Can we use targeted therapy to select patients who will benefit from surgery?

51 French Study Untreated Patients Metastatic RCC Primary in place Nephrectomy Followed by Suntininb Suntinib Powered for equivalence

52 EORTC Study 440 Untreated Patients Metastatic RCC Primary in place Nephrectomy Followed by Suntininb Suntinib Followed by Nephrectomy In non progressors Powered for superiority

53 Neoadjuvant Approach Conclusions Initial observations suggest that targeted agents are active in the primary tumor Nephrectomy after targeted therapy is safe and permits proper patient selection Future trials are needed to assess the use of neoadjuvant therapy in localized and metastatic RCC


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