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Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma

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Presentation on theme: "Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma"— 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
Author Outcome RT vs Obs 72 Kjaer Os 50 v 62% NS MPA vs Obs 136 Pizzocaro Relapse 33 v 33% NS Tumor + BCG v Obs 43 120 Adler Galligioni DFS NS DFS 63 vs 72% IFN vs Obs 283 Messing OS 5.1 vs 7.4 yrs NS HD-IL-2 vs Obs 69 Clark Relapse 76 v 65% NS Aut Tum Vacc vs Obs 553 Jocham PFS 77 v 68% (p=0.02) IL-2 + IFN v Obs 303 Passalacqua RFS OS NS HSPPC-96 vs Obs 818 Wood RFS NS IL-2 + IFN + 5FU vs Obs 309 Aitchison DFS 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
stage 1 2 3 4 Grade 1-2 3-4 >1 PS ≥1 Any Risk Low Intermediate High Zisman A. J Clin Oncol 23:

8 Prognostic Models Center Histology Surgery Clinical Variables Path
Recurr Accuracy Ext Validation MSKCC Papillary Chromo Partial Radical Disease related Histo, Size, pT Local distant 0.74 No ccRCC Size, pT, G,V.I., necrosis Distant 0.82 Yes Mayo Clinic CcRCC pT, N, size G,necrosis, histo UCLA All RCC ECOG PS TNM Grade NA 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
Treatment N Sponsor Outcome G250Ab v Placebo 856 Wilex Recruiting Sunitinib vs Placebo Sorefenib vs Placebo 1332 ECOG Sorafenib vs Placebo Sorafenib 1yr vs 3 yr 1656 MRC/EORTC 228 EAU/Pfizer

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† 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 1 Surgery Laparoscopic Open r a n d o m i z t Group B Sorafenib 400mg (2 tablets) orally b.i.d. 6 weeks for nine cycles† Group C Placebo Primary objective: disease-free survival *Accrual goal = 1,332; †one cycle = 6 weeks

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

14 Patients with resected RCC at high or intermediate risk of relapse
SORCE A phase III, randomised, double-blind controlled study comparing SOrafenib with placebo in patients with Resected primary renal CEll carcinoma at high or intermediate risk of relapse R A N D O M I S T Sorafenib (400mg b.i.d.) 3 years Patients with resected RCC at high or intermediate risk of relapse 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 + IFN 11.1 months IFN alone months P=0.05 Flanigan RC, NEJM 345:1655, 2001

22 SWOG Trial Median Survival
Stratified Subgroup IFN alone Nephr + IFN P All Patients 8.1 11.7 0.012 Performance status 17.4 0.08 1 4.8 6.9 Type of metastases Lung only 10.3 14.3 0.008 Other 6.3 10.2 Flanigan RC, NEJM 345:1655, 2001

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

24 Cytoreductive Surgery Combined Analysis
Group Year N Median Survival Nephrectomy + IFN MS IFN p SWOG 2001 246 11 9 <0.05 EORTC 85 18 < 0.05 Flanigan (combined) 2004 331 13.6 7.8 31% decrease in risk of death with nephrectomy Flanigan RC J Urol 171:1071, 2004

25 Cytoreductive Surgery Combined Analysis
Group RR % Nephrectomy + IFN IFN Unable to receive post-surgery IFN Operative mortality SWOG 3.6 3.3 NR 1 (0.8%) EORTC 19 12 1 (2.4 %) Flanigan (combined) 6.9 5.7 5.6% 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< ; HR:0.30) Bevacizumb + IFN improves PFS in first line (10.2 vs 5.4 months; p< ; HR:0.63) Motzer, NEJM 2007, 356: Escudier, NEJM 2007, 356: Hudes , NEJM 2007, 356: , Motzer, Lancet 2008, Jul 22 epub

28 Nephrectomy and targeted therapy Bevacizumab
Author Line Phase Drugs N Nephr % ORR PFS OS Bukowski 1 II Bev Bev/Erlotinib 53 51 100 13 14 8.5 9.9 NR Yang 2 Bev HD Bev LD Placebo 39 37 40 90 89 95 10 4.8 3.0 2.5 NS Avoren III Bev + IFN IFN 327 322 30.6 12.4 10.2 5.4 +

29 Nephrectomy and targeted therapy Sorafenib
Author Line Phase Drugs N Nephr % ORR PFS OS Szczylik 1 II Sorafenib IFN 97 92 98 95 5 9 5.7 5.6 NA TARGET 2 III Placebo 451 452 94 93 10 5.5 2.8 17.8 14.3

30 Nephrectomy and targeted therapy Sunitinib
Author Line Phase Drugs N Nephr % ORR PFS OS Motzer 1 III Sunitinib IFN 375 91 89 31 6 11 5 NR 2 II 106 100 34 8.3

31 Nephrectomy and targeted therapy Sunitinib
RR PFS months Median OS Prior nephrectomy 18% 12 19 No prior 9% 6.5 11.1 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
Author Line Phase Drugs N Nephr % ORR PFS OS ARCC 1 III Temsirolimus 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
Nephrectomy appropriate 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 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 Symptoms Nephrectomy Immunotherapy Targeted Therapy Metastatic burden Limited Extensive Good Yes Approp Appropr Uncertain No Poor Inappropr Halbert J Cancer 107: 2375, 2006

36 RAND Appropriateness Panel
Surgical risk Symptoms Nephrectomy Immunotherapy Targeted Therapy Metastatic burden Limited Extensive Good Yes Approp Appropr Uncertain No Poor Inappropr 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 Agent ORR Tumor shrinkage rate Sunitinib 40-45%
~70-75% Bevacizumab + IFN 10-15% 25-30% Sorafenib 2-10% Temsirolimus 9% ~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 ratio P value All complications 0.560 0.145 Re-exploration 1.100 0.993 Readmission 1.000 0.997 Thromboembolic 1.200 0.990 Cardiovascular 1.115 0.607 Pulmonary 0.765 0.447 Gastrointestinal 1.154 Infectious 1.009 0.995 Incision related 0.880 Margulis V. J Urol 180:94, 2008

47 Neoadjuvant Bevacizumab
Response Or stable Nephrectomy Continue Bevacizumab N=50 Metastatic Clear Cell No prior therapy Bevacizumab 10 mg/Kg Q 14 days (+Erlotinib 150 mg daily for 8 weeks) Progressive Good PS Nephrectomy New therapy Progressive Poor PS 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)
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
Stable Response Nephrectomy Continue Sunitinib N=50 Metastatic Clear Cell No prior therapy Sunitinib 50 mg/die 4wk/2wk Progressive Good PS Nephrectomy New treatment Progressive Poor PS 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 Powered for equivalence
French Study Nephrectomy Followed by Suntininb Untreated Patients Metastatic RCC Primary in place Suntinib Powered for equivalence

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