Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma Fabio Calabrò Department of Medical...
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Transcript of Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma Fabio Calabrò Department of Medical...
Adjuvant and Neoadjuvant Approaches to
Renal Cell Carcinoma
Fabio Calabrò
Department of Medical OncologySan Camillo-Forlanini Hospital
Highlights in the management of Kidney CancerRome, November 7-8, 2008
New Approaches to Renal Cell Carcinoma
• Adjuvant therapy• Cytoreductive surgery (upfront
nephrectomy)• Neoadjuvant therapy
New Approaches to Renal Cell Carcinoma
• Adjuvant therapy• Citoreductive suregry (upfront
nephrectomy)• Neoadjuvant therapy
Adjuvant treatment for RCC
Treatment N Author OutcomeRT vs Obs 72 Kjaer Os 50 v 62%
NS
MPA vs Obs 136 Pizzocaro Relapse 33 v 33% NS
Tumor + BCG v Obs 43120
AdlerGalligioni
DFS NSDFS 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
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
Adjuvant Therapy in the TKI’s EraEssentials
• Effective therapy• Feasible therapy• Selection of patients
UCLA Prognostic Groups
Tstage
1 2 3 4
Grade 1-2 3-4 1 >1
PS 0 ≥1 Any Any 0 ≥1
Risk Low Intermediate High
Zisman A. J Clin Oncol 23:4559 2002
Prognostic Models
Center Histology
Surgery
ClinicalVariables
PathVariables
Recurr Accuracy Ext Validation
MSKCC PapillaryChromo
PartialRadical
Disease related
Histo, Size, pT
Localdistant
0.74 No
MSKCC ccRCC PartialRadical
Disease related
Size, pT, G,V.I.,necrosis
LocalDistant
0.82 Yes
MayoClinic
CcRCC Radical pT, N, size G,necrosis, histo
Distant
0.82 No
UCLA All RCC PartialRadical
ECOG PS TNM Grade
LocalDistant
NA No
Crispen PL, Cancer 113:450, 2008
Adjuvant Therapy in RCCPrognostic 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
Molecular MarkersPrognostic Model
Kim HL Clin Cancer Res 10:5464, 2004
Adjuvant Trials for RCC
Treatment N Sponsor Outcome
G250Ab v Placebo 856 Wilex Recruiting
Sunitinib vs PlaceboSorefenib vs Placebo
1332 ECOG Recruiting
Sorafenib vs PlaceboSorafenib 1yr vs 3 yr
1656 MRC/EORTC Recruiting
Sunitinib vs Placebo 228 EAU/Pfizer Recruiting
ECOG 2805 (ASSURE)Adjuvant Sorafenib Sunitinib
Unfavorable REnal Cell Carcinoma
Group ASunitinib 50mg (4 capsules) orally q.d. 4 weeks followed by rest 2 weeks for nine cycles†
Group BSorafenib 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 ductor medullary)
ECOG PS 0 1
Surgery Laparoscopic Open
Group C
Placebo
Primary objective: disease-free survival
randomization
S-TRAC
High risk ptsT3 N0-x M0
Fuhrman’s grade >2PS >1
ORT4 N0-X
Fuhrman’s grade anyPS any
ORAny T, N1-2
Fuhrman’s grade anyPS any
RANDOMIZATION
Sunitinib 50 mg/die(4w/2w) for 1 year
Placebo for 1 year
SORCEA 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
Patients with resected RCC
athigh or
intermediate risk of relapse
RANDOMISATION
Sorafenib (400mg b.i.d.)
3 years
Sorafenib (400mg b.i.d.)
1yearPlacebo 2 years
Placebo3 years
Adjuvant Therapy in RCCThe Ideal Trial
• Innovative trial design• Translational component• Health economic component• Validation of prognostic models
Adjuvant therapy in RCCConclusions
• 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
New Approaches to Renal Cell Carcinoma
• Adjuvant therapy• Cytoreductive surgery (upfront
nephrectomy)• Neoadjuvant therapy
Cytoreductive surgeryAdvantages
• 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 (?)
Cytoreductive surgeryDisdvantages
• Growth of metastatic disease in the recovery period
• Morbidity and mortality associated with any major operation
• Potential for rapid progression despite surgery
Cytoreductive surgeryPhase 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
Cytoreductive SurgerySWOG 8949 n=246
Median survivalNephrectomy + IFN 11.1 monthsIFN alone 8.1 months P=0.05
Flanigan RC, NEJM 345:1655, 2001
SWOG TrialMedian Survival
Stratified Subgroup IFN alone Nephr + IFN P
All Patients 8.1 11.7 0.012
Performance status
0 11.7 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
Cytoreductive SurgeryEORTC Trial n=85
Time to progression Overall survival
Mickisch, Lancet 358:966, 2001
Cytoreductive SurgeryCombined Analysis
Group Year N Median SurvivalNephrectomy +
IFN
MSIFN
p
SWOG 2001 246 11 9 <0.05
EORTC 2001 85 18 11 < 0.05
Flanigan(combined)
2004 331 13.6 7.8 < 0.05
31% decrease in risk of death with nephrectomy
Flanigan RC J Urol 171:1071, 2004
Cytoreductive SurgeryCombined Analysis
Group RR %Nephrectomy
+ IFN
RR %IFN
Unable to receive post-surgery IFN
Operative mortality
SWOG 3.6 3.3 NR 1 (0.8%)
EORTC 19 12 NR 1 (2.4 %)
Flanigan(combined)
6.9 5.7 5.6% 2 (1.4%)
Flanigan RC J Urol 171:1071, 2004
Cytoreductive surgerySummary
• 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
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: 125-34Hudes , NEJM 2007, 356: 2271-81, Motzer, Lancet 2008, Jul 22 epub
Nephrectomy and targeted therapy Bevacizumab
Author Line Phase Drugs N Nephr%
ORR PFS OS
Bukowski 1 II BevBev/Erlotinib
5351
100100
1314
8.59.9
NR
Yang 2 II Bev HDBev LDPlacebo
393740
908995
1000
4.83.02.5
NS
Avoren 1 III Bev + IFNIFN
327322
100100
30.612.4
10.2
5.4
+
Nephrectomy and targeted therapy Sorafenib
Author Line Phase Drugs N Nephr%
ORR PFS OS
Szczylik 1 II SorafenibIFN
9792
9895
59
5.75.6
NA
TARGET 2 III SorafenibPlacebo
451452
9493
102
5.52.8
17.814.3
Nephrectomy and targeted therapy Sunitinib
Author Line Phase Drugs N Nephr%
ORR PFS OS
Motzer 1 III SunitinibIFN
375375
9189
316
115
NR
Motzer 2 II Sunitinib 106
100 34 8.3 NR
Nephrectomy and targeted therapy Sunitinib
RR PFSmonths
MedianOS
Prior nephrectomy
18% 12 19
No priornephrectomy
9% 6.5 11.1
Szczylik C. Proc ASCO 2008 abstr. # 5124
Nephrectomy and targeted therapy Sunitinib
Szczylik C. Proc ASCO 2008 abstr. # 5124
Nephrectomy and targeted therapy Temsirolimus
Author Line Phase Drugs N Nephr%
ORR PFS OS
ARCC 1 III TemsirolimusTem + IFNIFN
209210207
666767
8.68.14.8
3.83.71.9
10.98.47.3
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
RAND Appropriateness Panel
Surgical
risk
Symptoms
NephrectomyImmunotherapy
NephrectomyTargeted Therapy
Metastatic burden Metastatic burden
Limited Extensive
Limited Extensive
GoodYes Approp Approp Appropr Uncertai
n
No Appropr Uncertain
Uncertain
Uncertain
PoorYes Uncertai
nUncertain
Uncertain
Uncertain
No Uncertain
Inappropr
Inappropr
InapproprHalbert J Cancer 107: 2375, 2006
RAND Appropriateness Panel
Surgical
risk
Symptoms
NephrectomyImmunotherapy
NephrectomyTargeted Therapy
Metastatic burden Metastatic burden
Limited Extensive
Limited Extensive
GoodYes Approp Approp Appropr Uncertai
n
No Appropr Uncertain
Uncertain
Uncertain
PoorYes Uncertai
nUncertain
Uncertain
Uncertain
No Uncertain
Inappropr
Inappropr
InapproprHalbert J Cancer 107: 2375, 2006
Cytoreductive surgeryConclusions
• Survival advantage• Safe and effective in selected patients• Newer therapies may alter the
appropriateness of any given option• Well designed trials are clearly needed
New Approaches to Renal Cell Carcinoma
• Adjuvant therapy• Cytoreductive surgery (upfront
nephrectomy)• Neoadjuvant therapy
Neoadjuvant ApproachRationale
• 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
Neoadjuvant ApproachAdvantages
• 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
Neoadjuvant ApproachDisdvantages
• May add morbidity/mortality to surgery• May decondition good surgial
candidates• No proven benefit• Unclear timing of surgery
Neoadjuvant Approach
Agent ORR Tumor shrinkage rate
Sunitinib 40-45% ~70-75%
Bevacizumab+ IFN
10-15%25-30%
~70-75%
Sorafenib 2-10% ~70-75%
Temsirolimus 9% ~35%
Neoadjuvant ApproachBevacizumab
Four cycles of Bevacizumab in previously untreated patient
Neoadjuvant ApproachSorafenib
4 weeks of Sorafenib in previously untreated patient
Baseline: 9.5 cm Week 4: 7.9 cm
Neoadjuvant ApproachSurgical 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
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 1.000
Infectious 1.009 0.995
Incision related 0.995 0.880
Margulis V. J Urol 180:94, 2008
Neoadjuvant Bevacizumab
N=50MetastaticClear Cell
No prior therapyBevacizumab
10 mg/KgQ 14 days
(+Erlotinib 150 mg
daily for 8 weeks)
ResponseOr stable
ProgressiveGood PS
Progressive Poor PS
NephrectomyContinue Bevacizumab
NephrectomyNew therapy
New therapyBSC
Nephrectomy performed during week 2 or 3 of cycle 2Erlotinib discontinued after 25 patients
Neoadjuvant ApproachPresurgical 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
Pre and Post Surgical SunitinibMD Anderson n=50
N=50MetastaticClear Cell
No prior therapySunitinib
50 mg/die4wk/2wk
ProgressivePoor PS
Stable Response
ProgressiveGood PS
NephrectomyContinue Sunitinib
NephrectomyNew treatment
New treatmentBSC
Neoadjuvant Approach2 key questions
• Do patients who receive targeted therapy need a nephrectomy?
• Can we use targeted therapy to select patients who will benefit from surgery?
French Study
Untreated PatientsMetastatic RCCPrimary in place
Nephrectomy Followed bySuntininb
Suntinib
Powered for equivalence
EORTC Study
440 Untreated Patients
Metastatic RCCPrimary in place
Nephrectomy Followed bySuntininb
SuntinibFollowed by
NephrectomyIn non progressors
Powered for superiority
Neoadjuvant ApproachConclusions
• 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