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Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma

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Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma Fabio Calabr Department of Medical Oncology San Camillo-Forlanini Hospital Highlights in the management ... – PowerPoint PPT presentation

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Title: Adjuvant and Neoadjuvant Approaches to Renal Cell Carcinoma


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
Treatment N 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 (p0.02)
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 TKIs EraRationale
  • Poor prognosis for selected groups after
    nephrectomy
  • No proven adjuvant treatment
  • Efficacy of TKIs in advanced disease
  • TKIs are suitable for prolonged use

6
Adjuvant Therapy in the TKIs EraEssentials
  • Effective therapy
  • Feasible therapy
  • Selection of patients

7
UCLA Prognostic Groups
T stage 1 1 1 2 3 3 3 4
Grade 1-2 1-2 3-4 1 gt1 gt1
PS 0 1 Any Any 0 1
Risk Low Intermediate Intermediate Intermediate Intermediate Intermediate High High
Zisman A. J Clin Oncol 234559 2002
8
Prognostic Models
Center Histology Surgery Clinical Variables Path Variables Recurr Accuracy Ext Validation
MSKCC Papillary Chromo Partial Radical Disease related Histo, Size, pT Local distant 0.74 No
MSKCC ccRCC Partial Radical Disease related Size, pT, G,V.I., necrosis Local Distant 0.82 Yes
Mayo Clinic CcRCC Radical pT, N, size G,necrosis, histo Distant 0.82 No
UCLA All RCC Partial Radical ECOG PS TNM Grade Local Distant NA No
Crispen PL, Cancer 113450, 2008
9
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?

10
Molecular MarkersPrognostic Model
Kim HL Clin Cancer Res 105464, 2004
11
Adjuvant Trials for RCC
Treatment N Sponsor Outcome
G250Ab v Placebo 856 Wilex Recruiting
Sunitinib vs Placebo Sorefenib vs Placebo 1332 ECOG Recruiting
Sorafenib vs Placebo Sorafenib 1yr vs 3 yr 1656 MRC/EORTC Recruiting
Sunitinib vs Placebo 228 EAU/Pfizer Recruiting
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
  • Tumournodemetastases
  • 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

r a n d o m i z a t i o n
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 OMIZA T I O N
High risk pts T3 N0-x M0 Fuhrmans grade gt2 PS
gt1 OR T4 N0-X Fuhrmans grade any PS any OR Any
T, N1-2 Fuhrmans grade any PS any
Sunitinib 50 mg/die (4w/2w) for 1 year
Placebo for 1 year
14
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
Sorafenib (400mg b.i.d.) 3 years
R A N D O M I S A T I O N
Patients with resected RCC athigh or
intermediate risk of relapse
Sorafenib (400mg b.i.d.) 1year Placebo 2 years
Placebo 3 years
15
Adjuvant Therapy in RCCThe Ideal Trial
  • Innovative trial design
  • Translational component
  • Health economic component
  • Validation of prognostic models

16
Adjuvant therapy in RCCConclusions
  • Currently, there is NO evidence that targeted
    therapy will be active as adjuvant treatment
  • Immunotherapy and vaccine have limited activity
  • TKIs are under evaluation

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

18
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 (?)

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

20
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

21
Cytoreductive SurgerySWOG 8949 n246
Median survival Nephrectomy IFN 11.1 months IFN
alone 8.1 months
P0.05
Flanigan RC, NEJM 3451655, 2001
22
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
Performance status 1 4.8 6.9 0.08
Type of metastases Lung only 10.3 14.3 0.008
Type of metastases Other 6.3 10.2 0.008
Flanigan RC, NEJM 3451655, 2001
23
Cytoreductive SurgeryEORTC Trial n85
Time to progression
Overall survival
Mickisch, Lancet 358966, 2001
24
Cytoreductive SurgeryCombined Analysis
Group Year N Median Survival Nephrectomy IFN MS IFN p
SWOG 2001 246 11 9 lt0.05
EORTC 2001 85 18 11 lt 0.05
Flanigan (combined) 2004 331 13.6 7.8 lt 0.05
31 decrease in risk of death with nephrectomy
Flanigan RC J Urol 1711071, 2004
25
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 1711071, 2004
26
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

27
RCC in 2008
  • Sunitinib improves PFS in first-line RCC 11 vs 5
    months plt 0.001 HR 0.42)
  • Sorafenib improves PFS in second-line RCC 5.5 vs
    2.8 months plt 0.01 HR 0.44)
  • Temsirolimus improves OS in poor risk metastatic
    kidney cancer (10.9 vs 7.3 months plt 0.008
    HR0.73)
  • Everolimus (RAD 001) improves PFS in second line
    (4 vs 1.9 months plt 0.0001 HR0.30)
  • Bevacizumb IFN improves PFS in first line (10.2
    vs 5.4 months plt 0.0001 HR0.63)

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
Author Line Phase Drugs N Nephr ORR PFS OS
Bukowski 1 II Bev Bev/Erlotinib 53 51 100 100 13 14 8.5 9.9 NR
Yang 2 II Bev HD Bev LD Placebo 39 37 40 90 89 95 10 0 0 4.8 3.0 2.5 NS
Avoren 1 III Bev IFN IFN 327 322 100 100 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 Sorafenib Placebo 451 452 94 93 10 2 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 375 375 91 89 31 6 11 5 NR
Motzer 2 II Sunitinib 106 100 34 8.3 NR
31
Nephrectomy and targeted therapy Sunitinib
RR PFS months Median OS
Prior nephrectomy 18 12 19
No prior nephrectomy 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 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 Nephrectomy Immunotherapy Nephrectomy Targeted Therapy Nephrectomy Targeted Therapy
Metastatic burden Metastatic burden Metastatic burden Metastatic burden
Limited Extensive Limited Extensive
Good Yes Approp Approp Appropr Uncertain
Good No Appropr Uncertain Uncertain Uncertain
Poor Yes Uncertain Uncertain Uncertain Uncertain
Poor No Uncertain Inappropr Inappropr Inappropr
Halbert J Cancer 107 2375, 2006
36
RAND Appropriateness Panel
Surgical risk Symptoms Nephrectomy Immunotherapy Nephrectomy Immunotherapy Nephrectomy Targeted Therapy Nephrectomy Targeted Therapy
Metastatic burden Metastatic burden Metastatic burden Metastatic burden
Limited Extensive Limited Extensive
Good Yes Approp Approp Appropr Uncertain
Good No Appropr Uncertain Uncertain Uncertain
Poor Yes Uncertain Uncertain Uncertain Uncertain
Poor No Uncertain Inappropr Inappropr Inappropr
Halbert J Cancer 107 2375, 2006
37
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

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

39
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

40
Neoadjuvant ApproachAdvantages
  • Select for surgery responding patients
  • Downstaging
  • Eliminates morbidity and mortality in those that
    wouldn benefit anyway
  • Screen for patients with borderline PS
  • Harvest of treated tissue for mechanistic studies

41
Neoadjuvant ApproachDisdvantages
  • 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 70-75
Sorafenib 2-10 70-75
Temsirolimus 9 35
43
Neoadjuvant ApproachBevacizumab
Four cycles of Bevacizumab in previously
untreated patient
44
Neoadjuvant ApproachSorafenib
4 weeks of Sorafenib in previously untreated
patient
Week 4 7.9 cm
Baseline 9.5 cm
45
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

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 1.000
Infectious 1.009 0.995
Incision related 0.995 0.880
Margulis V. J Urol 18094, 2008
47
Neoadjuvant Bevacizumab
Response Or stable
Nephrectomy Continue Bevacizumab
N50 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
New therapy BSC
Progressive Poor PS
Nephrectomy performed during week 2 or 3 of cycle
2 Erlotinib discontinued after 25 patients
48
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
49
Pre and Post Surgical SunitinibMD Anderson n50
Stable Response
Nephrectomy Continue Sunitinib
N50 Metastatic Clear Cell No prior
therapy Sunitinib 50 mg/die 4wk/2wk
Progressive Good PS
Nephrectomy New treatment
New treatment BSC
Progressive Poor PS
50
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?

51
French Study
Nephrectomy Followed by Suntininb
Untreated Patients Metastatic RCC Primary in place
Suntinib
Powered for equivalence
52
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 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
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