Integration of Surgery And Systemic g g y y Therapy In The

Transcription

Integration
g
of Surgery
g y And Systemic
y
Therapy In The Treatment of
Ad
Advanced
dR
Renall C
Cellll C
Carcinoma
i
Christopher G. Wood, M. D., FACS
P f
Professor
and
dD
Deputy Ch
Chairman
i
Douglas E. Johnson, M. D. Professorship In Urology
Department of Urology
The University of Texas MD Anderson Cancer Center
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
g cytokines
y
((eg,
g, 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: http://www.nccn.org/professionals/
physician_gls/PDF/kidney.pdf. Yang et al. N Engl J Med. 2003;349:427-434. Ratain et al. J Clin Oncol. 2006;24:2505-2512.
Motzer et al. J Clin Oncol. 2006;24:16-24. Motzer et al. JAMA. 2006;295:2516-2524. Motzer et al. N Engl J Med. 2007;356:115-124.
Treatment options for RCC have been
revolutionized in a short period of time…
FDA approvals
Pazopanib
P
ib
(Oct 2009)6
Sunitinib
(Jan 2006)2
High dose interleukin-2
Temsirolimus
(May 2007)3
Sorafenib
(Dec 2005)1
1992
2005
1. US FDA. Sorafenib. 2005.
2. US FDA. Sunitinib malate. 2006.
3. US FDA. Temsirolimus. 2007.
4. US FDA. Everolimus. 2009.
5. US FDA. Bevacizumab. 2009.
6. US FDA. Pazopanib. 2009.
7. US FDA. Axitinib. 2012.
2006
Bevacizumab + IFN-α
(Jul 2009)5
Everolimus
(Mar 2009)4
2007
2009
Axitinib
(Jan 2012)7
2012
RCC Treatment Algorithm: 2014 *
Regimen
Setting
Therapy
MSK Risk : Good or Intermediate
Treatment Naïve
Patient
MSK Risk :
MSK
Ri k
Poor
Treatment
Refractory
Patient
( 2ndd Line)
(≥
i )
Cytokine C
t ki
Refractory
Refractory to Refractory
to
VEGF/VEGFR or mTOR Inhibitors
*Adapted from M Atkins, ASCO 2006
Sunitinib
Bevacizumab ± IFNα
Pazopanib
TTemsirolimus
i li
Sunitinib
Options
HD IL-2
? Sorafenib
?Sorafenib
Sorafenib
Sunitinib
Pazopanib
Axitinib
Everolimus
Axitinib
?Sequential ?Sequential
TKI’s or VEGFInhibitor
Non clear cell: Temsirolimus
Mechanisms of Therapeutic Effect and
Angiogenic Escape
Rini, B Clin Cancer Res, 2010
What is the proper integration of
surgery and systemic therapy in
the setting of advanced
disease?
62 y/o WM with hematuria
•
•
•
•
•
•
PMH: DM, Htn
PSH: Appy,
Appy Knee surgery
SH: Denies Tobacco/ETOH use
PE: unremarkable
PS = 1
CT abdomen
• Locally advanced right renal mass
• CT chest
• Bilateral pulmonary nodules
•
•
•
•
Hb 9.8
LDH 1000
All other labs WNL
Bone scan/MRI brain negative for mets
• Patient undergoes cytoreductive
p
y
nephrectomy
• T3aN0M1 Clear cell RCC, FG 4
• Follow
Follow-up
up scans at 6 weeks show modest
progression of pulmonary metastases
• Started on Sunitinib 4 weeks/2 weeks 50
g
mg
• Required dose reduction at 6 months to
37 5 mg due to toxicity
37.5
• Disease progression at 14 months out
g y
from surgery
• Changed to everolimus
• Currently
C
tl stable
t bl di
disease 2 years outt ffrom
surgery
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
and anemia
and anemia
and anemia
• Undergoes right radical nephrectomy with
RPLND. Mass noted in right fallopian tube
(metastatic renal cell carcinoma)
• T3aN1M1 ccRCC with 30 – 40%
sarcomatoid
t id and
d rhabdoid
h bd id features,
f t
FG 4
• 3/10 LN’s positive
p
• All surgical margins negative
and anemia
• Returns 1 month later, PS = 4
• Admitted through the emergency center
for failure to thrive
• Hb 8.2,
8 2 LDH 1094
1094, C
Ca2+ 12.3,
12 3 eGFR
GFR 33
and anemia
and anemia
and anemia
• Patient never received therapy due to poor
performance status
p
• Died of disease 45 days after surgery
Is there still a role for
cytoreductive
d i surgery in
i the
h
setting of metastatic disease?
Metastatic RCC
Nephrectomy & Immunotherapy
100
UCLA 1989-1999
% Surv
vival
75
50
Nx + IMT
25
NX
P<0.05
IMT
12
24
0
0
36
48
60
72
84
96
Months
J UROL 166: 1611, 2001
Effect of Nephrectomy on Survival
in Metastatic RCC
Radical Nephrectomy + IFN-
Patients with
metastatic
t t ti RCC
with PS 00-1
(SWOG,
(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.
Role of Cytoreductive Nephrectomy in the
Setting of Metastatic Disease: EORTC 30947
Time to Progression
Overall Survival
IFN + Nx 5 CR, 3 PR (19%)
IFN 1CR, 4 PR (12%)
Mickisch G et al. Lancet, 2001
Role of Cytoreductive Nephrectomy in the Setting
of Metastatic Disease: SWOG 8949
IFN + Nx 3 PR (3%)
IFN 1 CR, 2 PR (4%)
Flanigan R et al., NEJM, 2001
2001 SWOG vs. UCLA
.
Retrospective
100
P<0.05
S
Surviv
val
80
60
40
Nx + IL-2
20
IFN
Nx + IFN
0
0
Pantuck et al; NEJM, 2001
24
48
Months
72
96
RCC Treatment Algorithm: 2014 *
Regimen
Setting
Therapy
MSK Risk : Good or Intermediate
Treatment Naïve
Patient
MSK Risk :
MSK
Ri k
Poor
Treatment
Refractory
Patient
( 2ndd Line)
(≥
i )
Cytokine C
t ki
Refractory
Refractory to Refractory
to
VEGF/VEGFR or mTOR Inhibitors
*Adapted from M Atkins, ASCO 2006
Sunitinib
Bevacizumab ± IFNα
Pazopanib
TTemsirolimus
i li
Sunitinib
Options
HD IL-2
? Sorafenib
?Sorafenib
Sorafenib
Sunitinib
Pazopanib
Axitinib
Everolimus
Axitinib
?Sequential ?Sequential
TKI’s or VEGFInhibitor
Non clear cell: Temsirolimus
Cytoreductive Nephrectomy
Utilization
Tsao CK et. al., Clinical GU Cancer, 2011
How Does It Work?
• Reduction in major portion of tumor burden
• Immunologic: Surgery induces exposure of new
“t
“tumor
antigens”
ti
” or removall off immunologic
i
l 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
Arguments
g
Against
g
Cytoreductive
y
Nephrectomy
p
y
• Surgical morbidity/mortality significant
• Only proven benefit in combination with IFN (an
“inferior” therapy)
py)
• Spend majority of time left on this earth recovering
from surgery
• Significant disease progression or morbidity during
post operative recovery period may preclude
post-operative
systemic therapy
• Newer therapies may result in primary tumor
regression
Phase 3 Randomized Study Comparing Nephrectomy plus
Sunitinib versus Sunitinib without Nephrectomy in 1st line
Metastatic RCC
Nephrectomy
Sunitinib 50 mg 4/2
Randomization
N = 576
Sunitinib 50 mg 4/2
- Primary Objective:
- To
T show
h
th t Sunitinib
that
S iti ib alone
l
i nott inferior
is
i f i to
t Nephrectomy
N h
t
plus
l
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)
Sunitinib in Patient With or Without Prior
Nephrectomy in an Expanded Access Trial
of mRCC: Response
Response, n (%)
Patients with prior
Nx (n
(n=3014*)
3014 )
Patients without
prior Nx (N
(N=192)*
192)
538 (18)
31 ((1))
507 (17)
17 (9)
0
17 (9)
Stable disease
>3 months
1764 (59)
118 (61)
Clinical benefit†
2302 (76)
135 (70)
Objective response rate
Complete
p
response
p
Partial response
Nx=nephrectomy
*Only patients with evaluable efficacy data included
†Clinical benefit=ORR + SD ≥ 3 months
Szczylik et al. ASCO 2008. Abstract 5124
PFS probaability
Sunitinib in Patients With or Without Prior Nephrectomy in an
Expanded Access Trial of mRCC: PFS (No Prior Cytokine
Treatment)
1.0
Patients with prior nephrectomy (n=1020)
Median = 12.0 mo
(95% CI, 10.9-13.4)
0.8
Patients without prior nephrectomy (n
(n=146)
146)
Median = 6.5 mo
(95% CI, 5.4-10.2)
0.6
P=0.0021
0.4
0.2
0
0
5
10
15
20
Months
mRCC = metastatic renal cell carcinoma; PFS = progression‐free survival
Szczylik et al. ASCO, 2008. Abstract 5124.
25
30
OSS probability
Sunitinib in Patients With or Without Prior
Nephrectomy in an Expanded Access Trial of
mRCC: OS (No Prior Cytokine Treatment)
1.0
Patients with prior nephrectomy (n=1020)
Median = 19.0 mo
(95% CI, 18.2-21.4)
0.8
Patients without prior nephrectomy (n=146)
Median = 11.1 mo
(95% CI, 8.4-15.1)
P<0.0001
06
0.6
0.4
0.2
0
0
5
10
15
Months
OS = overall survival
Szczylik et al. ASCO, 2008. Abstract 5124.
20
25
30
Cytoreductive Nephrectomy In The Era of
Targeted Therapy: What do we do until the
prospective trials are completed?
KPS ≥ 80
KPS < 80
Yes= 201 No = 113
Choueiri, T et al., J Urol, 2011
Targeted Therapy (SEER 2005 – 2009)
Culp and Wood, Submitted
Cytoreductive Surgery For Metastatic
R
Renal
lC
Cellll C
Carcinoma:
i
It’s Not For Everyone!
Patient Selection Is CRITICAL!!!!!
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
p
rate 39%
• Response
» 18% CR
» 21% PR
• Median survival: 20.5 months
• Systemic therapy: IL-2
J Urol, 1997
Identifying Patients who will Not Benefit from
Cytoreductive Nephrectomy: MDACC
• 566 pts undergoing CN between 1991 and 2007
• 110 p
pts undergoing
g g medical therapy
py only
y
• Compared survival between groups and identified when
survival diverged between surgical and non-surgical
non surgical
groups
• Identified pre
pre-operative
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
Surgery vs
vs. No Surgery
Overall Survival
Overall Survival Based on Overall
Survival Based on
Follow‐up of 8.5 months
Pre operative Risk Factors
Pre-operative
•
•
•
•
•
•
•
Serum albumin < lower limit of normal
pp limit of normal
Serum LDH > upper
Liver metastasis
Symptoms at presentation due to metastasis
Retroperitoneal lymph node involvement
Supra-diaphragmatic lymph node involvement
Clinical T stage 3 or 4
Pre operative Assessment
Pre-operative
HR (95% CI)
P
Median Survival
(mos)
Referent
--
9.6
0
0.21 (0.15, 0.30)
<0.001
40.6
1
0.33 (0.25, 0.57)
<0.001
27.9
2
0.44 (0.34, 0.57)
<0.001
21.3
3
0.64 (0.48, 0.84)
0.002
12.8
4
0 77 (0
0.77
(0.54,
54 1
1.09)
09)
0 137
0.137
13 8
13.8
5
1.57 (0.88, 2.80)
0.124
7.5
6
0.99 (0.24, 4.00)
0.983
4.3
Medical Therapy
Only
CN - # of risk factors
Pre-operative
HR (95% CI)
P
Median Survival
(mos)
Referent
--
9.6
0
0.21 (0.15, 0.30)
<0.001
40.6
1
0.33 (0.25, 0.57)
<0.001
27.9
2
0.44 (0.34, 0.57)
<0.001
21.3
3
0.64 (0.48, 0.84)
0.002
12.8
4
0 77 (0
0.77
(0.54,
54 1
1.09)
09)
0 137
0.137
13 8
13.8
5
1.57 (0.88, 2.80)
0.124
7.5
6
0.99 (0.24, 4.00)
0.983
4.3
Medical Therapy
Only
CN - # of risk factors
Pre-operative
Targeted Therapy (SEER 2005 – 2009)
Predictive Clinical Factors
1.
2.
3.
4.
5.
Size > 7 cm
cT3 or cT4 Stage
High grade (3 or 4)
Clinically + LN’s
Sarcomatoid Histology
Culp and Wood, Submitted
Can we do better?
Is the relevant question whether or not
surgery should be incorporated into the
management of locally advanced/metastatic
renal cell carcinoma?
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”
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
py may
y alter biology
gy
of metastatic disease
adversely
VEGF rebound may
actually cause rapid
disease progression
Bevacizumab Presurgical Trial
M
Metastatic
i di
disease, no prior
i nephrectomy
h
or therapy
h
Bevacizumab
B
i
b
10 mg/kg IV
Q14 days
Opened 4/05
Accrual to date: 50
Response
Or Stable
Nephrectomy,
Nephrectomy
Continue
Bevacizumab
Progressive,
Good PS
Nephrectomy,
New Chemo
Progressive,
Poor PS
New Chemo,
or Best
B t
Supportive Care
50 patients
Clear Cell Histology
Jonasch E et al., JCO, 2009
Sunitinib Presurgical Trial
Metastatic disease, no prior
nephrectomy or therapy
Sunitinib 50mg
By mouth
2 Courses
Nephrectomy Mid
2nd Course
June 2008
50 patients
Clear Cell Histology
Stable/Respond:
Continue
Sunitinib
Rules of the Game in RCC
Surgical Therapy
Advances
1. Oncologic equipoise
2. Nephron sparing
3 Minimally invasive
3.
Neoadjuvant Therapy
Advances
1. Safety (Lack of disease
progression/increased
surgical morbidity)
2 IImproved
2.
d patient
ti t
outcomes (DFS/CSS)
3. Primary tumor
downstaging/downsizing
Is Neoadjuvant Therapy Safe?
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
Complications from cytoreductive nephrectomy
by timing of nephrectomy.
Event
Any Complication
(by patient)
Clavien > 3
(by event)
Complication
p
> 90 days
y
(by event)
>1 Complications
(by event)
Wound Complications+
Superficial Wound
Dehiscence
Wound Infection
All Patients
(n=173)
No. (%)
Immediate CN
(n=103)
Pre-surgical
Therapy (n=73)
p-value
99 (57.2)
(57 2)
53 (53.4)
(53 4)
39 (55.7)
(55 7)
0 085
0.085
69 (29.7)
32 (30.2.)
37 (29.4)
0.999
24 (10.3)
(10 3)
4 (3.8)
(3 8)
20 (15.9)
(15 9)
0 002
0.002
62 (62.6)
27 (50.9)
35 (76.1)
0.013
27 (15.6)
8 (7.8)
19 (27.1)
<0.001
23 (13.3)
6 (5.8)
17 (24.3)
<0.001
12 (6.9)
3 (2.9)
9 (12.9)
0.015
Fascial Dehiscence
2 (1.2)
0 (0)
2 (2.9)
0.162
Incisional Hernia
3 (1.7)
0 (0)
3 (4.3)
0.065
DVT
7 (4)
2 (1.9)
5 (7.1)
0.121
PE
13 (7.5)
6 (5.8)
7 (10)
0.382
+Wound Complications = Superficial wound dehiscence, wound infection and fascial
dehiscence
Predictors of Wound Complications After
Cytoreductive Nephrectomy
Characteristic
Univariable
Odds Ratio (95% CI)
Pre-surgical Targeted
Therapy*
BMI ≥ 30*
Diabetic*
Smoker*
Duration of surgery* (per
minute increase)
Clinical N1 or N2*
* included in multivariate analysis
Multivariate
p-value
Odds Ratio (95% CI)
p-value
4.42 (1.8-10.8)
<0.001
4.14 (1.6-10.6)
0.003
2.46 (1.1-5.7)
1.35 (0.5-4.0)
1.03 (0.4-3.0)
0.035
0.564
0.999
2.44 (0.96-6.2)
1.00 (0.3-3.3)
0.73 (0.2-2.3)
0.060
0.999
0.597
1 00 (1.0-1.0)
1.00
(1 0-1 0)
0 361
0.361
1 00 (1.00-1.00)
1.00
(1 00-1 00)
0 929
0.929
1.84 (0.8-4.2)
0.190
1.31 (0.5-3.3)
0.563
Predictors of Overall Post-operative
Complications After Cytoreductive
N h t
Nephrectomy
Analysis of Preoperative and Post-operative Characteristics by risk of overall complications for all patients
undergoing
d
i cytoreductive
t d ti nephrectomy.
h t
Characteristic
ECOG≥2*
Clinical N1 or N2*
Clinical T3 or T4*
Pre-surgical Targeted Therapy*
BMI ≥ 30
Univariable
Odds Ratio ((95% CI))
9.1 (1.2-72.3)
2.5 (1.3-4.8)
2 0 (1.1-3.8)
2.0
(1 1 3 8)
1.8 (0.97-3.4)
1.5 (0.8-2.9)
Multivariate
p
p-value
0.036
0.007
0 023
0.023
0.064
0.222
Odds Ratio ((95% CI))
9.0 (1.1-74.6)
1.83 (0.96-3.5)
8 95 (1.1-79.6)
8.95
(1 1 79 6)
1.50 (0.77-2.9)
p
p-value
0.003
0.068
0 042
0.042
0.237
Predictors of Overall Complications in Patients
Receiving Pre-Surgical Targeted Therapy
Ch
Characteristic
i i
Decline in Serum Albumin*
BMI ≥ 30*
Clinical T3 or T4*
ECOG ≥ 2*
Charlson
h l ≥8
Received bevacizumab
Univariable
Odds Ratio (95% CI)
4.3 (1.3-14.1)
3 8 (1.1-13.0)
3.8
(1 1 13 0)
2.7 (0.9-7.4)
3.5 (0.4-30.5)
1.3 (0.4-4.0)
(
)
1.4 (0.5-4.1)
Multivariate
p-value
0.015
0 031
0.031
0.063
0.265
0.633
0.515
Odds Ratio (95% CI)
4.20 (1.3-14.1)
2 35 (0.6-8.9)
2.35
(0 6 8 9)
1.74 (0.5-5.5)
2.59 (0.3-26.2)
p-value
0.021
0 208
0.208
0.352
0.420
Predictors of Overall Survival
Characteristic
Univariable
Odds Ratio (95% CI)
Pre-surgical Targeted
0.96 (0.67-1.37)
Therapy*
T-Stage 3 or 4*
1.97 (1.13-3.44)
P th l i Node
Pathologic
N d Positive*
P iti *
2 53 (1.64-3.90)
2.53
(1 64 3 90)
Sarcomatoid Histology*
2.53 (1.64-3.90)
Post-operative
2.23(1.54-3.23)
Complication*
Complication
ECOG>1 (at presentation)
0.87
Multivariate
p-value
Odds Ratio (95% CI)
p-value
0.818
0.71 (0.46-1.10)
0.125
<0.001
<0.001
0 001
<0.001
2.05 (0.98-4.31)
2 42 (1.25-3.26)
2.42
(1 25 3 26)
2.09 (1.26-3.48)
0.058
<0.001
0 001
0.004
<0.001
2.02 (1.25-3.26)
0.004
0.718
Accelerated Metastasis after Short-Term
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
p
of Medical Biophysics,
p y
University
y 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
Neoadjuvant Therapy: Axitinib
81 y/o WM s/p 12 weeks Axitinib
Bilateral T1b Gr 2
What about primary tumor
downstaging/sizing?
Results of Therapy with
Primary Tumor in Place
Institution
Number
Response
of
Rate
patients
Response
in
Primary
Tumor
Median
Survival
(mos)
NCI
51
6%
0%
13
Netherlands
Cancer
Institute
16
12.5%
0%
3
Presurgical targeted therapy
63 yo male treated with sunitinib prior to nephrectomy
Are These
A
Th
Anecdotes
A
d t Or
O Can
C We
W
Rely On These Agents To Reliably
Downstage Tumors?
Response of Primary Tumor Sunitinib
17 Evaluable Patients
4 PR
12 SD
1 PD
Response Rate in
Primary Tumor: 23%
Mean Volume
Reduction: 31%
Van der Veldt et al., CCR, 2008
Response of Primary Tumor Sunitinib
Thomas AA et al., J Urol 2009
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
11-20%
hi k
7
(16)
20-30% shrinkage
3
(7)
Jonasch E et al., JCO, 2009
Pre-surgical Sorafenib
*4 patients downstaged from T2 to T1
*2 patients with RV thrombus on imaging were neg. on path
*Median
Median tumor shrinkage 9.6%
tumor shrinkage 9 6%
Cowey et al., JCO, 2010
Patient characteristics
• 168 patients
u o ssize
e9
9.6
6 ccm
• Tumor
• Age 59.1
((1.8 – 22.1))
(18.3-79.8)
• Follow- up 11.6 months
• ECOG PS
– 0-1
123 (73.2)
– 2
29 (16.1)
– 3
16 (9.5)
Abel at al., Eur Urol, 2011
(1.8-60.6)
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
gy in biopsy
p y
30 ((17.9))
Doctor/ patient preference
17 (10.1)
P
Poor
PS/ comorbidities
biditi
16 (9.5)
(9 5)
Unresectable primary
7 (4.2)
Types of targeted therapy
RESULTS
N
%
sunitinib
75
44.6
bevicizumab
25
14.9
bevicizumab/
erlotinib
26
15.5
sorafenib
f
16
9
9.5
temsirolimus
16
9.5
bevicizumab/
chemo
7
4.2
erlotinib
2
1.2
pazopanib
1
0.6
Total
168
100
Sunitinib
Bevacizumab + Erlotinib
Temsirolimus
Erlotinib
Bevacizumab
Sorafenib
Bevacizumab + Chemo
Pazopanib
Maximum overall response in primary tumor
Median -7.1%
Impact of Pre-Surgical
Pre Surgical Targeted
Therapy On Venous Tumor Thrombus
Delacroix S et al., ASCO GU 2011
Clinically meaningful
changes occurred in
25% of p
patients ((12/48))
table 3
•Stable Disease in
75% 36/48
•Progression occurred
in 14.5%
% ((7/48)
/ )
•Regression in
10 4% (5/48)
10.4%
(5/48).
No Cases of
P l
Pulmonary
Embolism
Delacroix S et al., ASCO GU 2011
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
i still
is
till outt with
ith regards
d to
t the
th newer
generation of agents
g
g
in the p
pipeline.
p
Presurgical/Neoadjuvant Therapy
1. Is it safe? 
2. Does it reliably downsize/downstage
tumors? 
3. Is this treatment p
paradigm
g an advancement
in the care of patients?
Presurgical
g
Bevacizumab Therapy
y
• 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. 2009.
Is an Early Minor (>=10%)
( 10%)
Primary Tumor Response
Associated with Overall Survival?
• OBJECTIVE: to evaluate whether an early minor PT
response was associated
i t d with
ith improved
i
d overall
ll
survival in patients undergoing treatment with
sunitinib
Abel et al., Eur Urol, 2011
Maximum rate of decrease is early in
therapy
10
0
0
50
100
150
200
250
300
350
400
450
500
Pe
ercent R
Respons
se
-10
-20
-30
-40
-50
-60
Days of Treatment
Early response associated with higher
maximum primary tumor response
Patients with Multiple
Imaging Points
Maximum response
(
(range)
)
Time to maximum
response (days)
(range)
≥10% response iin 1st
60 days
(N=18)
<10% response iin 1st
60 days
(N=43)
-24.5 %
-7.2 %
(-53.4, -14.3)
(-33.8, 9.8)
175
154
(54, 839)
(37, 531)
Abel EJ, Culp SH et al. Eur Urol. 2011
Study Population
• 75 patients treated with sunitinib for
primary
y tumor in p
place
metastatic RCC with p
• Median follow-up of 15 mos (IQR: 7.5, 30.2)
• Median treatment time of 160 days (IQR:
83 260)
83,
Significant predictors of overall survival from
univariable analysis
HR
95% CI
<10%
Referent
.
≥ 10% and > 60 days
0.48
0.25, 0.91
≥ 10% and ≤ 60 days
0.26
0.08, 0.82
Venous thrombus
1 44
1.44
1 20 1
1.20,
1.73
73
Radiographic retroperitoneal lymphadenopathy
1.97
1.09, 3.59
Local symptoms at presentation
2.08
1.15, 3.77
ECOG performance status >=2
2.11
1.11, 4.00
Liver metastases
2 23
2.23
1 22 4
1.22,
4.08
08
Multiple bone metastases
2.27
1.20, 4.29
Lactate dehydrogenase > ULN
2.30
1.24, 4.26
Absolute lymphocyte count < LLN
2.63
1.34, 5.14
Number of metastatic sites >2
2.86
1.58, 5.18
PT response (decrease in diameter)
Independent predictors of overall
survival on multivariable analysis
HR
95% CI
0% PT response
espo se in 60 days
days*
≥ 10%
0.26
0
6
0.08,
0
08, 0
0.89
89
Renal vein or IVC thrombus
1.33
1.09, 1.63
Multiple bone metastases
2.05
1.00, 4.21
Lactate dehydrogenase > ULN
2.42
1.26, 4.63
Local symptoms at presentation
3.03
1.57, 5.84
Number of metastatic sites >2
3 28
3.28
1 65 6
1.65,
6.52
52
In targeted therapy: PT response better than
established prognostic criteria at estimating
overall survival
Abel EJ and Culp SH, European Urology December 2011
Phase II Presurgical Sunitinib: Response in
Primary Tumor Predicts Survival
2 cycles of Sunitinib
N = 22
Bex A, et al., Urology 2011
Cytoreductive Nephrectomy For
Metastatic Renal Cell Carcinoma in
The Era of Targeted Therapy:
Not a question of “if” but “when”?
Timing Of Cytoreductive Nephrectomy In
Metastatic Renal Cell Carcinoma
Untreated
Metastatic
Renal Cell
Carcinoma
With Primary
y
Tumor In
Place (PS 01, Surgical
Candidate)
Cytoreductive
C
t
d ti
Nephrectomy
Biopsy To
Establish Clear
Cell Histology;
Lack of Sarcomatoid
Non Clear Cell Histology;
Sarcomatoid Managed By
Standard of Care or Other
Clinical Protocol
Sunitinib
S
iti ib
4/2
Primary: PFS
Secondary: OS,
Response Rate
Rate, Surgical
morbidity/mortality
Sunitinib
4/2 X 2
cycles
l
Cytoreductive
Nephrectomy
A. Bex, EORTC
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
p
responses,
p
, surgery
g y remains integral
g
part of multi-disciplinary approach in metastatic disease
• Control of primary tumor
• Metastasectomy
• Reliable complete responses with any agent will force
re-examination
i ti off currentt paradigm
di
• Presurgical approach may have merit but needs further
study and validation
• Not clear when it is most appropriate to integrate surgery

Integration of Surgery And Systemic g g y y Therapy In The

Transcription

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