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“Continuum of care” en cáncer de colon metastásico no curableMauricio Lema Medina MDClínica de Oncología Astorga – Clínica SOMA – MedicáncerMedellín, Colombia
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QuimioterapiaA qué llegamos?
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Fluoropirimidines en mCRC
No cambio en la supervivencia mediana con diferentes esquemas
– Supervivencia mediana: ~ 12 meses
Regimen Respuesta, %5-FU en bolo 7-15
5-FU en infusión 20-30
5-FU/LV
Mayo, Roswell Park
de Gramont (LV5-FU2)
AIO (cada semana, 24-hour infusion)
12-35
28-33
25-44
Capecitabina 20-25
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
www.clinicaloptions.com
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IFL(n=264)
RFOLFOX
(n=267)
IROX(n=264)
diseño
n=795
Primary endpoint: PFS
IFL vs FOLFOX vs IROX (N9741)
Bolo (IFL) vs infusión (FOLFOX)
Goldberg et al, JCO 2004Goldberg et al, JCO 2004
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Page 5 N9741: Sanoff HK. J Clin Oncol 26:5721-5727.
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IFL FOLFOX IROX
n 264 267 264
RR (%) 31 45 35
PFS (m) 6.9 8.7 6.5
OS (m) 15 19.5 17.4
p 0.0001
N9741Resultados
Goldberg et al, JCO 2004Goldberg et al, JCO 2004
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FOLFIRI(n=144)
RmIFL
(n=141)
XELIRI(n=145)
Feb 2003 – April 2004
Initial design
n=430
Primary endpoint: PFS
Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design
* Celecoxib data not shown* Celecoxib data not shownFuchs et al, JCO 2008Fuchs et al, JCO 2008
Courtesy of: Paulo Hoff
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BICC-C Study: FOLFIRI vs mIFL vs CapeIRI
Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.
0 10 20 30
25
50
75
100
040
Months
Pro
gre
ssio
n F
ree
(%)
FOLFIRI vs mIFL: P = .004FOLFIRI vs Capelri: P = .015mIFL vs Capelri: P = .46
FOLFIRImIFLCapelri
FOLFIRI vs mIFL: P = .09FOLFIRI vs Capelri: P = .27mIFL vs Capelri: P = .93
0 10 20 30
25
50
75
100
040
Months
Aliv
e (%
) FOLFIRImIFLCapelri
50
Progression-Free Survival Overall Survival
Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786. Reprinted with permission from the American Society of Clinical Oncology.
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Access to Chemotherapy Improves Survival
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
22
20
18
16
14
12
Med
ian
OS
(M
os)
0 20 40 60 80
Patients With 3 Drugs (%)
LV5FU2
Bolus 5-FU/LV
Infusional 5-FU/LV+ irinotecanInfusional 5-FU/LV+ oxaliplatinBolus 5-FU/LV+ irinotecanIrinotecan+ oxaliplatin
First-line therapy
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Efficacy: Sequence FOLFIRI/FOLFOX
No statistically significant differences in first- or second-line therapy RR or TTP and OS
Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
ResultsArm A Arm B
FOLFIRI FOLFOX FOLFOX FOLFIRI
Patients, n 109 81 111 69
Confirmed RR, % 56 15 54 4
TTP, mos 8.5 4.2 8.0 2.5
Survival, mos 21.5 20.6
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FOLFOXIRI vs FOLFIRI: Trial Design
Patients with unresectable, previously untreated metastatic colorectal cancer
(N = 244)
Falcone A, et al. ASCO 2006. Abstract 3513.
Primary endpoint: RRStratification: study center, PS (0/1-2), adjuvant chemotherapy
FOLFOXIRIIrinotecan 165 mg/m2 Day 1Oxaliplatin 85 mg/m2 Day 1LV 200 mg/m2 over 2 hours Day 15-FU 3200 mg/m2 48-hour infusion Days 2, 3Every 2 wks
(n = 122)
FOLFIRIIrinotecan 180 mg/m2 Day 1LV 100 mg/m2 over 2 hours Days 1, 25-FU 400 mg/m2 bolus, then 600 mg/m2 22-hour infusion Days 1, 2Every 2 wks
(n = 122)
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FOLFOXIRI vs FOLFIRI: Efficacy and Tolerability
FOLFOXIRI, %(n = 122)
FOLFIRI, %(n = 122)
P Value
RR
Complete 7 6< .0001*
Partial 53 28
Stable disease 21 34 --
Median PFS, mos 9.8 6.9 .0006
Median OS, mos 22.8 16.7 .032
Grade 3/4 toxicity
Neutropenia 50 28 .0008
Neurotoxicity† 20 0 < .0001
Diarrhea 20 12 .08
Falcone A, et al. ASCO 2006. Abstract 3513.
*External review; 95% CI for overall response: 0.25-0.43 for FOLFIRI, 0.51-0.68 for FOLFOXIRI.†Includes grade 2 events.
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Quimioterapia más Bevacizumab
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Adapted from Folkman. Cancer.Principles and practice of oncology 2005
VEGF es expresado durante toda la historia natural
bFGF = basic fibroblast growth factorTGF-1 = transforming growth factor -1PIGF = placenta growth factor PD-ECGF = platelet-derived endothelial cell growth factor
PIGFPD-ECGF
Pleiotrophin
bFGFTGF-1
bFGFTGF-1bFGF
Evolución tumoral
TGF-1 PIGF PIGFPD-ECGF
bFGFTGF-1
VEGF VEGF VEGF VEGF VEGF
www.clinicaloptions.com
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Bevacizumab (Avastin®): Mecanismo de Acción
PP
PP
VEGFBevacizumab
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VEGFBevacizumab
PP
PP
BLOQUEO de la activación del VEGFR
Bevacizumab (Avastin®): Mecanismo de Acción
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Phase III Trial With Bevacizumab Therapy in First-Line MCRC
Bolus IFL + BVBolus IFL + BV(n = 403)(n = 403)
5-FU/LV + BV5-FU/LV + BV(n = 110):(n = 110):
Closed due to lack of Closed due to lack of efficacyefficacy
Bolus IFL + placeboBolus IFL + placebo(n = 412)(n = 412)
Hurwitz. NEJM, 2004
RR
AA
NN
DD
OO
MM
II
ZZ
EE
UntreatedUntreatedMCRCMCRC
Courtesy of: Paulo Hoff
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Median PFS (months)IFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + bevacizumab: 10.6 (95% CI: 9.0–1.0)HR=0.54 (95% CI: 0.45–0.66) p<0.001
Pro
bab
ilit
y o
f b
ein
g p
rog
ress
ion
-fre
e 1.0
0.8
0.6
0.4
0.2
00 10 20 30
PFS (months)
6.2 10.6
IFL + bevacizumab
IFL + placebo
Phase III Trial : PFS
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Courtesy of: Paulo Hoff
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Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81) p<0.001
Pro
bab
ilit
y o
f su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40
Survival (months)
IFL + bevacizumab
IFL + placebo
15.6 20.3
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Phase III Trial: Survival
Courtesy of: Paulo Hoff
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FOLFIRI(n=144)
RmIFL
(n=141)
XELIRI(n=145)
Feb 2003 – April 2004
Initial design
n=430
FOLFIRI+Bev.
mIFL+Bev.
(n=60)
(n=57)
May 2004 – Dec 2004n=117
Primary endpoint: PFS
Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design
Protocol amended due
to approval of bevacizumab
Amended design
R
* Celecoxib data not shown* Celecoxib data not shownFuchs et al, JCO 2008Fuchs et al, JCO 2008
Courtesy of: Paulo Hoff
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Overall Survival
Survival Time (months)
RegimenMedian OS (months) 1 Year P Value
FOLFIRI+ BEV 28 87% --
mIFL + BEV 19.2 61% 0.01
Pro
po
rtio
n o
f S
ub
ject
s W
ho
Su
rviv
ed
FOLFIRI + Bevacizumab
mIFL + Bevacizumab
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 4030
Fuchs et al. JCO 2008Courtesy of: Paulo Hoff
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Phase III Trial of Bevacizumab + Panitumumab-CT With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008
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Impact of bevacizumab on OS in mCRC: a population-based study
Renouf, et al. ASCO GI 2009
Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab) versus 2006 (post-bevacizumab)
Proportion of patients receiving
Addition of bevacizumab to systemic chemotherapy significantly improved OS:
23.6 vs 18.6 months (p<0.001)
Irinotecan or oxaliplatin and 5-FU:
no change (p=0.68)
Anti-EGFR therapy:
no change (p=0.63)
Bevacizumabtherapy:
increased 5.9% vs 30.6%
(p<0.001)
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Est
ima
ted
pro
ba
bilit
y
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24
Bevacizumab era (2006)30.6% received bevacizumab
Pre-bevacizumab (2003–2004)5.9% received bevacizumab p<0.001
OS (months)
Renouf, et al. ASCO GI 2009
30
Bevacizumab era (2006), n=448Pre-bevacizumab (2003–2004), n=969
Bevacizumab + standard chemotherapy significantly improved OS:
23.6 vs 18.6 months (p<0.001)
Impact of bevacizumab in mCRC: significantly improved OS
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Phase IV BRiTETherapy in First-Line MCRC
Bev + CTBev + CT
EE
NN
RR
OO
LL
LL
UntreatedUntreatedMCRCMCRC
Grothey, et al. JCO 2008
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Phase IV BRiTETherapy in First-Line MCRC
Bev + CTBev + CT
EE
NN
RR
OO
LL
LL
UntreatedUntreatedMCRCMCRC
Grothey, et al. JCO 2008
PFS FOLFIRI + Bev: 10.4 m (n=280)
PFS FOLFOX + Bev: 10 m (n=1092)
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BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death)
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008*Non-randomised, observational trial
OS (months)
12.6 19.9 31.8
Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57)
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
pro
ba
bilit
y
p<0.001
Post-progression therapy
Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531)No treatment (n=253)
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Quimioterapia más cetuximab
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Phase III MRC COIN
XELOX/OxMdG +XELOX/OxMdG +CetuximabCetuximab(n = 815)(n = 815)
XELOX/OxMdG +XELOX/OxMdG +CetuximabCetuximab(n = 815)(n = 815)
IntermitentIntermitent
XELOX/OxMdGXELOX/OxMdG(n = 815)(n = 815)
ESMO, 2009
RR
AA
NN
DD
OO
MM
II
ZZ
EE
UntreatedUntreatedMCRCMCRC
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COIN: K-ras WT OS
1.00
0.75
0.50
0.25
0
Survival probability
Time (months)0 6 12 18 24 30 36 42
No. at riskArm AArm B
367362
316306
250238
154149
8380
4442
1917
13
ITT analysisITT analysis Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + cetuximab)
Arm A Arm B Diff.
Median OS, months
17.9 17.0 –0.92
2-year survival, %
36.1 34.4 -1.66
HR point estimate = 1.03895% CI 0.90–1.20
p=0.68
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1.00
0.75
0.50
0.25
0
Survival probability
COIN: K-ras WT PFS
ITT analysisITT analysis
No. at riskArm A Arm B
0
367361
245249
92103
4142
1822
119
66
10
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + cetuximab)
Arm A Arm B Diff.
Median PFS, months
8.6 8.6 +0.07
HR point estimate = 0.95995% CI 0.84–1.09
p=0.60
6 12 18 24 30 36 42
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COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets
Survival Outcome, Mos
Cetuximab + Chemotherapy
Chemotherapy HR (95% CI) P Value
Wild-type KRAS
Median OS 17.0 17.9 1.038 (0.90-1.20) .68
Median PFS 8.6 8.6 0.959 (0.84-1.09) .60
All wild-type patients
Median OS 19.9 20.1 1.019 (0.86-1.20) .86
Median PFS 9.2 8.8 0.922 (0.80-1.07) .36
Patients with mutated KRAS, NRAS, or BRAF
Median OS 12.7 14.4 1.004 (0.87-1.15) .96
Median PFS 6.3 6.6 1.079 (0.95-1.23) .33
Maughan TS, et al. ASCO 2010. Abstract 3502.
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ITT Survival: WT K-Ras (n=729)
XELOX/OxMdG XELOX/OxMdG +
Cetuximab
HR
(p value)
OS
(months)
17,9 17,0 1,038
(0,68)
2y OS (%) 36,1 34,4
PFS
(months)
8,6 8,6 0,95
(0,60)
ESMO, 2009
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Page 34Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: K-RAS and Response
All patients K-ras WT K-ras MT
FOLFOX/XELOX(n=815)
Cetuximab + FOLFOX/
XELOX(n=815)
FOLFOX/XELOX(n=367)
Cetuximab + FOLFOX/
XELOX(n=362)
FOLFOX/XELOX(n=268)
Cetuximab + FOLFOX/
XELOX(n=297)
Best overall response (%)
51 53 57 64 46 43
Odds ratio 1.08 (p=0.428) OR=1.35 (p=0.049) OR=0.88 (p=0.449)
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NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W)
Nordic FLOX + CetuximabmCRC
Endpoint:• PFSRandomized patients: 571
R
Tveit KM, ESMO 2010
Nordic FLOX stop & go + Cetuximab
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NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W)
Nordic FLOX + CetuximabmCRC
Endpoint:• PFSRandomized patients: 571
R
Tveit KM, ESMO 2010
Nordic FLOX stop & go + Cetuximab
Outcome FLOX F+Cet Stop&Go-Cet
PFS 7.9 8.3 7.3
RR 41% 49% 47%
OS 20.4 19.7 20.3
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TRIALS IN mCRC 1st Line treatmentK-Ras status WT
TRIAL PH PFS OS
CRYSTAL 3
FOLFIRIFOLFIRI+
CETUXIMABP FOLFIRI
FOLFIRI + CETUXIMAB
P
8.4 9.90.001
720 23.5 0.0094
OPUS 2FOLFOX
FOLFOX +CETUXIMAB
P FOLFOXFOLFOX +
CETUXIMABP
7.2 8.3 0.006 18.5 22.8 0.3854
COIN 3
XELOX/FOLFOX
XELOX/FOLFOX+CETUXIMAB
PXELOX/FOLFOX
XELOX/FOLFOX + CETUXIMAB
P
8.6 8.6 0.6 17.9 17 0.68
NORDIC 3FLOX
FLOX + CETUXIMAB
P FLOXFLOX +
CETUXIMABP
7.9 8.3 0.3 20.4 19.7 0.30
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EPIC: Cetuximab + Irinotecan after Fluoropyrimidine + Oxaliplatin failure
Cetuximab 400 mg/m2 initial dose cycle 1, wk 1, 250 mg/m2 weeklyIrinotecan 350 mg/m2 (n=648)
Irinotecan (n=650)
mCRC with progression after
1st line fluoropyirimidine and Oxaliplatin
(n=1298)
Primary endpoint:Overall survival
R
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
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Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
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Cetuximab versus BSC
BSC(285)
Cetuximab + BSC(287)
Jonker et al. NEJM 2007; 357: 2040
R
A
N
D
O
M
I
Z
E
Metastatic colorectal cancer with prior 5-FU, irinotecan and
oxaliplatin(572 pts)
Courtesy of: Paulo Hoff
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NCIC CTG C0.17: Overall Survival in K-ras Wild-Type Patients
HR 0.55 95% CI (0.41,0.74)
Log rank p-value: <0.0001
Study arm MS (months) 95% CI
Cetuximab + BSC 9.5 7.7 – 10.3
BSC alone 4.8 4.2 – 5.5
Karapetis C et al, New Engl J Med 2008
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12 14 16 18
Time from Randomization (Months)
Pro
po
rtio
n A
live
CetuximabBSC
CetuximabBSC
117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3
Courtesy of: Paulo Hoff
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Continuum of care
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OPTIMOX2: Study Design
Patients with metastatic colorectal cancer
(N = 202)
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
Until progressionOPTIMOX1 (n = 100)
OPTIMOX2 (n = 102)
Started before tumor progression reached baseline measurements
Chemotherapy- free interval*
mFOLFOX76 cycles
s5-FU/LV2mFOLFOX76 cycles
mFOLFOX76 cycles
mFOLFOX76 cycles
Primary endpoint: duration of disease control (DDC)
*Median duration: 20 weeks
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OPTIMOX2: DDC and PFS
No difference observed in duration of disease control between study arms
Longer median PFS with OPTIMOX1 regimen
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
Results, mos OPTIMOX1 OPTIMOX2 P Value
DDC 12.9 11.7 .41
Median PFS 8.7 6.9 .009
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Alternating vs Continuous FOLFIRI
Labianca R, et al. ASCO 2006. Abstract 3505.
Evaluation for PD 2 mos from randomization, then every 4 mos thereafterPrimary endpoint: OS
Patients with advanced colorectal cancer without prior chemotherapy in the advanced setting
(N = 331)No treatment2 mos
Continuous FOLFIRIEvery 2 wks for 6 mos(n = 168)
Alternating FOLFIRIEvery 2 wks, 2 mos(n = 163)
Alternating FOLFIRIEvery 2 wks, 2 mos
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Alternating vs Continuous FOLFIRI in Advanced Colorectal Cancer (cont’d)
Labianca R, et al. ASCO 2006. Abstract 3505.
Alternating FOLFIRI not inferior to continuous FOLFIRI in terms of PFS and OS
– Median follow-up: 30 months
Results, mos A-FOLFIRI C-FOLFIRI HR (5% CI)
Median PFS 6.2 6.5 1.01 (0.78-1.27)
Median OS 16.9 17.6 1.03 (0.78-1.35)
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XELOX + Bevacizumab(n = 239)
Bevacizumab(n = 241)
Patients withpreviously
untreated mCRC
(N = 480)
Maintenance cycles administered q3w:Oxaliplatin 130 mg/m2 IV on Day 1Capecitabine 1000 mg/m2 BID PO on Days 1-14Bevacizumab 7.5 mg/kg IV on Day 1
InductionTherapyXELOX +
Bevacizumab6 cycles
Disease progression,
severe toxicity, or consent
withdrawal
Tabernero J, et al. ASCO 2010. Abstract 3501.
MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC
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MACRO: Duration of PFS Comparable Between Bev vs XELOX + Bev No significant difference between treatment arms in any efficacy outcome
Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed
– The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32
Outcome Bevacizumab(n = 241)
XELOX/Bevacizumab
(n = 239)
HR(95% CI)
OR(95% CI)
Median PFS,* mos 9.7 10.4 1.11(0.89-1.37)
--
Median OS,* mos 21.7 23.4 1.04(0.81-1.32)
--
Confirmed objective response, %
49 46 -- 0.89(0.62-1.27)
*Median follow-up: 20.4-21.1 mos.
Tabernero J, et al. ASCO 2010. Abstract 3501.
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BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death)
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008*Non-randomised, observational trial
OS (months)
12.6 19.9 31.8
Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57)
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
pro
ba
bilit
y
p<0.001
Post-progression therapy
Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531)No treatment (n=253)
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Advanced/mCRC Patients Can Tolerate Intensive Therapy
Primera línea Segunda línea Tercera línea
FOLFOX ± bevacizumab CapeOx ± bevacizumab FOLFIRI + bevacizumab FOLFIRI ± cetuximab*
5-FU/leucovorin + bevacizumab
FOLFOXIRI (2B)
FOLFIRI Irinotecan
FOLFOX CapeOx
Irinotecan + cetuximab*†
FOLFOX CapeOx
Irinotecan → Irinotecan + cetuximab*†
Clinical trial BSC
*KRAS no mutado.
NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V1.2010.
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FOLFOX + Bevacizumab
6 meses
“Continuum of care”
Bevacizumab
Hasta progresión1o línea
FOLFIRI + Bevacizumab
6 meses
Fluoruracilo + Bevacizumab
Hasta progresión2o línea
Cetuximab +/-
IrinotecánMitomicina-FU
Hasta progresión≥3o línea
Hasta progresión
Tabernero J, et al. ASCO 2010. Abstract 3501.
Grothey A, et al. JCO Nov 20, 2008:5326-5334
Cunningham D, et al. N Engl J Med 2004;351:337-45.
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Conclusiones
Debe recibir Irinotecán, Oxaliplatino y Fluoruracilo…
Bevacizumab + QT en primera línea metastásica
Cetuximab +/- Irinotecán en última línea
Disminución de intensidad (y toxicidad) es válida (sábados)
Suspender el tratamiento: disminuye la supervivencia (domingos)