tratamiento de cáncer de colon metastásico: de las guías de práctica, genómica a la realidad
TRANSCRIPT
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Tratamiento del cáncer colorectal metastásico: de las guías de práctica clínica, pasando por la genómica y la realidad
Mauricio Lema Medina MDClínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
Cartagena, Colombia09.07.2014
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FULV
Capec
Iri
Bev
Cet
Pan
Regor.
Surgery
Ablative Rx
Ox Aflib. Ramuc.
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FULV BevCapec Bev
FULVCapec
FULV Ox Iri
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FULV Ox Bev Capec Ox Bev
FULV Ox Iri Bev FULV Ox
FULV Iri Bev Capec Iri Bev
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FULV Ox Cet Capec Ox Cet
FULV Iri Iri Cet
FULV Iri Cet Capec Iri Cet
Cet
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FULV Ox Pani Capec Ox Pani
FULV Iri Iri Pani
FULV Iri Pani Capec Iri Pani
Pani
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FULV Ox Aflib Capec Ox Aflib
FULV Iri Iri Aflib
FULV Iri Aflib Capec Iri Aflib
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“Thou shall not use anti EGFR-agents in mutated RAS CRC patients”
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mCRC: ESMO Clinical Practice Guidelines
http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer
Group 0
Group 1
Group 2
Group 3
Resectable R0
Convertible
Unlikely resectable/High tumor burden
Never resectable
Surgery/ +/- Adj CT
Conversion CT/Surgery
Conversion CT/Surgery
Less-toxic CT
Cure
Cure
Long OS
QoL
Criticism: solely based on DISEASE characteristics
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mCRC: ESMO Clinical Practice Guidelines
http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer
Group 0
Group 1
Group 2
Group 3
Resectable R0
Convertible
Unlikely resectable/High tumor burden
Never resectable
Surgery/ +/- Adj CT
Conversion CT/Surgery
Conversion CT/Surgery
Less-toxic CT
FOLFOX
FOLFOXIRI-BevFOLFIRI-Cet
FOLFOX-BevXELOX-BevFOLFOX-CetFOLFIRI-Cet
FP-Bev
Criticism: solely based on DISEASE characteristics
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Do THESE guidelines, guide?
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CAPOX + Bevacizumab
6 meses
“Continuum of care” in mCRC – “blurring line descriptions”
Cape + Bevacizumab
Hasta progresión1o línea
FOLFIRI + Bevacizumab
Oxaliplatino hasta neuropatía
QT + Bevacizumab
Hasta progresión2o línea
Cetuximab +/- Irinotecán
Regorafenib
Hasta progresión≥3o línea (KRAS nativo)
Hasta progresión
CAIRO-3
TML
Cunningham D, et al. N Engl J Med 2004;351:337-45. CORRECT Trial (Van Cutsem 2012)
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In the RAS wt, which first-line agent?
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clinicaloptions.com/oncologyOptimizing Treatment of Metastatic Colorectal Cancer
Mutations in KRAS, NRAS, and BRAF Distribution and Prognostic Significance
BRAF mutation All patientsAny mutationKRAS mutation
KRAS WTAll WT
Mutation Status
0
6
12
Med
ian
PFS
(Mos
)
Arm A Arm B
0
6
12
18
Med
ian
OS
(Mos
)
57 340
268
815
367
289
45 366
297
815
362
2920
10
20
30
40
2-Yr
OS
(%)
Prognostic Effect of Mutational Status
“All WT”n = 581 (44%)
KRAS MTn = 565 (43%)
NRAS MTn = 50 (4%)
BRAF MTn = 102 (8%)
TotalN = 1316 (81%)
554
11
39
102
Population n (%) Arm A Arm B
ITT 1630 815 815
Assessed for mutations 1316 648 668
KRAS mutation NRAS mutation BRAF mutation
565 (43)50 (4)
102 (8)
2681857
2973245
KRAS WT 729 (55) 367 362
KRAS/NRAS/BRAF WT“All WT”
581 (44) 289 292
Maughan TS, et al. ASCO 2010. Abstract 3502.
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clinicaloptions.com/oncologyOptimizing Treatment of Metastatic Colorectal Cancer
Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC
Primary endpoint: OS
Secondary endpoints: ORR, PFS, TTF, duration of response
Patients with mCRC
and KRAS WT (codons 12, 13),
ECOG PS 0/1(N = 1137)
FOLFOX or FOLFIRI + Bevacizumab q2w
(n = 559)
ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..
FOLFOX or FOLFIRI + Cetuximab q1w
(N = 578)
A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009
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clinicaloptions.com/oncologyOptimizing Treatment of Metastatic Colorectal Cancer
CALGB/SWOG 80405: OS in the ITT Population
mOS (95% CI), mosCT + Cetux 29.9 (27.0-32.9)CT + Bev 29.0 (25.7-31.2)
HR 0.925 (0.78-1.09)P = 0.34
Venook AP, et al. ASCO 2014. Abstract LBA3.
012 24 36 48 60 72
Mos
80
100
60
40
0
OS
(%)
20
84
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Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in
patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Alan P. Venook.
Proc ASCO, 2016, 3504.
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Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in
patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Alan P. Venook.
Proc ASCO, 2016, 3504.
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Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in
patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Alan P. Venook.
Proc ASCO, 2016, 3504.
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Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in
patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Alan P. Venook.
Proc ASCO, 2016, 3504.
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Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in
patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Alan P. Venook.
Proc ASCO, 2016, 3504.
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Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in
patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Alan P. Venook.
Proc ASCO, 2016, 3504.
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The relationship between primary tumor sidedness and prognosis in colorectal cancer. Deborah Schrag
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Association of primary (1°) site and molecular features with progression-free survival (PFS) and
overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee
Proc ASCO, 2016, 3505.
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Side Matters. Kimmie Ng
Proc ASCO, 2016, Dicussion..
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What should we do with BRAF mutated mCRC?
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Continuum of care
FULV Ox Bev
What to do in second line?
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III ML18147 (TML): Continuing Bevacizumab Beyond Progression
Standard second-line CT (oxaliplatin or irinotecan based) until PD
(n = 411)
Bevacizumab 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or
irinotecan-based) until PD(n = 409)
Progressive mCRC after BEV + standard first-line CT (either oxaliplatin or
irinotecan based)(n = 820)
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS (≤ 9 vs > 9 mos), time
from last BEV dose (≤ 42 vs > 42 days),ECOG PS at baseline (0/1 vs 2)
Primary endpoint: OS
Secondary endpoints: PFS, ORR, safety
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Continuing Bevacizumab Beyond Progression (TML): OS, PFS
OS
(%)
MosCT (n = 410)BEV + CT (n = 409)
100
80
60
40
20
00 6 12 18 24 30 36 42 48
9.8 mos9.8 mos 11.2 mos11.2 mos
Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062)
Stratified† HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211)
*Primary analysis method. †Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS (≤ 9 mos, > 9 mos), time from last dose of BEV (≤ 42 days, > 42 days), ECOG PS at baseline (0, ≥ 1).
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
100
80
60
40
20
0PF
S (%
)0 6 12 18 24 30 36 42
Mos
Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P < .0001)
Stratified† HR: 0.67 (95% CI: 0.58-0.78; log-rank P < .0001)
4.1
mo
4.1
mo
5.7 mo5.7 mo
Overall Survival Progression-Free Survival
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III VELOUR Study: FOLFIRI ± ziv-Aflibercept as Second-line Therapy in mCRC
Primary endpoint: OS
Secondary endpoints: PFS, ORR, safety, immunogenicity
No correlatives
Patients with mCRC progressing on first-line
oxaliplatin-based chemotherapy*
(planned N = 1226)
FOLFIRI + ziv-Aflibercept 4 mg/kg q2w(n = 612)
FOLFIRI + Placebo q2w(n = 614)
*30% had previous bevacizumab.
Stratified by previous bevacizumab (yes vs no),ECOG PS (0 vs 1 vs 2)
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalTrials.gov. NCT00561470.
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
FOLFIRI ± ziv-Aflibercept as Second-line Therapy in mCRC (VELOUR): OS, PFS
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.
Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032)
Placebo/FOLFIRIMedian: 12.06 mos
Aflibercept/FOLFIRIMedian: 13.50 mos PFS
(%)
100
80
60
40
20
0
Mos0 3 6 9 12 15 18 21 24 27 30
Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P < .0001)
Placebo/FOLFIRIMedian: 4.67 mos
Aflibercept/FOLFIRIMedian: 6.90 mos
Overall Survival Progression-Free Survival
OS
(%)
100
80
60
40
20
0
Mos0 3 6 9 12 15 18 21 24 27 30 33 36 39
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Tabernero J, et al. Eur J Cancer. 2014;50:320-331.
OS
(%)
100
80
60
40
20
0
Mos0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR: 0.862 (95.34% CI: 0.673-1.104)
Placebo/FOLFIRIMedian: 11.7 mos
Aflibercept/FOLFIRIMedian: 12.5 mos
Pts at Risk, n PlaceboAFL
187186
170178
138150
115121
8189
5459
3736
2222
1313
Previous Bevacizumab
OS
(%)
100
80
60
40
20
0
Mos0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR: 0.788 (95.34% CI: 0.699-0.927)
Placebo/FOLFIRIMedian: 12.4 mos
Aflibercept/FOLFIRIMedian: 13.9 mos
Pts at Risk, n PlaceboAFL
427426
403388
347348
286295
205222
139157
94112
6582
3862
No Previous Bevacizumab
2nd-Line FOLFIRI ± ziv-Aflibercept in mCRC (VELOUR): OS by Prior Bevacizumab
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III RAISE Study: Second-Line Ramucirumab/FOLFIRI vs FOLFIRI
Patients with CRC and progression during or within 6
months of first-line bevacizumab,
oxaliplatin, and a fluoropyrimidine
(N = 1072)
Treat until PD or unacceptable
toxicity
Ramucirumab 8 mg/kg +FOLFIRI q2w per cycle
(n = 536)
Placebo +FOLFIRI q2w per cycle
(n = 536)
Stratified by geographic region, KRAS mutation status, TTP after start of first-line therapy
Ramucirumab: anti-VEGFR2 antibody
Primary endpoint: OS
Tabernero J, et al. Lancet Oncol. 2015;16:499-508.
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Ramucirumab + FOLFIRI
Placebo + FOLFIRI
Median OS, mo(95% CI)
13.3(12.4-14.5)
11.7(10.8-12.7)
HR (95% CI) 0.844 (0.73-0.976) (stratified)P Value (log-rank) .0219 (stratified)
Second-Line Ramucirumab/FOLFIRI vs FOLFIRI (RAISE): Overall Survival
Tabernero J, et al. Lancet Oncol. 2015;16:499-508.
497 345 195 78 34 12 0536 421 269 114 53 422 0
486 329 166 66 22 2 1536 400 228 108 44 210 0
Pts at Risk, n
Placebo +
FOLFIRI
Ram + FOLFIRI
Ramucirumab + FOLFIRI Placebo + FOLFIRI
Ove
rall
Surv
ival
0.2
0.4
0.6
0.8
1.0
00 6 12 18 24 30 3633 399 15 21 273 42
Mos
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Inhibition of neoangiogenesis
Inhibition of tumor microenvironment
signalingInhibition of proliferation
Regorafenib: Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways
Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. Mross K, et al. Clin Cancer Res. 2012;18:2658-2667. Strumberg D, et al. Expert Opin Invest Drugs. 2012;21:879-889.
KITPDGFR
RET
PDGFR-βFGFR
VEGFR1-3TIE2
RegorafenibF
Cl
F
F F
OO
O
NH
NH
NH
N
BiochemicalActivity
Regorafenib IC50 Mean ±SD nmol/L (n)
VEGFR1 13 ± 0.4 (2)
Murine VEGFR2 4.2 ± 1.6 (10)
Murine VEGFR3 46 ± 10 (4)
TIE2 311 ± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202 ± 18 (6)
KIT 7 ± 2 (4)
RET 1.5 ± 0.7 (2)
RAF-1 2.5 ± 0.6 (4)
B-RAF 28 ± 10 (6)
B-RAFV600E 19 ± 6 (6)
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III CORRECT: Regorafenib After Failure of Standard Therapy in mCRC
Primary endpoint: overall survival
Prior systemic, anticancer therapies (palliative)
– 1-2 prior lines: 26%
– 3 prior lines: 26%
– ≥ 4 prior lines: 48%
Patients with progression
after all available standard therapy
(N = 760)
Arm A: Regorafenib 160 mg po qd + BSC3 wks on, 1 wk off
(n = 505)
Arm B: Placebo + BSC3 wks on, 1 wk off
(n = 255)
Grothey A, et al. Lancet. 2013;381:303-312.
2:1
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clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Regorafenib After Failure of Standard Therapy in mCRC (CORRECT): OS, PFS
Primary endpoint met prespecified stopping criteria at second interim analysis (1-sided P ≤ .009279 at approximately 74% of events required for final analysis)
100
50
25
0
75
Mos From Randomization
OS
(%)
HR: 0.77 (95% CI: 0.64-0.94;P = .0052)
Regorafenib PlaceboMedian OS, mo 6.4 5.0
IQR 3.6-11.8 2.8-10.4
Placebo (n = 255)Regorafenib (n = 505)
Grothey A, et al. Lancet. 2013;381:303-312.
0 2 4 6 8 10 12 14
Regorafenib PlaceboMedian PFS, mo 1.9 1.7
IQR 1.6-3.9 1.4-1.9
0 2 4 6 8 10 12
Mos From Randomization
100
50
25
0
75
PFS
(%)
Placebo (n = 255)Regorafenib (n = 505)
HR: 0.49 (95% CI: 0.42-0.58; P < .0001 )
Overall Survival Progression-Free Survival
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Continuum of care
FULV Ox Bev
FULV Ox Bev
FULV Bev
FULV Iri Bev Regor.
L
TML
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Continuum of care
FULV Ox Bev
FULV Ox Bev
FULV Bev
FULV Iri Bev Cetuxi.
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Continuum de tratamiento en mCRC no resecableKRAS no mutado
Bev+CAPOX x6Bev+Cap
Bev+CAPOXFOLFIRI+Bev
Cet+/-IriRegorafenib
CAIRO-3 (2013) TML (2012) C0.17 (2008) CORRECT (2012)
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Continuum of care
FULV Ox Bev
FULV Ox Bev
FULV Bev
FULV Iri Bev Regor.
Capecitabina
Capecitabina
Capecitabina
Afliberce
tp
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Continuum of care
FULV Ox Bev
FULV Ox Bev
FULV Bev
FULV Iri Bev Regor.
Capecitabina
Capecitabina
Capecitabina
Afliberce
tp
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Continuum of care
FULV Ox Bev
FULV Ox Bev
FULV Bev
FULV Iri Bev Regor.
Capecitabina
Capecitabina
Capecitabina
Afliberce
tp
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Continuum of care
FULV Ox Bev
FULV Ox Bev
FULV Bev
FULV Iri Bev Regor.
Capecitabina
Capecitabina
Capecitabina
CetuxiCetuxi
Cetuxim
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Continuum of careKRAS mutated
Bev+CAPOX x6Bev+Cap
Bev+CAPOXFOLFIRI+Bev
Regorafenib
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What about patient related issues?
What to do with a patient only able to tolerate some chemo.
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Continuum of careKRAS wt, un-fit
Bev+CapBev+FOLFOX
FOLFIRI+BevCet+/-Iri
RegorafenibAVEX (2013)
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Continuum of careKRAS mutated, un-fit
Bev+CapBev+FOLFOX
FOLFIRI+Bev
Regorafenib
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Let’s go back to curative intent
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Continuum of care
Surgery FULV Ox
FULV Ox Iri Surgery
FULV Iri CetSurgery
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FOLFIRINOX combined to targeted therapy according RAS status for colorectal cancer patients
with liver metastases initially non-resectable: A phase II randomized Study—Prodige 14 – accord 21 (METHEP-2), a unicancer GI trial. Mark Ychou. Proc
ASCO, 2016, Abstract 3512
Proc ASCO, 2016, Discussion.
FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases (RCSM):
Results of the FFCD 1102 phase II trial. JB Bachet. Proc ASCO, 2016, Abstract 3513
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussion.
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Do THESE guidelines, guide?
Maybe, but a more comprehensive strategy NEEDS to be thought –out
BEFORE therapy initiation.
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Conclusions
Clinical presentation
Treatment toolkit
Rules of engagement
What WE desire
Patient preferenceTumor biology
Cost
Patient access
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As of today, clinical practice guidelines for mCRC are but a
repository of treatment options filled with soft statements aimed more to convince insurers rather
than to truly guide clinicians.
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