presentación de powerpoint - doctaforum · t3 t4 a, b % diagnosis of crc 15% 20-30% 30-40% 20-25%...
Post on 07-Jul-2020
5 Views
Preview:
TRANSCRIPT
ESTRATEGIAS DE TRATAMIENTO
ADYUVANTE EN CÁNCER DE COLON
EDUARDO DÍAZ-RUBIO
Hospital Clínico San Carlos
MADRID
21 Junio de 2014
CCR (ESPAÑA)
Todos:
215.534
CCR: 32.240 (15%)
1ª causa
Todos:
102.762
CCR: 14.700 (14%)
2ª causa
Todos:
581.688
CCR: 89.705 (15%)
3ª causa
INCIDENCIA
MORTALIDAD
PREVALENCIA
T1
T2
T3
T4 a, b
% Diagnosis of CRC
15% 20-30% 30-40% 20-25%
% Overall Survival at 5 years
85-95% 60-80% 30-60% <5%
Stage I Stage II Stage III (N+) Stage IV
IIB
IIA
N0,M0 N0, M0 M1
submucosa
muscularis propia
Pericolorectaltissues
T4a: visceral ptT4b: organs o
structures
IIIA:T1-2 N1, T1N2a
IIIB:T3-4 N1,T2-3 N2a
T1-2 N2b
IIIC: T4aN2a, T3-T4N
N1a: 1 N
N1b: 2-3 N
N1c: deposits*
N2a:4-6 N
N2b: >6 N
* subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues
AJCC (version 7) 2010
SEER population
N=109.953
ADJUVANT CT IN CRC (Steps Ahead: 1990-2014)
1990 5FU+Levamisol (Intergrupo)
1994 5FU+Leucovorin (NCCTG,NCIC,NSABP)
2003 CI 5-FU (LV5FU2, PVI5-FU) (André T)
Positive
Positive2003 FOLFOX (MOSAIC)
2005 FLOX (NSABP C-07)
2004 Oral FU (X-ACT: Cape), (NSABP-C-06: UFT)
Positive2009 XELOX (XELOXA)
FOLFOX (NEJM 2004, JCO 2009)
FLOX (JCO 2007, JCO 2011) ??
XELOX (JCO 2011)
ADJUVANT CT IN CRC (Negative results: 1990-2012)
2004 IFL (CALGB C89804)
2005 FOLFIRI (ACCORD-02)
2005 5FU CI+CPT-11 (PETACC3)
Negative
Negative2009 FOLFOX+BV (NSABP-C-08) (AVANT)
2011
Negative2010 FOLFOX+Cxmab (NCCTG-INT)
2012 PETACC-8
NSABP_ C-08: JCO 2011; AVANT: JCO: 2011
NCCTG0147: JAMA 2012; PETACC-8: ESMO 2012
MOSAIC: DFS AND STAGE (JCO 2009)
Stage II (all)*
Stage III
Abs: 3.8%
Rel: 16%
Abs: 7.5%
Rel: 22%
*Stage II High Risk (82.3% vs 74.6% (HR: 0.72) ns
(T4, perforation, obstruction, poorly.diff, venous invasion, <10 LN)
Benefit of Oxaliplatin
Abs: 0.1%
Rel: 0%
Abs: 4.2%
Rel: 20%
Stage II*
Stage III
*Stage II High Risk (85% vs 83.3%) (HR: 0.91, p=.648) ns
(T4, perforation, obstruction, poorly.diff, venous invasion, <10 LN)
MOSAIC: OS AND STAGE
Benefit of Oxaliplatin
Years
No curative CT
Cured with CT
Cured by
surgery alone
TO
XIC
ITY
Background of the studyAdjuvant Chemotherapy in Stage III Colon Cancer
0
20
40
60
80
100
0 1 2 3 4 5
Overall survival
Surgery alone
FU+LV
FOLFOX
50-55%
60-65%
70-75%
Stage III (N+):
Adjuvant Treatment
Surgery 50-55%
5FU+LV 60%
5FU IC 65%
Capecitabine 65%
FOLFOX 75%
FLOX 75%
XELOX 71%
1. Clear Benefit (DFS, OS)
2. All pts in good conditions
should be treated
3. FOLFOX, XELOX or
Capecitabine alone if pts are
not candidates for Ox (elderly)
4. Concern: Toxicity
5. Start: 8-12 w after surgery
6. Duration: 6 months (IDEA study)
IIIA:T1-2 N1
IIIB:T3-4 N1
IIIC: N2 (>3)
N1: 1-3, N2>3
CONCLUSIONS
Stage II (N0M0) IIA=T3, IIB=T4a-b
QUASAR (FU+LV) Yes (OS: 3.6%)
ACCENT DATA BASE Yes (OS:5.4%)
Meta-analysis (IMPACT: FU+LV) Yes
Cochrane systematic review Yes for DFS
MOSAIC (FOLFOX)
NSABP C-07 (FUOX)
No for OX (MOSAIC:
trend for DFS, no for
OS) (NSABP: 2-3% OS)
Expert opinions Yes in high risk
NCCN Guidelines Yes in high risk
Schedules of CT: FU+LV (Cape), FOLFOX,XELOX
Stage II : High Risk(T3-4,N0)
• T4 (IIB/IIC) (organs)
• Intestinal obstruction
• Colon perforation
• Perineural or lymphatic/vascular invasion
• Grade of differentiation G3-G4
• Positive margins
• Inadequate number of LN isolated (<12)
NCCN GUIDELINES 2013 ESMO GUIDELINES
(Ann Oncol 2012)
Copyright © American Society of Clinical Oncology
Andre, T. et al. J Clin Oncol; 27:3109-3116 2009
Fig 5. Proportion of patients treated with oxaliplatin plus fluorouracil and leucovorin with grade 1, 2, or 3 peripheral sensory neuropathy during treatment and after follow-up to 4 years
15,4%
Treatment of CRC in the elderly
>85 years oldThree or more comorbid diseasesOne or more geriatric symptoms:
- dementia - falling tendency- delirium - incontinence- depression - selft-neglect
Balducci L.- Cancer Control 2000
Elderly pts with Frailty
Should patients, according to the age, treated differently?
Sargent (adjuvant meta-analyisis NEJM 2001): similar
En España el 34% de los CCR tienen >80 años
ACCENT DATA BASE (*)
(MOSAIC, NSABP) II and III
YES
MOSAIC YES
X-ACT NO
XELOXA (III) NO
Individualized decision:
ESMO: 1) Single-agent FU is the treatment of choice
2) Ox: pts with good condition and younger biological features
Is the age a limitant factor?
(*): ASCO 2009 (FU IV vs +Iri, Ox, Cape, UFT)
ESMO Consensus Guidelines: Ann Oncol 2012
Elderly: Recent Data
Study Benefit
SEER-Medicare Databases
Hanna NN.- Colorectal Dis 2012
YES for CT >65 y
HR: 0.70
SEER-Medicare-NCCN
Sanoff HK.-JCO 2012
No for Oxaliplatin
NSABPC-07
Yothers G.- JCO 2011
No for Oxaliplatin
MOSAIC
Tournigand C.- JCO 2012
No for Oxaliplatin
Sanford Markowitz, Monica Bertagnolli.- NEJM December 2009
CIN: Chromosomal instability, PGDH: Prostaglandin dehydrogenase
Molecular Basis of CRC (Volgestein B.- NEJM 1988)
El fenómeno de la acumulación de mutaciones
10 años
The Cancer Genome Atlas Network Nature 487, 330-337 (2012) doi:10.1038/nature11252
Frecuencia de las
mutaciones en el CCR.
32 genes somáticos
mutados
N= 224 tumores
y tejido normal
ACVR2A: activin receptor type 2ª (TGF-B family)
Consorcio
Genoma
Humano
84%16%
77%
500-1200
mutaciones
50-100
mutaciones
83% esporádicos, 17% HNPCC
Stage II-III
5 studies (n=457)
(5FU based therapy)
Prognostic value
untreated pts treated pts
15% dMMR
MSI-H: better prognosis MSI-H: no benefit of CT
Predictive value
Sargent D.- JCO 2010
Stage II (dMMR)Stage III (dMMR)
Stage II (pMMR)Stage III (pMMR)
deleterous
benefitno benefit
no benefit
MSI-H and Stage II
Study Prognostic Predictive
Sargent
JCO 2010
YES YES
QUASAR
Hutchins G.-JCO 2011
YES NO
CALGB 9581, 89803
Bertagnolli MM.- JCO 2011
YES NO
Metilaciones en el promotor
Germinales: Lynch
somáticas
MMR-D = MSI-H
MMR-P = MSI-L/MSS
ASCO 2014
26 randomized studies
>37.800 pts
MMR: 7.803 (17 trials)
MSI: Factor pronóstico
Dado el excelente pronóstico en los MSI la QT no debe emplearse
ASCO 2014
N= 433 MSI CRC pts (57% stage II, 43% stage III)
Ox superior
Ox tendencia
Ox superior
Ox tendencia
B-Raf mutation: Prognostic Role
B-RAF is prognostic for OS
in MSI low and MSI-S
PETACC-3 (FU+LV±Iri) B-RAF mutation: 7.9% of pts.
Roth AD (PETACC study).- JCO 2010
HR: 2.2
Stage II-III
DFS OS
Prognostic groups: CALGB 89803
Ogino S et al.- Clin Cancer Res 2011
N=506 (Estadio III) Prognosis
BRAF mut + MSS Unfavourable
BRAF wt + MSI-H Favourable
BRAF wt + MSS Intermediate
BRAF mut + MSI-H Intermediate
FU+LV vs IFL
Years
0
20
40
60
80
100
0 1 2 3 4 5
Adjuvant Chemotherapy in Colon Cancer
Overall survival
Objetives of the study (III + FOLFOX)
All pts
Bad prognosis
Good prognosis MARKERS
CTC
KRAS
BRAF
MSI
microRNAs
Good Signature
(Good prognosis)
Bad signature
Bad prognosis)
TTD-RTICC (2009): 500 ptes
Gene Expression Profiles and Molecular Markers to Predict Recurrence od Dukes´B Colon Cancer: Wang Y et al.- JCO 22: 1564, 2004
P=0.0001
Stage II
N=23 genes identified
Validated in 36 pts
First example in CRC of a genomics approach identifying
molecular markers (DNA microarray)
Interesting data: we need more information
1
2
3
4
5
6
7
1.- Schlicker A: BMC Medical Genomics 2012, 2.- Sadanandam A: Nature Med 2013, 3.- Budinska E: J
Pathol 2013, 4.- De Sousa F: Nature Med 2013, 5.- Marisa L: Plos Med 2013, 6.- Roepman P: Int J Cancer
2013, 7.- Perez-Villamil B: BMC Cancer 2012
Rodrigo Dienstmann, Ramón Salazar, Josep Tabernero
Educational Book: ASCO 2014
GENETIC SIGNATURESPlatforms Tissue Nº Genes Stage
N
Groups
HR
Veridex Paraffine 23 (7) II
n=123
2
HR: 6.89
Coloprint
(Agendia)
Fresh 18 II
n=188
2
HR: 2.5
Oncotype
(Genomic Health)
Paraffine 12 (7) III
n=1.436
3
HR: 1.38
Almac Fresh 634 II
n=215
2
HR: 2.53
Clear pronostic role, but not predictive
Aspirina y NSAIDs y CCR
① Prevención de los pólipos adenomatosos
esporádicos: Nivel de evidencia 1
① Prevención del CCR hereditario (APC, HNPCC)
① Prevención del CCR esporádico
Aspirina en el tto adyuvante del CCR (2005-2014)
Prospective cohort studies:
①CALGB 89803 (IFL).- Fuchs ASCO 2005
②Nurses´Health Study and the Health Professionals Follow-
up Study (Chan AT: Jama 2009; Liao X NEJM: 2012; Nishihara
R: JAMA 2013)
③California Teachers Study (Zell JA, Cancer 2009)
④USA and Australian study (Kothari ASCO GI 2014)
Cancer Registry studies:
⑤Seatle Colon Cancer Family Registry (Coghill GUT 2011)
⑥Netherlands study (Bastiaannet E: BrJ Cancer 2012,
Reimers MS: JAMA 2014)
Comienzo: 1.976
121.701 mujeres
enfermeras
Comienzo: 1.986
51.529 varones
profesionales salud
Análisis salud, estilo de vida, hábitos nutricionales, medicación usada,
incidencia enfermedades cardiovasculares, diabetes, cáncer, etc
Estudios de cohortes (USA)
Regular Use of Aspirine (81-325 mgr) (in diagnosed CRC pts)
COX-2 expression (IHC) (PTGS2)
N= 459 pts
CRC specific deaths
Overexpression HR: 0.39
Weak or absent HR: 1.22
Negative Positive
Chan AT.- JAMA 2009
Observational study: 1.279 pts CRC (stages: I,II,III)
(Nurses and Health Professionals studies)
Participants who used aspirine only after
diagnosis of CRC (n=719)
HR: 0.53 ( riesgo 47%)
CRC deaths
COX-2 = prostaglandina endoperóxido sintasa-2
HR:0.18
HR:0.54
N=161/964 (17%)N=803 (83%)
Liao X.- NEJM 2012
PI3K mutado (pirosecuenciación: exones 9 y 20) en CCR: 17%
Nurses´s Health Study Health Professionals Follow-up Study
riesgo 82%
PI3K
PTGS2 (COX-2) Prostaglandin E2
PTGS2: Prostaglandin-endoperoxide synthase-2
PIK3CA: phosphatidylinositol-4,5-biphosphonate-3 kinase)
Inhibición de la Apoptosis
ASPIRINA
PI3K mutado en CCR: 17%
inducción
apoptosis
mutada
amplificación
señal
Chia, W. K. et al. (2012) Aspirin as adjuvant therapy for colorectal cancer—reinterpreting paradigms
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2012.137
(Singapur, China, India, Indonesia, Corea,Malasia,Arabia Saudi, Taiwan)
Primary Endpoint: DFS
Secondary Endpoint: OS
N=2.660 pts
Inicio 2.008-datos finales 2.020
NCT00565708
ASCOLT Trial (CRC): Dukes C (III) and High Risk Dukes B (II)
Surgery and completed standard therapy (QT and RXT)
R
Herramientas para una Decisión
• Guía NCCN 2014
• Guía TTD: Clin Transl Oncol 2006
• Consensus Word GI: Eur J Cancer 2002
• ESMO GuideLines: Ann Oncol 2012
• http:/www.mayoclinic.com/calcs:
• http:/www.adjuvantonline.com/colonstandard.jsp
• www.nomograms.org
• Consenso Español (Clin Trans Oncol 2011)
top related