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EDUARDO DÍAZ-RUBIOCatedrático y Jefe ServicioDepartamento de Oncología MédicaHospital Clínico San CarlosUniversidad Complutense, Madrid [email protected]
17 Junio 2017
Académico de Número de la RANMVicepresidente de la RANM
ESTRATEGIAS DE TRATAMIENTO ADYUVANTE EN CÁNCER DE COLON
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
NECESIDAD DE PROGRESO
INFORME SEOM 2017
T1
T2
T3
T4 a, b
% Diagnosis of CRC15% 20-30% 30-40% 20-25%
% Overall Survival at 5 years85-95% 60-80% 30-60% <5%
Stage I Stage II Stage III (N+) Stage IV
IIB
IIAN0,M0 N0, M0 M1
submucosa
muscularis propia
Pericolorectaltissues
T4a: visceral ptT4b: organs o
structures
IIIA:T1-2 N1, T1N2aIIIB:T3-4 N1,T2-3 N2a
T1-2 N2bIIIC: T4aN2a, T3-T4N
N1a: 1 NN1b: 2-3 NN1c: deposits*N2a:4-6 NN2b: >6 N
* subserosa, mesentery, or nonperitonealized pericolic or perirectal tissuesAJCC (version 7) 2010
SEER population
N=109.953T3: tejido pericolorrectalT4a: peritoneo visceralT4b: órganos o estructuras
ADJUVANT CT IN CRC (Steps Ahead: 1990-2017)
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: MOSAIC (NEJM 2004, JCO 2009, JCO 2015)XELOX: XELOXA (JCO 2011)FLOX: NSABP-C-07 (JCO 2007, JCO 2011) ?? > toxicity
ADJUVANT CT IN CRC (Negative results: 1990-2017)
2004 IFL (CALGB C89804)2005 FOLFIRI (ACCORD-02)2005 5FU CI+CPT-11 (PETACC3)
Negative
Negative2009 FOLFOX+BV (NSABP-C-08) (AVANT)2014 QUASAR-2
Negative2010 FOLFOX+Cxmab (NCCTG-INT)2012 PETACC-8 (ESMO)
Bevacizumab: 1) NSABP_ C-08: JCO 20112) AVANT: JCO: 20113) QUASAR-2 ASCO 2014
Cetuximab: 1) NCCTG 0147: JAMA 2012 2) PETACC-8: Lancet Oncol 2014
Acta Oncol 54, 5, 2015
N= 25 studies, stage II (15.559 pts), stage III (18.425 pts)
Stage No CT Adjuvant CT
Δ
II 81.4% 79.3% - 2,1%III 49% 63.6% +14.6%
5-years DFS
MOSAIC: OS AND STAGE (Anfré T. Dec JCO 2015) 10 years follow-up
overall
71.7%67.1%
(+4.6%)
78.4%79.5%
67.1%59%
(+8.1%)
Stage III
N=2.246 pts
NS
Stage II
Importancia del Oxaliplatino
Stage II low-risk Stage II high-risk
Stage III N1 Stage III N2
71.4%65.4%(+6%)
59.5 %46.6 %
(+12,9%)
André T.- JCO Dec 2015
MOSAIC: OS AND STAGE (JCO 2015) 10 y follow-up
NS NS
NS
N1: 1-3 N2: ≥4
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%
Stage III (N+): OS 5 yAdjuvant 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 conditionsshould be treated3. FOLFOX, XELOX orCapecitabine alone if pts arenot candidates for Ox (elderly)4. Concern: Toxicity5. Start: 8-12 w after surgery6. Duration: 6 months? (IDEA study)
IIIA:T1-2 N1IIIB:T3-4 N1IIIC: N2 (>3)
N1: 1-3, N2>3
CONCLUSIONS
Stage II (N0M0) IIA=T3, IIB=T4a-bQUASAR (FU+LV) Yes (OS: 3.6%) (64% <12LN)
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)
ASCO 2004NCCN GUIDELINES 2016
ESMO GUIDELINES(Ann Oncol 2013)
Different consensus definition
IDEA (ASCO 2017): non-inferiority margin 1.12
Study N DFS 3 y (Δ) Conclusions
FRENCH 2.010 3.6%HR: 1.24
(CI 1.05-1.46)
6 m is superior to 3 m(inferiority demostrated)
TOSCA 3.759 <3%HR: 1.14
(CI 0.99-1.31)
Not able to demostrate that 3 m is not inferior(non inferiority not proven)
SCOT 6.088 0.6%HR: 1.008
(CI 0.910-1.17)
3 m is not inferior(not inferiority proven)
SOLUCIÓN A ESTA CONFUSA “IDEA”:INDIVIDUALIZACIÓN
IDEA: Pooled analysis of 6 clinical trials6 m vs 3 m of CT (Stage III)
N=12.800 pts 6 m 3 m Δ DFSTOTAL 74.6% 75.5% +0.9%CAPOX 74.8% 75.9% +1.1%FOLFOX 76% 73.6% -2.4%LOW RISK (N1-3)
83.3% 83.1% -0.2%
Follow-up: 39 m
NEW STANDARD OF CARE3 months
INDIVIDUALIZATION
Plenary session ASCO 2017
≥ 2 Neuropathy 6 m 3 m ΔCAPOX 45% 15% -30%FOLFOX 48% 17% -31%
IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer
Presented By Qian Shi at 2017 ASCO Annual Meeting
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 benefit with FU+LV (>70 y)
En España el 34% de los pacientes con CCR tienen >80 años>75 años 40%
Slide 16
Presented By Hanna Sanoff at 2015 ASCO Annual Meeting
Slide 17
Presented By Hanna Sanoff at 2015 ASCO Annual Meeting
The Cancer Genome Atlas Network Nature 487, 330-337 (2012) doi:10.1038/nature11252
32 genes somáticosmutados
N= 224 tumoresy tejido normal
ACVR2A: activin receptor type 2ª (TGF-B family)
Consorcio Genoma Humano
84%16%
77%
500-1200mutaciones
50-100mutaciones
1. Metilación Promotores (esporádicos)fenotipo metilador en las islas CpG (CIMP)
2. Mutacion Reparadores (Lynch: HNPCC)(MLH1,MLH3,MSH2,MSH3,MSH6, PMS2)
(Fenotipo Hipermutador) (MSI) 16%
(*) Roth AD (PETACC-3).- JCO 2010(**) Koopman M.- Br J Cancer 2009
STAGE FRECUENCY OF MSI-H
STAGE II 22% (*)STAGE IIII 12% (*)STAGE IV 3.5% (**)
FRECUENCIA DE LA INESTABILIDADDE MICROSATÉLITES Y ESTADIO
Stage II-III5 studies (n=457)(5FU based therapy)
Prognostic and predictive 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
Prognostic Impact of Defective Mismatch Repair in Stage II/III Colon Cancer: A Pooled Individual Patient Data Analysis of 17 Adjuvant Trials
from the ACCENT Database
D Sargent, Q Shi, G Yothers, S Tejpar, M Bertagnolli, S Thibodeau, T Andre, R Labianca, S Gallinger, SR
Hamilton, G Monges, K Pogue-Geile, S Paik, D Klingbiel, A Roth, E Pavey, G Kim, F Sinicrope for
the ACCENT Collaborative Group
26 randomized studies>37.800 ptsMMR: 7.803 (17 trials)ASCO 2014
TTR & OSStage II, Surgery Alone (N=307)
Time to Recurrence Overall Survival
TTR & OSStage II, 5-FU Based Rx (N=1155)
Time to Recurrence Overall Survival
Metilaciones en el promotor
Germinales: Lynch
somáticas
MMR-D = MSI-HMMR-P = MSI-L/MSS
mononucleótidomonomórfico
Nature Medicine 2015SCNA: somatic copy number alterations
N= 4.151 samples (Markov Cluster Algorithm)
Consensus Molecular SubtypesConsortium of 6 independent groups
Guinney J.- Nature Medicine 2015
GENETIC SIGNATURESPlatforms Tissue Nº Genes Stage
NGroups
HR
Veridex Paraffine 23 (7) IIn=123
2HR: 6.89
Coloprint(Agendia)
Fresh 18 IIn=188
2HR: 2.5
Oncotype(Genomic Health)
Paraffine 12 (7) IIIn=1.436
3HR: 1.38
Almac Fresh 634 IIn=215
2HR: 2.53
Clear pronostic role, but not predictive (NCCN nov 2016)
Circulating tumor DNA and Stage II Colon Cancer
Tie J (Australia).- Science Trasl Med 2016
230 pts Stage IIctDNA (NGS = Illumina) Análisis de mutaciones
ctDNA antes de la CT
ctDNA tras la CT
Único con test diagnóstico validadoCDX2: Factor transcripcional
2115 muestras de CCR
Análisis bioinformático para buscar marcadores negativamente relacionados con la molécula de adhesión leucocitaria ALCAM/CD16
16 genes candidatos
Universidad de Columbia
Validation data set:N=314
12% 88%
La CT beneficia a los CDX2-negativos
II
III
Dienstmann RJCO 2015
Comentarios (EDR):- Determinación de MSI: Obligada para estadios II- Firmas Genómicas: Posible utilidad estadios II (pronóstica)- CTC: No son de utilidad en estadios II y III (HCSC: Ann Oncol 2015)- ctDNA: datos prometedores- Expresión CDX2: datos interesantes
April 2016
Conclusiones e Implicaciones:Hasta tener ensayos randomizados, los estudios observacionalesdeben ser tenidos en cuenta, y por tanto los pacientesdiagnosticados de cáncer deben ser informados del potencialbeneficio de la aspirina para que decidan si desean tomarla o no.
CCR: 9 estudios observacionales (que analizaban mortalidadespecifica por CCR) HR: 0.76 (95% CI: 0.66-0.88)
ColonMamaPróstata
Bibbins-Domingo.- Ann Intern Med: April 2016
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%
Conclusiones: Tto Adyuvante C.Colon
• Estadio III: Quimioterapia XELOX, FOLFOX, por 6 meses (3 meses T1-3N1). Mayor beneficio en los N2 vs N1.
• En los pacientes ancianos no está claro el beneficio del oxaliplatino (menor que los <70 años).
• En los estadios II de alto riesgo determinar la MSI es obligado (CDX2?).
• El ctDNA podría ser un excelente marcador pronóstico.• La clasificación molecular pueden tener utilidad y
separan grupos que van a ser claves en el futuro. El papel de las firmas genómicas es pronóstico.
• La aspirina ha mostrado su utilidad en estudios observacionales, pero no hay estudios prospectivos randomizados por lo que la decisión debe ser individual.
