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)