ESTRATEGIAS DE TRATAMIENTO ADYUVANTE EN CÁNCER DE COLON. EDUARDO DÍAZ-RUBIO Hospital Clínico San Carlos MADRID

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1 ESTRATEGIAS DE TRATAMIENTO ADYUVANTE EN CÁNCER DE COLON EDUARDO DÍAZ-RUBIO Hospital Clínico San Carlos MADRID 21 Junio de 2014

2 CCR (ESPAÑA) Todos: INCIDENCIA CCR: (15%) 1ª causa MORTALIDAD Todos: CCR: (14%) 2ª causa Todos: PREVALENCIA CCR: (15%) 3ª causa

3 Stage I Stage II Stage III (N+) Stage IV N0,M0 N0, M0 M1 IIA T1 submucosa T2 muscularis propia T3 Pericolorectal tissues IIB T4 a, b T4a: visceral pt T4b: organs o structures N1a: 1 N N1b: 2-3 N N1c: deposits* N2a:4-6 N N2b: >6 N IIIA:T1-2 N1, T1N2a IIIB:T3-4 N1,T2-3 N2a T1-2 N2b IIIC: T4aN2a, T3-T4N % Diagnosis of CRC 15% 20-30% 30-40% 20-25% % Overall Survival at 5 years 85-95% 60-80% 30-60% <5% * subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues AJCC (version 7) 2010

4 SEER population N=

5 ADJUVANT CT IN CRC (Steps Ahead: ) Positive FU+Levamisol (Intergrupo) FU+Leucovorin (NCCTG,NCIC,NSABP) 2003 CI 5-FU (LV5FU2, PVI5-FU) (André T) 2003 FOLFOX (MOSAIC) Positive 2005 FLOX (NSABP C-07) 2004 Oral FU (X-ACT: Cape), (NSABP-C-06: UFT) 2009 XELOX (XELOXA) Positive FOLFOX (NEJM 2004, JCO 2009) FLOX (JCO 2007, JCO 2011)?? XELOX (JCO 2011)

6 ADJUVANT CT IN CRC (Negative results: ) 2004 IFL (CALGB C89804) 2005 FOLFIRI (ACCORD-02) FU CI+CPT-11 (PETACC3) Negative 2009 FOLFOX+BV (NSABP-C-08) (AVANT) 2011 Negative 2010 FOLFOX+Cxmab (NCCTG-INT) 2012 PETACC-8 Negative NSABP_ C-08: JCO 2011; AVANT: JCO: 2011 NCCTG0147: JAMA 2012; PETACC-8: ESMO 2012

7 MOSAIC: DFS AND STAGE (JCO 2009) Benefit of Oxaliplatin Stage II (all)* Abs: 3.8% Rel: 16% Stage III 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)

8 MOSAIC: OS AND STAGE Stage II* Abs: 0.1% Rel: 0% Stage III Abs: 4.2% Rel: 20% Benefit of Oxaliplatin *Stage II High Risk (85% vs 83.3%) (HR: 0.91, p=.648) ns (T4, perforation, obstruction, poorly.diff, venous invasion, <10 LN)

9 Background of the study Adjuvant Chemotherapy in Stage III Colon Cancer Overall survival 100 No curative CT FOLFOX 70-75% FU+LV 60-65% 50-55% Surgery alone Cured with CT Cured by surgery alone TOXICITY Years

10 Stage III (N+): Adjuvant Treatment Surgery 50-55% 5FU+LV 60% 5FU IC 65% Capecitabine 65% FOLFOX 75% FLOX 75% XELOX 71% N1: 1-3, N2>3 IIIA:T1-2 N1 IIIB:T3-4 N1 IIIC: N2 (>3) CONCLUSIONS 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)

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12 Stage II (N0M0) IIA=T3, IIB=T4a-b QUASAR (FU+LV) Yes (OS: 3.6%) ACCENT DATA BASE Meta-analysis (IMPACT: FU+LV) Cochrane systematic review MOSAIC (FOLFOX) NSABP C-07 (FUOX) Expert opinions NCCN Guidelines Yes (OS:5.4%) Yes Yes for DFS No for OX (MOSAIC: trend for DFS, no for OS) (NSABP: 2-3% OS) Yes in high risk Yes in high risk Schedules of CT: FU+LV (Cape), FOLFOX,XELOX

13 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)

14 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% Andre, T. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

15 Treatment of CRC in the elderly En España el 34% de los CCR tienen >80 años Elderly pts with Frailty >85 years old Three or more comorbid diseases One or more geriatric symptoms: - dementia - falling tendency - delirium - incontinence - depression - selft-neglect Balducci L.- Cancer Control 2000 Should patients, according to the age, treated differently? Sargent (adjuvant meta-analyisis NEJM 2001): similar

16 Is the age a limitant factor? ACCENT DATA BASE (*) (MOSAIC, NSABP) II and III MOSAIC X-ACT XELOXA (III) YES YES NO NO Individualized decision: ESMO: 1) Single-agent FU is the treatment of choice 2) Ox: pts with good condition and younger biological features (*): ASCO 2009 (FU IV vs +Iri, Ox, Cape, UFT) ESMO Consensus Guidelines: Ann Oncol 2012

17 Elderly: Recent Data Study SEER-Medicare Databases Hanna NN.- Colorectal Dis 2012 Benefit YES for CT >65 y HR: 0.70 SEER-Medicare-NCCN Sanoff HK.-JCO 2012 NSABPC-07 Yothers G.- JCO 2011 MOSAIC Tournigand C.- JCO 2012 No for Oxaliplatin No for Oxaliplatin No for Oxaliplatin

18 Molecular Basis of CRC (Volgestein B.- NEJM 1988) 10 años El fenómeno de la acumulación de mutaciones CIN: Chromosomal instability, PGDH: Prostaglandin dehydrogenase Sanford Markowitz, Monica Bertagnolli.- NEJM December 2009

19 Frecuencia de las mutaciones en el CCR. 83% esporádicos, 17% HNPCC Consorcio Genoma Humano mutaciones mutaciones 16% 84% N= 224 tumores y tejido normal 77% 32 genes somáticos mutados ACVR2A: activin receptor type 2ª (TGF-B family) The Cancer Genome Atlas Network Nature 487, (2012) doi: /nature11252

20 Prognostic value Stage II-III 5 studies (n=457) (5FU based therapy) 15% dmmr untreated pts treated pts MSI-H: better prognosis MSI-H: no benefit of CT

21 Predictive value deleterous Stage II (dmmr) no benefit Stage III (dmmr) no benefit Stage II (pmmr) benefit Stage III (pmmr) Sargent D.- JCO 2010

22 MSI-H and Stage II Study Prognostic Predictive Sargent JCO 2010 QUASAR Hutchins G.-JCO 2011 CALGB 9581, Bertagnolli MM.- JCO 2011 YES YES YES YES NO NO

23 Metilaciones en el promotor somáticas Germinales: Lynch MMR-D = MSI-H MMR-P = MSI-L/MSS

24 ASCO randomized studies > pts MMR: (17 trials)

25 MSI: Factor pronóstico

26 Dado el excelente pronóstico en los MSI la QT no debe emplearse

27 ASCO 2014 N= 433 MSI CRC pts (57% stage II, 43% stage III)

28 Ox superior Ox tendencia

29 Ox superior Ox tendencia

30 B-Raf mutation: Prognostic Role PETACC-3 (FU+LV±Iri) Stage II-III B-RAF mutation: 7.9% of pts. HR: 2.2 DFS OS B-RAF is prognostic for OS in MSI low and MSI-S Roth AD (PETACC study).- JCO 2010

31 Prognostic groups: CALGB Ogino S et al.- Clin Cancer Res 2011 FU+LV vs IFL N=506 (Estadio III) Prognosis BRAF mut + MSS BRAF wt + MSI-H BRAF wt + MSS BRAF mut + MSI-H Unfavourable Favourable Intermediate Intermediate

32 Overall survival Adjuvant Chemotherapy in Colon Cancer Objetives of the study (III + FOLFOX) TTD-RTICC (2009): 500 ptes Good prognosis All pts Bad prognosis MARKERS CTC KRAS BRAF MSI micrornas Years Good Signature (Good prognosis) Bad signature Bad prognosis)

33 Gene Expression Profiles and Molecular Markers to Predict Recurrence od Dukes B Colon Cancer: Wang Y et al.- JCO 22: 1564, 2004 N=23 genes identified Validated in 36 pts Stage II P= First example in CRC of a genomics approach identifying molecular markers (DNA microarray) Interesting data: we need more information

34 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

35 Rodrigo Dienstmann, Ramón Salazar, Josep Tabernero Educational Book: ASCO 2014

36 GENETIC SIGNATURES Platforms Tissue Nº Genes Stage N Veridex Paraffine 23 (7) II n=123 Groups HR 2 HR: 6.89 Coloprint (Agendia) Oncotype (Genomic Health) Fresh 18 II n=188 Paraffine 12 (7) III n= HR: HR: 1.38 Almac Fresh 634 II n=215 2 HR: 2.53 Clear pronostic role, but not predictive

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38 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

39 Aspirina en el tto adyuvante del CCR ( ) Prospective cohort studies: 1CALGB (IFL).- Fuchs ASCO Nurses Health Study and the Health Professionals Followup 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)

40 Análisis salud, estilo de vida, hábitos nutricionales, medicación usada, incidencia enfermedades cardiovasculares, diabetes, cáncer, etc Estudios de cohortes (USA) Comienzo: mujeres enfermeras Comienzo: varones profesionales salud

41 Regular Use of Aspirine ( mgr) (in diagnosed CRC pts) Participants who used aspirine only after diagnosis of CRC (n=719) HR: 0.53 ( riesgo 47%) CRC deaths COX-2 = prostaglandina endoperóxido sintasa-2 Negative Positive COX-2 expression (IHC) (PTGS2) N= 459 pts CRC specific deaths Overexpression HR: 0.39 Weak or absent HR: 1.22 Observational study: pts CRC (stages: I,II,III) (Nurses and Health Professionals studies) Chan AT.- JAMA 2009

42 Nurses s Health Study Health Professionals Follow-up Study N=161/964 (17%) HR:0.18 N=803 (83%) riesgo 82% HR:0.54 PI3K mutado (pirosecuenciación: exones 9 y 20) en CCR: 17% Liao X.- NEJM 2012

43 PI3K mutada ASPIRINA PTGS2 (COX-2) amplificación señal Prostaglandin E2 Inhibición de la Apoptosis inducción apoptosis PI3K mutado en CCR: 17% PTGS2: Prostaglandin-endoperoxide synthase-2 PIK3CA: phosphatidylinositol-4,5-biphosphonate-3 kinase)

44 Chia, W. K. et al. (2012) Aspirin as adjuvant therapy for colorectal cancer reinterpreting paradigms Nat. Rev. Clin. Oncol. doi: /nrclinonc

45 ASCOLT Trial (CRC): Dukes C (III) and High Risk Dukes B (II) Surgery and completed standard therapy (QT and RXT) N=2.660 pts R (Singapur, China, India, Indonesia, Corea,Malasia,Arabia Saudi, Taiwan) Inicio datos finales NCT Primary Endpoint: DFS Secondary Endpoint: OS

46 Herramientas para una Decisión Guía NCCN 2014 Guía TTD: Clin Transl Oncol 2006 Consensus Word GI: Eur J Cancer 2002 ESMO GuideLines: Ann Oncol Consenso Español (Clin Trans Oncol 2011)