Sº Oncología Médica Hospital Universitario Virgen del Rocío Instituto de Investigaciones Biomédicas de Sevilla (IBIS)

Transcripción

1 Tto Adyuvante del Cáncer de Colon: Situación actual y perspectivas p futuras Rocío García Carbonero Sº Oncología Médica Hospital Universitario Virgen del Rocío Instituto de Investigaciones Biomédicas de Sevilla (IBIS)

2 Introducción Indicación de QT adyuvante Origen y evolución de las FP en adyuvancia Exitos y fracasos de otros citotóxicos Oxaliplatino Irinotecan Decepción de los nuevos fármacos dirigidos Bevacizumab Cetuximab

3 Tratamiento con QT adyuvante Beneficio establecido en Estadío III Balance beneficio/riesgo controvertido en Estadío II Disease Stage % of Pts at Diagnosis % OS (5 years) Estadío I 15% ~90% Estadío II (T3-4 N0) 20-30% 70-80% Estadío III (T3-4 N1-N2) 30-40% 40-60% Estadío IV 20-25% 5-10% (20-50% if met surg)

4 Estadío II: Indicación de QT adyuvante? Buen pronóstico (aunque 20-30% recidivan tras Cx) Beneficio de QT adyuvante: - datos controvertidos / análisis retrospectivos - magnitud del beneficio menor -falta de poder estadístico Indicación de QT: - individualizar (factores de riesgo, opinión del pte..)

5 FACTORES PRONOSTICOS Factores clínico-patológicos -T4 vs T3 - Nº de ganglios examinados < 12 - Pobre diferenciación - Obstrucción o perforación - Invasión vascular - Edad y comorbilidad Factores moleculares - MSI-H (dmmr) - 18q LOH? - Gene profiling? -...

6 META-ANALISIS ANALISIS (20,898 ptes) Quimioterapia Adyuvante SG (8y): 72% SG (8y): 67% ESTADIO II Sargent D, JCO 2009

7 META-ANALISIS ANALISIS (20,898 ptes) Quimioterapia Adyuvante ESTADIO III SG (8y): 53% SG (8y): 43% Sargent D, JCO 2009

8 Single Agent Therapy (Fluoropyrimidines) The 80s: Chemotherapy vs Observation The 90s: - 5-FU + Levamisol (LEV) - 5-FU + Folinic Acid (LV) - FU/LEV vs FU/LV (high or low) vs FU/LV/LEV - 6 m vs 12 m Beginning of 21 st century - FU iv bolo vs ic - Oral FP

9 1990 NCI Consensus Conference 12 months of 5-FU + LEV superior to surgery alone STANDARD OF CARE for Stage III CCR patients INT-0035 Estadio C (929 pts) - SLE: HR SG: HR 0.67 Moertel, NEJM 1990

10 5-FU + LV iv bolo (QT vs Observación) NCCTG 5FU/lowLV(6m) vs Observation 1 5-year DFS 5-year OS (%) p value (%) p value 74 vs vs pts Colon IIB(18%) and III IMPACT 5FU/highLV(6m) vs Observation 2 71 vs 62 < vs pts Colon B(56%) and C 1 O Connell MJ et al. J Clin Oncol 1997;15: IMPACT investigators. Lancet 1995;345:939 44

11 5-FU/LV vs 5-FU/LEV vs 5-FU/LV/LEV N Stage Treatment arms INT II and III 5FU/LEV 12 m 5FU/LV (Mayo) 6 m 5FU/LV (RP) 8m 5FU/LV/LEV 6 m INT II-HR and III 5FU/LEV 6 m 5FU/LEV 12 m 5FU/LV 6 m 5FU/LV/LEV 12 m DFS OS (% at 5y) (% at 5y) NSABP C II and III 5FU/LEV 12 m FU/LV 12 m FU/LV/LEV 12 m QUASAR II and III 5FU/LV m Colon & Rectal Ca 5FU/LV 25 6 m 5FU/LEV/LV 6 m 5FU/LV/placebo 6 m

12 5-FU/LV vs 5-FU/LEV vs 5-FU/LV/LEV 5FU/LV (Mayo o RP) > 5FU/LEV 5FU/LV + LEV: No additional benefit 6 months = 12 months Low dose LV = high dose LV

13 5FU/LV (Mayo) x 6 months becomes Standard of Care for resected colon cancer at high risk of relapse following surgery

14 Continuous infusion 5-FU/LV GERCOR C96.1 Andre T. JCO 2003/2007 SAFFA Chau et al. Br J Ca 2003 INT 0153/ SWOG 9415 Poplin et al. JCO 2005 PETACC-02 ASCO pacientes Estadíos II y III 2x2 factorial - LVFU2 (de Gramont) vs 5FU/LV (Mayo) - 6 meses vs 8 meses 801 pacientes Estadío II y III - 5FU/LV (Mayo) x 6 meses - ci 5FU (300 mg/m2/d) x 3 meses 1135 pacientes Estadíos II alto riesgo y III - 5FU/LV (Mayo) + LEV x 7 m - ci 5FU (250 mg/m2/d x 56d q 9w) + LEV x 7 m 1601 pacientes Estadío III - 5FU/LV (Mayo) - varios regímenes de 5FU ic ( AIO/TTD/EORTC/FFCD)

15 Continuous infusion 5-FU/LV 5FU/LV continuous infusion = bolus (similar DFS and OS) 5FU/LV continuous infusion less toxic (less neutropenia, diarrhea and mucositis) 6 months = 8 months (bolus or ci) 3 months ci = 6 months iv bolus

16 Fluoropirimidinas Orales NSABP C pts estadíos II-III - UFT/LV vs FU/LV (RP) X-ACT pts estadío III - Capecitabina vs FU/LV (Mayo) L b k B JCO 2006 Lembersky B. JCO 2006 Twelves C. NEJM 2005

17 Fluoropirimidinas Orales SLE de FPO al menos equivalente a 5FU iv bolo (Capecitabina algo mejor?) NSABP C-06 X-ACT DFS DFS

18 X-ACT pre-planned multivariate analysis: superior DFS with Xeloda Factor Treatment effect (Xeloda vs 5-FU/LV) p-value Age (< vs 65 years) Gender (female vs male) Regional lymph nodes (PN1 vs PN0, PN2, PNx) Baseline CEA (< vs ULN) Time from surgery to randomisation (days) < < Twelves et al. ASCO GI 2008 HR and 95% CI 2. Xeloda SPC

19 X-ACT pre-planned multivariate analysis: superior OS with Xeloda Factor Treatment effect (Xeloda vs 5-FU/LV) p-value Age (< vs 65 years) Gender (female vs male) Regional lymph nodes (PN1 vs PN0, PN2, PNx) Baseline CEA (< vs ULN) Time from surgery to randomisation (days) < < Twelves et al. ASCO GI Xeloda SPC HR and 95% CI

20 Fluoropirimidinas Orales Mejor perfil de toxicidad con FPO vs FU iv bolo - menos neutropenia, vómitos, diarrea, mucositis -más Sd mano-pie e hiperbilirrubinemia i

21 Combination Chemotherapy Role of IRINOTECAN Role of OXALIPLATIN

22 Irinotecan combinations: no survival advantage for stage III disease Trial DFS HR DFS (%) p OS HR OS (%) p CALGB NR NR 0.85 PETACC ACCORD NR 0.44 NR NR 0.74 NR NR = not reported 1. Saltz et al. JCO Van Cutsem et al. JCO 2009; 3. Ychou et al. Ann Oncol 2009

23 Oxaliplatin combinations MOSAIC pts estadíos II-III (40%-60%) - FOLFOX-4 vs LV5FU2 NSABP C pts estadíos II-III III (28%-72%) - FLOX vs FU/LV (RP) XELOX-A pts estadío III - XELOX vs FU/LV (Mayo o RP)

24 MOSAIC: significantly improved 5-year DFS in stage II/III FOLFOX4 LV5FU2 HR=0.80 =5.9% p= Years André et al. NEJM 2004/JCO 2009

25 MOSAIC: significantly improved 6-year OS in stage II/III FOLFOX4 LV5FU2 HR=0.84 =2.5% p= Years André et al. JCO 2009

26 DFS by Stage: No benefit in Stage II Stage II =3.8% p= FOLFOX4 LV5FU2 Stage II HR=0.84 Stage III HR=0.78 Stage III =7.5% p= Years André et al. JCO 2009

27 OS by Stage: No benefit in Stage II Stage II =0.1% p= FOLFOX4 LV5FU2 Stage II HR=1.00 Stage III HR=0.80 Stage III =4.2% 42% p= Years André et al. JCO 2009

28 MOSAIC: toxicity and long-term safety NCI-CTC Grade 3 FOLFOX4 LV5FU2 Neutropenia Neutropenia with fever or infection Diarrhea Stomatitis 41.0% (Gr 4, 12.2%) 1.8% 10.8% 2.7% 4.7% 0.2% 6.7% 2.2% Vomiting 59% 5.9% 14% 1.4% Allergy 3.0% 0.2% Alopecia (Gr 2) 5.0% 5.0% Neuropathy (Gr 3) 12.4% 0.0% Neuropathy (Gr 3) after 18 months 0.7% 0.0% All cause mortality 0.5% 0.5% Second cancer 40% 4.0% 36% 3.6% de Gramont et al. ASCO 2005;Abstract 3501

29 NSABP C-07: FLOX vs FULV 2409 pts Stage II-III III CRC Follow-up: 8 years DFS: improved for FLOX (HR 0.82, P=0.002) OS: borderline increase for FLOX (HR 0.88, P=0.08) Yothers et al, JCO 2011

30 DFS Oxaliplatin benefit by Age <70years > 70 years N HR P N HR P - MOSAIC <01 < NSABP < OS - MOSAIC NSABP

31 NO16968 (XELOXA): study design Chemo/ radiotherapy-naive stage III CC N=1886 R A N D O M I S A T I O N n=944 n=942 XELOX Xeloda 1000mg/m 2 bid d1 14 oxaliplatin 130mg/m 2 d1 q3w Bolus 5-FU/LV Mayo Clinic or Roswell Park Primary endpoint: superior DFS Secondary endpoints: relapse-free survival, overall survival, safety

32 Superior DFS with XELOX Estimated probability year 4-year 5-year DFS DFS DFS XELOX (n=944) 70.9% 68.4% 66.1% 5-FU/LV (n=942) 66.5% 62.3% 59.8% HR=0.80 (95% CI: ) Absolute difference at 3 years: 4.5% p= Absolute difference at 5 years: 6.3% No left: XELOX FU/LV ITT population

33 Trend to superior overall survival with XELOX Estimated probability year overall survival XELOX (n=944) 77.6% 5-FU/LV (n=942) 74.2% Absolute difference at 5 years: 3.4% HR=0.87 (95% CI: ) p= Years No. left: XELOX FU/LV ITT population

34 Safety Grade 3/4 AEs (%) XELOX n=938 5-FU/LV n=926 Febrile neutropenia Neutropenia Diarrhoea Stomatitis Nausea Vomiting HFS Neurosensory Schmoll et al. JCO 2007

35 Role of adjuvant CETUXIMAB NCCTG N pts Stage III (1864 pts final design Kras WT) - FOLFOX vs FOLFOX + Cetuximab - Results: PETACC-08 Negative trial even in Kras WT Cetuxi may be harmful in pts > 70 y and in KrasMUT pts Stage III (62.5% Kras WT) - FOLFOX vs FOLFOX + Cetuximab - Results: Negative trial even in Kras WT Cetuxi may be harmful in pts > 70 y

36 Final Design for N0147 June 2008 Stage III Colon Cancer (N = 3768) P R E R E G I S T E R K-ras WT Centralized K-ras analysis K-ras Mut R A N D O M I Z E R E G I S T E R Arm A mfolfox6 N= 1864 Arm D mfolfox6 + Cetuximab Arm G Adjuvant therapy per primary oncologist Report therapy given Annual status through year 8

37 DFS: FOLFOX +/- Cmab by K-ras status K-Ras WT K-Ras Mut e Disease Fre % Alive and FOLFOX FOLFOX + Cmab Arm FOLFOX 3 Year Rates (95% CI) 75.8% HR (95% CI) 1.2 N=902 ( %) 79.6%) (0.96- FOLFOX 72.3% 1.5) + Cmab ( %) N=945 P- value 0.22 Disease Free e %Alive and FOLFOX FOLFOX + Cmab Arm FOLFOX 3 Year Rates (95% CI) 67.2% HR (95% CI) 1.2 N=374 ( %) ( ) 16) FOLFOX + Cmab N= % ( %) 70.2%) P- value Time (Months) Time (Months)

38 100 DFS in K-Ras WT Age>70 (N=258) 90 % Alive and Diseas se Free Fr ree FOLFOX FOLFOX + Cmab Arm 3 Year Rates (95% CI) HR (95% CI) P-value FOLFOX 80.9% N=112 (73.0%-89.8%) 20 FOLFOX O % Cmab 10 0 N=146 (56.8%-77.0%) ( ) Time (Months)

39 Oi Original i l2-arm design for PETACC8 Fully resected stage III colon cancer (N = 2000) R Stratification factors: N-status (N1 vs N2) T-status (T1-3 vs T4) Obstruction/perforation status FOLFOX4 (12 cycles) Every 2 weeks: Oxaliplatin 85 mg/m 2 with LV 200 mg/m 2 on d1 and 5-FU bolus 400 mg/m 2 followed by 5-FU 600mg/m 2 22-hour IV on d1 and d2 FOLFOX4 + cetuximab (12 cycles) FOLFOX4 Cetuximab d1 and d8-400 mg/m 2 initial dose mg/m 2 weekly

40 Disease-free survival: KRAS wt (N=1602) FOLFOX4 + cetuximab FOLFOX4 S rate DF FOLFOX4 + FOLFOX4 cetuximab n=791 n=811 No. of Events DFS-Year [95% CI], % [71.7, 78.1] [74.8, 80.8] HR for DFS [95% CI] [0.853, 1.286] p-value (log-rank) Years Number of patients at risk FOLFOX4 + cetuximab FOLFOX

41 1.0 Overall survival: KRAS wt (N=1602) FOLFOX4 + cetuximab FOLFOX4 0.8 OS rate FOLFOX4 + cetuximab n=791 FOLFOX4 n=811 No. of Events Survival-Year 3 [95% CI], % 88.3 [85.6, 90.6] 90.5 [87.9, 92.5] HR for OS [95% CI] [0.813, 1.466] p-value (log-rank) Years Number of patients at risk FOLFOX4 + cetuximab FOLFOX

42 Disease-free survival: KRAS mut (N=742) FOLFOX4 + cetuximab FOLFOX4 S rate DF FOLFOX4 + FOLFOX4 cetuximab N=368 N= No. of Events HR for DFS [95% CI] [0.819, 1.374] p-value (log-rank) Years Number of mkras patients at risk FOLFOX4 + cetuximab FOLFOX

43 Forest plot for DFS: KRAS wt Control Treatment Strata O/N O/N Treatment effect within subgroup AdjustedHR (CI) p-value * Sex Male 118 / / (0.68, 1.15) Female 61 / / (1.03, 2.03) p=0.349 p=0.031 Age category Age < / / (0.80, 1.23) p=0.960 Age > / / (0.99, 3.93) p=0.051 Tumor localization Right localization 66 / / (1.01, 1.94) Left localization 111 / / (0.67, 1.15) p=0.043 p=0.354 *Log rank FOLFOX4 + Cetuximab better FOLFOX 4 better

44 DFS: KRAS wt pt4n2 tumors 1.0 FOLFOX4 + cetuximab FOLFOX4 0.8 S rate DF FOLFOX4 + FOLFOX4 cetuximab n=79 n=67 No. of Events HR for DFS [95% CI] [0.348, 0.885] p-value (log-rank) Years Number of patients at risk FOLFOX4 + cetuximab FOLFOX

45 Adjuvant Cetuximab: Conclusions No benefit to add Cetuximab in patients with resected stage III K-ras WT expressing colon cancer Potential explanations Decreased tolerance with cetuximab Differences in dose intensity Interaction with age: Worse outcomes in older pts receiving cetuximab Lessened ability to complete therapy Differences in biology of earlier stage disease Current focus of correlative studies

46 Role of adjuvant BEVACIZUMAB NSABP C-08 AVANT Negative results!! E5202 QUASAR-2

47 2710 0pts Stage II-III (24%-76%)

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53 E5202: stage II colon cancer S U R G E R Y Tumour risk assessment based on biology (18q/MSI) High-risk (MSS and 18q LOH) Low-risk (MSI or no 18q LOH) Arm A mfolfox6 Arm B mfolfox6 + Beva Observation Accrual goal = 3,125 patients

54 QUASAR - 2 Chemotherapy-naive stage II/III colon cancer N=1900 R A N D O M I S A T I O N Capecitabine Capecitabine + Bevacizumab Primary end-point: DFS

55 CONCLUSIONS Adjuvant Therapy in Colon Cancer Indication: - Most stage III - Selected stage II (informed discussion with pt) Chemotherapy schedule: FOLFOX /XELOX stage III & < 70 y Capecitabine Biologicals: so far disappointing Future perspectives: - More biology and stop empirism!!

56 Muchas gracias!!