ASCO大肠癌辅助化疗进展2003年

1、大肠癌辅助化疗的新进展 ASCO 03,辅助化疗在大肠癌治疗中的作用,1988: NSABP C-O1 BSC vs MOF ( MeCCNU, Oncovin, 5FU) 三年生存率改善 1988: Meta-analysis by M. Buyse 17 随机对照研究证实 5FU 辅助化疗能改善1年生存率,减少复发危险40% 减少死亡危险33%,5FU IV + Levamisole,P 0.0001 (control versus 5FU + Levamisole) P 0.0007 (control versus 5FU + Levamisole),5FU + levamisole(n

2、 = 304) Levamisole(n = 310) Follow-up only(n = 315),100 90 80 70 60 50 40 30 20 10 0,0123456789,Years from Registration,1Moertel CG et al. Ann Intern Med. 1995;122(5):321-326.,Patients free from recurrence (%),Patients surviving (%),At risk,5FU + levamisole(n = 304) Levamisole(n = 310) Follow-up onl

3、y(n = 315),100 90 80 70 60 50 40 30 20 10 0,0123456789,Years from Registration,At risk,Main steps in adjuvant treatment of colon cancer,6 months = 12 months,Surgery,5FU leucovorin 5FU levamisole,1990,1996,5FU IV + CF,减少死亡危险22% 减少复发危险35%,IMPACT 分析三个针对B2和C期病人的随机对照研究,5FU=370-400 mg/m2 D1 to D5 + FA 200

4、 mg/m2 D1 to D5 (每 28天重复 6疗程 )n=736 对照组n=757,1.0 0.8 0.6 0.4 0.2 0,0123,Stage B Stage C,Time from randomization (years),Probability of survival,Patients at risk Control, Stage B423403327189 Fluorouracil/folinic acid Stage B418399328188 Control, Stage C334298225125 Fluorouracil/folinic acid Stage C31

5、8300231161,Overall survival,1.0 0.8 0.6 0.4 0.2 0,01234,Stage B Stage C,Time from randomization (years),Probability of survival,Patients at risk Control, Stage B42334725613956 Fluorouracil/folinic acid Stage B41835726214060 Control, Stage C3342231416928 Fluorouracil/folinic acid Stage C3182501791184

6、2,Overall survival,1IMPACT investigators. Lancet.1995;345:939-944.,*Leucovorin,ASCO 1996,比较不同方案的化疗疗效: 5FU + AF 5FU + Levamisole 5FU + AF + Levamisole 有三个大宗临床研究报道: NSABP C-04(2151 patients) INT 0089 (3759 patients) NCCTG-NCIC (915 patients),辅助化疗方案：- ASCO 1996结论,5FU +CF每月方案化疗6个月: - 与5FU + Levamisole 化

7、疗 1 年相当 -优于 5FU + Levamisole 化疗 6 个月 -绝对 5 年生存率增加: 12 to 26% -主要获益者为Duck C期的病人,Main steps in adjuvant treatment of colon cancer,6 months = 12 months,Surgery,5FU leucovorin 5FU levamisole,1990,1996,大肠癌辅助化疗存在的问题,B2的病人是否需要治疗 5FU Bolus 或 CIV 新药的地位 Oxaliplatine, CPT-11 口服氟脲嘧啶类：CAPECITABINE, UFT,正在进行的临床研究

8、:FUFOL CPT11 or oxaliplatin?,研 究 分期 治疗分组 MOSAIC B2/C LV5FU2 OXA RPR B2/C LV5FU2 CPT11 FFCDC(4)LV5FU2 CPT11 NSABP C07 B2/CFUFOL OXA,OXALIPLATIN/5-FU/LV IN ADJUVANT COLON CANCER: RESULTS OF THE INTERNATIONAL RANDOMIZED Phase III “MOSAIC” TRIAL,A. de Gramont, M. Banzi, M. Navarro, J. Tabernero, T. Hick

9、ish, J. Bridgewater, F. Rivera, A. Figer, G. Fountzilas, T. Andr,MOSAIC: Treatment arms,Primary: Disease Free Survival (DFS) Secondary: Safety (including long-term) Overall Survival (OS),Endpoints,de Gramont A et al. J Clin Oncol 2000 Goldberg R et al. ASCO 2002, 2003,FOLFOX4 in metastatic colon can

10、cer,Compared to LV5FU2: improved efficacy manageable toxicity: neutropenia, sensory neuropathy,Compared to IFL: improved efficacy decreased toxicity,LV,OXA,MOSAIC: Treatment arms,*Baxter LV5 infusors,LV5FU2,FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m,Every 2 weeks, 6 months of treatment (12 cycles),MOSAIC:

11、 Main inclusion criteria,Stage II (Dukes B2: T3, T4, N0, M0) and Stage III (Dukes C: any T; N1, N2, M0) Complete resection of the primary tumor Treatment within 7 weeks following surgery No prior chemo-, immuno-, or radiotherapy Age 1875 years old ECOG PS 2,MOSAIC: Statistical hypotheses,Stage II /

12、III ratio = 40 / 60% 2.5 year enrollment Expected 3-year DFS: 79% for test arm and 73% for control arm or 25% reduction in risk of recurrence,N = 2200 for a statistical power of 90% (a=0.05),MOSAIC: Randomization,Treatment assignment was stratified for: Center Extent of invasion of the primary tumor

13、 (T2, T3, or T4) Number of lymph nodes involved (N0, N1, N2) Bowel obstruction or tumor perforation,MOSAIC: Follow-up and recurrence,Every 6 months: Clinical examination, imaging, CEA Diagnosis of recurrence: - imaging - cytology or biopsy,an elevated CEA, as a solitary finding, was not considered a

14、s acceptable evidence of recurrence,MOSAIC: Accrual curve,2246 pts,Number of patients,Months,Oct 98,Feb 99,Jun 99,Oct 99,Feb 00,Jun 00,Oct 00,Jan 01,2246 patients,病例分布,2246 patients,477 patients 364 patients 294 patients 249 patients 135 patients 133 patients 107 patients,103 patients 69 patients 58

15、 patients 51 patients 37 patients 36 patients,27 patients 26 patients 22 patients 21 patients 17 patients 17 patients 3 patients,Cy,Au,UK,B,MOSAIC: Patient characteristics,MOSAIC: Treatment administration,FOLFOX4 LV5FU2 Patients randomized11231123 Patients treated11081111 Total no. of cycles11829125

16、06 Mean10.711.3 12 cycles 74.7%86.5% Median Relative Dose Intensity % Oxaliplatin81NA 5-FU8598,Status of the study by treatment arm (ITT population),FOLFOX4LV5FU2,N 1123 1123 Median follow-up range 37.2 26-53 37.1 26-53 Number of events (%) 234 (20.8) 288 (25.6),DFS by treatment arm (ITT),DFS (month

17、s),Probability,Hazard ratio: 0.77 0.65 0.92 p 0.01,FOLFOX4 (n=1123) 77.8% LV5FU2 (n=1123) 72.9%,23% risk reduction in the FOLFOX4 arm,3-year,Disease-Free Survival Stage III patients,Probability,DFS (months),24% risk reduction for stage III patients in the FOLFOX4 arm,Hazard ratio: 0.76 0.62-0.92,FOL

18、FOX4 (n=672) 71.8% LV5FU2 (n=675) 65.5%,3-year,Disease Free Survival Stage II patients,Hazard ratio: 0.82 0.57-1.17,Probability,DFS (months),18% risk reduction for stage II patients in the FOLFOX4 arm,FOLFOX4 (n=451) 86.6% LV5FU2 (n=448) 83.9%,3-year,DFS analysis according to prognostic factors,ITT

19、population Male Female 65 years old 5 Baseline CEA 5 Well/moderately differentiated Poorly differentiated Venous invasion No venous invasion,FOLFOX4 better,LV5FU2 better,MOSAIC: Safety results Toxicity per patient,NCI Gr 3 % FOLFOX4 LV5FU2 (n=1108) (n=1111) Thrombocytopenia 1.6 0.4 Neutropenia 41.0

20、(Gr 4: 12.2) 4.7 Febrile neutropenia 0.7 0.1 Neutropenic sepsis1.10.1 Diarrhea 10.8 6.7 Stomatitis 2.7 2.2 Vomiting 5.9 1.4 Allergy 3.0 0.2 Alopecia (Gr2) 5.0 5.0 All cause mortality 0.5 0.5,MOSAIC:Peripheral sensory neuropathy,Paresthesias FOLFOX4 arm Per patientOne year(n=1108)after Grade 08 %71 % Grade 148.1 %24 % Grade 231.5 %4 % Grade 312.4 %1 %,(NCI version 1),Recovery from grade 3 neuropathy,% of patients with Grade 3,N=137,MOSAIC: Conclusions 1,FOLFOX4 is safe in adjuvant colon cancer All cause mortality under treatment 0.5% in both arms 2% febrile neutropenia Limited GI toxi