李進(jìn)晚期大腸癌方案選擇PPT學(xué)習(xí)教案

1、會(huì)計(jì)學(xué)1李進(jìn)晚期大腸癌方案選擇李進(jìn)晚期大腸癌方案選擇第1頁/共37頁第2頁/共37頁第3頁/共37頁mFOLFOX6XELOXmFOLFIRI第4頁/共37頁De Gramont et al., ASCO 20046x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7FOLFOX4623 例例 R總劑量總劑量 Oxa7801560 FOLFOX4 FOLFOX7RR (%) 58.5 58.3PFS 9.0 9.2OS 20.0 21.6G3/4 神經(jīng)毒性神經(jīng)毒性 18.7 13.3第5頁/共37頁OPTIMOX-1OPTIMOX-2P 值ORR60%59%NS2nd ORR

2、21%25%NS奧沙利鉑再應(yīng)用52%60%NSPFS(周)36290.08OS(月)24.618.90.05第6頁/共37頁XELOX +placebo (n=350)FOLFOX4 +placebo (n=351)XELOX +Avastin(n=350)FOLFOX4 +Avastin(n=349)XELOX (n=317)FOLFOX4 (n=317)(n=634)方案修正為方案修正為 2x2 安慰劑對(duì)照的安慰劑對(duì)照的III期臨床研究期臨床研究 (n=1400)入組病人入組病人Feb 2004Feb 2005Cassidy et al. ASCO GI 2009第7頁/共37頁Estim

3、ated probability *ITT populationCassidy et al. ASCO GI 2009MonthsXELOX/XELOX + placebo/XELOX + Avastin(n=1017)FOLFOX4/FOLFOX4 + placebo/FOLFOX4 + Avastin(n=1017)HR=0.95 (97.5% CI: 0.85 1.06)1.00.80.60.40.20.00102030405060總分析總分析與貝伐聯(lián)合與貝伐聯(lián)合Months0102030405060Estimated probabilityXELOX + Avastin(n=350)F

4、OLFOX4 + Avastin(n=349)HR=0.95 (97.5% CI: 0.78 1.15) 最初的研究最初的研究XELOX(n=317)FOLFOX4(n=317)HR=0.87 (97.5% CI: 0.72 1.05) 1.00.80.60.40.20.0Months0102030405060Estimated probability無貝伐組無貝伐組XELOX/XELOX + placebo(n=667)FOLFOX4/FOLFOX4 + placebo(n=668)HR=0.95 (97.5% CI: 0.83 1.09) Months0102030405060Estima

5、ted probabilityX+PF+PX+AF+AXFX+PF+PX+AF+AXFX+PF+PX+AF+AXFX+PF+PX+AF+AXF1.00.80.60.40.20.01.00.80.60.40.20.0第8頁/共37頁0204060病人病人 (%)腹瀉腹瀉神經(jīng)毒性神經(jīng)毒性靜脈血栓靜脈血栓手足綜合癥手足綜合癥心臟毒性心臟毒性粒細(xì)胞減少粒細(xì)胞減少發(fā)熱性粒缺發(fā)熱性粒缺XELOX 或或 XELOX+安慰劑安慰劑 (n=655)FOLFOX4 或或 FOLFOX4+安慰劑安慰劑 (n=649) *Safety populationCassidy et al. ASCO GI 2009第9頁/

6、共37頁 轉(zhuǎn)移病灶轉(zhuǎn)移病灶是否能創(chuàng)造再次手術(shù)的機(jī)會(huì)是否能創(chuàng)造再次手術(shù)的機(jī)會(huì)? ?第10頁/共37頁手術(shù)與非手術(shù)措施的對(duì)比生生存存概概率率治治 療療手術(shù)切除（手術(shù)切除（n=340）局部化療（局部化療（n-123）全身化療（全身化療（n=70）無治療（無治療（n=484）診斷后年數(shù)診斷后年數(shù)Stangl R et al. Lancet 1994;343:1405-10第11頁/共37頁入組病人入組病人:晚期或復(fù)發(fā)晚期或復(fù)發(fā)RFOLFIRICPT-11 180 mg/m2 d1LV 100 mg/m2 d1,25-FU 400 mg/m2 靜注靜注 d1,25-FU 600 mg/m2 22h d1

7、,2FOLFOXIRICPT-11 165 mg/m2 Oxali 85 mg/m2 LV 200 mg/m2 5-FU 3200 mg/m2 48hFalcone et al., ASCO 2007第12頁/共37頁FOLFIRIN=122FOLFOXIRIN=122P-valueRR* (%)34600.0001CR+PR+SD* (%)6881R0 切除(%) (所有病人)6150.033R0 切除 (%) (肝臟)12360.017PFS (月)6.99.80.0006OS (月)16.723.60.042* 獨(dú)立評(píng)價(jià)獨(dú)立評(píng)價(jià); 67% 2 線線 FOLFOXFalcone et al

8、., ASCO 2007第13頁/共37頁目的：1.提高手術(shù)切除率2.降低術(shù)后復(fù)發(fā)率第14頁/共37頁第15頁/共37頁隨隨機(jī)機(jī)分分組組手術(shù)手術(shù)FOLFOX4FOLFOX4手術(shù)手術(shù)6 周期周期 (3 月月)病例數(shù)病例數(shù)=364 病人病人6 周期周期(3 月月)第16頁/共37頁接受化接受化療療接受手接受手術(shù)術(shù)% 3-年年 PFS絕對(duì)差異絕對(duì)差異HazardRatio (Confidence Interval)P-value所有患者所有患者182182+7.3% (28.1% to 35.4%)0.79(0.62-1.02)P=0.058符合條件符合條件患者患者171171+8.1% (28.1

9、% to 36.2%)0.77 (0.60-1.00)P=0.041切除患者切除患者151152+9.2% (33.2% to 42.4%)0.73(0.55-0.97)P=0.025第17頁/共37頁Wong, et al. ECCO-ESMO 2009 (abstract No. 6076)第18頁/共37頁有效率有效率, 例數(shù)例數(shù) (%)CRPRSDPDORR , N (%)95% CI4 (9)31 (69)7 (16)3 (7)35 (78)6389生存生存中位中位 PFS, 月月6個(gè)月個(gè)月 PFS, %12個(gè)月個(gè)月 PFS, %1-年年 OS, %12.0735086Wong, e

10、t al. ECCO-ESMO 2009 (abstract No. 6076)第19頁/共37頁不良事件不良事件, (n=46) 3度度 4度度貧血貧血白細(xì)胞減少白細(xì)胞減少感染感染惡心嘔吐惡心嘔吐腹瀉腹瀉乏力乏力手足綜合癥手足綜合癥外周神經(jīng)毒性外周神經(jīng)毒性1 4418114500000000胃腸穿孔胃腸穿孔靜脈血栓靜脈血栓高血壓高血壓122020Wong, et al. ECCO-ESMO 2009 (abstract No. 6076)第20頁/共37頁Wong, et al. ECCO-ESMO 2009 (abstract No. 6076)第21頁/共37頁NCCN專家的建議:第22

11、頁/共37頁第23頁/共37頁Crystal：無進(jìn)展生存期分析Progression-free survival time (months)PFS estimate1.00.80.90.00.10.20.30.40.50.60.702468101214161820HR = 0.851; 95% CI = 0.726-0.998Stratified log-rank p-value = 0.04798.9 mo8.0 moFOLFIRI, n=599Cetuximab + FOLFIRI, n=5991-year PFS rate23% vs 34%Subjects at riskFOLFIRI

12、 alone 599492402293178833516741Cetuximab + FOLFIRI59949939229819610358291251 2007.ASCO annual meeting .Abstract No.4000第24頁/共37頁總生存的分層分析(wK-ras)第25頁/共37頁第26頁/共37頁西妥昔加西妥昔加 FOLFOX4 對(duì)照對(duì)照 FOLFOX4(n=179)OS, 月月22.8 vs 18.5 (HR=0.855; p=0.3854)PFS, 月月8.3 vs 7.2 (HR=0.567; p=0.0064)ORR, %57.3 vs 34.0(OR=2.5

13、512; p=0.0027)Bokemeyer et al. ECCO-ESMO 2009 (abstract No. 6079) 第27頁/共37頁Continuous* XELOX 或或 FOLFOXArm AR一線治療一線治療 mCRC( 2445例例)Arm BContinuous XELOX or FOLFOX + 西妥昔西妥昔Arm CIntermittent*XELOX 或或 FOLFOX65% XELOX; 35% FOLFOX(根據(jù)患者或醫(yī)生的選擇根據(jù)患者或醫(yī)生的選擇)Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)第28頁

14、/共37頁OutcomeXELOX/FOLFOX + 西妥昔西妥昔(n=362)XELOX/FOLFOX(n=367)HR (95% CI)PFS,月月8.68.60.959 (0.841.09)p=0.60OS, 月月17.017.91.038 (0.901.20)p=0.6812周周ORR%59501.44* p=0.015*Odds ratioMaughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)第29頁/共37頁1.000.750.500.250生存生存時(shí)間時(shí)間(月月)野生型患者 PFSITT analysisNo. at riskArm

15、A Arm B0612182430364236736124524992103414218221196610Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + 西妥昔西妥昔)Arm A Arm BDiff.中位 PFS,8.68.6+0.07HR point estimate = 0.95995% CI 0.841.09p=0.60第30頁/共37頁生存曲線1.000.750.500.250生存概率生存概率Time (months)06121824303642No.

16、 at riskArm AArm B36736231630625023815414983804442191713ITT analysisMaughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + 西妥昔西妥昔)Arm AArm BDiff.中位 OS, 17.917.00.922-年生存, %36.134.4-1.66HR point estimate = 1.03895% CI 0.901.20p=0.68第31頁/共37頁IFL推注 5-FU 500 mg/m2亞葉酸

17、鈣 20 mg/m2依立替康 125 mg/m2用藥 4/6 周疾病進(jìn)展后疾病進(jìn)展后不接受貝伐單抗治療不接受貝伐單抗治療Hurwitz H, et al. N Engl J Med 2004;350:2335425-FU/LV推注推注5-FU 500 mg/m2 亞葉酸鈣亞葉酸鈣 500 mg/m2 用藥用藥6/8周周貝伐單抗5 mg/kg 每2周1次先前未曾治療的轉(zhuǎn)移性 CRCPDPDPD推注IFL + 安慰劑（n=412）推注IFL + 貝伐單抗（n=403）5-FU/LV +貝伐單抗 （n=110）疾病進(jìn)展后疾病進(jìn)展后可接受貝伐單抗治療可接受貝伐單抗治療疾病進(jìn)展后疾病進(jìn)展后可接受貝伐單抗治療可接受貝伐單抗治療第32頁/共37頁0.2010203000.81.00.40.6Progression-free survival (mo)Proportion progression-freeTreatment GroupIFL + placeboIFL + bevacizumabHurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646 and oral presentation.Avastin PI.HR=0.54, P0.00001mPFS: 6.2 10.6 mo第33頁/共37頁HR=0.66, P=0