交大沈琳教授讲课

如何提高晚期结直肠癌患者的生存期

——化疗的合理应用

北京大学临床肿瘤学院北京肿瘤医院消化内科沈琳提高晚期结直肠癌（ACRC）生存期的关键合理的综合治疗手术与放化疗的合理结合化疗与其它局部治疗手段的合理结合化疗的合理性ACRC化疗的作用可延长患者生存期改善生活质量新的化疗药物可提高近期有效率，降低毒性反应，合理应用可改善总的生存情况常用药物5-FU类药物:5-FU、UFT、

Cape、S-1CPT-11L-OHPMMC

以5-FU类为基础的联合方案5-FU/LV+CPT-11/OXA方案CAPE+CPT-11/OXA方案常用化疗方案进展期结直肠癌化疗进程

RR

10%

20%20-30%

50%±1960-851985-901990-20002000-5-fuFTHCFULF+OXA/IRICAPE+OXA/IRIBioLV/5FU（ci）S-1CAPENew-AdjLV/5FU（b）UFTDFURAdjCPT-11,Oxa，Cape,S-1BiotherapeuticsOS

9-11m10-12m14m>16m

OS>24m5-FU类药物—是进展期结直肠癌化学治疗的基础和主要组成

5-FUUFTCapeS-1卡培他滨

一种肿瘤内激活的5-FU前体药物经过三个酶的催化在肿瘤细胞内转化为5-FU，最后一个是TP（胸腺嘧啶脱氧核苷磷酸化酶）疗效与5-FU持续静脉滴注相似一线治疗有效率比Mayo方案高，毒性低主要毒性：腹泻、手足综合征Capecitabinevs5-FU/FA1°lineMCRC

—phaseIIItrials：responserate

VanCutsemEetal,BritJCancer2004TwelvesC.EurJCancer2002Capecitabinemonotherapy:

equivalentTTPtoi.v.5-FU/LVVanCutsemEetal,BritJCancer2004

0 5 10 15 20 254.64.71.00.80.60.40.20.0EstimatedprobabilityHazardratio=0.997

Capecitabine(n=603)5-FU/LV(n=604)MonthsCapecitabinemonotherapy:

equivalentOStoi.v.5-FU/LV12.812.9Xeloda(n=603)5-FU/LV(n=604)VanCutsemEetal,BritJCancer2004 0 5 10 15 20 25 30 35 40 45Months1.00.80.60.40.20.0EstimatedprobabilityHazardratio=0.96Capecitabine(n=596)5-FU/LV(n=593)Patients(%)*p<0.0001***Grade3/4treatment-relatedAEsCapecitabinevs5-FU/FA:safetyprofile*403020100NeutropeniaNeutropenic

fever+sepsisVomitingNauseaHand-foot

syndromeStomatitisDiarrhoeaCassidyJetal.AnnOncol2002;13:566–75VanCutsemEetal,BritJCancer2004奥沙利铂(L-OHP)第三代铂类药物，克服了一、二代铂类的主要毒性DACH基团避开了一、二代铂类的主要耐药机制，体外实验显示对DDP耐药的结肠癌有效剂量限制性毒性为外周神经毒性单药一线治疗有效率约20%，二线治疗有效率约10%与5-FU/LV联合，一线有效率34%-55%，二线有效率10%-30%5-FU/FA+/-oxaliplatininmetastaticCRC:1°linetreatment.

ASCO2003-Randomizedphase3secondlinestudy-EFC4584

Accrual:816patientswithmetastaticCRCwithPDon orwithin6moafterIFL Primaryendpoint:overalsurvival

infusional5-FU/LVLV5FU2

oxaliplatinOXALI

infusional5-FU/LV+OxaliplatinFOLFOX4

RothenbergMetal,JClinOncol2003

RANDOMIZEASCO2003-Randomizedphase3secondlinestudy-EFC458428**1015Symptomaticrelief(%)9.6**1.10.7Resp.rate(%)5.6**1.92.6Med.TTP(m.)9.8*8.18.7Med.surv.(m.)FOLFOX4(N=270)OXALI(N=274)LV5FU2(N=272)RothenbergMetal,JClinOncol2003*p-valuecomparedtoLV5FU2:0.07;**p-value:<0.05CPT-11(伊立替康)拓扑异构酶Ⅰ抑制剂，喜树碱的半合成衍生物活性产物为SN-38主要毒性为骨髓抑制和延迟性腹泻单药一线治疗有效率15%-32%，二线治疗有效率17%-27%联合5-FU/LV，一线有效率39%-55%5-FU/FA+/-CPT-11一线治疗mCRC.p<0.0520.116.98.5*6.454*315-FU/FA/irinotecan5-FU/FA(AIO)EORTC-ASCO2003p<0.0514.8*12.812.07.0*4.34.239*21185-FU/FA/irinotecan5-FU/FA(Mayo)irinotecanSaltzNEJM2000p<0.0517.4*14.16.7*4.441*235-FU/FA/irinotecan5-FU/FA(LV5FU2/AIO)DouillardLancet2000PMedSurvmoTTP/PFSmoRR%RegimenEORTC40986:Progressionfreesurvival(PFS)

(majorstudyendpoint)

(months)061218243036420102030405060708090100NNumberofpatientsatrisk:2161103182002131445718621HDFU/FAHDFU/FA/CPT11

Median [95%CI]AIO+IRI 8.5mo [7.6–9.6]AIO 6.4mo [5.3–7.2]P=0.0001KöhneH,VanCutsemEetal,ProcASCO2003EORTC40986:OverallSurvival

(SecondaryEndpoint)

(months)061218243036420102030405060708090100NNumberofpatientsatrisk:216186136884316421419615310452184HDFU/FAHDFU/FA/CPT11

Median 95%CIAIO+IRI 20.1 [18.0–21.9]AIO 16.9 [15.3–19.0]

p=0.2779log-rankp=0.0509WilcoxonKöhneH,VanCutsemEetal,ProcASCO2003Secondlinetreatment:irinotecanin

5-FUresistantCRC:phaseIIIstudies

*p=0.0001;**p=0.035

Cunninghametal,Lancet1998;Rougier,VanCutsemetal,Lancet1998XELIRIinfirst-lineMCRC:

USphaseIIstudy(n=52)Male/female(%)=56/44;medianage=58yearsPrimarytumour=84%colon,12%rectum,4%both14patients65treatedat750/200Irinotecan250mg/m2

asa90-minutei.v.infusionXeloda

1,000mg/m2twicedailyRepeatcycleatday22DayDay1(pm)–15(am)Rest181521PattYZetal.EurJCancer2003;1(Suppl.5):S93(Abst304)Xeliri:ResponseratePatients(%) Overall Yes No £80 >80 <60 ³60 (Neo)adjuvant KPS Age

chemotherapy n=52 n=10 n=42 n=15 n=35 n=30 n=22PattYZetal.EurJCancer2003;1(Suppl.5):S93(Abst304)605040302010045305032525142Xeliri:timetodiseaseprogression1.00.80.60.40.20.00 2 4 6 8 10 12 14 16 18 20MonthsEstimatedprobabilityTTP:7.1(95%CI:5.0–11.1)PattYZetal.EurJCancer2003;1(Suppl.5):S93(Abst304)XELIRIandFOLFIRIorIFLregimens:similarefficacy?1PattYZetal.EurJCancer2003

2GoldbergRetal.JClinOncol2004

3DouillardJYetal.Lancet2000Patients(%)*Nograde4eventsXELIRI:incidenceofgrade3/4AENotreatment-relateddeathsPattYZetal.EurJCancer2003;1(Suppl.5):S93(Abst304)100806040200 Nausea/ Diarrhoea* Hand-foot Abdominal Neutropenia

vomiting syndrome* pain*1PattYZetal.EurJCancer2003 2GoldbergRetal.JClinOncol2004; 3DouillardJYetal.Lancet2000XELIRI:favourablesafetyprofilecomparedwithFOLIRIorIFLregimensOXAvsCPT-11inmCRCUSIntergroupstudy-N9741

Accrual:795patientsin1°linemetastaticCRC (initially6armstudy)Primaryendpoint:TTPofFolfoxandIroxvsIFL

bolus5-FU/LV+CPT-11IFL infusional5-FU/LV+OxaliplatinFOLFOX4 CPT-11/Oxaliplatin IROX

GoldbergRetal,JClinOnc2004

RANDOMIZE

USIntergroupstudy-N9741GoldbergRetal,JClinOncol2004USIntergroup:OverallSurvivalGoldbergRetal,JClinOncol2004USIntergroupstudy–N9741:

post-trialtreatment50%40%41%5-FU9%8%24%Oxaliplatin32%60%25%CPT-1170%75%67%ReceivedtreatmentOxaliplatin+CPT-11(N=262)FOLFOX(N=259)IFL(N=251)GoldbergRetal,JClinOncol2004

5-FU24h5-FU24h/LV-AIO 5-FUBolus/LV-MayoMedian(months) 4.4 6.4 4.1p=0.04p=0.02p=0.7

EORTC40952:ProgressionFreeSurvival(ITTpopulation)%ofpatientsKöhneHetal,JClinOncol2003IFLFOLFOX0102030F.neutropeniaNauseaVomitingDiarrheaParesthesia%15%16%4%6%28%12%14%3%3%18%40USIntergroupN9741

Toxicitygrade>3forcombinationsP>0.002forallc