如何提高晚期結直腸癌患者的生存期

——化療的合理應用

北京大學臨床腫瘤學院北京腫瘤醫院消化內科沈琳提高晚期結直腸癌（ACRC）生存期的關鍵合理的綜合治療手術與放化療的合理結合化療與其它局部治療手段的合理結合化療的合理性ACRC化療的作用可延長患者生存期改善生活質量新的化療藥物可提高近期有效率，降低毒性反應，合理應用可改善總的生存情況常用藥物5-FU類藥物:5-FU、UFT、

Cape、S-1CPT-11L-OHPMMC

以5-FU類為基礎的聯合方案5-FU/LV+CPT-11/OXA方案CAPE+CPT-11/OXA方案常用化療方案進展期結直腸癌化療進程

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類藥物—是進展期結直腸癌化學治療的基礎和主要組成

5-FUUFTCapeS-1卡培他濱

一種腫瘤內激活的5-FU前體藥物經過三個酶的催化在腫瘤細胞內轉化為5-FU，最后一個是TP（胸腺嘧啶脫氧核苷磷酸化酶）療效與5-FU持續靜脈滴注相似一線治療有效率比Mayo方案高，毒性低主要毒性：腹瀉、手足綜合征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奧沙利鉑(L-OHP)第三代鉑類藥物，克服了一、二代鉑類的主要毒性DACH基團避開了一、二代鉑類的主要耐藥機制，體外實驗顯示對DDP耐藥的結腸癌有效劑量限制性毒性為外周神經毒性單藥一線治療有效率約20%，二線治療有效率約10%與5-FU/LV聯合，一線有效率34%-55%，二線有效率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)拓撲異構酶Ⅰ抑制劑，喜樹堿的半合成衍生物活性產物為SN-38主要毒性為骨髓抑制和延遲性腹瀉單藥一線治療有效率15%-32%，二線治療有效率17%-27%聯合5-FU/LV，一線有效率39%-55%5-FU/FA+/-CPT-11一線治療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=0.0001K?hneH,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=0.0509WilcoxonK?hneH,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)%ofpatientsK?hneHetal,JClinOncol2003IFLFOLFOX0102030F.neutropeniaNauseaVomitingDiarrheaParesthesia%15%16%4%6%28%12%14%3%3%18%40USIntergroupN9741

Toxicitygrade>3forcombinationsP>0.002forallc