AdjuvantChemotherapyforGastricCancer

withS-1,anOralFluoropyrimidine

--ACTS-GCIntroductionMeta-analyseshaveshownthatadjuvantchemotherapyiseffectiveintreatinggastriccancer.However,theeffectivenessofspecificregimenshasnotbeenverifiedinlargeclinicaltrials.BackgroundAdvancedgastriccancercanrespondtoS-1,anoralfluoropyrimidine.WetestedS-1asadjuvantchemotherapyinpatientswithcurativelyresectedgastriccancer.

METHODS

IntheS-1group,administrationofS-1wasstartedwithin6weeksaftersurgeryandcontinuedfor1year.Thetreatmentregimenconsistedof6-weekcyclesinwhich,inprinciple,80mgoforalS-1persquaremeterofbody-surfaceareaperdaywasgivenfor4weeksandnochemotherapywasgivenforthefollowing2weeks.Theprimaryendpointwasoverallsurvival.

EligibilityCriteriaThecriteriaforeligibilitywerehistologicallyprovengastriccancerofstageII,IIIA,orIIIB;D2ormoreextensivelymph-nodedissectionwithR0surgery;nohepatic,peritoneal,ordistantmetastasis;notumorcellsinperitonealfluidoncytologicanalysis;anageof20to80years;noprevioustreatmentforcancerexceptfortheinitialgastricresectionfortheprimarylesion;andadequateorganfunction.

StudyDesignandTreatment

Theprimaryendpointwasoverallsurvival;secondaryendpointswererelapse-freesurvivalandthedegreeofsafetyofS-1.Patientswereenrolled,within6weeksaftersurgeryandrandomlyassignedtoeithertheS-1grouporthesurgery-onlygroup.

RESULTSWerandomlyassigned529patientstotheS-1groupand530patientstothesurgeryonlygroupbetweenOctober2001andDecember2004.Thetrialwasstoppedonthe

recommendationoftheindependentdataandsafetymonitoringcommittee,because

thefirstinterimanalysis,performed1yearafterenrollmentwascompleted,showedthattheS-1

grouphadahigherrateofoverallsurvivalthanthesurgery-onlygroup

(P=0.002).

RESULTSAnalysisoffollow-updatashowedthatthe3-yearoverallsurvivalratewas80.1%intheS-1groupand70.1%inthesurgery-onlygroup.ThehazardratiofordeathintheS-1group,ascomparedwiththesurgery-onlygroup,was0.68(95%confidenceinterval,0.52to0.87;P=0.003).

RESULTSAdverseeventsofgrade3orgrade4(definedaccordingtotheCommonToxicityCriteriaoftheNationalCancerInstitute)thatwererelativelycommonintheS-1groupwereanorexia(6.0%),nausea(3.7%),anddiarrhea(3.1%).OverallSurvivalandRelapse-FreeSurvivalOverallSurvivalandRelapse-Free

SurvivalTherateofrelapse-freesurvivalat3yearswas72.2%intheS-1group

and59.6%inthesurgery-onlygroup.Amongeligiblepatients,thehazardratiofordeathintheS-1group,ascomparedwiththesurgery-onlygroup,was0.66.

OverallSurvivalandRelapse-Free

Survival

SiteofFirstRelapseInthesurgery-onlygroup,84patients(15.8%)hadperitonealrelapse,and46patients(8.7%)hadlymph-noderelapse.IntheS-1group,59patients(11.2%)hadperitonealrelapse,and27(5.1%)hadlymph-noderelapse.

SubgroupAnalysis

Theoverallsurvivalofeligiblepatientswasanalyzedaccordingtosex,age,cancerstage,tumorstage,nodalstage,andhistologictype.Therewasnosignificantinteractionbetweenthetreatmentgroupandanyofthevariablesstudied.HazardRatiosforDeathandPValuesfortheInteractionofTreatmentGroupandBaselineCharacteristicamongEligiblePatients.TheINT-0116study,showedthatadjuvantchemoradiotherapyprolongedoverallsurvivalandrelapse-freesurvival.MostpatientsintheINT-0116studyunderwenteitherD0orD1surgery,withonly10%undergoingD2surgery.ThecharacteristicsofpatientsintheINT-0116studydifferedfromthoseinourtrial.DISCUSSION

IntheMAGICtrial,conductedmainlyintheUnitedKingdom,perioperativeandpostoperativechemotherapywithepirubicin,cisplatin,andinfusedfluorouracilsignificantlyprolongedoverallsurvivalandrelapse-freesurvival.Inthatstudy,D2surgerywasnotperformedasastandardprocedure.DISCUSSION2.Thesurvivalrate3yearsaftersurgerywas80.5%intheS-1groupand70.1%inthesurgery-onlygroup.Theresultsmaychangemarginallyatthe5-yearfollow-up.However,thenumberofeventsinthesurgery-onlygrouphasalreadyreachednearly80%ofthatinitiallypredictedfor5years.DISCUSSION3.AlthoughithassometimesbeensuggestedthattheremaybedifferencesincertainaspectsofgastriccancerinJapanandtheWest,therehavebeennosignificantdifferencesidentifiedbetweenJapanandtheUnitedKingdomwithregardtopossiblegeneticinfluencesorbetweenJapanandEuropeancountriesinthedistributionofimportantprognosticfactors.DISCUSSION

Moreover,Italianinvestigatorshavereportedthatpancreas-preservingD2dissectionperformedatcenterswithexperienceinthisprocedurecanprovideasurvivalbenefit.IfadequateD2dissectionwereperformed,webelievethattreatmentoutcomesinWesterncountrieswouldbesimilartothoseinJapan.WeacknowledgethattheresultsofourtrialmaynotbevalidincountrieswhereD2surgeryisnotconsideredthestandardoperation.DISCUSSIONDISCUSSIONDISCUSSIONS-1單藥輔助化療在ⅢB期胃癌患者中未達到統計學差異，而且還看到單藥S-1與單純手術