霍奇金淋巴瘤治療進展

霍奇金淋巴瘤治療進展霍奇金淋巴瘤治療進展第1頁1960’s1970’s1980’s1990’s10yJoeConnors霍奇金淋巴瘤治療進展第2頁不一樣預(yù)后組治療療效:EuropeandNorth-America

Europe

Stage CureRates(GSHGandEORTC)早期預(yù)后良好組

CSI,IIA,Bnoriskfactors 98%早期預(yù)后不良組

CSI,IIA,Bwithriskfactors 93% 進展期

CSIII–IV,SelectedCSIIB

withABVD(NorthAmerica)

65-80%

(intermediate)霍奇金淋巴瘤治療進展第3頁霍奇金淋巴瘤治療進展第4頁

CausesofDeathamong2733PatientswithHodgkin’sDisease(1960-97)Hodgkin’sDisease 383 41.2%SecondaryCancers 200 21.5%MDS 11 1.2%Cardiovascular 148 15.9%Pulmonary 41 4.4%Infection 35 3.8%Trauma/Suicide 16 1.7%Other/Unknown 96 10.3%Total 930 100.%

Stanford,R.Hoppe霍奇金淋巴瘤治療進展第5頁Didwelearnfromourmistakes

over40years?霍奇金淋巴瘤治療進展第6頁個體化治療！對于早期患者怎樣在確保療效情況下盡可能降低副作用？能否深入降低化療療程？減小放療劑量？晚期患者怎樣深入提升治愈率？霍奇金淋巴瘤治療進展第7頁早期預(yù)后良好組: CSI/II無不良預(yù)后原因早期預(yù)后不良組: CSI/II有不良預(yù)后原因*進展期: CSIII/IV;CSIIB(LMM)*a)bulk;b)E-lesion;c)highESR;d)>=3involvedareasGHSG–臨床預(yù)后分組霍奇金淋巴瘤治療進展第8頁預(yù)后不良(Unfavorable)早期HL年紀≥50歲≥4個淋巴結(jié)區(qū)域受侵單獨ESR≥50B癥狀和ESR≥30縱隔大腫塊，或腫塊直徑大于10cm≥2個結(jié)外部位受累霍奇金淋巴瘤治療進展第9頁預(yù)后良好(Favorable)早期HL不符合預(yù)后不良組條件其它臨床I/II期HL霍奇金淋巴瘤治療進展第10頁

HodgkinLymphoma:

早期預(yù)后不良組

Islessmore?尋找高效和低毒間最正確平衡點霍奇金淋巴瘤治療進展第11頁CSI–IIwithoutriskfactorsABVDABVD30GyIFABVDABVDABVDABVDABVDABVDABVDABVDABVDABVD30GyIF20Gy

IF20Gy

IF:1375patientsrecruited.Trialclosed1/.早期預(yù)后良好組

:

GHSG:

HD10-Trial

霍奇金淋巴瘤治療進展第12頁HD10,4thInterimAnalysis,August1OS(CT-Comparison)5764xABVD561534454323208925762xABVD2.56152246433820097Pts.atRiskOverallSurvival[months]4xABVD2xABVDProbability0.00.10.20.30.40.50.60.70.80.91.0012243648607284

OSratesand95%CIat5years*: 4xABVD: 97%; [95%;98%] 2xABVD:96%; [94%;98%]霍奇金淋巴瘤治療進展第13頁HD10,4thInterimAnalysis,AugustSurvivalcurvesareKaplan-Meierestimates.Medianobservationtimeis53months,N=1109OS(RT-Comparison)

55330Gy54551343932520610055620Gy54351145331418680Pts.atRiskOverallSurvival[months]30Gy20GyProbability0.00.10.20.30.40.50.60.70.80.91.0012243648607284

OSratesand95%CIat5years: 30Gy: 97%; [95%;98%] 20Gy:96%; [94%;98%]霍奇金淋巴瘤治療進展第14頁HD10結(jié)論2×ABVDisnon-inferiorto4×ABVD20GyIF-RTisnon-inferiorto30GyIF-RT

霍奇金淋巴瘤治療進展第15頁HD13Trial:早期無不良預(yù)后

問題降低化療療程可能性?DoweneedbleomycinanddacarbacininABVD?霍奇金淋巴瘤治療進展第16頁CSI/IIwithoutRF*ABVDABVDABVABVAVDAVDAVAV30GyIF30GyIF30GyIF30GyIF*Largemediastinalmass;extranodaldisease;highERS;3ormoreareasinvolvedHD13Trialforpatientswithearlyfavourablestage

Design霍奇金淋巴瘤治療進展第17頁FFTFat18months 91%,95%CI[88,94]OSat18months 100%,95%CI[99,100]OverallSurvivalandFFTF

Medianobservationtime:18months霍奇金淋巴瘤治療進展第18頁HD16Trial:早期預(yù)后良好組

Questions對于反應(yīng)良好者化療是否足夠?霍奇金淋巴瘤治療進展第19頁CSI/IIwithoutRF*2xABVDPET-30GyIF2xABVDPET+2xABVDPET(+/-)Followup30GyIFStandardArmExperimentalArms*a)largemediastinalmass;b)extranodaldisease;c)highERS;d)3ormoreareasHD16Trialforpatientswithearlyfavourablestage

PlannedDesignwithPET霍奇金淋巴瘤治療進展第20頁早期患者

聯(lián)合治療VS單化療聯(lián)合ABVDTotal2673（9trials）330（3trials）EFS80~99%（84%）89.5，86，87%OS88~99%（94%）90,96,96霍奇金淋巴瘤治療進展第21頁早期預(yù)后良好患者2ABVD+20GyIF-RT是標準治療！單化療、減藥化療+放療尚待隨機研究結(jié)果霍奇金淋巴瘤治療進展第22頁Earlyfavourablestages: CSI/IIwithoutrisikfactor*Earlyunfavourablestages: CSI/IIwithrisikfactor*Advancedstages: CSIII/IV;CSIIB(LMM)*a)bulk;b)E-lesion;c)highESR;d)>=3involvedareasGHSG–ClinicalRiskGroups霍奇金淋巴瘤治療進展第23頁HodgkinLymphoma

IntermediateStages

Fact:Combinedchemo-andradiotherapyislargelyconsideredasstandard:4ABVD+30GyIF-RTResult:90%tumorfreesurvivalafter5years93%overallsurvivalafter5years霍奇金淋巴瘤治療進展第24頁HD14Trialforpatientswithearlyunfavourablestage

Questions1)BetterResultswithintensifiedchemotherapy?霍奇金淋巴瘤治療進展第25頁HD14Trialforpatientswithearlyunfavourablestage

DesignStagesI,IIAwithRFa-d;IIBwithRFc,dBEACOPPescalatedBEACOPPescalated

ABVDABVDABVDABVDABVDABVD30GyIF30GyIF*a)bulk;b)extranodaldisease;c)highERS;d)3ormoreareas1450patsrecruitedsince霍奇金淋巴瘤治療進展第26頁HD14Trialforpatientswithearlyunfavourablestage

FFTFandOSAt18months FFTF: 93%

95%CI:[90;96]

OS: 100%

95%CI:[99;100]GHSG04/霍奇金淋巴瘤治療進展第27頁EORTCTrials:H10+H11StandardArm :3ABVD+30GyIF-RT Neg1ABVDnoRTPos2BEACOPPesc+RTEarlyFavorable:H102ABVDPETNeg+2ABVDnoRTEarlyUnfavorable:H112ABVD

PETExperim.ArmExperim.ArmStandardArm

4ABVD+30GyIF-RT霍奇金淋巴瘤治療進展第28頁HodgkinLymphoma

EarlyandIntermediateStages

Summary

TheGHSGexperience

Standardoutsideclinicaltrials:

Earlyfavorable:2ABVD+20GyIF-RT

Earlyunfavorable:4ABVD+20-30GyIF-RT(intermediate)

霍奇金淋巴瘤治療進展第29頁Earlyfavourablestages: CSI/IIwithoutrisikfactor*Earlyunfavourablestages: CSI/IIwithrisikfactor*Advancedstages: CSIII/IV;CSIIB(LMM)*a)bulk;b)E-lesion;c)highESR;d)>=3involvedareasGHSG–ClinicalRiskGroups霍奇金淋巴瘤治療進展第30頁HodgkinLymphoma

AdvancedStages

CurrentPracticeIntensiveChemotherapyCR:noRT PR:30GyIF-RT

Chemotherapy:IF-RT

6-8ABVD(45%RT) Or 6-8BEACOPP(<15%RT)

霍奇金淋巴瘤治療進展第31頁AdvancedStages:

-ABVD-

theGoldStandard??

No!

Itisnot!

Atleastnotforallriskgroups!霍奇金淋巴瘤治療進展第32頁Long-TermFollow-upAdvancedHL:onlystagesIIB-LMM,III,IV!!Failure-freesurvivalOverallsurvivalYearsafterstudyentryCanellosetal.NEJM,霍奇金淋巴瘤治療進展第33頁FourthGenerationRegimens:

aretheysuperiortoABVD??

1.StanfordV2.ClVP/EVA

3.MEC(Gobbi:10drugregimen!)(JCO)

4.BEACOPP霍奇金淋巴瘤治療進展第34頁GobbiPG,etal.JClinOncol.;23(36):9198-9207.EpubSeptember19.MOPP-EBV-CAD:Meclorethamine,CCNU,Vindesine,Alkeran,Prednisone,Epidoxorubicin,Vincristine,Procarbazine,Vinblastine,Bleomycin355patients,RTbulk+residualdisease.ABVD

vs

StanfordV

vs

MEC

Logrank27.48 P<0.0001Logrank3.05 P=0.22FFS(%)OS(%)FFS(%)Time,MonthsTime,MonthsMECABVDStanfordV霍奇金淋巴瘤治療進展第35頁ItalianStudy

AdvancedHodgkinLymphoma

ABVD vs

4BEACOPP-esc+4BEACOPP-base vs

MEC

(Italian10drugregimen)霍奇金淋巴瘤治療進展第36頁

ChemotherapyRadiotherapyCT-Intensity

ABVDBEAescStanfordVAdvancedHL(5-10%)(45%)(90%)RTIntensityNeedforRT:霍奇金淋巴瘤治療進展第37頁BBleomycinEEtoposideAAdriamycinCCyclophos.OVincristinPProcarbazinPPrednisonBasis[mg/m2]10100256501,410040TheBEACOPP-schedule

Escalated[mg/m2]102003512501,410040G-CSFsc123456789101112131415

22

restart霍奇金淋巴瘤治療進展第38頁CSIIB-IIIAwithriskfactorsCSIIIB-IVArmA4

×COPP+ABVD

RTArmB8×BEACOPP

baseline

RTArmC8×

BEACOPPescalated*

RTRTtoinitialbulkandresidualtumorGHSG:HD9TrialDesign(1992-96)*withG-CSFRandomisationDiehletal,NEJM,霍奇金淋巴瘤治療進展第39頁HD9-10ysFFTFbytreatmentarmLog-ranktests:AvBvC p<0.0001AvB p=0.040BvC p<0.0001AvC p<0.0001

BEAescC/ABVD82%64%霍奇金淋巴瘤治療進展第40頁GHSGHD9HD9-10ys-OSbytreatmentarmLog-ranktests:AvBvC p=0.0005AvB p=0.19BvC p=0.0053AvC p<0.0001

BEAescC/ABVD86%75%霍奇金淋巴瘤治療進展第41頁OverallSurvival(years)Probability1098765432101,00,90,80,70,60,50,40,30,20,10,0onlyalkylatingagents(1965)notreatment(1940)BEACOPPescC/ABVD1988

BEACOPPbaseline1998HodgkinLymphomaProgressinthetreatmentofadvancedstagesGHSGdata10%resttocureC/MOPP1978霍奇金淋巴瘤治療進展第42頁OpenQuestions:1.Howtoidentifythegoodandbadriskgroupsatdiagnosis?2.Howcanweavoid30%progressionandrelapses?霍奇金淋巴瘤治療進展第43頁OverallSurvival(years)Probability1098765432101,00,90,80,70,60,50,40,30,20,10,0HodgkinLymphoma:AdvancedStagesHowtoidentifythegoodandbadriskgroupsatdiagnosis?70%ofpatientscuredwithABVD:-30%failureswithABVD霍奇金淋巴瘤治療進展第44頁

Whatarethediscriminatingfactorsatdiagnosis?

IPSandPET

Tailortherapyusing

-IPS

asriskindicatorfortherapyfailure

-PET

asearlyresponseindicator!

IsPETcorrelatedto–

orindependentofIPS?霍奇金淋巴瘤治療進展第45頁Tailortherapyaccordingtotheriskoffailure-

usingthe

InternationalPrognosticScore(IPS)

I.IPS霍奇金淋巴瘤治療進展第46頁PrognosticFactorsinAdvancedStages

ResultsoftheInternationalPrognosticFactorsProject(IPS)IPS:

Patient

Age >45years Sex Male

Tumor

StageIV

LaboratoryVariables

Anemia Hgb<10.5g/dL Albumin <4g/dL Leukocytosis >15,000/mm3 Lymphopenia <600/mm3or

<8%ofleukocytesHasencleverD,DiehlV.NEnglJMed.1998;339(21):1506-1514.霍奇金淋巴瘤治療進展第47頁SurvivalratesaccordingtoIPSat10ysFFTFOS

(%,10y)C/ABVDn=261BEAbasen=469BEAescn=466log-rankp(Avs.C)IPS0-1n=3077888798591940.0150.27IPS2-3n=464597371848387<0.00010.0027IPS4-7n=1705461566371700.0200.16GHSGHD9Freqency28%40%13%霍奇金淋巴瘤治療進展第48頁II.PET

TailortherapyusingPETasearlyresponseindicator!

Is

PET

correlatedto

–

orindependentofIPS?霍奇金淋巴瘤治療進展第49頁260patients–2-yFFSGallaminiA,HutchingsM,RigacciL,etal.:JCO,accepted.After2ABVD霍奇金淋巴瘤治療進展第50頁260patients-PETvs.IPSGallaminiA,HutchingsM,RigacciL,etal.:JCO,accepted.PETafter2ABVD霍奇金淋巴瘤治療進展第51頁BEACOPPescalatedHodgkinLymphomaAdvancedStages

HowtoIdentifytheGood&BadRiskGroups?OverallSurvival(y)Probability1098765432101.00.80.60.40.20.0Onlyalkylatingagents(1965)Notreatment(1940)C/ABVD

BEACOPPbase30%failureswithABVD

IPS3–7

PETpositiveafter2ABVD?70%ofpatientscuredwithABVD

IPS0–2PETnegativeafter2ABVD?霍奇金淋巴瘤治療進展第52頁2cyclesABVDPETnegativePETpositiveCT2+PET1CT1(Staging)CT3CT3+PET2BCRT:PET+ResidualonCT>2.5cm(involvednode)

IPS0–7randomizeCT3AN=1,100ptsFollow-up(noradiation)6cyclesBEACOPP-14TransatlanticStudy4cyclesABVD4cyclesAVD霍奇金淋巴瘤治療進展第53頁

EarlyorLateIntensification?

Howcanweavoid30%failures?

IsHigh-dosetherapy+StemCellSupport

theonlysolutionforfailures?

Or-

shouldweaimtoavoidthem

alreadyfromstartoftherapy?

Thismeans:earlyintensification

霍奇金淋巴瘤治療進展第54頁Theearlyintensification

inadvancedHL2-4BEACOPPescProg/Relapse5-10%6-8ABVDProgr/Relapse30-40%(IPS:>3)HDCT/SCT?2ndhit“in30-40%?1sthit“?1sthit“?2ndhit“in5-10%HDCT/SCT0.9%AML/MDS!!5-10%AML/MDS4BEAbase霍奇金淋巴瘤治療進展第55頁HD15:studyOngoingStudy:1530patsDosedensityandreductionoftoxicityABC8xBEACOPP14(baseline)

6xBEACOPPescalated8xBEACOPPescalatedRandomizationResidualtumormass?(>2.5cm)followupNoPET-studyPETnegative:followupPETpositive:RT30Gy15%ofallpats!Yes霍奇金淋巴瘤治療進展第56頁HD15Trialforpatientswithadvancedstage

FFTFandOSMedianobservationtime:21months21-monthOS: 95%(95%CI:93%-97%)21-monthFFTF: 86%(95%CI:83%-89%)559FFTF515437283133370560OS541492336185581Pts.atRiskTime[months]FFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.0061218243036霍奇金淋巴瘤治療進展第57頁HD15Trial

8vs6BEAescvs8BEA-14

(550pats)

PETafterendofchemotherapyfor>2,5cmrests:

Patientswithrests>2,5cm:

245(78,8%)PETneg:noRT:2444,1%relapses