霍奇金淋巴瘤治療進展培訓課件

1、霍奇金淋巴瘤治療進展霍奇金淋巴瘤治療進展1960s1970s1980s1990s10 yJoe Connors霍奇金淋巴瘤治療進展21960s1970s1980s1990s10 yJo不同預后組的治療療效:Europe and North- America EuropeStage Cure Rates(GSHG and EORTC)早期預后良好組 CS I,IIA,B no risk factors98%早期預后不良組 CS I,IIA,B with risk factors93%進展期 CS III IV, Selected CS IIB with ABVD (North America)

2、65-80%(intermediate)霍奇金淋巴瘤治療進展3不同預后組的治療療效: EuropeSt霍奇金淋巴瘤治療進展4霍奇金淋巴瘤治療進展4Causes of Death among 2733 Patients with Hodgkins Disease (1960-97)Hodgkins Disease38341.2%Secondary Cancers20021.5%MDS111.2%Cardiovascular 14815.9%Pulmonary 414.4%Infection 353.8%Trauma/Suicide161.7%Other/Unknown9610.3%Total93

3、0100.%Stanford, R. Hoppe霍奇金淋巴瘤治療進展5Causes of Death among 2733 Did we learn from our mistakesover 40 years?霍奇金淋巴瘤治療進展6Did we learn from our mistakes個體化治療！對于早期患者如何在保證療效的情況下盡可能減少副作用？能否進一步減少化療療程？減小放療劑量？晚期患者如何進一步提高治愈率？霍奇金淋巴瘤治療進展7個體化治療！對于早期患者霍奇金淋巴瘤治療進展7早期預后良好組: CS I/II 無不良預后因素早期預后不良組: CS I/II 有不良預后因素*進展期:

4、CS III/IV; CS IIB ( LMM )*a) bulk; b) E-lesion; c) high ESR; d) = 3 involved areasGHSG 臨床預后分組霍奇金淋巴瘤治療進展8早期預后良好組: CS I/II 無不良預后因素*a)預后不良 (Unfavorable) 早期HL年齡50歲4個淋巴結區(qū)域受侵單獨ESR50B癥狀和ESR30縱隔大腫塊，或腫塊直徑大于10cm2個結外部位受累霍奇金淋巴瘤治療進展9預后不良 (Unfavorable) 早期HL年齡50歲霍預后良好(Favorable)早期HL不符合預后不良組條件的其它臨床I/II期HL霍奇金淋巴瘤治療進展

5、10預后良好(Favorable)早期HL不符合預后不良組條件的 Hodgkin Lymphoma: 早期預后不良組 Is less more?尋找高效和低毒間的最佳平衡點霍奇金淋巴瘤治療進展11 Hodgkin Lymphoma: 早期CS III without risk factorsABVDABVD30 Gy IFABVDABVDABVDABVDABVDABVDABVDABVDABVDABVD30 Gy IF20 Gy IF20 Gy IF2003: 1375 patients recruited.Trial closed 1/2003.早期預后良好組 : GHSG: HD10- Tr

6、ial 霍奇金淋巴瘤治療進展12CS III without risk factorsABHD10, 4th Interim Analysis, August 20061OS (CT-Comparison)5764xABVD561534454323208925762xABVD2.56152246433820097Pts. at RiskOverall Survival months4xABVD2xABVDProbability0.00.10.20.30.40.50.60.70.80.91.0012243648607284OS rates and 95% CI at 5 years * : 4x

7、ABVD: 97%; 95%; 98% 2xABVD: 96%;94%; 98% 霍奇金淋巴瘤治療進展13HD10, 4th Interim Analysis, AuHD10, 4th Interim Analysis, August 2006Survival curves are Kaplan-Meier estimates. Median observation time is 53 months, N=1109OS (RT-Comparison)55330Gy54551343932520610055620Gy54351145331418680Pts. at RiskOverall Sur

8、vival months30Gy20GyProbability0.00.10.20.30.40.50.60.70.80.91.0012243648607284OS rates and 95% CI at 5 years: 30Gy: 97%; 95%; 98% 20Gy: 96%;94%; 98% 霍奇金淋巴瘤治療進展14HD10, 4th Interim Analysis, AuHD10結論2ABVD is non-inferior to 4ABVD20Gy IF-RT is non-inferior to 30Gy IF-RT 霍奇金淋巴瘤治療進展15HD10結論2ABVD is non-

9、inferior HD13 Trial :早期無不良預后 問題減少化療療程的可能性?Do we need bleomycin and dacarbacin in ABVD?霍奇金淋巴瘤治療進展16HD13 Trial :早期無不良預后 問題減少化療療程的CS I/II without RF*ABVDABVDABVABVAVDAVDAVAV30 Gy IF30 Gy IF30 Gy IF30 Gy IF*Large mediastinal mass; extranodal disease; high ERS; 3 or more areas involvedHD13 Trial for pati

10、ents with early favourable stage Design霍奇金淋巴瘤治療進展17CS I/II without RF*ABVDABVAVDAFFTF at 18 months91 %, 95% CI 88 , 94OS at 18 months 100 %, 95% CI 99 , 100Overall Survival and FFTF Median observation time : 18 months霍奇金淋巴瘤治療進展18FFTF at 18 months91 %, 95% CIHD16 Trial :早期預后良好組 Questions 對于反應良好者化療是否足

11、夠?霍奇金淋巴瘤治療進展19HD16 Trial :早期預后良好組 QuestionsCS I/II without RF*2 x ABVDPET-30 Gy IF2 x ABVDPET+2 x ABVDPET (+/-)Follow up30 Gy IFStandardArmExperimental Arms*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areasHD16 Trial for patients with early favourable stage Planned De

12、sign with PET霍奇金淋巴瘤治療進展20CS I/II without RF*2 x ABVD30 早期患者聯(lián)合治療VS 單化療聯(lián)合ABVDTotal2673（9 trials）330（3 trials）EFS8099%（84%）89.5，86，87%OS8899%（94%）90,96,96霍奇金淋巴瘤治療進展21早期患者聯(lián)合治療VS 單化療聯(lián)合ABVDTotal2673早期預后良好患者2ABVD+ 20 Gy IF-RT是標準治療！單化療、減藥化療+放療尚待隨機研究結果霍奇金淋巴瘤治療進展22早期預后良好患者2ABVD+ 20 Gy IF-RT是標準治Early favourabl

13、e stages: CS I/II without risik factor*Early unfavourable stages: CS I/II with risik factor*Advanced stages:CS III/IV; CS IIB (LMM)*a) bulk; b) E-lesion; c) high ESR; d) = 3 involved areasGHSG Clinical Risk Groups霍奇金淋巴瘤治療進展23Early favourable stages: CSHodgkin LymphomaIntermediate StagesFact:Combined

14、 chemo- and radiotherapy islargely considered as standard: 4 ABVD+ 30 Gy IF-RTResult: 90% tumorfree survival after 5 years 93% overall survival after 5 years霍奇金淋巴瘤治療進展24Hodgkin LymphomaIntermediate HD14 Trial for patients with early unfavourable stage Questions1) Better Results with intensified chem

15、otherapy?霍奇金淋巴瘤治療進展25HD14 Trial for patients with eHD14 Trial for patients with early unfavourable stage DesignStages I, IIA with RF a-d; IIB with RF c,d BEACOPP escalatedBEACOPP escalated ABVDABVDABVDABVDABVDABVD30 Gy IF30 Gy IF*a) bulk; b) extranodal disease; c) high ERS; d) 3 or more areas1450 pa

16、ts recruited since 2003霍奇金淋巴瘤治療進展26HD14 Trial for patients with eHD14 Trial for patients with early unfavourable stage FFTF and OS At 18 monthsFFTF : 93 %95% CI: 90 ; 96 OS : 100 %95% CI: 99 ; 100 GHSG 04/2006霍奇金淋巴瘤治療進展27HD14 Trial for patients with eEORTC Trials: H10 + H11Standard Arm: 3 ABVD+ 30Gy

17、 IF-RTNeg 1 ABVD no RTPos 2 BEACOPP esc + RTEarly Favorable: H102 ABVD PETNeg + 2 ABVD no RTEarly Unfavorable: H112 ABVD PETExperim. ArmExperim. ArmStandard Arm 4 ABVD + 30Gy IF-RT霍奇金淋巴瘤治療進展28EORTC Trials: H10 + H11StandarHodgkin LymphomaEarly and Intermediate Stages Summary The GHSG experience Stan

18、dard outside clinical trials: Early favorable: 2ABVD + 20 Gy IF-RT Early unfavorable: 4 ABVD + 20-30 Gy IF-RT (intermediate) 霍奇金淋巴瘤治療進展29Hodgkin LymphomaEarly and IntEarly favourable stages: CS I/II without risik factor*Early unfavourable stages: CS I/II with risik factor*Advanced stages:CS III/IV;

19、CS IIB (LMM)*a) bulk; b) E-lesion; c) high ESR; d) = 3 involved areasGHSG Clinical Risk Groups霍奇金淋巴瘤治療進展30Early favourable stages: CSHodgkin Lymphoma Advanced Stages Current PracticeIntensive Chemotherapy CR: no RT PR: 30 Gy IF-RT Chemotherapy: IF-RT6-8 ABVD (45%RT)Or 6-8 BEACOPP (15% RT)霍奇金淋巴瘤治療進展3

20、1Hodgkin Lymphoma Advanced StaAdvanced Stages:-ABVD-the Gold Standard?No!It is not!At least not for all risk groups!霍奇金淋巴瘤治療進展32Advanced Stages:-ABVD-the Long-Term Follow-upAdvanced HL: only stages IIB-LMM, III, IV !Failure-free survivalOverall survivalYears after study entryCanellos et al. NEJM, 20

21、02霍奇金淋巴瘤治療進展33Long-Term Follow-upFailure-freFourth Generation Regimens:are they superior to ABVD? 1.Stanford V 2.ClVP/EVA 3.MEC (Gobbi: 10 drug regimen!) (JCO 2005) 4.BEACOPP霍奇金淋巴瘤治療進展34Fourth Generation Regimens:arGobbi PG, et al. J Clin Oncol. 2005;23(36):9198-9207. Epub 2005 September 19.MOPP-EBV

22、-CAD: Meclorethamine, CCNU, Vindesine, Alkeran, Prednisone, Epidoxorubicin, Vincristine, Procarbazine, Vinblastine, Bleomycin355 patients, RT bulk + residual disease.ABVD vs Stanford V vs MECLog rank 27.48P0.0001Log rank 3.05P=0.22FFS (%)OS (%)FFS (%)Time, MonthsTime, MonthsMECABVDStanford V霍奇金淋巴瘤治療

23、進展35Gobbi PG, et al. J Clin Oncol.Italian StudyAdvanced Hodgkin LymphomaABVD vs 4 BEACOPP- esc + 4 BEACOPP- base vs MEC (Italian 10 drug regimen)霍奇金淋巴瘤治療進展36Italian StudyAdvanced Hodgkin ChemotherapyRadiotherapyCT-Intensity ABVDBEAescStanfordVAdvanced HL(5-10%)(45%)(90%)RT IntensityNeed for RT:霍奇金淋巴

24、瘤治療進展37 ChemotherapyRadiothB BleomycinE EtoposideA AdriamycinC Cyclophos.O VincristinP ProcarbazinP PrednisonBasismg/m210100256501,410040The BEACOPP - schedule Escalatedmg/m2102003512501,410040G-CSF sc1 2 3 4 5 6 7 8 9 10 11 12 13 14 1522 restart霍奇金淋巴瘤治療進展38B BleomycinBasisThe BEACOPP - CS IIB-IIIA

25、with risk factorsCS IIIB-IVArm A4 COPP+ABVD RTArm B8 BEACOPP baseline RTArm C8 BEACOPP escalated* RTRT to initial bulk and residual tumorGHSG: HD9 Trial Design (1992- 96)* with G-CSFRandomisationDiehl et al, NEJM, 2003霍奇金淋巴瘤治療進展39CS IIB-IIIA with risk factorsAHD9- 10 ys FFTF by treatment armLog-rank

26、 tests:A v B v Cp0.0001A v Bp=0.040B v Cp0.0001A v Cp0.0001 BEA escC/ABVD82%64%霍奇金淋巴瘤治療進展40HD9- 10 ys FFTF by treatment aGHSG 2007 HD9HD9-10 ys- OS by treatment armLog-rank tests:A v B v Cp=0.0005A v Bp=0.19B v Cp=0.0053A v Cp45 yearsSexMaleTumorStage IVLaboratory VariablesAnemiaHgb 10.5 g/dLAlbumin

27、15,000/mm3Lymphopenia600/mm3 or8% of leukocytesHasenclever D, Diehl V. N Engl J Med. 1998;339(21):1506-1514.霍奇金淋巴瘤治療進展47Prognostic Factors in AdvancedSurvival rates according to IPS at 10 ysFFTF OS (%, 10 y)C/ABVDn=261BEAbasen=469BEAescn=466log-rank p (A vs. C)IPS 0-1n=3077888798591940.0150.27IPS 2-

28、3n=4645973718483872.5cm (involved node) IPS 0 7randomizeCT3 AN=1,100 ptsFollow-up (no radiation)6 cycles BEACOPP-14Transatlantic Study4 cycles ABVD4 cycles AVD霍奇金淋巴瘤治療進展532 cycles ABVDPET negativePET p Early or Late Intensification? How can we avoid 30% failures?Is High-dose therapy + Stem Cell Supp

29、ortthe only solution for failures?Or- should we aim to avoid themalready from start of therapy?This means: early intensification 霍奇金淋巴瘤治療進展54 Early or Late IntensifThe early intensification in advancedHL2-4 BEACOPP escProg/Relapse 5-10%6-8 ABVDProgr/Relapse 30-40%(IPS: 3)HDCT/SCT2nd hit“ in 30-40%1s

30、t hit“1st hit“2nd hit“ in 5-10%HDCT/SCT0.9% AML/MDS!5-10% AML/MDS4 BEA base霍奇金淋巴瘤治療進展55The early intensification in HD15: study Ongoing Study: 1530 patsDose density and reduction of toxicityABC8 x BEACOPP 14( baseline) 6 x BEACOPP escalated8 x BEACOPP escalatedRandomizationResidual tumor mass?(2.5 c

31、m)follow upNoPET-studyPET negative:follow upPET positive:RT 30 Gy15% of all pats!Yes霍奇金淋巴瘤治療進展56HD15: study ABC8 x BEACOPP 146HD15 Trial for patients with advanced stage FFTF and OSMedian observation time: 21 months21-month OS:95% (95% CI: 93%-97%)21-month FFTF:86% (95% CI: 83%-89%)559FFTF5154372831

32、33370560OS541492336185581Pts. at RiskTime monthsFFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.0061218243036霍奇金淋巴瘤治療進展57HD15 Trial for patients with aHD 15 Trial8 vs 6 BEAesc vs 8 BEA-14 (550 pats) PET after end of chemotherapy for 2,5cm rests: Patients with rests 2,5 cm: 245 (78,8%)PET neg: no RT

33、: 244 4,1% relapses 311 66 (21,2%) PET pos: IF-RT: 62 15,3% relapses 霍奇金淋巴瘤治療進展58HD 15 Trial8 vs 6 BEAesc vs2x BEACOPP esc.PET positivePET negative2x BEACOPP esc.2 BEA esc.-4 baseABCRT PET+ Rests 2,5cm (involved node-technique) No RT No RTFuture GHSG Study: HD18 Advanced HL IPS 0 -72 BEA esc-4 base+ Rituximab2B