霍奇金淋巴瘤治疗进展

1、霍奇金淋巴瘤治疗进展1960s1970s1980s1990s10 yJoe Connors不同预后组的治疗疗效:Europe and North- America EuropeStage Cure Rates(GSHG and EORTC)早期预后良好组 CS I,IIA,B no risk factors98%早期预后不良组 CS I,IIA,B with risk factors93%进展期 CS III IV, Selected CS IIB with ABVD (North America) 65-80%(intermediate)Causes of Death among 2733

2、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%Total930100.%Stanford, R. HoppeDid we learn from our mistakesover 40 years?个体化治疗！对于早期患者如何在保证疗效的情况下尽可能减少副作用？

3、能否进一步减少化疗疗程？减小放疗剂量？晚期患者如何进一步提高治愈率？早期预后良好组: CS I/II 无不良预后因素早期预后不良组: CS I/II 有不良预后因素*进展期:CS III/IV; CS IIB ( LMM )*a) bulk; b) E-lesion; c) high ESR; d) = 3 involved areasGHSG 临床预后分组预后不良 (Unfavorable) 早期HL年龄50岁4个淋巴结区域受侵单独ESR50B症状和ESR30纵隔大肿块，或肿块直径大于10cm2个结外部位受累预后良好(Favorable)早期HL不符合预后不良组条件的其它临床I/II期HL

4、Hodgkin Lymphoma: 早期预后不良组 Is less more?寻找高效和低毒间的最佳平衡点CS III without risk factorsABVDABVD30 Gy IFABVDABVDABVDABVDABVDABVDABVDABVDABVDABVD30 Gy IF20 Gy IF20 Gy IF2003: 1375 patients recruited.Trial closed 1/2003.早期预后良好组 : GHSG: HD10- Trial HD10, 4th Interim Analysis, August 20061OS (CT-Comparison)5764

5、xABVD561534454323208925762xABVD2.56152246433820097Pts. at RiskOverall Survival months4xABVD2xABVDProbability012243648607284OS rates and 95% CI at 5 years * : 4xABVD: 97%; 95%; 98% 2xABVD: 96%;94%; 98% HD10, 4th Interim Analysis, August 2006Survival curves are Kaplan-Meier estimates. Median observati

6、on time is 53 months, N=1109OS (RT-Comparison)55330Gy54551343932520610055620Gy54351145331418680Pts. at RiskOverall Survival months30Gy20GyProbability0.00.10.20.30.40.5012243648607284OS rates and 95% CI at 5 years: 30Gy: 97%; 95%; 98% 20Gy: 96%;94%; 98% HD10结论2ABVD is non-inferior to 4ABVD20Gy IF-RT

7、is non-inferior to 30Gy IF-RT HD13 Trial :早期无不良预后 问题减少化疗疗程的可能性?Do we need bleomycin and dacarbacin in ABVD?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 patients with early favo

8、urable stage DesignFFTF at 18 months91 %, 95% CI 88 , 94OS at 18 months 100 %, 95% CI 99 , 100Overall Survival and FFTF Median observation time : 18 monthsHD16 Trial :早期预后良好组 Questions 对于反应良好者化疗是否足够?CS I/II without RF*2 x ABVDPET-30 Gy IF2 x ABVDPET+2 x ABVDPET (+/-)Follow up30 Gy IFStandardArmExper

9、imental Arms*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areasHD16 Trial for patients with early favourable stage Planned Design with PET早期患者联合治疗VS 单化疗联合ABVDTotal2673（9 trials）330（3 trials）EFS8099%（84%）89.5，86，87%OS8899%（94%）90,96,96早期预后良好患者2ABVD+ 20 Gy IF-RT是标准治疗！单化疗

10、、减药化疗+放疗尚待随机研究结果Early favourable 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 GroupsHodgkin LymphomaIntermediate StagesFact:Combined chemo-

11、and radiotherapy islargely considered as standard: 4 ABVD+ 30 Gy IF-RTResult: 90% tumorfree survival after 5 years 93% overall survival after 5 yearsHD14 Trial for patients with early unfavourable stage Questions1) Better Results with intensified chemotherapy?HD14 Trial for patients with early unfav

12、ourable 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 pats recruited since 2003HD14 Trial for patients with early unfavourable stage FFTF and OS At

13、 18 monthsFFTF : 93 %95% CI: 90 ; 96 OS : 100 %95% CI: 99 ; 100 GHSG 04/2006EORTC Trials: H10 + H11Standard Arm: 3 ABVD+ 30Gy 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

14、IF-RTHodgkin LymphomaEarly and Intermediate Stages Summary The GHSG experience Standard outside clinical trials: Early favorable: 2ABVD + 20 Gy IF-RT Early unfavorable: 4 ABVD + 20-30 Gy IF-RT (intermediate) Early favourable stages: CS I/II without risik factor*Early unfavourable stages: CS I/II wit

15、h risik factor*Advanced stages:CS III/IV; CS IIB (LMM)*a) bulk; b) E-lesion; c) high ESR; d) = 3 involved areasGHSG Clinical Risk GroupsHodgkin 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 (45 yearsSexMale

16、TumorStage IVLaboratory VariablesAnemiaHgb 10.5 g/dLAlbumin15,000/mm3Lymphopenia600/mm3 or8% of leukocytesHasenclever D, Diehl V. N Engl J Med. 1998;339(21):1506-1514.Survival rates according to IPS at 10 ysFFTF OS (%, 10 y)C/ABVDn=261BEAbasen=469BEAescn=466log-rank p (A vs. C)IPS 0-1n=3077888798591

17、940.0150.27IPS 2-3n=4645973718483872.5cm (involved node) IPS 0 7randomizeCT3 AN=1,100 ptsFollow-up (no radiation)6 cycles BEACOPP-14Transatlantic Study4 cycles ABVD4 cycles AVD Early or Late Intensification? How can we avoid 30% failures?Is High-dose therapy + Stem Cell Supportthe only solution for

18、failures?Or- should we aim to avoid themalready from start of therapy?This means: early intensification The early intensification in advancedHL2-4 BEACOPP escProg/Relapse 5-10%6-8 ABVDProgr/Relapse 30-40%(IPS: 3)HDCT/SCT2nd hit“ in 30-40%1st hit“1st hit“2nd hit“ in 5-10%HDCT/SCT0.9% AML/MDS!5-10% AM

19、L/MDS4 BEA baseHD15: 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 cm)follow upNoPET-studyPET negative:follow upPET positive:RT 30 Gy15% of all pats!YesHD15 Trial for pa

20、tients 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%)559FFTF515437283133370560OS541492336185581Pts. at RiskTime monthsFFTFOSProbability0.00.10.20.30.40.50.60.70.80.91.0061218243036HD 15 Trial8 vs 6 BEAesc vs 8 BEA

21、-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: 244 4,1% relapses 311 66 (21,2%) PET pos: IF-RT: 62 15,3% relapses 2x 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+ Rituximab2BEA esc-4 base 0 RituximabNFkB (p50/RelA)IKKa/b/gp50/RelAProteasomal degradation(e.g. Bortezomib; MG-132)26S proteasomeIkB-a/Selective Ikk-b in