霍奇金淋巴瘤治疗进展

1、霍奇金淋巴瘤治疗进展 hodgkins lymphoma by era n = 2167 overall survival (y) 403020100 cum survival 1.0 .8 .6 .4 .2 0.0 1960s 1970s 1980s 1990s 10 y joe connors 不同预后组的治疗疗效不同预后组的治疗疗效: europe and north- america europestage cure rates (gshg and eortc) 早期预后良好组早期预后良好组 cs i,iia,b no risk factors98% 早期预后不良组早期预后不良组 cs

2、 i,iia,b with risk factors93% 进展期进展期 cs iii iv, selected cs iib with abvd (north america) 65-80% (intermediate) causes 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% t

3、rauma/suicide161.7% other/unknown9610.3% total930100.% stanford, r. hoppe did we learn from our mistakes over 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？ 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？ 预后不良 (unfavorable) 早期hl u年龄年龄50岁岁 u4个淋巴结区域受侵个淋巴结区域受侵 u单独单独esr50 ub症状和症状和esr30 u纵隔大肿块，或肿块直径大于纵隔大肿块，或肿块直径大于10c

4、m u2个结外部位受累个结外部位受累 预后良好(favorable)早期hl u不符合预后不良组条件的不符合预后不良组条件的其它其它 临床临床i/ii期期hl 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 factors abvd abvd 30 gy if abvd abvd abvd abvd abvd abvd abvd abvd abvd abvd 30 gy if20 gy if20 gy if 早期预后良好组 : ghsg: hd10- trial hd10, 4th inter

5、im analysis, august 2006 1 os (ct-comparison) 5764xabvd561534454323208 92 5762xabvd2.561522464 33820097 pts. at risk overall survival months 4xabvd2xabvd probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 012243648607284 os rates and 95% ci at 5 years * : 4xabvd: 97%; 95%; 98% 2xabvd: 96%;94%;

6、98% hd10, 4th interim analysis, august 2006 survival curves are kaplan-meier estimates. median observation time is 53 months, n=1109 os (rt-comparison) 55330gy545513439325206100 55620gy54351145331418680 pts. at risk overall survival months 30gy20gy probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

7、 1.0 012243648607284 os rates and 95% ci at 5 years: 30gy: 97%; 95%; 98% 20gy: 96%;94%; 98% hd10结论 2abvd is non-inferior to 4abvd 20gy if-rt is non-inferior to 30gy if-rt 1) 减少化疗疗程的可能性减少化疗疗程的可能性? 2) do we need bleomycin and dacarbacin in abvd? 413fftf38826917084 413os408314219114 pts. at risk time m

8、onths kaplan-meier-analysen gesamt survival und fftf fftfos probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 06121824 fftf at 18 months91 %, 95% ci 88 , 94 os at 18 months 100 %, 95% ci 99 , 100 overall survival and fftf median observation time : 18 months 对于反应良好者化疗是否足够对于反应良好者化疗是否足够? cs i/ii

9、without rf* 早期患者 联合治疗vs 单化疗 联合abvd total2673（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！是标准治疗！ 单化疗、减药化疗+放疗尚待随机研究结果 hodgkin lymphoma intermediate stages fact: combined chemo- and radiotherapy is largely considered as standard: 4 abvd+ 30 gy i

10、f-rt result: 90% tumorfree survival after 5 years 93% overall survival after 5 years 1) better results with intensified chemotherapy? 1450 pats recruited since 2003 447fftf427361233111 449os444397290150 pts. at risk time months fftfos probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 06121824

11、at 18 monthsfftf : 93 %95% ci: 90 ; 96 os : 100 %95% ci: 99 ; 100 ghsg 04/2006 eortc trials: h10 + h11 standard arm: 3 abvd+ 30gy if-rt neg 1 abvd no rt pos 2 beacopp esc + rt early favorable: h10 2 abvd pet neg + 2 abvd no rt early unfavorable: h11 2 abvd pet experim. arm experim. arm standard arm

12、4 abvd + 30gy if-rt hodgkin lymphoma early 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) hodgkin lymphoma advanced stages current practice intensive chemotherapy cr:

13、 no rt pr: 30 gy if-rt chemotherapy: if-rt 6-8 abvd (45%rt) or 6-8 beacopp (15% rt) advanced stages: -abvd- the gold standard? no! it is not! at least not for all risk groups! long-term follow-up advanced hl: only stages iib-lmm, iii, iv ! failure-free survivaloverall survival years after study entr

14、y canellos et al. nejm, 2002 fourth generation regimens: are they superior to abvd? 1.stanford v 2.clvp/eva 3.mec (gobbi: 10 drug regimen!) (jco 2005) 4.beacopp gobbi pg, et al. j clin oncol. 2005;23(36):9198-9207. epub 2005 september 19. mopp-ebv-cad: meclorethamine, ccnu, vindesine, alkeran, predn

15、isone, epidoxorubicin, vincristine, procarbazine, vinblastine, bleomycin 355 patients, rt bulk + residual disease. abvd vs stanford v vs mec log rank 27.48p0.0001log rank 3.05p=0.22 ffs (%)os (%) ffs (%) time, monthstime, months mec abvd stanford v italian study advanced hodgkin lymphoma abvd vs 4 b

16、eacopp- esc + 4 beacopp- base vs mec (italian 10 drug regimen) chemotherapy radiotherapy ct-intensity abvd beaesc stanfordv advanced hl (5-10%) (45%)(90%) rt intensity need for rt: b bleomycin e etoposide a adriamycin c cyclophos. o vincristin p procarbazin p prednison basis mg/m2 10 100 25 650 1,4

17、100 40 the beacopp - schedule escalated mg/m2 10 200 35 1250 1,4 100 40 g-csf sc 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1522 restart cs iib-iiia with risk factors cs iiib-iv arm a 4 copp+abvd rt arm b 8 beacopp baseline rt arm c 8 beacopp escalated* rt rt to initial bulk and residual tumor ghsg: hd9 trial

18、 design (1992- 96) * with g-csf randomisation diehl et al, nejm, 2003 261a19417314611075190 469b378332282222106260 466c41238432123492140 p = .001 pts. at risk years abc probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123456789101112131415 hd9- 10 ys fftf by treatment arm log-rank tests: a v

19、 b v c p0.0001 a v bp=0.040 b v cp0.0001 a v cp0.0001 bea esc c/abvd 82% 64% ghsg 2007 hd9 261a238218196147107300 469b436392344272134360 466c441412357270113180 p = .001 pts. at risk years abc probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123456789101112131415 hd9-10 ys- os by treatment ar

20、m log-rank tests: a v b v c p=0.0005 a v bp=0.19 b v cp=0.0053 a v cp45 years sexmale tumorstage iv laboratory variablesanemiahgb 10.5 g/dl albumin15,000/mm3 lymphopenia600/mm3 or 8% of leukocytes hasenclever d, diehl v. n engl j med. 1998;339(21):1506-1514. survival rates according to ips at 10 ys

21、fftf os (%, 10 y) c/abvd n=261 beabase n=469 beaesc n=466 log-rank p (a vs. c) ips 0-1 n=307 78 88 79 85 91 94 0.015 0.27 ips 2-3 n=464 59 73 71 84 83 87 2.5cm (involved node) ips 0 7 randomize ct3 a n=1,100 pts follow-up (no radiation) 6 cycles beacopp-14 transatlantic study 4 cycles abvd 4 cycles

22、avd early or late intensification? how can we avoid 30% failures? is high-dose therapy + stem cell support the only solution for failures? or- should we aim to avoid them already from start of therapy? this means: early intensification the early intensification in advancedhl 2-4 beacopp esc prog/rel

23、apse 5-10% 6-8 abvd progr/relapse 30-40% (ips: 3) hdct/sct 2nd hit“ in 30-40% 1st hit“ 1st hit“ 2nd hit“ in 5-10% hdct/sct 0.9% aml/mds! 5-10% aml/mds 4 bea base hd15: study ongoing study: 1530 pats dose density and reduction of toxicity abc 8 x beacopp 14 ( baseline) 6 x beacopp escalated 8 x beaco

24、pp escalated randomization residual tumor mass? (2.5 cm) follow up no pet-study pet negative: follow up pet positive: rt 30 gy 15% of all pats! yes median observation time: 21 months 21-month os:95% (95% ci: 93%-97%) 21-month fftf:86% (95% ci: 83%-89%) 559fftf515437283133370 560os541492336185581 pts

25、. at risk time months fftfos probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 061218243036 hd 15 trial 8 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: 244 4,1% relapses 311 66 (21,2%) pet pos: if-rt: 62 15,3% relapses 2x beacopp esc. pet positivepet negative 2x beacopp esc.2 bea esc.-4 base abc rt pet+ rests 2,5cm (involved node-technique) no rt no rt future ghsg study: hd18 advanced hl ips 0 -7 2 bea esc-4 base + rituximab 2bea esc-4 base 0 rituximab nfkb (p50