Which is the best induction regimen in Hodgkin Lymphoma: ABVD or BEACOPP? Volker Diehl, MD Honorary Chairman, German Hodgkin Study Group University Hospital of Cologne
The Best Treatment of Hodgkin Lymphoma is the one with the highest cure rates and the least toxicity? Cure dependent on: a. salvagebility after failure b. stage
Hodgkin Lymphoma Hodgkin Lymphoma OS after salvage for relapse OS after salvage for relapse according to primary treatment according to primary treatment Overall Survival 1,0 1,0 Primary RT (14/107) Primary RT (14/107) ,8 ,8 Probability Probability 2 cycles CT (12/35) 2 cycles CT (12/35) ,6 ,6 4 cycles CT (92/193) 4 cycles CT (92/193) ,4 ,4 8 cycles CT (162/341) 8 cycles CT (162/341) ,2 ,2 p < 0.0001 < 0.0001 p 0,0 0,0 0 0 12 12 24 24 36 36 48 48 60 60 72 72 84 84 96 96 108 108 120 120 Months Months
GHSG Risk groups • Early favorable stages: CS I/II without risk factors* • Early unfavorable stages: CS I/II with risk factors* • Advanced stages: CS III/IV; selected CS IIB *a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
GHSG HD10 trial for early favorable HL CS I/II without risk factors* 4 x 4 x 2 x 2 x ABVD ABVD ABVD ABVD 30 Gy IF 20 Gy IF 30 Gy IF 20 Gy IF *Large mediastinal mass; extranodal disease; high ERS; 3 or more areas involved NEJM, 2010
HD10 trial CT-comparison (FFTF) 1.0 Freedom from Treatment Failure 0.9 0.8 0.7 0.6 5y-FFTF difference -1,9%; 0.5 95% CI [-5,2%; 1,4%] 0.4 0.3 0.2 p=0,39 0.1 4xABVD 2xABVD 0.0 0 12 24 36 48 60 72 84 96 108 120 Time [months] Pts. at Risk 4xABVD 596 554 532 506 479 430 330 226 131 57 6 2xABVD 594 555 530 498 473 410 314 225 131 54 9 NEJM, 2010
HD10 trial RT-comparison (FFTF) 1.0 Freedom from Treatment Failure 0.9 0.8 0.7 0.6 0.5 Arm difference in 5y-FFTF = -0,5% 0.4 95% CI [-3,6%; 2,6%] 0.3 0.2 p= 0,90 0.1 30 Gy RT 20 Gy RT 0.0 0 12 24 36 48 60 72 84 96 108 120 Time [months] Pts. at Risk 30 Gy RT 575 553 526 499 471 426 328 235 139 61 8 20 Gy RT 588 550 531 502 478 411 314 215 123 50 7 NEJM,2010
HL: Individualized Estimates of 2NPL Risks after Contemporary RT Breast Cancer Reduced 77% Lung Cancer Reduced 57%w Age 20 Age 30 Hodgson et al, Cancer 110: 2576, 2007
HodgkinLymphoma: Best Chemotherapy 2010 State of the Art Early Favorable : 2 ABVD+ 20 Gy IFRT Early Unfavorable : 4 ABVD or 2eBEA+2 ABVD + 20-30 Gy RT Advanced: Low Risk (IPS 0-2): 2 ABVD PET - : 4-6 ABVD +/- 30 Gy RT 2 ABVD PET+:4-6 esc BEA + 30 Gy RT High Risk (IPS>3) 2 escBEA PET -: 2 esc BEA: +/- RT 2 esc BEA PET+ 6esc BEA +/- RT 9
GHSG Risk groups • Early favorable stages: CS I/II without risk factors* • Early unfavorable stages: CS I/II with risk factors* • Advanced stages: CS III/IV; selected CS IIB *a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
Overall results (all evaluable patients) 1,0 Overall results SV ,8 [95%CI] at 5 years: FFTF ,6 FFTF 82,6% 4 C/ABVD [80;85] + 30 GY RT SV 91,1% ,4 [89;93] Probability Probability ,2 0,0 0 24 48 72 96 120 Time (months months) ) Time (
Progress in Intermediate stages GHSG data ABVD or BEACOPP or Both?? Trial Chemotherapy + IF-RT Failure Rate HD 8 4 COPP/ABVD 18% HD11 4 ABVD 15% 4 BEACOPP 13% HD14 4 ABVD 13% 2 BEAesc + 2 ABVD 5%
BEACOPP Baseline (base) and escalated (esc) Drug base 2 esc 2 route schedule Bleomycin 10 10 iv 8 Etoposide 100 200 iv 1-3 Adriamycin 25 35 iv 1 Cyclophosphamide 650 1250 iv 1 Vincristine 1.4 1 1.4 1 iv 8 Procarbazine 100 100 po 1-7 Prednison 40 40 po 1-14 G-CSF - + sc 8-14 1 max. 2,0 mg 2 mg/m 2
HD11 trial: 30Gy arms CT comparison (FFTF) 1.0 0.9 Freedom from Treatment Failure 0.8 0.7 5 year estimate [95%-CI] 0.6 4xABVD: 85.3% [81.1% to 88.7%] 0.5 4xBEACOPP: 87.0% [82.8% to 90.2%] 0.4 0.3 p = 0.654 0.2 0.1 ABVD + 30Gy BEACOPP + 30Gy 0.0 0 12 24 36 48 60 72 84 96 108 Time [months] Pts. at Risk 356 330 308 293 271 255 206 136 73 40 ABVD+30Gy 341 313 293 278 275 249 203 138 78 34 BEACOPP+30Gy
Progress in Intermediate stages GHSG data ABVD or BEACOPP or Both?? Trial Chemotherapy + IF-RT Failure Rate HD 8 4 COPP/ABVD 18% HD11 4 ABVD 15% 4 BEACOPP 13% HD14 4 ABVD 13% 2 BEAesc + 2 ABVD 5%
Early unfavorable HL Effective-dose calculation (4 cycles) Regimen D´ration ED ABVD 16 15.0 BEACOPP base 12 15.2 BEACOPP14 8 16.3 B esc /ABVD (2+2) 14 17.3 BEACOPP esc 12 19.8 GHSG, modified from Hasenclever, D .
HD14 study (GHSG) for early unfavorable HL Stages I, IIA with RF a-d; IIB with RF c,d BEACOPP escalated ABVD BEACOPP escalated ABVD ABVD ABVD ABVD ABVD 30 Gy IF 30 Gy IF *a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
FFTF median observation time = 42 months 1.0 2eBEA+2ABVD 0.9 4 ABVD 0.8 P < 0.001 0.7 5-year FFTF 95%CI 0.6 FFTF Arm A 87,3% [83,8% - 90,2%] 0.5 Arm B 95,0% [93,0% - 96,4%] 0.4 difference 7,6% [4,0% - 11,3%] 0.3 0.2 0.1 A B 0.0 0 12 24 36 48 60 Time [months] Pts. at Risk A 761 723 698 637 557 466 388 306 238 184 103 B 758 722 695 653 561 490 413 331 259 199 127 18
HD14 for early unfavorable HL Treatment outcome and events (% of pts) 4xABVD 2+2 n=476 n=479 CR/CRu 93.7 95.5 Progress 3.9 1.4 Early relapse 2.3 0.6 Late relapse 3.1 1.4 Death 2.2 1.0
Progress in Intermediate stages GHSG data ABVD or BEACOPP or Both?? Trial Chemotherapy Failure Rate HD 8 4 COPP/ABVD 18% HD11 4 ABVD 15% 4 BEACOPP 13% HD14 4 ABVD 13% 2 BEAesc + 2 ABVD 5%
HodgkinLymphoma: Best Chemotherapy 2010 State of the Art Early Favorable : 2 ABVD+ 20 Gy IFRT Early Unfavorable : 4 ABVD +RT or 2eBEA+2 ABVD + 30 Gy IFRT Advanced: Low Risk (IPS 0-2): 2 ABVD PET - : 4-6 ABVD +/- 30 Gy RT 2 ABVD PET+:4-6 esc BEA + 30 Gy RT High Risk (IPS>3) 2 escBEA PET -: 2 esc BEA: +/- RT 2 esc BEA PET+ 6esc BEA +/- RT 21
GHSG Risk groups • Early favorable stages: CS I/II without risk factors* • Early unfavorable stages: CS I/II with risk factors* • Advanced stages: CS III/IV; selected CS IIB *a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
Advanded Stages: -ABVD- the Gold Standard?? No! It is not! At least not for all risk groups! Nancy Bartlett : „One size does not fit all!“
ABVD compared with BEACOPP in advanced stage HL trials (% of pts) Source Chemotherapy 5-y FFS 5-y OS Canellos 1992 6-8 ABVD 61 73 6 (MOPP+ABVD) 65 75 Duggan 2003 8-10 ABVD 63 82 8-10 MOPP/ABV 66 81 Diehl 2003 4 (COPP+ABVD) 68 83 8 BEACOPP esc. 88 92
The GHSG- Successor- Trials De-escalation of BEACOPP Advanced Stages of HL HD-9 1994- 2001 8eBEA +RT (70%) HD-12 2001-2004 4eBEA +4 base BEA +/-RT (39%) HD-15 2004-2007 6 eBEA vs 8 BEA-14 +RT (12%) HD-18 2008-2012 2 eBEA PET- 2eBEA +RT (12%) ongoing Total: > 4500 patients treated
GHSG HD9 trial FFTF by treatment arm 1.0 0.9 Esc BEACOPP 0.8 18% 0.7 Percentage 0.6 C/ABVD 0.5 0.4 A (64%) 0.3 B (70%) p <0,001 0.2 C (82%) 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years Engert et al; JCO 2009
HD15-PET trial for advanced-stage HL HD15-PET trial for advanced-stage HL PFS in pts with PET + and PET - residues (n=275) PFS in pts with PET + and PET - residues (n=275) 1.0 1.0 PT neg No RT PFS 0.9 0.9 PET pos + RT 0.8 0.8 0.7 0.7 0.6 0.6 8 eBEA vs 6 eBEA vs 8 BEA-14 : PET end of chemo: PFS PFS 0.5 0.5 0.4 0.4 0.3 0.3 p = 0.011 p = 0.011 0.2 0.2 0.1 0.1 0.0 0.0 0 0 6 6 12 12 18 18 24 24 Months Months - Pts at Risk Pts at Risk PET+ PET+ 216 216 211 211 207 207 151 151 95 95 PET - PET - 59 59 52 52 50 50 38 38 18 18 GHSG 2007 GHSG 2007
Comparison of GHSG trials HD9, HD12, HD15 for Comparison of GHSG trials HD9, HD12, HD15 for advanced-stage HL (PFS) advanced-stage HL (PFS) 1.0 1.0 0.9 0.9 0.8 0.8 Progression-free Survival Progression-free Survival PFS:91% in >4500 patients 0.7 0.7 0.6 0.6 HD9 HD9 0.5 0.5 HD15 HD15 0.4 0.4 HD12 B+D HD12 B+D 0.3 0.3 p = 0.266 p = 0.266 0.2 0.2 HD12 A+C HD12 A+C 0.1 0.1 0.0 0.0 0 6 12 18 24 0 6 12 18 24 Months after Randomisation Months after Randomisation
Trials in advanced HL comparing BEACOPP and ABVD or Variants* GHSG HD9 Italian Study Italian Study HD2000 GITIL&IIL COPP/ABVD BEACOPP ABVD BEACOPP ABVD BEACOPP 8esc 4+2 4+4 N 260 466 95 91 166 155 FFTF 69 87 63 78 69 85 P< 0,001 OS 83 91 86 91 86 87 But: two times more patients needed HDCT+SCT after ABVD than after BEAesc!! * @ 5 years
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