Beacopp Chemotherapy for Advanced Hodgkin’s Disease: Results of Further Analyses of the HD9- and HD12- Trials of the German Hodgkin Study Group (GHSG).
Authors: Diehl Volker , Brillant C. , Franklin J. , Hermann R. , Greil R. , Engert A. , Pfistner B. ,   for the German Hodgkin Lymphoma Study Group (GHSG),   for the Competence Network Malignant Lymphoma.
Published: April 2020

Background: The BEACOPP regimen has proved to be superior to the conventional drug combination COPP/ABVD in the HD9 trial. In the HD12 trial, the GHSG aimed to confirm these results but at the same time attempted to reduce acute and late toxicity. Objectives: HD 9: In the recent analysis of HD9, we aim to demonstrate the benefits of BEACOPP and of dose increase after longer follow-up. In particular, we reassess the occurrence of second malignancies and the impact on OS. HD12: The HD12 trial (closed in 1/2003) aimed at de-escalating chemotherapy by comparing 8 courses of escalated BEACOPP (8 esc.BEA) with 4 escalated and 4 baseline courses of BEACOPP (4+4BEA), with or without consolidatory radiation to initial bulky and residual disease.

Methods: HD9: In 1993-98, 1201 eligible patients (aged 16-65, in stages IIB and IIIA with risk factors and stages IIIB and IV) were randomised to (A) 4 double cycles COPP/ABVD, (B) 8 cycles baseline BEACOPP or (C) 8 cycles esc.BEACOPP, followed by radiation of initial bulky or residual disease.

HD12: In 1999-2002, 1396 eligible patients aged 16-65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised according to a factorial design between: (A) 8 esc.BEA + RT, (B) 8 esc.BEA no RT, (C) 4+4BEA+ RT, (D) 4+4BEA no RT. An expert panel evaluated all cases immediately after chemotherapy and, where appropriate, recommended additional radiotherapy independent of randomisation.

Results: HD9: In the recent update of this trial (7/2004) with a median follow-up of 82 months, the estimated FFTF and OS rates were: arm A 67% and 79%, arm B 75% and 84%, arm C 85% and 90% (p&lt;0.001 and p=0.004) respectively. 61 second neoplasia were documented, with similar proportions in each arm. Second AML/MDS was more frequent in arm C (11/466) than in arms B (5/469) or A (1/260). HD12: In the fourth interim analysis of HD12 (7/2004) with a median follow-up of 30 months, the FFTF rate was 88% (95%-CI: 86-90) and the OS rate 94% (92-95) for the total cohort. Radiation was given in arms A+C in 60% and in arms B+D in 9% (mostly due to panel recommendation). There were 29 secondary neoplasia, but the rate of AML/MDS (11/1396=0.8%) at this early analysis was lower than in the HD9 trial. The sequential intent-to-treat analysis demonstrated no significant differences neither between the 8 esc.BEA and 4+4BEA arms nor between the groups with or without RT.

Conclusions: The results of the updated HD9 analysis convincingly demonstrate, despite an increased second leukemia rate, superior overall survival due to dose escalation of BEACOPP. Up to now the interim analysis of the HD12 trial shows no statistical difference between 8 cycles of escalated BEACOPP and 4 escalated and 4 baseline BEACOPP cycles. With a larger cohort of patients the excellent efficacy of the escalated BEACOPP regime for FFTF and OS seems to be confirmed in the HD12 trial.