Eight Cycles of BEACOPP Escalated Compared with 4 Cycles of BEACOPP Escalated Followed by 4 Cycles of BEACOPP Baseline with Our without Radiotherapy in Patients in Advanced Stage Hodgkin Lymphoma (HL): Final Analysis of the Randomised HD12 Trial of the German Hodgkin Study Group (GHSG).

Purpose: The GHSG HD9 trial had established BEACOPP escalated (BE) as new standard of care for advanced-stage HL patients by showing significant superiority in terms of failure-free survival (FFTF) and overall survival (OS) over COPP/ABVD and BEACOPP baseline (BB) (each 8 cycles). The successor study, HD12, evaluated a possible reduction in toxicity by comparing 8 cycles of BE with 4 cycles BE followed by 4 cycles BB. The second question in this trial related to the need of additional radiotherapy (RT) to initial bulk and residual disease.

Patients and methods: HL patients in stage IIB with large mediastinal mass and/or E-lesions or stage III/IV were randomised according to a 2×2-factorial design between: 8BE + RT, 8BE no RT, 4BE+4BB + RT, 4BE+4BB no RT. Reviewing CT-images before and after chemotherapy treatment, fields for RT were centrally planned by a multidisciplinary diagnostic panel blinded for the randomisation arm. Primary endpoint of the trial was FFTF. Between 9/1999 and 1/2003, a total of 1,670 patients aged 16–65 were randomized. For this final analysis at a median follow up of 78 months, 99 patients were excluded (42 HL not confirmed, 20 revision of stage, 20 no study treatment or documentation, 17 others) resulting in 1,571 eligible patients.

Results: Patient characteristics in the 4 groups were comparable with 49% of patients in stage III, 35% in stage IV, 68% reporting B-symptoms and 28% having a large mediastinal tumor. An IPS of 3 or greater was reported for 38% of patients, predominant histology was nodular sclerosis with 57% of cases. Treatment-related toxicity of WHO grade III/IV was observed in 97% of patients. Most prominent differences between pooled chemotherapy arms were anemia (65% 8BE vs 51% 4BE+4BB) and thrombopenia (65% vs 51%). Treatment outcome: complete remission 92.4%; early progression 2.2%; progression/relapse 7.8% (6.6% and 8.5%). A total of 156 (9.9%) deaths (72 vs 84) have been observed (22 vs 32 acute or salvage treatment toxicity; 15 vs 24 HL; 22 vs 13 secondary neoplasia). Most treatment related deaths occurred in the >60 years age group, the first 4 cycles and the IPS> 3 RF groups. Secondary neoplasias were observed in 77 patients (4.9%): AML/MDS 1.5% vs 1.4%, NHL 1.4% vs 0.6% and solid tumors/others 2.5% vs 2.3%. At 5 years, OS was 91%, FFTF 85.5% and progression free survival (PFS) 86.2% (Kaplan- Meier estimates). Estimates for the difference at 5 years are 1.8% for OS, 2.3% for FFTF and 2.7% for PFS favoring BE. However, there was no statistical difference between 8x BE and 4BE+4BB in all outcome parameters (p>0.19, log rank test). There is also no significant difference between the RT or no-RT arms in this study with the caveat that a number of high-risk patients receiving RT based on the blinded panel decision.

Conclusion: The adoption of 4BE+4BB as a new standard in the future GHSG studies will depend on a refined analysis of the total data set and will be presented.