An aggressive strategy combining an escalated BEACOPP regimen plus ABVD and radiotherapy improved tumor control compared with standard treatment (ie, ABVD plus radiation) in patients with early unfavorable Hodgkin lymphoma in the German Hodgkin Study Group HD14 trial. Lead author Andreas Engert, MD, University Hospital Cologne in Cologne, Germany, presented final results of the trial at the 52nd American Society of Hematology (ASH) Annual Meeting.¹ Although tumor control, measured by the rate of freedom from treatment failure, was superior with the more aggressive strategy, overall survival was not improved. This study was also published in the Journal of Clinical Oncology.²

"We achieved overall better tumor control with more aggressive treatment, and this treatment is now our standard of care for continuing studies. Hematologic toxicity was slightly higher with the escalated BEACOPP regimen, but this did not result in more treatment-related deaths," Dr. Engert said. He added that with short follow-up of 5 years, no overall survival difference was seen.

Study Details

Standard treatment for early unfavorable Hodgkin lymphoma consists of four cycles of ABVD chemotherapy and involved-field radiotherapy. The previous HD8 study by the same group of investigators showed that standard therapy achieved a 5-year overall survival rate of 91% and freedom from treatment failure rate of 83%. In the present study, the escalated BEACOPP regimen improved the 5-year freedom from treatment failure rate by approximately 6% to 7%.

In the HD14 trial, patients in the experimental arm received two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, and cyclophosphamide, plus vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), followed by involved-field radiotherapy of 30 Gy. The control arm received four cycles of ABVD followed by the same radiotherapy. The primary endpoint was freedom from treatment failure.

The study enrolled 1,655 patients aged 16 to 60 years with early unfavorable Hodgkin lymphoma. Stage I-IIA patients (two-thirds of the study population) were required to have at least one of the following risk factors: large mediastinal mass, extranodal disease, erythrocyte sedimentation rate ≥ 50 mm/h or ≥ 30 mm/h and B symptoms, or at least three nodal areas. Stage IIB patients had a sedimentation rate ≥ 50 mm/h or ≥ 30 mm/h and B symptoms or at least three nodal areas.

In the final intention-to-treat analysis of 1,528 patients, at 5 years 87.6% of patients receiving standard treatment were free from treatment failure (relapses and deaths) vs 94.3% receiving escalated BEACOPP (P < .0001).

"This absolute difference of about 7% was highly significant and met predefined criteria for stopping the trial in July of 2008," Dr. Engert stated. "We now consider the escalated BEACOPP regimen a new standard of care."

Results

The more aggressive regimen achieved superior results on other measures as well, including progressive disease, early relapse, and late relapse. With standard treatment vs escalated BEACOPP, respectively, disease progression was observed in 3.0% vs 0.8% of patients, respectively; early relapse occurred in 3.0% vs 0.9%, respectively; and late relapse occurred in 2.4% vs 0.8%, respectively.

"These were stunning differences in tumor control," he commented.

Response rates were similar with the two regimens: about 95%. Twenty patients in each arm died; treatment-related deaths occurred in five control patients and four patients in the experimental arm.  Secondary neoplasias were observed in 19 patients after standard therapy and in 16 patients with escalated BEACOPP.

Grade 3/4 acute toxicities occurred in 51% of the ABVD-alone arm vs 87% of those in the escalated BEACOPP arm. Grade 3/4 hematologic toxicity was observed in about 30% of the control arm compared with 70% receiving escalated BEACOPP. The more aggressive regimen had higher rates of hematologic toxicities: 24% for controls and 80% for escalated BEACOPP, and of leukopenia with infections:

1.2% and 9.8%, respectively. More acute myeloid leukemia occurred with the escalated BEACOPP regimen: 0 for controls and 3 cases, respectively; whereas more cases of non-Hodgkin lymphoma were reported in the control arm: 10 vs 5 cases, respectively.

Despite these positive results from a large phase III trial, some hematologists consider escalated BEACOPP too toxic and are concerned about treatment-induced secondary malignancies and fertility. ■

References

1. Engert A, Borchmann P, Pluetschow A, et al: Dose-escalation with BEACOPP escalated is superior to ABVD in the combined-modality treatment of early unfavorable Hodgkin lymphoma: Final analysis of the German Hodgkin Study Group (GHSG) HD14 trial. 52nd ASH Annual Meeting. Abstract 765. Presented December 6, 2010.

2. Eich HT, Diehl V, Gorgen H, et al: Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: Final analysis of the German Hodgkin Study Group HD11 trial.  J Clin Oncol 28:4199-4206, 2010.