BEACOPP and ABVD Regimens in Patients with Advanced Hodgkin Lymphoma

Should an intensive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen replace the commonly used ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen as front-line therapy for advanced Hodgkin lymphoma, as the German Hodgkin Lymphoma Study Group (GHSG) has proposed? After comparing the safety and effectiveness of BEACOPP and ABVD as initial therapy in patients with previously untreated or unfavorable Hodgkin lymphoma, a team of Italian researchers are not convinced [N Engl J Med. 2011;365(3):203-212]. They found that although BEACOPP was associated with higher rates of response and complete remission (CR) and lower rates of relapse, the regimen did not significantly extend overall survival or long-term freedom from progression compared with ABVD and was associated with higher rates of toxicity. The randomized clinical trial, conducted at 3 medical centers in Italy, enrolled 331 men and women, 17 to 60 years of age, who had untreated advanced Hodgkin lymphoma. Prognosis for these patients was considered unfavorable either because their disease was staged at IIB, III, or IV, or because they had an international prognostic score ≥3. Approximately half (n=168) the participants were randomly assigned to 8 cycles of ABVD, although the number of cycles was reduced to 6 for those patients who achieved CR with the first 4 cycles. The remaining 163 patients were assigned to 4 cycles of an intensified BEACOPP regimen followed by 4 cycles of a standard-dose BEACOPP regimen. Patients in both therapy groups who did not experience CR were eligible for salvage therapy, which involved several cycles of ifosfamide-based chemotherapy consolidated with autologous hematopoietic stem-cell rescue and an intensive course of carmustine, etoposide, cytarabine, and melphalan. Patients with a very good partial response or better with initial chemotherapy could then receive local radiotherapy, if indicated. The authors reported a high rate of adherence, with 90% of the study population completing all cycles of initial treatment; 48% of patients assigned to ABVD completed 6 cycles. The proportion of patients experiencing CR with front-line therapy was slightly higher in the BEACOPP group than in the ABVD arm (70% vs 64%, respectively), whereas the rate of partial remission (>80% response) in the BEACOPP arm was slightly lower (11 patients vs 12 patients, respectively). Nearly equal proportions of patients in the BEACOPP and ABVD arms had subsequent radiotherapy (67% vs 66%, respectively), which increased the rate of CR to 81% in the BEACOPP group and 76% in the ABVD arm. Of those patients achieving CR, 16% who received front-line ABVD relapsed compared with 6% given BEACOPP. Progression during or after therapy was more frequent in the ABVD arm than in the BEACOPP group (15% vs 7%, respectively), as was relapse (11% vs 4%, respectively). The 7-year rate of freedom from first progression was estimated at 85% in the BEACOPP arm versus 73% in the ABVD group, representing a significant 12% difference (P=.004). The 7-year rate of event-free survival, which factored in discontinuations due to life-threatening toxicity or secondary leukemia, was estimated at 78% in the BEACOPP group and 71% in the ABVD arm, a difference that was not significant. The BEACOPP arm reported 9 discontinuations due to treatment-related toxicity and 3 due to lymphoma progression. Only 1 patient discontinued ABVD because of toxicity, whereas progression caused 8 discontinuations in this group. Progression and toxicity accounted for the deaths of 15 (9%) patients treated with BEACOPP and 22 (13%) who received ABVD. Acute grade 3 and 4 adverse events occurred far more often with BEACOPP. Of the 156 evaluable BEACOPP-treated patients, 81% (n=127) developed at least 1 severe hematologic adverse event and 19% (n=30) had at least 1 severe nonhematologic adverse event. In the ABVD arm, 43% (n=72) of the 166 evaluable patients had at least 1 severe hematologic event and 7% (n=12) suffered at least 1 severe nonhematologic event. Following initial therapy, 45 patients treated up front with ABVD and 20 given BEACOPP required salvage therapy, and similar proportions of patients in each group completed the entire salvage regimen (65% vs 67%, respectively). More patients from the ABVD group than from the BEACOPP group had a complete response to salvage therapy (51% vs 35%, respectively). At data cutoff, 15 (33%) patients assigned to ABVD and 3 (15%) patients assigned to BEACOPP remained alive and free of lymphoma. The authors estimated the 7-year rate of freedom from second progression for the intent-to-treat population at 88% in the BEACOPP arm compared with 82% in the ABVD group. The estimated 7-year rate of overall survival was 89% in the BEACOPP arm versus 84% in the ABVD group. Although the rates for both end points were slightly higher with BEACOPP, the difference for both comparisons was not significant. The authors concluded that “the choice of the initial treatment did not significantly influence long-term survival,” a finding they acknowledged contradicts the GHSG study, which found significant improvement with BEACOPP. They said the difference might be because the GHSG reported lower efficacy with its comparator regimen of COPP-ABVD than the current study observed with ABVD. Given the similarity between the regimens in terms of 7-year progression and survival, the authors recommended giving patients an opportunity to weigh the risks versus benefits of each one, especially the higher risk of toxicity associated with an intensified BEACOPP regimen and the increased need for equally toxic salvage therapy associated with ABVD.