European Trial Indicates That Neither Dacarbazine Nor Bleomycin Should Be Omitted From ABVD Regimen for Early-Stage Favorable Hodgkin Lymphoma
In a European open-label noninferiority trial (German Hodgkin Study Group [GHSG)] HD13) reported in The Lancet, Behringer et al found poorer outcomes with omission of dacarbazine or bleomycin from treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with early-stage favorable Hodgkin lymphoma, indicating that these agents should not be excluded from treatment in hopes of reducing toxicity.
Study Details
The trial examined freedom from treatment failure rates with two cycles of ABVD vs two cycles of ABV (omitting dacarbazine), AVD (omitting bleomycin), or AV (omitting both) in patients with newly diagnosed classic or nodular lymphocyte–predominant Hodgkin lymphoma. All patients received involved-field radiotherapy at 30 Gy after completion of both cycles of chemotherapy.
Beginning in January 2003, patients were randomly assigned 1:1:1:1 to the four groups. However, randomization to AV (September 2005) and ABV (February 2006) was stopped early due to high event rates; 1:1 randomization to ABVD and AVD continued until September 2009. The primary objective of the trial was to show noninferiority of the experimental treatments vs ABVD in freedom from treatment failure by excluding a difference of 6% after 5 years that corresponded to a hazard ratio (HR) of 1.72 via 95% confidence interval (CI).
No Noninferiority Shown
Among the 1,502 qualified patients, 566 were randomly assigned to ABVD, 198 to ABV, 571 to AVD, and 167 to AV. Five-year freedom from treatment failure was 93.1% with ABVD, 81.4% with ABV, 89.2% with AVD, and 77.1% with AV.
Inferiority to ABVD was established for treatments excluding dacarbazine, with 5-year differences in rates of –11.5 (95% CI = –18.3 to –4.7) and a hazard ratio of 2.06 with a 95% confidence interval of 1.21 to 3.52 for ABV and –15.2% (95% CI = –23.0 to –7.4) and a hazard ratio of 2.57 with a 95% confidence interval of 1.51 to 4.40 for AV. Noninferiority of AVD (excluding bleomycin) compared with ABVD also could not be demonstrated, with the 5-year difference of –3.9% (95% CI = -7.7 to –0.1) being associated with a hazard ratio of 1.50 with a 95% confidence interval of 1.00 to 2.26, which included the noninferiority margin of 1.72.
Toxicity
World Health Organization grade III or IV toxicity occurred in 33% of the ABVD group, 28% of the ABV group, 26% of the AVD group, and 26% of the AV group. Leukopenia was the most common grade III or IV event and was more common in patients receiving bleomycin, occurring in 17% of the ABVD group, 18% of the ABV group, 11% of the AVD group, and 12% of the AV group. Alopecia, the next most common event, occurred in 12%, 10%, 11%, and 11%, respectively.
The investigators concluded: “Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin’s lymphoma should remain ABVD followed by [involved-field radiotherapy].”
Andreas Engert, MD, of University Hospital of Cologne, is the corresponding author for The Lancet article. Karolin Behringer, MD, and Helen Goergen, Dipl Math, of University Hospital of Cologne, contributed equally to the article.
The study was funded by Deutsche Krebshilfe and Swiss State Secretariat for Education and Research. The study authors reported no potential conflicts of interest.
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