ABVD Chemotherapy without Radiation Associated with Increased Survival in Hodgkin’s Lymphoma

A randomized study has found that doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy was associated with a higher rate of 12-year overall survival than subtotal nodal radiation therapy, with or without ABVD, in patients with stage IA or IIA nonbulky Hodgkin’s lymphoma. The findings were published online in the New England Journal of Medicine [10.1056/NEJMoa11111961]. The trial, the HD.6 (Hodgkin’s Disease.6), was initiated in 1994 to determine if ABVD chemotherapy alone could control disease to a similar degree as radiation-based therapy in patients with stage IA or IIA nonbulky Hodgkin’s lymphoma, without the lasting concerns associated with radiation treatment. Ongoing health concerns with radiation therapy include the emergence of secondary cancers and cardiovascular disease, the authors noted. In an initial report with a median follow-up of 4.2 years, patients randomized to radiation-based therapy were less likely to experience disease progression, but no differences in survival rates between the treatment groups were observed. The trial was designed and conducted by the NCIC Clinical Trials Group in Kingston, Ontario. Patients were enrolled through centers at the NCIC Clinical Trials Group and at centers of the Eastern Cooperative Oncology Group. Patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma were randomized to receive ABVD alone, or treatment that included subtotal nodal radiation therapy. In the group randomized to receive radiation therapy, those with a favorable risk profile received subtotal nodal radiation therapy alone, while those with an unfavorable risk profile received 2 cycles of ABVD followed by subtotal nodal radiation therapy. Patients randomized to the ABVD group, regardless of risk profile, received 4 cycles of ABVD, with a restaging of disease after 2 and 4 cycles of therapy. The study was initiated in January 1994 and was closed to enrollment in April 2002, with a total of 405 patients enrolled. The closure of the trial was based on the publication of data from the European Organization for Research and Treatment of Cancer, reporting favorable outcomes with a combination therapeutic strategy that included involved-field radiation therapy. Based on these findings, the investigators determined that it would be inappropriate to continue a clinical trial involving subtotal nodal radiation therapy. After a median follow-up of 11.3 years, the rates of overall survival were 94% and 87% in the ABVD and radiation-based treatment groups, respectively. While there was a lower rate of freedom from disease progression in the ABVD group compared with the radiation-based therapy group (87% vs 92%), there were no significant differences between groups in the rate of event-free survival. In patients with a favorable risk profile, no significant differences in outcomes were observed between patients randomized to ABVD alone or subtotal nodal radiation therapy alone. However, in patients with an unfavorable risk profile, overall survival rates were higher with ABVD versus radiation-based therapy. In addition, the rate of freedom from disease progression was higher with radiation-based therapy in this patient subgroup, similar to the overall study group analysis. The analysis revealed 12 deaths in the ABVD-only group versus 24 deaths in the radiation therapy group. In the radiation therapy group, there were more deaths due to second cancers and causes other than Hodgkin’s lymphoma or second cancers. Patients in the radiation therapy group were also more likely to experience second cancers or cardiac events. The investigators cited a major limitation to their findings, namely that subtotal nodal radiation therapy is now an outdated treatment strategy in light of data that emerged during the course of the study. They noted that this specific radiation protocol could have contributed to the excess deaths found with radiation-based therapy. Nevertheless, they extrapolated their findings to those reported in similar trials, concluding that ABVD alone is a viable treatment option in patients with stage IA or IIA nonbulky Hodgkin’s lymphoma.