Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) Randomized HD11 Trial

Combined modality treatment consisting of 4-6 cycles of chemotherapy (CT) followed by involved field radiotherapy (IF-RT) is the standard treatment for early unfavorable HL. However, the optimal CT regimen and adequate radiation dose is unclear. The previous trial for this group of patients (HD8), revealed an overall survival (OS) and freedom from treatment failure (FFTF) at 5 years of 91% and 83%, respectively. The HD11 trial thus addressed two major questions: (1) improving outcome by intensifying CT (4xABVD vs. 4xBEACOPPbaseline; Bbas) and (2) defining the best radiation dose (30 Gy vs. 20 Gy IF-RT). Between May 1998 and January 2003, 1395 eligible patients aged 16-75 years with untreated early unfavorable stage HL (CS I, IIA with at least one of the risk factors large mediastinal mass (a), extranodal disease (b), elevated ESR (c) or ≥ 3 nodal areas (d); IIB with risk factors c and/or d) were randomized into one of the following 4 treatment arms: 4xABVD + 30 Gy (A), 4xABVD + 20 Gy (B), 4x Bbas + 30 Gy (C) or 4x Bbas + 20 Gy (D). Since there are strong indications for an interaction between CT- and RT-doses, a comparison of pooled treatment arms (A+B vs. C+D for comparison of 4xABVD vs. 4x Bbas and A+C vs. B+D for comparison of 30 Gy IF-RT vs. 20 Gy IF-RT) would be misleading. Therefore, all treatment arms were analyzed separately. Patient characteristics were well balanced between the 4 arms (median age 33 years; 49% male; 6% stage I; 29% B-symptoms). CT- and RT-related acute toxicity occurred significantly more often in the arms with the more intensive therapy (CT: 74.1% vs. 51.8%; RT: 12.3% vs. 5.5%). The complete remission rate 3 months after end of therapy was 94.1% for the whole group and did not differ significantly between the 4 arms. The 5-year estimate of FFTF (primary endpoint) is 85.0% (OS 94.5%, PFS 86.0%). Bbas is more effective than ABVD if followed by 20 Gy IF-RT (5y-FFTF difference 5.7%, 95%-CI [0.1%; 11.3%]). This effect does not exist in combination with 30 Gy IF-RT (5y-FFTF difference 1.6% [-3.6%; 6.9%]). Similar results are observed for the RT-question: After 4 cycles of Bbas, 20 Gy is not inferior to 30 Gy (5y-FFTF difference -0.1%, 95%-CI [-5.1%; 4.9%]), whereas after 4xABVD, a relevant inferiority of 20 Gy cannot be excluded (-4.0% [-9.5%; 1.4%]). A reduction of RT dose from 30 Gy to 20 Gy IF-RT seems to be justified only in combination with Bbas, but not with a less effective chemotherapy such as 4xABVD. Four cycles of ABVD followed by 30 Gy IFRT is the standard of care for HL patients in early unfavorable stages.