Beacoppescalated Followed By Radiotherapy of Initial Bulk or Residual Disease in Advanced Stage Hodgkin Lymphoma: Long-Term Follow up of the HD9 and HD12 Trials of the German Hodgkin Study Group
Authors: Kreissl Stefanie , von Tresckow Bastian , Goergen Helen , Haverkamp Heinz , Sasse Stephanie , Diehl Volker , Engert Andreas , Borchmann Peter 
Published: October 2019

Abstract
Background:
The HD9 trial established 8 cycles of BEACOPPescalated followed by radiotherapy (RT) of initial bulk or residual tumors as German Hodgkin Study Group (GHSG) standard of care for advanced stage Hodgkin Lymphoma (HL) at that time. The succeeding HD12 trial aimed at reducing treatment intensity while maintaining efficacy. It compared 8 cycles of BEACOPPescalated with 4 cycles of BEACOPPescalated followed by 4 cycles of BEACOPPbaseline ("4+4" regimen) as well as RT with no RT of initial bulk or residual disease.
Although tumor control is outstanding, long-term safety of BEACOPPescalated still is a matter of concern, and the need of consolidating RT in advanced stage HL is discussed controversially. We therefore performed a long-term follow up of the HD9 and HD12 trials in order to address these open questions.
Patients and Methods:
Between February 1993 and March 1998, 1,282 patients in the HD9 trial were treated with either 8 cycles of COPP/ABVD, 8 cycles of BEACOPPbaseline, or 8 cycles of BEACOPPescalated.
Between January 1999 and January 2003, 1,670 HD12 patients were randomized for two questions in a factorial design: first, for 8 cycles of BEACOPPescalated or "4+4", and second for consolidation RT or no RT to regions of initial bulk or residual disease. Patients with inadequate response or skeletal involvement were irradiated irrespective of randomized RT group based on the recommendation of a central diagnostic panel blinded to treatment groups.
Results:
In HD9-patients treated with COPP/ABVD, BEACOPPbaseline, and BEACOPPescalated, the 15-year progression-free survival (PFS) was 57%, 66.8%, and 74% with overall survival (OS) rates of 72.3%, 74.5%, and 80.9%, respectively. BEACOPPescalated remains significantly better than COPP/ABVD in terms of PFS (difference 17.0%; 95%-CI 8.3% to 25.6%) and OS (difference 8.6%; 95%-CI 1.4% to 15.7%) with consistent effects in subgroups by gender, IPS and ages up to 60 years. A total of 123 second malignancies corresponding to 15-year cumulative secondary malignancy incidences of 7.2%, 13%, and 11.4% were reported for COPP/ABVD, BEACOPPbaseline, and BEACOPPescalated, respectively, without a difference between COPP/ABVD and BEACOPPescalated (p=0.5). Standardized incidence ratios (SIR) with 95%-CI showed elevation compared to the general German population in all groups: 2.0 [1.2 to 3.2], 2.6 [1.9 to 3.4] and 2.6 [1.9 to 3.4].
Regarding HD12, the 10-year PFS and OS rates in the two chemotherapy groups were not significantly different with 82.6% and 87.3% in the BEACOPPescalated group and 80.6% and 86.8% in the 4+4 group, respectively. After chemotherapy, 153 of 1,481 (10.3%) patients with complete information had an RT recommendation irrespective of group and 378 (25.5%) had neither bulk nor residual disease. Amongst the remaining 950 patients (64.1%) with bulk or residual disease, patients randomized to no RT showed a significantly inferior 10-year PFS of 83.5% compared to patients in the RT group (88.6%, difference -5.1%; 95%-CI,-9.9% to -0.4%, hazard ratio [HR] 1.47) and a trend towards inferior OS in no RT patients (RT 93%; no RT 90.2%; difference -2.7%; 95%-CI,-6.5% to 1%). Patients with residual lesions without RT had both an inferior PFS and OS as compared to patients with RT (as treated comparison: 10-year PFS RT 89.7%; no RT 83.4%; difference -6.3%; 95%-CI,-12.8% to -0.1%; 10-year OS RT 94.4%; no RT 88.4%; difference -6%; 95%-CI,-11.4% to -0.5%). 10-year cumulative incidence of second malignancies ranged between 6.4% (4+4) and 9.7% (BEACOPPescalated+RT) without a significant difference between pooled chemo- or radiotherapy groups.
Conclusions:
These long-term follow-up observations indicate an ongoing benefit of an intensive first-line therapy strategy for the PFS and OS of patients with newly diagnosed advanced stage HL. The observed OS benefit suggests an important role of consolidating RT for patients with newly diagnosed advanced stage HL. The OS benefit does not seem to be relevantly compromised by the incidence of second malignancies.

Disclosures
von Tresckow: Novartis: Consultancy, Other: travel grants, Research Funding; Takeda: Consultancy, Other: travel grants; Millenium: Consultancy. Engert:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.