ArticlesReduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial
Introduction
The introduction of multi-agent chemotherapy and improved radiation techniques has rendered Hodgkin's lymphoma one of the most favourable cancers in terms of likelihood of cure. Accordingly, the goal of most recent clinical trials in this malignancy has been to minimise intensity of treatment while maintaining previous levels of tumour control, particularly in early stage disease.1, 2 An example is the German Hodgkin Study Group's (GHSG) HD10 study3 of patients with favourable limited stage disease, which showed that reduction in both number of chemotherapy cycles and radiation dose was possible without loss of efficacy.
By contrast with the impressive cure rates in early stages, only 65–70% of patients diagnosed with advanced stage Hodgkin's lymphoma are disease-free at 5 years when treated with ABVD or similar chemotherapy.4, 5 For more than 20 years of clinical research, attempts were made to improve on the efficacy of ABVD in this group of patients.6, 7, 8 The most promising regimens emerging were BEACOPPescalated9, 10 and Stanford-V.11 However, results from randomised trials in advanced Hodgkin's lymphoma showed no benefit of Stanford-V over ABVD.12, 13, 14 By contrast, BEACOPPescalated resulted in improved tumour control and overall survival in the GHSG HD9 study when compared with a variant of the ABVD regimen.9, 10 Better tumour control as compared with ABVD was confirmed in two randomised trials.15, 16
Although clearly more effective, there has been some concern about the higher toxic effects of eight cycles of BEACOPPescalated (8×Besc) compared with ABVD. To reduce treatment-related toxic effects for patients with advanced stage Hodgkin's lymphoma, the GHSG did a follow-up study (HD15) comparing 8×Besc with two less intensive regimens: six cycles of BEACOPPescalated (6×Besc) or eight cycles of a time intensified baseline-dose BEACOPP variant given in 14-day intervals (8×B14).17 The primary objective of the trial presented here was to show non-inferiority of tumour control for the experimental groups. By contrast with previous studies in which radiotherapy was applied to initial bulky and residual disease, we assessed if radiotherapy given only to patients with a persistent mass measuring 2·5 cm or more, and positive on PET scan after chemotherapy, was adequate.
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Study design and patients
HD15 was an unmasked, multicentre, randomised, group-sequential, non-inferiority trial for patients with advanced stage Hodgkin's lymphoma. Patients with newly diagnosed, histology-proven Hodgkin's lymphoma in Ann-Arbor stage IIB having large mediastinal mass (a third or more of the maximal thoracic diameter) or extranodal lesions, and all patients in stages III and IV were recruited and treated in 408 hospitals and practices in Germany, the Czech Republic, Switzerland, The Netherlands, and
Results
2182 patients were randomly assigned to treatment groups between Jan 28, 2003, and April 18, 2008. 44 patients were excluded from all analyses since Hodgkin's lymphoma was not confirmed by reference histology (figure 1). Also excluded were nine patients who became part of a different study and three who withdrew their informed consent. Thus, the intention-to-treat analysis set included 2126 patients (705 assigned to the 8×Besc group, 711 to the 6×Besc group, and 710 to the 8×B14 group). A total
Discussion
The goal of the three-arm HD15 study presented here was to reduce toxic effects of treatment while maintaining efficacy in patients with advanced stage Hodgkin's lymphoma. The primary endpoint in this trial, non-inferiority in terms of freedom from treatment failure, was clearly proven for 6×Besc and 8×B14 groups 3 years ahead of the planned final analysis. When freedom from treatment failure was compared between 8×Besc and 6×Besc groups, it did not differ in the sequential analysis but did,
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