Abstract

BACKGROUND
The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy.
METHODS
In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041.
FINDINGS
Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy.
INTERPRETATION
Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting.
FUNDING
Deutsche Krebshilfe and the Swiss Federal Government.

Links

Publisher Full Text

Authors

Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, Zijlstra J, Král Z, Fuchs M, Hallek M, Kanz L, Döhner H, Dörken B, Engel N, Topp M, Klutmann S, Amthauer H, Bockisch A, Kluge R, Kratochwil C, Schober O, Greil R, Andreesen R, Kneba M, Pfreundschuh M, Stein H, Eich HT, Müller RP, Dietlein M, Borchmann P, Diehl V, German Hodgkin Study Group, Swiss Group for Clinical Cancer Research, Arbeitsgemeinschaft Medikamentöse Tumortherapie

Institution

University Hospital of Cologne, Department of Internal Medicine I, Köln, Germany. a.engert@uni-koeln.de

Source

Lancet 379:9828 2012 May 12 pg 1791-9

MeSH

Adolescent
Adult
Antineoplastic Combined Chemotherapy Protocols
Bleomycin
Cyclophosphamide
Doxorubicin
Etoposide
Female
Hodgkin Disease
Humans
Male
Middle Aged
Neoplasm Staging
Positron-Emission Tomography
Prednisone
Procarbazine
Proportional Hazards Models
Prospective Studies
Radiotherapy Dosage
Survival Analysis
Treatment Failure
Treatment Outcome
Vincristine

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22480758