title: Reduced-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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Deutsche Krebshilfe and the Swiss Federal Government.
authors.affiliation: University Hospital of Cologne, Department of Internal Medicine I, Köln, Germany. a.engert@uni-koeln.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Heinz
authors.initials: H
authors.lastname: Haverkamp
authors.forename: Carsten
authors.initials: C
authors.lastname: Kobe
authors.forename: Jana
authors.initials: J
authors.lastname: Markova
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
authors.forename: Antony
authors.initials: A
authors.lastname: Ho
authors.forename: Josée
authors.initials: J
authors.lastname: Zijlstra
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Král
authors.forename: Michael
authors.initials: M
authors.lastname: Fuchs
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Nicole
authors.initials: N
authors.lastname: Engel
authors.forename: Max
authors.initials: M
authors.lastname: Topp
authors.forename: Susanne
authors.initials: S
authors.lastname: Klutmann
authors.forename: Holger
authors.initials: H
authors.lastname: Amthauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Bockisch
authors.forename: Regine
authors.initials: R
authors.lastname: Kluge
authors.forename: Clemens
authors.initials: C
authors.lastname: Kratochwil
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Hans Theodor
authors.initials: HT
authors.lastname: Eich
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Müller
authors.forename: Markus
authors.initials: M
authors.lastname: Dietlein
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.forename: Volker
authors.initials: V
authors.lastname: Diehl
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001761:Bleomycin / Q000009:adverse effects / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D011344:Procarbazine / Q000009:adverse effects / Q000627:therapeutic use; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D016019:Survival Analysis; D017211:Treatment Failure; D016896:Treatment Outcome; D014750:Vincristine / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone