BACKGROUND: The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. METHODS: HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1-3], 100 mg/m2 oral procarbazine [day 1-7], 40 mg/m2 oral prednisone [day 1-14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. FINDINGS: Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]). INTERPRETATION: Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. FUNDING: Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

3rd Medical Department Paracelsus Medical University and Salzburg Cancer Research Institute Salzburg Austria; Salzburg Cancer Research Institute and Arbeitsgemeinschaft Medikamentöse Tumortherapie Salzburg Austria

Berlin Reference Center for Lymphoma and Haematopathology Berlin Germany

Cantonal Hospital of St Gallen St Gallen Switzerland

Department of Haematology and Oncology Robert Bosch Hospital Stuttgart Germany

Department of Haematology Oncology and Palliative Care Ernst von Bergmann Hospital Potsdam Germany

Department of Hematology and Oncology Charité University of Medicine Berlin Germany

Department of Hematology Oncology University Hospital of Munich Munich Germany

Department of Internal Medicine 1 Klinikum Bremen Mitte Bremen Germany

Department of Internal Medicine 3 Städtisches Klinikum Karlsruhe Karlsruhe Germany

Department of Internal Medicine 3 University Hospital of Ulm Ulm Germany

Department of Internal Medicine Hematology University Hospital Kralovske Vinohrady 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Medical Oncology Oncology Institute of Southern Switzerland Bellinzona Switzerland; Swiss Group for Clinical Cancer Research Bern Switzerland

Department of Nuclear Medicine University Hospital of Cologne University of Cologne Cologne Germany

Department of Radiotherapy University Hospital of Cologne University of Cologne Cologne Germany

Department of Radiotherapy University Hospital of Münster Münster Germany

German Hodgkin Study Group Department 1 of Internal Medicine and Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf German Hodgkin Study Group Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany

HELIOS Medical Center Berlin Buch Berlin Germany

Karl Lennert Cancer Center University Hospital Schleswig Holstein Kiel Germany

Medical Department Division of Hematology and Oncology at Campus Benjamin Franklin Berlin Germany

Medizinische Klinik und Poliklinik 2 Universitätsklinikum Würzburg Würzburg Germany

Salzburg Cancer Research Institute and Arbeitsgemeinschaft Medikamentöse Tumortherapie Salzburg Austria; Medical University Innsbruck Internal Medicine 5 Hematology and Oncology Innsbruck Austria; Oncotyrol Center for Personalized Cancer Medicine Innsbruck Austria

Swiss Group for Clinical Cancer Research Bern Switzerland; Department of Medical Oncology Inselspital Bern Bern Switzerland

University Hospital Mainz Mainz Germany

University of Heidelberg Heidelberg Germany

University of Tübingen Tübingen Germany

VU University Medical Center Amsterdam Netherlands

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NCT00515554