Michael Fuchs1, Helen Goergen1, Carsten Kobe2, Georg Kuhnert2, Andreas Lohri3,4, Richard Greil5,6, Stephanie Sasse1, Max S Topp7, Erhardt Schäfer8, Bernd Hertenstein9, Martin Soekler10, Martin Vogelhuber11, Josée M Zijlstra12, Ulrich Bernd Keller13, Stefan W Krause14, Martin Wilhelm15, Georg Maschmeyer16, Julia Thiemer17, Ulrich Dührsen18, Julia Meissner19, Andreas Viardot20, Hans Eich21, Christian Baues22, Volker Diehl1, Andreas Rosenwald23, Bastian von Tresckow1, Markus Dietlein2, Peter Borchmann1, Andreas Engert1. 1. German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany. 2. Department of Nuclear Medicine, University of Cologne, Cologne, Germany. 3. Cantonal Hospital Baselland, Liestal, Switzerland. 4. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland. 5. IIIrd Medical Department, Paracelcus Medical University and Salzburg Cancer Research Institute, Salzburg, Austria. 6. Salzburg Cancer Research Institute and AGMT (Arbeitsgemeinschaft Medikamentöse Tumortherapie), Salzburg, Austria. 7. Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. 8. Dres. med. Just/Düwel/Riesenberg/Steinke/Schäfer, Studiengesellschaft, Bielefeld, Germany. 9. Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany. 10. University of Tübingen, Tübingen, Germany. 11. Medizinische Klinik III, Universitätsklinik Regensburg, Regensburg, Germany. 12. Amsterdam University Medical Center, Vrije Universiteit, Department of Hematology, Amsterdam, Netherlands. 13. Department of Internal Medicine III, Klinikum "Rechts der Isar", Munich, Germany. 14. Department of Internal Medicine 5, Haematology/Oncology, University of Erlangen, Erlangen, Germany. 15. Department of Medical Oncology, Klinikum Nürnberg, Paracelsus Medical University, Nürnberg, Germany. 16. Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany. 17. Clinic for Hematology, Oncology and Immunology, Philipps University, Marburg, Germany. 18. Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 19. University of Heidelberg, Heidelberg, Germany. 20. Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany. 21. Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany. 22. Department of Radiotherapy, University of Cologne, Cologne, Germany. 23. Institute of Pathology, Julius Maximilian University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
Abstract
PURPOSE:Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment. METHODS:Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2-negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients. RESULTS:We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2-negative, per-protocol-treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2-negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2-positive patients (P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011). CONCLUSION: In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2-negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.
RCT Entities:
PURPOSE: Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment. METHODS: Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2-negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients. RESULTS: We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2-negative, per-protocol-treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2-negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2-positive patients (P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011). CONCLUSION: In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2-negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.
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