Peter Borchmann1, Annette Plütschow1, Carsten Kobe2, Richard Greil3, Julia Meissner4, Max S Topp5, Helmut Ostermann6, Judith Dierlamm7, Johannes Mohm8, Julia Thiemer9, Martin Sökler10, Andrea Kerkhoff11, Miriam Ahlborn12, Teresa V Halbsguth13, Sonja Martin14, Ulrich Keller15, Stefan Balabanov16, Thomas Pabst17, Martin Vogelhuber18, Andreas Hüttmann19, Martin Wilhelm20, Josée M Zijlstra21, Alden Moccia22, Georg Kuhnert2, Paul J Bröckelmann1, Bastian von Tresckow23, Michael Fuchs1, Beate Klimm24, Andreas Rosenwald25, Hans Eich26, Christian Baues27, Simone Marnitz27, Michael Hallek28, Volker Diehl29, Markus Dietlein2, Andreas Engert30. 1. Department I of Internal Medicine, Center for Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, Faculty of Medicine and University of Cologne, Cologne, Germany; German Hodgkin Study Group, Faculty of Medicine and University of Cologne, Cologne, Germany. 2. Department of Nuclear Medicine, Faculty of Medicine and University of Cologne, Cologne, Germany. 3. Illrd Medical Department, Paracelsus Medical University, Salzburg Austria; Salzburg Cancer Research Institute and AGMT, Salzburg, Austria. 4. Medicine V, University of Heidelberg, Heidelberg, Germany. 5. Medizinische Klinik Und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. 6. LMU, University Hospital of Munich, Munich, Germany. 7. Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. Onkopraxis Dresden, Dresden, Germany. 9. Department of Hematology and Oncology, Klinikum der Philipps-Universität Marburg, Marburg, Germany. 10. Innere Medizin II, University Hospital Tübingen, Tübingen, Germany. 11. Medizinische Klinik A, University Hospital Münster, Münster, Germany. 12. Medizinische Klinik III, Städtisches Klinikum Braunschweig, Braunschweig, Germany. 13. Department of Medicine II, Hematology/Oncology, Goethe University Hospital, Frankfurt, Frankfurt, Germany. 14. Department of Hematology and Oncology, Robert-Bosch-Hospital, Stuttgart, Germany. 15. Klinikum rechts der Isar der TU München, München, Germany. 16. Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. 17. Department of Medical Oncology, Institute of Medical Oncology, Bern, Switzerland. 18. Klinik und Poliklinik für Innere Medizin III, Universitätsklinik Regensburg, Regensburg, Germany. 19. Department of Hematology, University Hospital of Essen, Essen, Germany. 20. Klinikum Nurnberg and Paracelsus Medical University, Nurnberg, Germany. 21. Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands. 22. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Swiss Group for Clinical Cancer Research, Bern, Switzerland. 23. Department I of Internal Medicine, Center for Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, Faculty of Medicine and University of Cologne, Cologne, Germany; German Hodgkin Study Group, Faculty of Medicine and University of Cologne, Cologne, Germany; Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 24. Klinik für Hämatologie, Onkologie und Gastroenterologie, Kliniken Maria Hilf, Mönchengladbach, Germany. 25. Institute of Pathology, Julius Maximilian University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany. 26. Department of Radiotherapy, University Hospital Münster, Münster, Germany. 27. Department of Radiooncology and Cyberknife Center, Faculty of Medicine and University of Cologne, Cologne, Germany. 28. Department I of Internal Medicine, Center for Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, Faculty of Medicine and University of Cologne, Cologne, Germany. 29. German Hodgkin Study Group, Faculty of Medicine and University of Cologne, Cologne, Germany. 30. Department I of Internal Medicine, Center for Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, Faculty of Medicine and University of Cologne, Cologne, Germany; German Hodgkin Study Group, Faculty of Medicine and University of Cologne, Cologne, Germany. Electronic address: a.engert@uni-koeln.de.
Abstract
BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.
BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.
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