Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial
Gerhard Held,
Lorenz Thurner,
Viola Poeschel,
German Ott,
Christian Schmidt,
Konstantinos Christofyllakis,
Andreas Viardot,
Peter Borchmann,
Walburga Engel-Riedel,
Norbert Frickhofen,
Maike Nickelsen,
Ofer Shpilberg,
Mathias Witzens-Harig,
Frank Griesinger,
Beate Krammer-Steiner,
Andreas Neubauer,
Peter de Nully Brown,
Massimo Federico,
Bertram Glass,
Norbert Schmitz,
Gerald Wulf,
Lorenz Truemper,
Moritz Bewarder,
Niels Murawski,
Stephan Stilgenbauer,
Andreas Rosenwald,
Bettina Altmann,
Marianne Engelhard,
Heinz Schmidberger,
Jochen Fleckenstein,
Christian Berdel,
Markus Loeffler,
Marita Ziepert,
on behalf of the German Lymphoma Alliance (GLA)
Affiliations
Gerhard Held
1 Department of Internal Medicine 1, Westpfalz-Klinikum, Kaiserslautern, Germany
Lorenz Thurner
2 Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany
Viola Poeschel
2 Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany
German Ott
3 Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
Christian Schmidt
4 Department of Medicine III, University Hospital, Munich, Germany
Konstantinos Christofyllakis
2 Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany
Andreas Viardot
5 Department of Internal Medicine III, University Hospital Ulm, Germany
Peter Borchmann
6 Department of Hematology and Oncology, University Hospital of Cologne, Germany
8 Department of Internal Medicine III, Helios Dr.Horst-Schmidt-Kliniken, Wiesbaden, Germany
Maike Nickelsen
9 Oncology Lerchenfeld, Hamburg, Germany
Ofer Shpilberg
10 Department of Hematology, Rabin Medical Center, Beilinson Hospital, Petah-Tiqwa, Israel
Mathias Witzens-Harig
11 Department of Internal Medicine V, University of Heidelberg, Germany
Frank Griesinger
12 Department of Internal Oncology, Pius-Hospital, Oldenburg, Germany
Beate Krammer-Steiner
13 Department of Internal Medicine, Klinikum Rostock Südstadt, Germany
Andreas Neubauer
14 Department of Hematology, Oncology and Immunology, University Hospital Marburg, Germany
Peter de Nully Brown
15 Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Massimo Federico
16 CHIMOMO Department, University of Modena and Reggio Emilia, Italy
Bertram Glass
17 Department of Hematology and Stem Cell Transplantation, Helios Klinikum Berlin-Buch, Germany
Norbert Schmitz
18 Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Germany
Gerald Wulf
19 Department of Hematology and Oncology, Georg August University of Goettingen, Germany
Lorenz Truemper
19 Department of Hematology and Oncology, Georg August University of Goettingen, Germany
Moritz Bewarder
2 Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany
Niels Murawski
2 Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany
Stephan Stilgenbauer
2 Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany
Andreas Rosenwald
20 Institute of Pathology, University of Wuerzburg, and Comprehensive Cancer Center Mainfranken, Germany
Bettina Altmann
21 Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Germany
Marianne Engelhard
22 Department of Radiotherapy, University Hospital Essen, Germany
Heinz Schmidberger
23 Department of Radiooncology and Radiotherapy, University Medical Center, Mainz, Germany
Jochen Fleckenstein
24 Department of Radiotherapy and Radiation Oncology, Saarland University Medical School, Homburg/Saar, Germany
Christian Berdel
24 Department of Radiotherapy and Radiation Oncology, Saarland University Medical School, Homburg/Saar, Germany
Markus Loeffler
21 Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Germany
Marita Ziepert
21 Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Germany
UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.
