Emilie Le Rhun1, Felix Boakye Oppong2, Maureen Vanlancker2, Roger Stupp3,4, Burt Nabors5, Olivier Chinot6, Wolfgang Wick7, Matthias Preusser8, Thierry Gorlia2, Michael Weller9. 1. Departments of Neurosurgery and Neurology & Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland. 2. EORTC Headquarters, Brussels, Belgium. 3. Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. 4. Malnati Brain Tumor Center of the Lurie Comprehensive Cancer Center and Departments of Neursurgery and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 5. Department of Neurology, Division of Neuro-Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. 6. Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France. 7. Department of Neurology and Neuro-oncology Program at the National Center for Tumor Diseases, University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany. 8. Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria. 9. Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
Abstract
BACKGROUND: Myelosuppression is the major toxicity encountered during temozolomide chemoradiotherapy for newly diagnosed glioblastoma. METHODS: We assessed the association of myelosuppression (neutropenia, thrombocytopenia, anemia, and lymphopenia) during temozolomide chemoradiotherapy alone or in combination with experimental agents with progression-free survival (PFS) or overall survival (OS) in 2073 patients with newly diagnosed glioblastoma enrolled into five clinical trials: CENTRIC, CORE, EORTC 26082, AVAglio, and EORTC 26981. A landmark Cox model was used. For each primary association analysis, a significance level of 1.7% was used. RESULTS: Lower neutrophil counts at baseline were associated with better PFS (P = .011) and OS (P < .001), independently of steroid intake. Females experienced uniformly more myelotoxicity than males. Lymphopenia during concomitant chemoradiotherapy was associated with OS (P = .009): low-grade (1-2) lymphopenia might be associated with superior OS (HR 0.78, 98.3% CI 0.58-1.06), whereas high-grade (3-4) lymphopenia might be associated with inferior OS (HR 1.08, 98.3% CI 0.75-1.54). There were no associations of altered hematological parameters during concomitant chemoradiotherapy with PFS. During maintenance chemoradiotherapy, no significant association was found between any parameter of myelosuppression and PFS or OS, although exploratory analysis at 5% significance level indicated that either mild-to-moderate (HR 0.76, 95% CI 0.62-0.93) or high-grade lymphopenia (HR 0.65, 95% CI 0.46-0.92) was associated with superior OS (P = .013), but not PFS. CONCLUSIONS: The association of higher neutrophil counts at baseline with inferior PFS and OS requires further prospective evaluation. The link of therapy-induced lymphopenia to better outcome may guide the design for immunotherapy trials in newly diagnosed glioblastoma.
BACKGROUND: Myelosuppression is the major toxicity encountered during temozolomide chemoradiotherapy for newly diagnosed glioblastoma. METHODS: We assessed the association of myelosuppression (neutropenia, thrombocytopenia, anemia, and lymphopenia) during temozolomide chemoradiotherapy alone or in combination with experimental agents with progression-free survival (PFS) or overall survival (OS) in 2073 patients with newly diagnosed glioblastoma enrolled into five clinical trials: CENTRIC, CORE, EORTC 26082, AVAglio, and EORTC 26981. A landmark Cox model was used. For each primary association analysis, a significance level of 1.7% was used. RESULTS: Lower neutrophil counts at baseline were associated with better PFS (P = .011) and OS (P < .001), independently of steroid intake. Females experienced uniformly more myelotoxicity than males. Lymphopenia during concomitant chemoradiotherapy was associated with OS (P = .009): low-grade (1-2) lymphopenia might be associated with superior OS (HR 0.78, 98.3% CI 0.58-1.06), whereas high-grade (3-4) lymphopenia might be associated with inferior OS (HR 1.08, 98.3% CI 0.75-1.54). There were no associations of altered hematological parameters during concomitant chemoradiotherapy with PFS. During maintenance chemoradiotherapy, no significant association was found between any parameter of myelosuppression and PFS or OS, although exploratory analysis at 5% significance level indicated that either mild-to-moderate (HR 0.76, 95% CI 0.62-0.93) or high-grade lymphopenia (HR 0.65, 95% CI 0.46-0.92) was associated with superior OS (P = .013), but not PFS. CONCLUSIONS: The association of higher neutrophil counts at baseline with inferior PFS and OS requires further prospective evaluation. The link of therapy-induced lymphopenia to better outcome may guide the design for immunotherapy trials in newly diagnosed glioblastoma.
Authors: Patrick Y Wen; Michael Weller; Eudocia Quant Lee; Brian M Alexander; Jill S Barnholtz-Sloan; Floris P Barthel; Tracy T Batchelor; Ranjit S Bindra; Susan M Chang; E Antonio Chiocca; Timothy F Cloughesy; John F DeGroot; Evanthia Galanis; Mark R Gilbert; Monika E Hegi; Craig Horbinski; Raymond Y Huang; Andrew B Lassman; Emilie Le Rhun; Michael Lim; Minesh P Mehta; Ingo K Mellinghoff; Giuseppe Minniti; David Nathanson; Michael Platten; Matthias Preusser; Patrick Roth; Marc Sanson; David Schiff; Susan C Short; Martin J B Taphoorn; Joerg-Christian Tonn; Jonathan Tsang; Roel G W Verhaak; Andreas von Deimling; Wolfgang Wick; Gelareh Zadeh; David A Reardon; Kenneth D Aldape; Martin J van den Bent Journal: Neuro Oncol Date: 2020-08-17 Impact factor: 12.300
Authors: L Burt Nabors; Karen L Fink; Tom Mikkelsen; Danica Grujicic; Rafal Tarnawski; Do Hyun Nam; Maria Mazurkiewicz; Michael Salacz; Lynn Ashby; Vittorina Zagonel; Roberta Depenni; James R Perry; Christine Hicking; Martin Picard; Monika E Hegi; Benoit Lhermitte; David A Reardon Journal: Neuro Oncol Date: 2015-03-11 Impact factor: 12.300
Authors: Monika E Hegi; Annie-Claire Diserens; Thierry Gorlia; Marie-France Hamou; Nicolas de Tribolet; Michael Weller; Johan M Kros; Johannes A Hainfellner; Warren Mason; Luigi Mariani; Jacoline E C Bromberg; Peter Hau; René O Mirimanoff; J Gregory Cairncross; Robert C Janzer; Roger Stupp Journal: N Engl J Med Date: 2005-03-10 Impact factor: 91.245
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316
Authors: Wolfgang Wick; Thierry Gorlia; Pierre Bady; Michael Platten; Martin J van den Bent; Martin J B Taphoorn; Jonathan Steuve; Alba A Brandes; Marie-France Hamou; Antje Wick; Markus Kosch; Michael Weller; Roger Stupp; Patrick Roth; Vassilis Golfinopoulos; Jean-Sebastien Frenel; Mario Campone; Damien Ricard; Christine Marosi; Salvador Villa; Astrid Weyerbrock; Kirsten Hopkins; Krisztian Homicsko; Benoit Lhermitte; Gianfranco Pesce; Monika E Hegi Journal: Clin Cancer Res Date: 2016-05-03 Impact factor: 12.531
Authors: Kenneth L Pitter; Ilaria Tamagno; Kristina Alikhanyan; Amira Hosni-Ahmed; Siobhan S Pattwell; Shannon Donnola; Charles Dai; Tatsuya Ozawa; Maria Chang; Timothy A Chan; Kathryn Beal; Andrew J Bishop; Christopher A Barker; Terreia S Jones; Bettina Hentschel; Thierry Gorlia; Uwe Schlegel; Roger Stupp; Michael Weller; Eric C Holland; Dolores Hambardzumyan Journal: Brain Date: 2016-03-28 Impact factor: 13.501
Authors: Natalia Filippova; Jeffrey M Grimes; Jianmei W Leavenworth; David Namkoong; Xiuhua Yang; Peter H King; Michael Crowley; David K Crossman; L Burt Nabors Journal: Neurooncol Adv Date: 2022-09-15