PMID- 26809751 OWN - NLM STAT- MEDLINE DCOM- 20171012 LR - 20220331 IS - 1523-5866 (Electronic) IS - 1522-8517 (Print) IS - 1522-8517 (Linking) VI - 18 IP - 7 DP - 2016 Jul TI - Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy. PG - 991-1001 LID - 10.1093/neuonc/nov300 [doi] AB - BACKGROUND: The proposed use of bevacizumab with radiotherapy/temozolomide for newly diagnosed glioblastoma raised potential safety concerns. Bevacizumab has been linked with stroke, bleeding events, and wound-healing complications in other tumor types; these events are of particular concern for glioblastoma (highly vascular tumors that are usually resected). Published data on the interaction of bevacizumab with radiotherapy/temozolomide are also limited. We report safety data from a phase III randomized trial (Avastin in Glioblastoma), focusing on these considerations. METHODS: Eligible patients received: radiotherapy and temozolomide plus bevacizumab/placebo, 6 cycles; a 4-week treatment break; temozolomide plus bevacizumab/placebo, 6 cycles; and bevacizumab/placebo until progression. Data on adverse events (AEs) were collected throughout. RESULTS: Bevacizumab-treated patients (n = 461) had a longer median safety follow-up time (12.3 vs 8.5 mo), and a higher proportion completed 6 cycles of maintenance temozolomide (64.6% vs 36.9%) versus placebo (n = 450). The incidences of relevant AEs (bevacizumab vs placebo, respectively) were: arterial thromboembolic events (5.9% vs 1.6%); cerebral hemorrhage (3.3% vs 2.0%); wound-healing complications (6.9% vs 4.7%); thrombocytopenia (34.1% vs 27.3%); radiotherapy-associated skin injury (8.2% vs 9.3%); alopecia (39.0% vs 36.0%); gastrointestinal perforation (including gastrointestinal abscesses and fistulae, 1.7% vs 0.4%); and radiotherapy-associated injury (0.4% vs 0.0%). Overall, 15.8% and 23.8% of bevacizumab- and placebo-treated patients had surgery (including biopsy) after progression. Within 30 days of postprogression surgery, AE incidence was 10.9% (bevacizumab) and 23.4% (placebo). CONCLUSION: The safety profile was consistent with that expected from radiotherapy/temozolomide plus bevacizumab. The increased AE incidence with bevacizumab did not impact patients' ability to receive standard-of-care treatment or to undergo further surgery. CI - (c) The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Saran, Frank AU - Saran F AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Chinot, Olivier L AU - Chinot OL AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Henriksson, Roger AU - Henriksson R AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Mason, Warren AU - Mason W AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Wick, Wolfgang AU - Wick W AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Cloughesy, Timothy AU - Cloughesy T AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Dhar, Sunita AU - Dhar S AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Pozzi, Emanuela AU - Pozzi E AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Garcia, Josep AU - Garcia J AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). FAU - Nishikawa, Ryo AU - Nishikawa R AD - The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umea University, Forvaltningshuset, Universitetstorget, Umea, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.). LA - eng SI - ClinicalTrials.gov/NCT00943826 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial DEP - 20160124 PL - England TA - Neuro Oncol JT - Neuro-oncology JID - 100887420 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 7GR28W0FJI (Dacarbazine) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use MH - Bevacizumab/administration & dosage MH - Brain Neoplasms/*drug therapy MH - *Chemoradiotherapy/adverse effects MH - Dacarbazine/administration & dosage/analogs & derivatives MH - Disease Progression MH - Female MH - Glioblastoma/*drug therapy MH - Humans MH - Male MH - Middle Aged MH - Temozolomide MH - Treatment Outcome MH - Young Adult PMC - PMC4896538 OTO - NOTNLM OT - AVAglio OT - adverse events OT - bevacizumab OT - glioblastoma OT - safety EDAT- 2016/01/27 06:00 MHDA- 2017/10/13 06:00 PMCR- 2017/07/01 CRDT- 2016/01/27 06:00 PHST- 2015/07/24 00:00 [received] PHST- 2015/11/05 00:00 [accepted] PHST- 2016/01/27 06:00 [entrez] PHST- 2016/01/27 06:00 [pubmed] PHST- 2017/10/13 06:00 [medline] PHST- 2017/07/01 00:00 [pmc-release] AID - nov300 [pii] AID - 10.1093/neuonc/nov300 [doi] PST - ppublish SO - Neuro Oncol. 2016 Jul;18(7):991-1001. doi: 10.1093/neuonc/nov300. Epub 2016 Jan 24.