Jia-Shu Chen1,2, Ross Clarke1, Alexander F Haddad3, Elaina J Wang1, Michel Lacroix4, Indra Neil Sarkar1,2,5, Ramin Zand4, Elizabeth S Chen1,2, Steven A Toms6,7,8. 1. The Warren Alpert Medical School of Brown University, Providence, RI, USA. 2. Center for Biomedical Informatics, Brown University, Providence, RI, USA. 3. Department of Neurological Surgery, University of California, San Francisco, CA, USA. 4. Geisinger Health, Neuroscience Institute, Danville, PA, USA. 5. Rhode Island Quality Institute, Providence, RI, USA. 6. The Warren Alpert Medical School of Brown University, Providence, RI, USA. Steven.Toms@lifespan.org. 7. Department of Neurosurgery, Rhode Island Hospital, Providence, RI, USA. Steven.Toms@lifespan.org. 8. Department of Neurosurgery, The Warren Alpert Medical School of Brown University, Lifespan Health System, 593 Eddy Street, APC7, Providence, RI, 02903, USA. Steven.Toms@lifespan.org.
Abstract
BACKGROUND: Levetiracetam (LEV) is an anti-epileptic drug (AED) that sensitizes glioblastoma (GBM) to temozolomide (TMZ) chemotherapy by inhibiting O6-methylguanine-DNA methyltransferase (MGMT) expression. Adding LEV to the standard of care (SOC) for GBM may improve TMZ efficacy. This study aimed to pool the existing evidence in the literature to quantify LEV's effect on GBM survival and characterize its safety profile to determine whether incorporating LEV into the SOC is warranted. METHOD: A search of CINAHL, Embase, PubMed, and Web of Science from inception to May 2021 was performed to identify relevant articles. Hazard ratios (HR), median overall survival, and adverse events were pooled using random-effect models. Meta-regression, funnel plots, and the Newcastle-Ottawa Scale were utilized to identify sources of heterogeneity, bias, and statistical influence. RESULTS: From 20 included studies, 5804 GBM patients underwent meta-analysis, of which 1923 (33%) were treated with LEV. Administration of LEV did not significantly improve survival in the entire patient population (HR 0.89, p = 0.094). Significant heterogeneity was observed during pooling of HRs (I2 = 75%, p < 0.01). Meta-regression determined that LEV treatment effect decreased with greater rates of MGMT methylation (RC = 0.03, p = 0.02) and increased with greater proportions of female patients (RC = - 0.05, p = 0.002). Concurrent LEV with the SOC for GBM did not increase odds of adverse events relative to other AEDs. CONCLUSIONS: Levetiracetam treatment may not be effective for all GBM patients. Instead, LEV may be better suited for treating specific molecular profiles of GBM. Further studies are necessary to identify optimal GBM candidates for LEV.
BACKGROUND: Levetiracetam (LEV) is an anti-epileptic drug (AED) that sensitizes glioblastoma (GBM) to temozolomide (TMZ) chemotherapy by inhibiting O6-methylguanine-DNA methyltransferase (MGMT) expression. Adding LEV to the standard of care (SOC) for GBM may improve TMZ efficacy. This study aimed to pool the existing evidence in the literature to quantify LEV's effect on GBM survival and characterize its safety profile to determine whether incorporating LEV into the SOC is warranted. METHOD: A search of CINAHL, Embase, PubMed, and Web of Science from inception to May 2021 was performed to identify relevant articles. Hazard ratios (HR), median overall survival, and adverse events were pooled using random-effect models. Meta-regression, funnel plots, and the Newcastle-Ottawa Scale were utilized to identify sources of heterogeneity, bias, and statistical influence. RESULTS: From 20 included studies, 5804 GBM patients underwent meta-analysis, of which 1923 (33%) were treated with LEV. Administration of LEV did not significantly improve survival in the entire patient population (HR 0.89, p = 0.094). Significant heterogeneity was observed during pooling of HRs (I2 = 75%, p < 0.01). Meta-regression determined that LEV treatment effect decreased with greater rates of MGMT methylation (RC = 0.03, p = 0.02) and increased with greater proportions of female patients (RC = - 0.05, p = 0.002). Concurrent LEV with the SOC for GBM did not increase odds of adverse events relative to other AEDs. CONCLUSIONS: Levetiracetam treatment may not be effective for all GBM patients. Instead, LEV may be better suited for treating specific molecular profiles of GBM. Further studies are necessary to identify optimal GBM candidates for LEV.
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: H S Friedman; R E McLendon; T Kerby; M Dugan; S H Bigner; A J Henry; D M Ashley; J Krischer; S Lovell; K Rasheed; F Marchev; A J Seman; I Cokgor; J Rich; E Stewart; O M Colvin; J M Provenzale; D D Bigner; M M Haglund; A H Friedman; P L Modrich Journal: J Clin Oncol Date: 1998-12 Impact factor: 44.544
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: Roger Stupp; Sophie Taillibert; Andrew Kanner; William Read; David Steinberg; Benoit Lhermitte; Steven Toms; Ahmed Idbaih; Manmeet S. Ahluwalia; Karen Fink; Francesco Di Meco; Frank Lieberman; Jay-Jiguang Zhu; Giuseppe Stragliotto; David Tran; Steven Brem; Andreas Hottinger; Eilon D. Kirson; Gitit Lavy-Shahaf; Uri Weinberg; Chae-Yong Kim; Sun-Ha Paek; Garth Nicholas; Jordi Bruna; Hal Hirte; Michael Weller; Yoram Palti; Monika E. Hegi; Zvi Ram Journal: JAMA Date: 2017-12-19 Impact factor: 56.272
Authors: J Nathan Cantrell; Mark R Waddle; Maarten Rotman; Jennifer L Peterson; Henry Ruiz-Garcia; Michael G Heckman; Alfredo Quiñones-Hinojosa; Steven S Rosenfeld; Paul D Brown; Daniel M Trifiletti Journal: Mayo Clin Proc Date: 2019-06-20 Impact factor: 7.616
Authors: Linda M Liau; Keyoumars Ashkan; David D Tran; Jian L Campian; John E Trusheim; Charles S Cobbs; Jason A Heth; Michael Salacz; Sarah Taylor; Stacy D D'Andre; Fabio M Iwamoto; Edward J Dropcho; Yaron A Moshel; Kevin A Walter; Clement P Pillainayagam; Robert Aiken; Rekha Chaudhary; Samuel A Goldlust; Daniela A Bota; Paul Duic; Jai Grewal; Heinrich Elinzano; Steven A Toms; Kevin O Lillehei; Tom Mikkelsen; Tobias Walbert; Steven R Abram; Andrew J Brenner; Steven Brem; Matthew G Ewend; Simon Khagi; Jana Portnow; Lyndon J Kim; William G Loudon; Reid C Thompson; David E Avigan; Karen L Fink; Francois J Geoffroy; Scott Lindhorst; Jose Lutzky; Andrew E Sloan; Gabriele Schackert; Dietmar Krex; Hans-Jorg Meisel; Julian Wu; Raphael P Davis; Christopher Duma; Arnold B Etame; David Mathieu; Santosh Kesari; David Piccioni; Manfred Westphal; David S Baskin; Pamela Z New; Michel Lacroix; Sven-Axel May; Timothy J Pluard; Victor Tse; Richard M Green; John L Villano; Michael Pearlman; Kevin Petrecca; Michael Schulder; Lynne P Taylor; Anthony E Maida; Robert M Prins; Timothy F Cloughesy; Paul Mulholland; Marnix L Bosch Journal: J Transl Med Date: 2018-06-29 Impact factor: 5.531