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A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma

David A. Reardon, Scott Turner, Katherine B. Peters, Annick Desjardins, Sridharan Gururangan, John H. Sampson, Roger E. McLendon, James E. Herndon II, Lee W. Jones, John P. Kirkpatrick, Allan H. Friedman, James J. Vredenburgh, Darell D. Bigner, and Henry S. Friedman

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

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NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017

Louis Burt Nabors, Jana Portnow, Mario Ammirati, Joachim Baehring, Henry Brem, Nicholas Butowski, Robert A. Fenstermaker, Peter Forsyth, Jona Hattangadi-Gluth, Matthias Holdhoff, Steven Howard, Larry Junck, Thomas Kaley, Priya Kumthekar, Jay S. Loeffler, Paul L. Moots, Maciej M. Mrugala, Seema Nagpal, Manjari Pandey, Ian Parney, Katherine Peters, Vinay K. Puduvalli, John Ragsdale III, Jason Rockhill, Lisa Rogers, Chad Rusthoven, Nicole Shonka, Dennis C. Shrieve, Allen K. Sills Jr, Lode J. Swinnen, Christina Tsien, Stephanie Weiss, Patrick Yung Wen, Nicole Willmarth, Mary Anne Bergman, and Anita Engh

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

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NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022

Featured Updates to the NCCN Guidelines

Craig Horbinski, Louis Burt Nabors, Jana Portnow, Joachim Baehring, Ankush Bhatia, Orin Bloch, Steven Brem, Nicholas Butowski, Donald M. Cannon, Samuel Chao, Milan G. Chheda, Andrew J. Fabiano, Peter Forsyth, Pierre Gigilio, Jona Hattangadi-Gluth, Matthias Holdhoff, Larry Junck, Thomas Kaley, Ryan Merrell, Maciej M. Mrugala, Seema Nagpal, Lucien A. Nedzi, Kathryn Nevel, Phioanh L. Nghiemphu, Ian Parney, Toral R. Patel, Katherine Peters, Vinay K. Puduvalli, Jason Rockhill, Chad Rusthoven, Nicole Shonka, Lode J. Swinnen, Stephanie Weiss, Patrick Yung Wen, Nicole E. Willmarth, Mary Anne Bergman, and Susan Darlow

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2–3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2–4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of gliomas.

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Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

Louis Burt Nabors, Jana Portnow, Manmeet Ahluwalia, Joachim Baehring, Henry Brem, Steven Brem, Nicholas Butowski, Jian L. Campian, Stephen W. Clark, Andrew J. Fabiano, Peter Forsyth, Jona Hattangadi-Gluth, Matthias Holdhoff, Craig Horbinski, Larry Junck, Thomas Kaley, Priya Kumthekar, Jay S. Loeffler, Maciej M. Mrugala, Seema Nagpal, Manjari Pandey, Ian Parney, Katherine Peters, Vinay K. Puduvalli, Ian Robins, Jason Rockhill, Chad Rusthoven, Nicole Shonka, Dennis C. Shrieve, Lode J. Swinnen, Stephanie Weiss, Patrick Yung Wen, Nicole E. Willmarth, Mary Anne Bergman, and Susan D. Darlow

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.