title: Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma.
abstract: Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy.
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lu-Emerson
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Kyrre E
authors.initials: KE
authors.lastname: Emblem
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Jennie W
authors.initials: JW
authors.lastname: Taylor
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Loeffler
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: All authors, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA. jain@steele.mgh.harvard.edu.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C500926:cediranib; D007211:Indoles