title: Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.
abstract: Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.
authors.affiliation: Department of Neurology, Department of Radiation Oncology, Department of Radiology, and Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.forename: Kyrre E
authors.initials: KE
authors.lastname: Emblem
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Jayashree
authors.initials: J
authors.lastname: Kalpathy-Cramer
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Pavlina
authors.initials: P
authors.lastname: Polaskova
authors.forename: Marco C
authors.initials: MC
authors.lastname: Pinho
authors.forename: Dominique
authors.initials: D
authors.lastname: Jennings
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.forename: April F
authors.initials: AF
authors.lastname: Eichler
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.forename: Fred H
authors.initials: FH
authors.lastname: Hochberg
authors.forename: Christine
authors.initials: C
authors.lastname: Lu-Emerson
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rosen
authors.forename: Jay S
authors.initials: JS
authors.lastname: Loeffler
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: A Greg
authors.initials: AG
authors.lastname: Sorensen
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives; D004797:Enzyme-Linked Immunosorbent Assay; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D010100:Oxygen / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018709:Statistics, Nonparametric; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine; D010100:Oxygen; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins; C515491:MGMT protein, human; C500926:cediranib; D007211:Indoles
keywords: brain tumor; personalized treatment