title: A "vascular normalization index" as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients.
abstract: Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti-vascular endothelial growth factor (VEGF) therapy can "normalize" brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging-measured changes in vascular permeability/flow (i.e., K(trans)) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K(trans), microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P < 0.05). When we combined these three parameters into a "vascular normalization index," we found that it closely associated with overall survival (rho = 0.54; P = 0.004) and progression-free survival (rho = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials.
authors: A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA 02114, USA. sorensen@nmr.mgh.harvard.edu
authors: A Gregory
authors: AG
authors: Sorensen
authors: Tracy T
authors: TT
authors: Batchelor
authors: Wei-Ting
authors: WT
authors: Zhang
authors: Poe-Jou
authors: PJ
authors: Chen
authors: Priscilla
authors: P
authors: Yeo
authors: Meiyun
authors: M
authors: Wang
authors: Dominique
authors: D
authors: Jennings
authors: Patrick Y
authors: PY
authors: Wen
authors: Johanna
authors: J
authors: Lahdenranta
authors: Marek
authors: M
authors: Ancukiewicz
authors: Emmanuelle
authors: E
authors: di Tomaso
authors: Dan G
authors: DG
authors: Duda
authors: Rakesh K
authors: RK
authors: Jain
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001810:Blood Volume; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D003094:Collagen / Q000097:blood; D018572:Disease-Free Survival; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006403:Hematologic Tests / Q000706:statistics & numerical data*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011799:Quinazolines / Q000627:therapeutic use*; D015996:Survival Rate; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D003094:Collagen; D011799:Quinazolines; C500926:cediranib; D007211:Indoles