Early changes in glioblastoma metabolism measured by MR spectroscopic imaging during combination of anti-angiogenic cediranib and chemoradiation therapy are associated with survival

• Published in: NPJ precision oncology 2017-06, Vol.1 (1), p.1-9, Article 20
• Main Authors: Andronesi, Ovidiu C., Esmaeili, Morteza, Borra, Ronald J. H., Emblem, Kyrre, Gerstner, Elizabeth R., Pinho, Marco C., Plotkin, Scott R., Chi, Andrew S., Eichler, April F., Dietrich, Jorg, Ivy, S. Percy, Wen, Patrick Y., Duda, Dan G., Jain, Rakesh, Rosen, Bruce R., Sorensen, Gregory A., Batchelor, Tracy T.
• Format: Article
• Language: English
• Subjects: 692/4028/67/1059/99; 692/4028/67/2321; Brain cancer; Cancer Research; Chemotherapy; Clinical outcomes; Clinical trials; Gene Therapy; Human Genetics; Inhibitor drugs; Internal Medicine; Magnetic resonance imaging; Medicine; Medicine & Public Health; Metabolism; Oncology; Precision medicine; Radiation therapy; Targeted cancer therapy; Tumors
• ISSN: 2397-768X; 2397-768X
• DOI: 10.1038/s41698-017-0020-3

Precise assessment of treatment response in glioblastoma during combined anti-angiogenic and chemoradiation remains a challenge. In particular, early detection of treatment response by standard anatomical imaging is confounded by pseudo-response or pseudo-progression. Metabolic changes may be more specific for tumor physiology and less confounded by changes in blood–brain barrier permeability. We hypothesize that metabolic changes probed by magnetic resonance spectroscopic imaging can stratify patient response early during combination therapy. We performed a prospective longitudinal imaging study in newly diagnosed glioblastoma patients enrolled in a phase II clinical trial of the pan-vascular endothelial growth factor receptor inhibitor cediranib in combination with standard fractionated radiation and temozolomide (chemoradiation). Forty patients were imaged weekly during therapy with an imaging protocol that included magnetic resonance spectroscopic imaging, perfusion magnetic resonance imaging, and anatomical magnetic resonance imaging. Data were analyzed using receiver operator characteristics, Cox proportional hazards model, and Kaplan–Meier survival plots. We observed that the ratio of total choline to healthy creatine after 1 month of treatment was significantly associated with overall survival, and provided as single parameter: (1) the largest area under curve (0.859) in receiver operator characteristics, (2) the highest hazard ratio (HR = 85.85, P  = 0.006) in Cox proportional hazards model, (3) the largest separation ( P  = 0.004) in Kaplan–Meier survival plots. An inverse correlation was observed between total choline/healthy creatine and cerebral blood flow, but no significant relation to tumor volumetrics was identified. Our results suggest that in vivo metabolic biomarkers obtained by magnetic resonance spectroscopic imaging may be an early indicator of response to anti-angiogenic therapy combined with standard chemoradiation in newly diagnosed glioblastoma. Metabolic imaging reveals anti-angiogenic (AA) therapy mechanisms in glioblastoma (GBM) GBM is the most common and aggressive type of malignant primary brain tumors (glioma). Patients with GBM have less than 5% survival at 5 years with the best existing treatment and progress is desperately needed to improve patient outcome. Imaging can guide development and clinical translation of new treatments, and can help to understand mechanisms of response and to optimize drug regimens in patients.